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Etiology, management, and outcomes of patients with coronary artery disease in a resource-poor Indonesian setting Learning from the local evidence Qanitha, A.

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Download date:09 Oct 2021 Andriany Qanitha Andriany Learning f�om the local evidence local the Learning f�om in a resource-poor Indonesian setting Etiology, management, and outcomes outcomes and management, Etiology, of patients with coronary artery with coronary of patients disease

Etiology, management, and outcomes of patients with coronary artery disease in a resource-poor Indonesian setting Andriany Qanitha

ETIOLOGY, MANAGEMENT, AND OUTCOMES OF PATIENTS WITH CORONARY ARTERY DISEASE IN A RESOURCE-POOR INDONESIAN SETTING

LEARNING FROM THE LOCAL EVIDENCE

ANDRIANY QANITHA Etiology, management, and outcomes of patients with coronary artery disease in a resource- poor Indonesian setting: Learning from the local evidence AMC Heart Center, Amsterdam University Medical Center. Thesis. Faculty of Medicine, University of Amsterdam, The Netherlands, with a summary in Dutch.

ISBN 978-94-6361-210-4 Author Andriany Qanitha Cover design Iliana Boshoven-Gkini (www.AgileColor.com) Layout Redpastel Graphic, The Hague, The Netherlands (www.redpastel.nl) Printed by Optima, Rotterdam, The Netherlands (www.ogc.nl)

Copyright © 2018 by Andriany Qanitha, Amsterdam, The Netherlands.

This thesis was accomplished with financial support from Directorate General of Higher Education/ Direktorat Jenderal Pendidikan Tinggi (DIKTI), Ministry of National Education Republic of Indonesia and Faculty of Medicine, University of Hasanuddin. Financial supports by the Dutch Heart Foundation and Academic Medical Center, University of Amsterdam for the publication of this thesis are gratefully acknowledged. ETIOLOGY, MANAGEMENT, AND OUTCOMES OF PATIENTS WITH CORONARY ARTERY DISEASE IN A RESOURCE-POOR INDONESIAN SETTING

LEARNING FROM THE LOCAL EVIDENCE

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam

op gezag van de Rector Magnificus

prof. dr. ir. K.I.J. Maex

ten overstaan van een door het College voor Promoties ingestelde commissie,

in het openbaar te verdedigen in de Agnietenkapel

op dinsdag 19 maart 2019, te 14.00 uur

door

Andriany Qanitha

geboren te Ujung Pandang PROMOTIECOMMISIE

Promotores : Prof. mr. dr. B.A.J.M. de Mol AMC-UvA Prof. dr. J.P.S. Henriques AMC-UvA

Copromotor : Dr. C.S.P.M. Uiterwaal Universiteit Utrecht

Overige leden: Prof. dr. A.C. van der Wal AMC-UvA Prof. dr. B.J.M. Mulder AMC-UvA Prof. dr. R.J.G. Peters AMC-UvA Prof. dr. J.J. Piek AMC-UvA Prof. dr. H.M. Verkooijen Universiteit Utrecht Dr. M.J.M. Cramer Universitair Medisch Centrum Utrecht

Faculteit der Geneeskunde

So which of the favors of your Lord would you deny? TABLE OF CONTENTS

Chapter 1 General introduction 9

PART I Early-life determinants as cardiovascular risk factors

Chapter 2 Infections in early life and premature acute coronary syndrome: 17 A case-control study Eur J Prev Cardiol, 2016

Chapter 3 Pregnancy-related conditions and premature coronary heart 31 disease in adult offspring Heart Asia, 2017

PART II Coronary artery disease: characteristics, management, and outcomes

Chapter 4 Characteristics and the average 30-day and 6-month clinical 51 outcomes of patients with coronary artery disease: The first cohort from Makassar Cardiac Center, Indonesia BMJ Open, 2018

Chapter 5 Predictors of medium-term mortality in patients hospitalized 73 with coronary artery disease in a resource-limited South-East Asian setting Open Heart, 2018

Chapter 6 Adherence to guideline recommendations for coronary 93 angiography in a poor South-East Asian setting: Impact on short- and medium-term clinical outcomes Under review

PART III Organizing challenges and affordable technology

Chapter 7 Tele-ECG consulting and outcomes on primary care patients in 113 a low-to-middle income population: The first experience from Makassar Telemedicine Program Submitted Chapter 8 General discussion 137 Position paper : Clinical cardiology in a poor South-East Asian setting – Lessons from the present towards improvement Submitted

Chapter 9 Summary and final remarks 159 Samenvatting Rangkuman

Chapter 10 Appendix 175 Press release of publications Manuscripts presented in this thesis Contributing authors PhD portfolio Acknowledgment Curriculum vitae

Chapter 1 General Introduction Chapter 1

BACKGROUND AND OBJECTIVES

Worldwide, many people die from cardiovascular disease (CVD) each year. In 2015, there were approximately 422 million prevalent cases and over 17 million premature deaths due to CVD globally.1,2 Around 75% of coronary heart disease and stroke-related deaths occur in the low- and middle-income countries (LMICs),3 and half of the world’s cardiovascular burden is estimated to occur in Asia.4

South-East Asia is a sub-region of Asia and comprised geographically of southern China, eastern India, western New Guinea, northern Australia and the states of the Association of South-East Asian Nations (ASEAN), i.e. Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Vietnam.5 Almost a quarter of the world’s population lives in the South-East Asia Region (SEAR) where lifestyle changes and epidemiological transition have occurred very rapidly.6 For these reasons, the burden of cardiovascular disease is growing fast in SEAR,7 and CVD manifests at a younger age in these populations.7,8 Most likely as a consequence, this region has high rates of premature CVD death (<60 years of age).5,7 Despite the high cardiovascular burden, there is a lack of reliable data and current estimates of CVD prevalence are poor. Indeed, data on patients’ clinical outcomes related to the quality of care in these resource-poor settings are also limited, and virtually unavailable in Indonesia.

This thesis aims to capture a general picture of the current state of atherosclerotic CVD in the low-to- middle income South-East Asian population, particularly in Indonesia. As relatively little investigation has been done in this area, this thesis is dedicated to the exploration and study of the unmet needs of cardiovascular practices in eastern Indonesia by identifying the risk factors, patient characteristics, management strategies, and outcomes that may be of considerable importance to the organization of local healthcare systems in the future.

OUTLINE OF THE THESIS

This thesis consists of three parts. The first part focuses mainly on assessing those local factors that may potentially act in the etiology of the development of premature coronary artery disease in a low- to-middle income population.

We begin the first part by showing the association between exposure to infection from early childhood to adolescence and the occurrence of coronary artery disease (CAD) in adulthood (Chapter 2).

In Chapter 3, we step back into the intrauterine period. We study if unfavourable conditions suffered by the participants’ mothers during pregnancy could impact the vulnerable in utero environment adversely. We hypothesize that an adverse intrauterine environment could potentially be associated with – or even trigger – the atherosclerotic process during the vasculature development of the fetus, and later in life develop into clinically manifest CAD. Chapters 2 and 3 are based on a population- based, case-control study conducted at Makassar Cardiac Center, Dr. Wahidin Sudirohusodo Hospital, Indonesia from 2013 to 2014. We enrolled 153 newly-diagnosed patients with premature acute coronary syndrome (ACS) and 153 sex- and age-matched controls of healthy subjects living in the same neighborhood as the cases.

10 General introduction

1 Figure 1 . Outline of the thesis Figure

11 Chapter 1

In the second part of the thesis, we focus specifically on patients hospitalized with CAD, both on acute and chronic events. We cross-sectionally quantified the clinical profiles, management, quality of care, prognostic factors, and adherence to guideline recommendations and assessed their rela- tionship with the short- and mid-term clinical outcomes. The primary endpoints were all-cause mor- tality and major adverse cardiovascular events (MACE).

In Chapters 4, 5 and 6, we describe a cohort of 477 patients hospitalized with ACS and stable CAD at Makassar Cardiac Center, Indonesia, enrolled from February 2013 to December 2014. Follow-up was conducted during hospitalization, at 30 days, 6 months, 1 year, and thereafter annually up to January 2018.

In Chapter 4, we provide a detailed description of patient characteristics at hospital admission and their clinical outcomes at 30-day and 6-month follow-up.

In Chapter 5, we measured the medium-term all-cause mortality and analyzed the determinants of this adverse event. In this chapter, we also explored lifestyle corrections and adherence to medication following discharge from hospital.

Chapter 6 describes the relationship between invasive diagnostic procedures, outcomes, and sever- ity of disease including the SYNTAX (SYNergy between PCI with TAXus and cardiac surgery) score, as well as factors associated with adherence to guideline recommendations on undergoing coronary angiography in a resource-poor setting.

In the third and last part, we assess the feasibility of piloting telemedicine in a less affluent country. This is followed by advice on policy making. At the start of the study we envisioned that early de- tection and awareness of symptoms of CVD would be relevant to the prevention and reduction of mortality and disability. We hypothesized that the use of telemedicine would have a positive impact. In Chapter 7, we explore the implementation of the first telemedicine pilot in eastern Indonesia by assessing the performance of tele-electrocardiogram (ECG) at the primary care level, and its impact on clinical practice.

The Discussion and Conclusions are presented in Chapter 8 in the format of a position paper for interested stakeholders. Our ultimate objective was that the local evidence provided in this thesis should assist the policy-makers and stakeholders to generate effective strategies for prevention and for improving quality of care in the field of cardiovascular medicine, with the aim of reducing the CVD burden and improving patient outcomes, in Indonesia in particular.

12 General introduction

REFERENCES 1. Hadley MB, Vedanthan R, Fuster V. Air pollution and cardiovascular disease: a window of opportunity. Nature Reviews Cardiology 2018; 15: 193-194. 2. Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, Abyu G, et al. Global, Regional, and 1 National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol 2017; 70: 1-25. 3. World Health Organization. HEARTS Technical package for cardiovascular disease man- agement in primary health care: evidence-based treatments protocols. Geneva, 2018. 4. Ohira T, Iso H. Cardiovascular disease epidemiology in Asia: an overview. Circ J 2013; 77: 1646-1652. 5. Lam CSP. Heart failure in Southeast Asia: facts and numbers. ESC Heart Failure 2015; 2: 46-49. 6. Moran A, Vedanthan R. Cardiovascular disease prevention in South Asia: gathering the evidence. Glob Heart 2013; 8: 139-140. 7. World Health Organization: Regional Office for South-East Asia. Noncommunicable Dis- eases in the South-East Asia Region: 2011 Situation and Response. New delhi, 2011. 8. Dhillon PK, Jeemon P, Arora NK, Mathur P, Maskey M, Sukirna RD, et al. Status of epide- miology in the WHO South-East Asia region: burden of disease, determinants of health and epidemiological research, workforce and training capacity. Int J Epidemiol 2012; 41: 847-860.

13 14 15 16 17 Chapter 2

ABSTRACT

Background Infections in young children may affect the vasculature and initiate early atherosclerosis. Whether infections experienced in childhood play a part in adult clinical cardiovascular disease remains unclear. We investigated the association between infections in early life and the occurrence of premature coronary heart disease.

Methods We conducted a population-based case-control study of 153 patients with a first acute coronary syndrome before the age of 56 years and 153 age- and sex-matched controls. History of severe infections in childhood and adolescence was obtained together with the clinical and laboratory measurements and other cardiovascular risk factors. We developed an infection score for the overall burden of early-life infections. Conditional logistic regression was performed to assess the associations.

Results Infections experienced in early life increased the risk of acquiring acute coronary syndrome at a young age with an odds ratio (OR) of 2.67 (95% confidence interval (CI) 1.47-4.83, p=0.001). After adjustments for traditional risk factors, lifestyle, dietary pattern, socio-economic status, and parental history of cardiovascular events, these associations remained significant and changed only slightly. There was an indication for an interaction between infections in early life and current cardiovascular risk (Framingham Risk Score (FRS); p-interaction=0.052). Within participants with a low FRS (<10%), the OR of early-life infection for acute coronary syndrome was 1.49 (95% CI 0.72-3.08, p=0.283); within participants with an intermediate FRS (10-20%), the OR was 4.35 (95% CI 1.60-11.84, p=0.004), and within participants with a high FRS (>20%), the OR was 10.00 (95% CI 1.21-82.51, p=0.032).

Conclusion Infections in early life may partly explain premature coronary heart disease in adulthood and may potentiate traditional cardiovascular risk factor effects.

Keywords Childhood infection, premature cardiovascular disease, cardiovascular risk factors.

18 Infections in early life and premature acute coronary syndrome

INTRODUCTION

Cardiovascular disease (CVD) is responsible for 17.5 million deaths worldwide in 2012, representing almost 31% of all global deaths.1,2 Compared to high-income countries, many 0people who suffer from 2 CVD in low- and middle-income countries are relatively young (< 60 years).1 Since infectious diseases are highly prevalent in these low- and middle-income countries,3 the emerging hypothesis on the possible relationships between infection and atherosclerotic CVD may be particularly relevant in these settings. Although clinically manifest in adulthood, the development of atherosclerosis, the underlying pathology of CVD, begins in early life4-8 and chronic inflammation in response to injury of the arterial wall is central to the pathogenesis.9-11 Many traditional CVD risk factors affect the vasculature in childhood,9,12-15 but less is known about early-life infection – a ubiquitous stimulus of host inflammation.10,16 Early-life infections are pervasive and elicit repeated inflammatory responses from the developing immune system17 that may adversely affect the young vasculature.9,16,18-21

We investigated whether infections in early life are associated with early coronary heart disease in adulthood and if this association was modified by traditional risk factors. We conducted a population- based case-control study of incident patients with a first acute coronary syndrome (ACS) at a young age in Makassar cardiac center, Indonesia to determine the relationship between ACS and infections experienced in childhood and adolescence.

METHODS

This study was conducted in Makassar cardiac center Wahidin Sudirohusodo hospital, Indonesia, between February 2013 and December 2014. Ethical approval was obtained from the Institutional Review Board of the Faculty of Medicine, University of Hasanuddin Makassar, based on the letter number 030/H4.8.4.5.31/PP 36-KOMETIK/2013.

Cases The cases, with premature ACS, were defined as patients with an ACS event occurring at age ≤55 years. After obtaining a written informed consent, we enrolled 153 consecutive new patients who were admitted to the cardiovascular care unit with a first ACS, a spectrum of clinical presentations consistent with acute cardiac ischemia within 24 hours of hospital presentation, ranging from unstable angina (UA) to non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI).22,23

Cardiologists made an initial diagnosis of ACS in patients presenting with acute cardiac chest pain based on clinical presentations, electrocardiography, and cardiac enzymes changes. Patients were diagnosed with STEMI when they had new or presumed new ST-segment elevation ≥1 mm seen in any location, or new left bundle branch block on the index or any subsequent electrocardiogram (ECG), with at least 1 positive cardiac biochemical marker of necrosis.24,25

Unstable angina and NSTEMI are closely related conditions, their clinical presentations are indistinguishable, but they differ in severity.22,23 For NSTEMI diagnosis, at least 1 positive cardiac biochemical marker of necrosis, without new ST-segment elevation seen on the index or subsequent ECG had to be present. Unstable angina was diagnosed when ischemic chest pain lasted more than

19 Chapter 2

20 minutes23 with no evidence of myocardial necrosis or ST elevation.24,25 Patients were excluded if they had a history of previous CVD, or negative finding on coronary angiography.

Controls We sampled young adult controls every weekend from the general population to obtain the identical numbers with the cases. The controls were sampled from the same neighborhood that the cases came from, and invited to visit a primary health care center, after matching for age (±3 years) and sex. To ensure a proper incidence-density sampling, every time a case was selected, a control was recruited at that same time within one week. Subjects were excluded if they had any previous diagnosis of heart disease, presented current symptoms and signs of cardiovascular events, or were incapable of giving consent.

Measurements A detailed questionnaire was developed and applied to all cases and controls. In all participants, we recorded data on sociodemographic characteristics such as age, sex, occupation, monthly income, educational level, dietary pattern, physical activity, smoking status, family history of heart disease, diabetes, and sudden cardiac death, as well as known history of hypertension and diabetes. A positive family history of CVD was defined as ≥1 first degree and/or ≥2 second degree family members with CVD before the age of 55 years in men and 65 years in women.26-28

Anthropometric measurements including height, weight, and waist circumference were collected. Two readings of blood pressure were recorded in sitting position with a mercury sphygmomanometer. Nurses were trained as research assistants and administered all measurements using standardized protocols. Fasting plasma glucose, lipid profiles, uric acid, renal and liver functions were measured within 24 hours of hospital admission for all cases. We collected the similar data cross-sectionally from all controls at the primary health care center.

For overall burden of infections in early life, we developed an infection score based on the questionnaire data on history of previous infections during four periods of life: infancy and pre-school (0-5 years of age), elementary school (6-13 years), junior high school (14-17 years), and senior high school (18-21 years). All documented severe infections during a given time period were scored as 1 and were added up to a continuous infection score (minimum 0, maximum 4). We then dichotomized the score to either exposed with early-life infections or unexposed (yes/no). Positive experienced early-life infection was defined as an infection score ≥2 when the subjects reported severe infections in at least in two periods early in life. Severe infection was defined as a fever for 3 days or more, or hospitalisation due to an infectious disease.

We asked the patients and close family members (parents, partner, siblings, aunts, uncles, or others) who accompanied them at the time of data collection in hospital, to answer the questionnaire interview regarding the patient’s history of diagnosed or experienced from any infections during childhood and adolescence. If patients or family were in doubt, we invoked to crosscheck with other family members who were present during patient’s early-life. Meanwhile, for the controls, we gathered this information with exactly the same questionnaire and interview methods as used for the cases; while visiting their houses to invite them to participate to this study and obtain their informed consents. To ensure there were no differences in recall or remember the past events between cases

20 Infections in early life and premature acute coronary syndrome and controls, we verified the answers of cases and controls to the parents, siblings, or closest family members before the cases discharged from hospital, and by phone-calling or home-visiting for the control subjects at the end of this study. 2 Using diagnostic test results in cases and contemporary tests in controls, we calculated regular Framingham Risk Scores (FRS) for all participants in order to arrive at a summary value. FRS was calculated not for clinical purposes but for accurate ranking of traditional CVD risks for later analysis.

Statistical Analysis Comparisons of general characteristics between cases and controls were first made. Paired t-tests were performed with normal distributions and non-parametric Wilcoxon signed-rank tests for skewed distributions. For categorical variables, McNemar’s chi-square tests were used. Uni- and multivariable conditional logistic regression analyses were conducted for the early-life infection variable to obtain unadjusted and adjusted odds ratios (OR) and their 95% confidence interval (CI), corresponding to 2-sided p-values <0.05.

We used four adjustment models for multivariable logistic regression to show the respective influences of each model in modifying the OR for early-life infection. Regarding to sample size, we restricted the analyses to less than 15 variables in one model. Model 1 was adjusted for lifestyle and diet factors (current smoking, sedentary life, consumption of fatty food, salty food and monosodium glutamate, fried food, and less fiber). Model 2 was adjusted for socio-economic status (monthly income and college education). Model 3 was adjusted for history of mother and father with cardiovascular disease, history of parents with diabetes mellitus, maternal and paternal history of premature sudden cardiac death (at age <60 years29). And lastly, Model 4 was adjusted for traditional risk factors (hypertension, raised fasting plasma glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol, and obesity). It is basically unknown if an effect of childhood infection on vasculature, if any, would be direct or indirect through other CVD risk factors. Therefore, we finally performed an interaction analysis using an interaction term experienced early-life infection * Framingham Risk Score in multivariable modeling. Finally, for graphical evaluation of that interaction, we re-performed both the crude and adjusted main analyses, within the following strata of Framingham Risk Scores: low risk (FRS < 10%), intermediate risk (FRS 10-20%), and high risk (FRS > 20%).30 All analyses were performed using the IBM SPSS 22.0 statistical package.

RESULTS

The baseline characteristics of cases and controls are shown in table 1. Their mean (SD) age was 47 (6.3) years (range 28-55 years) and 81.7 % were male. Compared with the controls, the cases had higher fasting plasma glucose, lower HDL-cholesterol, lower LDL-cholesterol, and higher serum creatinine levels. The cases more often had a known history of hypertension, medication for hypertension, a history of diabetes, a higher education level (formal college education). Cases were more often current smokers, ate more fatty food and more salt and monosodium glutamate. Cases and controls had approximately equal monthly income and similar body mass index.

21 Chapter 2

Table 1. Comparison of baseline characteristics between cases and controls Case Control Total Variable p-value (n= 153) (n= 153) (n= 306) Male sex 125 (81.7) 125 (81.7) 250 (81.7) 1.000 Age (years) 47.1 6.2 46.9 (6.4) 47.0 (6.3) 0.121 Systolic BP (mmHg) 120.7 (21.2) 120.3 (21.6) 120.5 (21.4) 0.867 Diastolic BP (mmHg) 78.2 (13.7) 80.2 (14.1) 79.2 (13.9) 0.221 Fasting plasma glucose (mmol/L)a 6.9 (5.7-9.6) 4.8 (4.3-5.6) 5.6 (4.7-7.5) <0.001 Raised plasma glucoseb 103 (67.3) 25 (16.3) 128 (41.8) <0.001 Total cholesterol (mmol/L)a 5.1 (4.4-5.9) 5.3 (4.8-5.9) 5.2 (4.6-5.9) 0.541 Triglycerides (mmol/L)a 1.6 (1.1-2.4) 1.5 (1.2-2.3) 1.6 (1.2-2.3) 0.287 HDL-chol (mmol/L) 0.9 (0.2) 1.2 (0.3) 1.0 (0.3) <0.001 LDL-chol (mmol/L) 3.5 (1.3) 3.9 (0.9) 3.7 (1.1) 0.002 Creatinine (µmol/L)a 88.4 (70.7-106.1) 81.3 (69.4-88.4) 82.2 (70.7-97.2) <0.001 BMI (kg/m2) 24.4 (3.1) 24.4 (4.1) 24.4 (3.6) 0.962 Obese (BMI ≥ 25) 55 (35.9) 62 (40.5) 117 (38.2) 0.494 Waist circumference (cm) 86.3 (7.8) 88.7 (10.2) 87.5 (9.1) 0.013 Metabolic syndrome 92 (60.1) 30 (19.6) 122 (39.9) <0.001 History of hypertension 99 (64.7) 60 (39.2) 159 (52.0) <0.001 On medication for hypertension 57 (37.3) 38 (24.8) 95 (31.0) 0.020 History of diabetes mellitus 44 (28.8) 17 (11.1) 61 (19.9) <0.001 Maternal history of CVDc 21 (13.7) 27 (17.6) 48 (15.7) 0.430 Paternal history of CVDd 22 (14.4) 25 (16.3) 47 (15.4) 0.755 Monthly income (≥Rp.1,810,000)e 82 (53.6) 68 (44.4) 150 (49.0) 0.146 College education 67 (43.8) 48 (31.4) 115 (37.6) 0.034 Current smoker 70 (45.8) 49 (32.0) 119 (38.9) 0.015 Ex-smoker 36 (23.5) 46 (30.1) 82 (26.8) 0.203 Sedentary life 101 (66.0) 117 (76.5) 218 (71.2) 0.060 High intake of fatty food 31 (20.3) 9 (5.9) 40 (13.1) <0.001 High intake of salty food and MSG 73 (47.7) 47 (30.7) 120 (39.2) 0.002 Data are presented as n (%) or means ± SD values unless stated otherwise. Comparison of baseline characteristics between cases and controls was performed using a paired samples t-test for continuous variables and McNemar’s Chi-square test for categorical variables. aData are presented as median (Q1–Q3). Comparison was performed using the Wilcoxon signed-rank test for paired samples. bDefined as fasting plasma glucose ≥ 6.1 mmol/L. cMaternal history of CVD defined as mother had CVD at age <65 years. dPaternal history of CVD defined as father had CVD at age <55 years. eUS$ 1= Rp.12,700 (Indonesian Rupiah). This was the cut-off point based on the national average of proper life minimum income in 2015. BP: blood pressure; HDL: chol, high density lipoprotein-cholesterol; LDL-chol: low density lipoprotein-cholesterol; BMI: body mass index; CVD, cardiovascular disease; MSG: monosodium glutamate.

22 Infections in early life and premature acute coronary syndrome

Table 2 shows that, in univariable analysis, early-life infection was associated with an almost 3-fold higher odds for acquiring premature acute coronary syndrome. None of the adjustments (models 1-4) materially changed these findings. 2 Table 2. Odds ratios for severe infection in early life

Infection experienced in early life OR (95% CI) p-value Crude 2.67 (1.47-4.83) 0.001 Model 1 2.67 (1.39-5.10) 0.003 Model 2 2.57 (1.41-4.69) 0.002 Model 3 2.73 (1.50-4.98) 0.001 Model 4 3.88 (1.29-11.68) 0.016 Univariable and multivariable analyses were performed by conditional logistic regression for matched data. Model 1 was adjusted for lifestyle and diet factors (current smoking, sedentary life, consumption of fatty food, salty food and monosodium glutamate, fried food, and less fiber). Model 2 was adjusted for socio-economic status (monthly income and college education). Model 3 was adjusted for history of mother with CVD at the age <65 years and father with CVD at the age <55 years, history of parents with diabetes mellitus, maternal and paternal history of premature sudden cardiac death (at age <60 years). Model 4 was adjusted for traditional risk factors (hypertension, raised fasting plasma glucose, triglycerides, HDL-cholesterol, LDL-cholesterol, and obesity). Considerable differences on the overall infections burden between cases and controls are observed (see figure 1). In the entire study population, the most prevalent infectious diseases were varicella/ chickenpox (28.1%), typhoid fever (23.9%), morbili/measles (21.6%), gastrointestinal infection/ diarrhea (11.8%), lower respiratory infections (5.6%), malaria (4.3%), dengue fever (3.9%), hepatitis A (2.6%), and tonsillitis (2.6%). Majority of the participants (80.7%) had at least one episode of acute upper respiratory infections in childhood and adolescence.

In table 3, we analyzed the association between early-life infections and premature ACS using the continuous score, which reflects the actual cumulative number of infectious diseases for each participant during their childhood and adolescence, irrespective of the severity. The odds ratio for premature ACS was significant for the total period of childhood and adolescence with OR 1.42 (95% CI 1.17-1.71, p<0.001), and appeared to be stronger in early childhood (0-5 years), even after adjustments.

The adjusted model included the term early-life infection x FRS indicated interaction (p=0.052). Figure 2 shows how the overall association was modified by the predefined classes of FRS. Within the low risk group (FRS <10%), the OR of early-life infection for ACS was 1.49, 95% CI 0.72-3.08, p=0.283; within the intermediate risk (FRS 10-20%), OR 4.35, 95% CI 1.60-11.84, p=0.004, and within the high risk (FRS >20%), OR 10.00, 95% CI 1.21-82.51, p=0.032. After adjustment of these within-risk strata analyses for SES (education and income) and paternal and maternal histories of cardiovascular disease, these estimates were: low risk (FRS <10%) OR 1.50 (95% CI 0.72-3.12, p=0.282); intermediate risk (FRS 10-20%) OR 5.29 (95% CI 1.79-15.62, p=0.003), and high risk (FRS >20%) OR 12.58 (95% CI 1.18-134.31, p=0.036), respectively.

23 Chapter 2

Figure 1. Number of overall infections during childhood and adulthood between cases and controls Infectious diseases included in the score (the continuous score of overall infections based on the summation of each positive infectious disease, regardless of the severity; minimum= 0, maximum= 18) were: typhoid fever, measles, varicella (chickenpox), bronchitis, tuberculosis, pertussis, tonsillitis, acute upper respiratory tract infection, malaria, dengue fever, gastrointestinal infection (diarrhoea), febrile convulsions, hepatitis A, meningitis, dermatitis, oral infection, conjunctivitis, and unknown fever ≥ 3 days.

Table 3. Unadjusted and adjusted odds ratios for overall infections in early life Crude OR Model 1 Model 2 Time period p-value p-value p-value (95% CI) (95% CI) (95% CI) Early childhood 2.56 2.68 3.67 <0.001 <0.001 <0.001 (0-5 years) (1.66-3.96) (1.66-3.96) (1.87-7.22) Total period 1.42 1.44 1.64 <0.001 0.001 0.002 (0-21years) (1.17-1.71) (1.15-1.79) (1.21-2.23) Univariable and multivariable analyses were done by conditional logistic regression for matched data, using the cumulative number of infectious diseases of each participant during childhood and adolescence. Model 1 was adjusted for history of mother and father with cardiovascular disease, socio-economic status (monthly income and college education), lifestyle, and diet factors (current smoking, sedentary life, consumption salty food and monosodium glutamate, and less fiber). Model 2 was adjusted for traditional risk factors (hypertension, diabetes mellitus, triglycerides, HDL- cholesterol, LDL-cholesterol, and obesity).

DISCUSSION

In this study, we found that infection experienced during childhood and adolescence was associated with the higher occurrence of premature ACS later in life. There was an indication that this association became stronger with increasing levels of CVD risks.

24 Infections in early life and premature acute coronary syndrome

To our knowledge, we are the first to report on early-life infection and acute coronary syndrome at a young age of South-East Asians. We took some measures to ensure that our case-control findings could be validly interpreted as an incidence rate ratio from a cohort study. As an important part of our study design, we enrolled newly diagnosed patients or incident cases during the study period. 2 One advantage is that the recall of past events in personal histories may be more accurate among new cases31 and they are less likely to have changed their habits or exposures that are beneficial on acquiring the disease. Our method of randomly selecting age- and sex-matched controls from the residential neighborhoods of the cases ensures that controls came from the same source that the cases came from. Finally, to assure sampling from equal incidence-densities in cases and controls, we sampled controls every time the cases occurred.

Figure 2. Odds ratios for early-life infection (for acquiring premature ACS) among Framingham Risk Score (FRS) classification groups 1Univariable analysis was performed using conditional logistic regression to obtain overall crude odds ratio (OR). 2Multivariable analyses were performed using logistic regression separately within the FRS classification groups: low risk (FRS <10%), intermediate risk (FRS 10-20%), and high risk (FRS >20%). 3Models were adjusted for socio-economic status (formal education and monthly income) and family (maternal and paternal) histories of cardiovascular diseases. *p<0.05; **p≤0.01; ***p≤0.001

There is consistent evidence showing that inflammation plays a substantial role in the pathogenesis of atherosclerosis.6,32 It is increasingly recognized that both chronic low-grade inflammation,20 and also bacterial and viral infections are associated with increased CVD risk.33-35 There are a number of possible, non-exclusive mechanisms by which infection may act to potentiate atherosclerosis development. Individual or – more plausibly – multiple infectious agents may result in a local or systemic inflammatory response,11,32 or elicit an injury to the vascular endothelium that affect both arterial structure and function.10 In addition, Pessi et al. identified bacterial material from coronary arteries and thrombus aspirates,36 whereas Ott et al. demonstrated the presence of the widely varied bacterial DNA in atherosclerotic coronary plaques.37

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Infection may also potentiate traditional risk factors such as dyslipidemia. Liuba et al. reported that acute infections in young children were accompanied by increased oxidized LDL-cholesterol, decreased HDL-cholesterol, and followed by carotid intima-media thickening.19 Notably in young individuals, these changes might accumulate in time and increase the vulnerability of vessels to early atherosclerosis.

Most studies on infections and CVD have been carried out in adults, whereas atherosclerosis development begins in early life.4-10 Recent research has shown that severe childhood infection is independently associated with CVD hospitalization,38 subclinical atherosclerosis17 and adverse metabolic profiles in adulthood.39

Our findings are in line with the most recent Cardiovascular Risk in Young Finns Study17 and the SAPALDIA Youth Study,9 which provided further evidence of the association between childhood infections and adult atherosclerosis. While Burgner et al. used hospitalization records as a measure of more severe infections in the first 5-years of life, we collected the history of various infectious diseases regardless of the severity over childhood and adolescence, an approach also used in the SAPALDIA Youth Study.9 The SAPALDIA childhood infection score summarized the cumulative number of specific types of infections, although the precise age of onset was not given.9 In our study, we used age categories based on school years to facilitate parental and subject recall of infections. We primarily analyzed severe and systemic infections with a history of fever ≥3 days or that resulted in admission to hospital, on the assumption that these reflected a more severe inflammatory response and were more likely to be recalled by families.

The observed association between early-life infections with early atherosclerotic CVD could be of major importance for future prevention strategies to reduce the CVD burden. This may be especially relevant in South-East Asia region where infectious diseases continue to be highly prevalent amongst a young and rapidly increasing population.40 Therefore, we consider our findings an aetiologically important signal that early-life infections could play a role in the high incidence of premature coronary heart disease in South-East Asia.

Numerous studies suggested that infection in childhood may affect the vasculature.9,16-19,38 The precise mechanisms by which infection, alone or in combination with traditional risk factors may contribute to atherosclerosis remains unclear.10 We assessed whether early-life infection modified the effect of traditional CVD risk factors by applying the Framingham Risk Score (FRS) to our study group. FRS measures the absolute CVD risk burden continuously and therefore provides a more precise and accurate score. Instead of estimating the 10 year-risks for developing CHD in each individual, we used FRS to rank all participants based on their traditional risks burden. We classified them as low, intermediate, and high-risk classes. From the analyses, we then attained appreciable differences in the ORs of early-life infection between the low, the intermediate and the high-risk classes.

Limitations This study has some potential limitations. First, as a result of the unavailability of registry data on infection-related admission to hospital and exposure to antibiotics, we relied on participant and parental recall of infection. Therefore, the possibility of recall bias and differential recall of past infections because of current disease status is acknowledged. To minimize recall bias, we verified

26 Infections in early life and premature acute coronary syndrome the infection data from the cases and controls with first-degree family members. In addition, questionnaires about early-life exposures collected other data unrelated to infection, and participants were not aware of the main research question. Second, the lack of specificity of infections observed in this study limited the conclusions that can be drawn regarding potential mechanisms that may 2 act in the inflammatory process; however no consensus exists on which infectious diseases are most relevant for CVD. Third, the absence of serological data limits the ability to validate the exposure to specific infectious agents, although this approach has inherent limitations, as it is not informative about clinical symptoms or severity.21 Fourth, we excluded fatal ACS cases, which may introduce a bias in the assessment of early-life infection and premature ACS association, if the association differed with CVD mortality. If anything, we speculate that in deceased ACS patients the association is more likely to be stronger (as they may have had more severe CVD), and therefore the strength of the association may be underestimated.

Conclusion This study confirms that infection experienced in early life is associated with early coronary heart disease in adulthood and may potentiate the effects of traditional CVD risk factors.

Acknowledgements The authors gratefully acknowledge all participants who enrolled as cases and controls in this study and their family members for the cooperation. Prof. dr. Irawan Yusuf, PhD and the staff of cardiovascular care unit (CVCU) Wahidin Sudirohusodo Hospital Makassar are acknowledged for their contributions to the success of this research project. The cadres of community healthcare center (Puskesmas) Batua Makassar are acknowledged for their dedicated assistance, staff of Prodia clinical laboratory Makassar for the assistance in blood sampling and the sample storage, and all research assistants for the data collection and data management.

Information Abstract has been presented and published for a press-release in Acute Cardiovascular Care (ACCA) Congress by European Society of Cardiology (ESC), 17-19 October 2015, in Hofburg, Vienna. Presented abstract has been published as a supplement of European Heart Journal: Acute Cardiovascular Care, volume 4, issue 1_suppl, October 2015. Adverse early-life environment and premature acute coronary syndrome: a case-control study. Eur Heart J Acute Card Care. 2015;4:S39.

Funding This project was fully funded by a grant from Directorate General of Higher Education (DGHE) Ministry of National Education Republic of Indonesia, based on letter No. 600/E4.4/K/2011, dated July 12, 2011.

Declaration of Conflicting Interests The authors declared that there is no conflict of interest.

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REFERENCES 1. WHO. Cardiovascular Diseases (CVDs), http://www.who.int/research/en/ (2015, ac- cessed 25 March 2015). 2. Hong Y. Burden of Cardiovascular Disease in Asia: Big Challenges and Ample Opportuni- ties for Action and Making a Difference. Clinchem 2009; 55: 1450-1452. 3. WHO. The Global Burden of Disease: 2004 Update. Switzerland: World Health Organi- zation, 2004. 4. Skilton MR, Evans N, Griffiths KA, Harmer JA and Celermajer DS. Aortic wall thickness in newborns with intrauterine growth restriction. The Lancet 2005; 365: 1484-1486. 5. Sun C, Burgner DP, Ponsonby AL, et al. Effects of early-life environment and epigenetics on cardiovascular disease risk in children: highlighting the role of twin studies. Pediatr Res 2013; 73: 523-530. 6. Ross R. Atherosclerosis - an inflammatory disease. N Engl J Med 1999; 340: 115-126. 7. Nakashima Y, Wight TN and Sueishi K. Early atherosclerosis in humans: role of diffuse in- timal thickening and extracellular matrix proteoglycans. Cardiovasc Res 2008; 79: 14-23. 8. Berenson GS, Srinivasan SR, Bao W, Newman WPI, Tracy RE and Wattigney WA. Associ- ation between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med 1998; 338: 1650-1656. 9. Dratva J, Caviezel S, Schaffner E, et al. Infectious diseases are associated with carotid intima media thickness in adolescence. Atherosclerosis 2015; 243: 609-615. 10. Liuba P and Pesonen E. Infection and early atherosclerosis: does the evidence support causation? Acta Paediatr 2005; 94: 643-651. 11. Rosenfeld ME and Campbell LA. Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis. Thromb Haemost 2011; 106: 858-867. 12. Laitinen TT, Pahkala K, Venn A, et al. Childhood lifestyle and clinical determinants of adult ideal cardiovascular health: the Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Princeton Follow-Up Study. Int J Cardiol 2013; 169: 126-132. 13. Berenson GS. Childhood Risk Factors Predict Adult Risk Associated with Subclinical Car- diovascular Disease: The Bogalusa Heart Study. Am J Cardiol 2002; 90(suppl): 3L-7L. 14. Geerts CC, Evelein AM, Bots ML, van der Ent CK, Grobbee DE and Uiterwaal CS. Body fat distribution and early arterial changes in healthy 5-year-old children. Ann Med 2012; 44: 350-359. 15. Huang RC, Burke V, Newnham JP, et al. Perinatal and childhood origins of cardiovascular disease. Int J Obes 2007; 31: 236-244. 16. Charakida M, Donald AE, Terese M, et al. Endothelial dysfunction in childhood infection. Circulation 2005; 111: 1660-1665. 17. Burgner DP, Sabin MA, Magnussen CG, et al. Early childhood hospitalisation with infec- tion and subclinical atherosclerosis in adulthood: the Cardiovascular Risk in Young Finns Study. Atherosclerosis 2015; 239: 496-502. 18. Pesonen E, Paakkari I and Rapola J. Infection-associated intimal thickening in the coro- nary arteries of children. Atherosclerosis 1999; 142: 425-429. 19. Liuba P. Acute infections in children are accompanied by oxidative modification of LDL and decrease of HDL cholesterol, and are followed by thickening of carotid intima–me- dia. Eur Heart J 2003; 24: 515-521. 20. Evelein AM, Visseren FL, van der Ent CK, Grobbee DE and Uiterwaal CS. Allergies are as- sociated with arterial changes in young children. Eur J Prev Cardiol 2015; 22: 1480-1487.

28 Infections in early life and premature acute coronary syndrome

21. Burgner D, Liu R, Wake M and Uiterwaal CS. Do Childhood Infections Contribute to Adult Cardiometabolic Diseases? Pediatr Infect Dis J 2015; 34: 1253-1255. 22. Kumar A and Cannon CP. Acute Coronary Syndromes: Diagnosis and Management, Part I. Mayo Clin 2009; 84: 917-938. 2 23. Grech ED and Ramsdale DR. ABC of interventional cardiology, Acute coronary syn- drome: unstable angina and non-ST segment elevation myocardial infarction. BMJ 2003; 326: 1259-1261. 24. Pieper KS, Gore JM, FitzGerald G, et al. Validity of a risk-prediction tool for hospital mor- tality: the Global Registry of Acute Coronary Events. Am Heart J 2009; 157: 1097-1105. 25. Tang EW, Wong CK and Herbison P. Global Registry of Acute Coronary Events (GRACE) hospital discharge risk score accurately predicts long-term mortality post acute coro- nary syndrome. Am Heart J 2007; 153: 29-35. 26. Mulders TA, Meyer Z, van der Donk C, et al. Patients with premature cardiovascular disease and a positive family history for cardiovascular disease are prone to recurrent events. Int J Cardiol 2011; 153: 64-67. 27. Lloyd-Jones DM, Nam B, D’Agostino RB, et al. Parental Cardiovascular Disease as a Risk Factor for Cardiovascular Disease in Middle-aged Adults: A Prospective Study of Parents and Offspring. JAMA 2004; 291: 2204-2211. 28. Nasir K, Budoff MJ, Wong ND, et al. Family history of premature coronary heart disease and coronary artery calcification: Multi-Ethnic Study of Atherosclerosis (MESA). Circula- tion 2007; 116: 619-626. 29. Ranthe MF, Carstensen L, Oyen N, et al. Family history of premature death and risk of early onset cardiovascular disease. J Am Coll Cardiol 2012; 60: 814-821. 30. Bosomworth NJ. Practical use of the Framingham risk score in primary prevention. Can Fam Physician 2011; 57: 417-423. 31. Grobbee DE and Hoes AW. Case-Control Studies. In. Clinical Epidemiology - Principles, Methods, and Applications for Clinical Research. Massachusetts: Jones and Bartlett Pub- lishers, 2009, pp. 226-269. 32. Espinola-Klein C, Rupprecht HJ, Blankenberg S, et al. Impact of Infectious Burden on Pro- gression of Carotid Atherosclerosis. Stroke 2002; 33: 2581-2586. 33. Zhu J, Nieto FJ and Horne BD. Prospective study of pathogen burden and risk of myocar- dial infarction or death. Circulation 2001; 103: 45-51. 34. Maniar A, Ellis C, Asmuth D, Pollard R and Rutledge J. HIV infection and atherosclerosis: evaluating the drivers of inflammation. Eur J Prev Cardiol 2013; 20: 720-728. 35. Kiechl S, Egger G, Mayr M and al e. Chronic infections and the risk of carotid atherosclero- sis: Prospective results from a large population study. Circulation 2001; 103: 1064-1070. 36. Pessi T, Karhunen V, Karjalainen PP, et al. Bacterial signatures in thrombus aspirates of patients with myocardial infarction. Circulation 2013; 127: 1219-1228, e1211-1216. 37. Ott SJ, El Mokhtari NE, Musfeldt M, et al. Detection of diverse bacterial signatures in ath- erosclerotic lesions of patients with coronary heart disease. Circulation 2006; 113: 929- 937. 38. Burgner DP, Cooper MN, Moore HC, et al. Childhood hospitalisation with infection and cardiovascular disease in early-mid adulthood: a longitudinal population-based study. PLoS One 2015; 10: e0125342. 39. Burgner DP, Sabin MA, Magnussen CG, et al. Infection-Related Hospitalisation in Child- hood and Adult Metabolic Outcomes. Pediatrics 2015; 136: e554-562. 40. WHO. Health Situation in the South-East Region 2001-2007. India: WHO Regional Office for South-East Asia, 2008.

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ABSTRACT

Objective To investigate the association between complications during pregnancy and premature coronary heart disease in adult offspring.

Methods We conducted a population-based case-control study of 153 Indonesian patients with a first acute coronary syndrome (ACS) (age ≤55 years) and 153 age- and sex-matched controls. Data on complications during pregnancy (high blood pressure, preterm delivery) and maternal infections in pregnancy were obtained, together with socio-demographic data, clinical profiles, laboratory measurements and adulthood CVD risk factors at hospital admission or enrolment. Conditional logistic regression was performed to assess the association between overall pregnancy complications, and specific groupings of complications and premature ACS.

Results Pregnancy-related hypertension and infection were more common in mothers of cases than controls. Pregnancy complications were associated with premature offspring ACS (odds ratio (OR) 2.9, 95% confidence interval (CI), 1.4–6.0, p=0.004), and the association persisted in fully adjusted analyses (ORadjusted 4.5, 1.1–18.1, p=0.036). In subgroup analyses, pregnancy-related high blood pressure (ORadjusted 5.0, 1.0–24.7, p=0.050) and maternal infections (ORadjusted 5.2, 1.1–24.2, p=0.035) were associated with offspring ACS.

Conclusion Offspring of mothers with complications during pregnancy have an increased risk for premature ACS in adulthood, which may be of particular relevance in populations in transition, where the incidence of both pregnancy-related morbidity and CVD are high.

Keywords Pregnancy complication, maternal infection, maternal high blood pressure, premature CVD, cardiovascular risk factors

32 Pregnancy-related conditions and premature CAD in adult offspring

INTRODUCTION

Increasing evidence indicates that in utero exposures contribute to adult disease, in addition to childhood and adulthood exposures.1 In this light, numerous studies and meta-analyses have been 3 conducted on maternal pregnancy complications and their relationship to adult cardiovascular disease (CVD) risk factors in the offspring. The associations between gestational hypertension,2,3 preeclampsia,3-5 and preterm birth6 with adult obesity, glucose intolerance, hypertension, and metabolic syndrome in the offspring are widely accepted. Although the underlying mechanisms are poorly understood, a range of disruptions in fetal growth and unfavorable intrauterine environment – to which a variety of pregnancy-related complications may contribute – might act through common pathways,7 leading to early metabolic8 and arterial vasculature changes9 that may initiate earlier and accelerated atherosclerosis.9 Recent studies show that offspring of mothers with complications during pregnancy have increased CVD risk factors in childhood and adolescence.4,5,10 However, it is uncertain if these pregnancy complications are related with the development of clinically manifest CVD, particularly in young adult offspring, nor whether specific complications have more marked effects.

The World Health Organization (WHO) has reported that 99% of all global maternal deaths due to pregnancy complications occur in the low- and middle-income countries.11 In contrast to Western populations, the major causes of maternal pregnancy complications in these regions are unsafe abortion (8%), infections (11%), high blood pressure (14%), severe bleeding (27%), and pre-existing conditions (28%).11 In addition, approximately 80% of global CVD deaths occur in low- and middle- income countries,12 and an estimated half of the global CVD burden occurs in Asia.13 South-East Asia has a population of over 600 million – the majority younger than 65 years – and has faced a rapid epidemiological transition.14 Compared with the high-income countries, South-East Asia countries has a higher prevalence of cardiovascular risk factors in young adults15 that is reflected in high rates of premature deaths (age <60 years15) due to non-communicable diseases (NCD), primarily CVD.14,15 Of the 7.9 million annual NCD deaths in this region, 34% occurred before the age of 60 years compared with 16% in the European region and 23% in the rest of the world.15 A striking observation is that deaths from CVD occur 5-10 years earlier in Asia compared with Western countries.16 Both maternal pregnancy complications and premature CVD are major health issues, particularly in South-East Asia.

We hypothesized that complications in pregnancy may contribute to the increased incidence of premature CVD in this setting. Therefore, we conducted a population-based case-control study of a first acute coronary syndrome (ACS) episode in Indonesia to investigate the association between complicated pregnancy and the occurrence of early coronary heart disease (CHD) in adult offspring.

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METHODS

This study was conducted between February 2013 and December 2014 in Makassar Cardiac Center, Wahidin Sudirohusodo Hospital, the general academic and referral hospital in East Indonesia. Ethical approval was obtained from the Institutional Review Board of the Faculty of Medicine, University of Hasanuddin Makassar.

Cases Cases were defined as patients with a first ACS event occurring at age ≤55 years. After obtaining written informed consent, we enrolled 153 consecutive new patients, who were admitted to cardiovascular care unit with ACS, defined as unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI).17

Cardiologists made a diagnosis of ACS in patients with acute cardiac chest pain based on clinical presentations, electrocardiogram (ECG), and elevated biomarker of cardiomyocyte injury (cardiac troponin (cTn) and/or creatine kinase muscle and brain (CKMB)). Patients were diagnosed with STEMI if they had new or presumed new significant ST-segment–T wave (ST–T) changes or new left bundle branch block (LBBB), and/or development of pathological Q waves on ECG, with an increase of cTnT and/or CKMB, at least one value above the 99th percentile of a normal reference population (upper reference limit (URL)).18,19 NSTEMI diagnosis was defined if clinical presentation is compatible with myocardial ischemia, followed by an increased cTnT and/or CKMB, without new ST-segment elevation on the presentation or subsequent ECG. Unstable angina was defined as ischemic chest pain at rest or minimal exertion persisting for >20 minutes in the absence of cardiomyocyte necrosis18. Patients were excluded if they had a history of previous CVD, or showed no evidence of significant atherosclerosis on coronary angiography.

Controls We enrolled young adult controls from the general population in equal numbers to cases. We matched the cases and controls for age (±3 years) and sex. Controls were sampled from the same residential neighborhood as the cases and were invited to visit a primary health care center for clinical examination, laboratory measurements, and a questionnaire interview. To ensure incidence-density sampling, a control was recruited in the same week as a case was enrolled. Controls were excluded if they had any previous diagnosis of CVD, had current clinical features of a cardiovascular event, or were unable to give written informed consent.

Data collection A detailed questionnaire was administered to all cases and controls. In the cases group, we obtained baseline data from medical records, physical examination, and interview, including age, sex, occupation, monthly income, educational level, dietary pattern, physical activity, smoking status, parental history of CVD, as well as previous history of hypertension and diabetes (detailed methods were presented as supplementary material). Plasma glucose, lipid profiles, uric acid, renal and liver function were measured following a minimum 8 hour fast in hospital laboratories using standard techniques within 24 hours of hospital admission for all cases. We collected identical data from controls at their primary health care center visit.

34 Pregnancy-related conditions and premature CAD in adult offspring

Pregnancy complications Exposure to pregnancy complication was considered positive if the mother of participants reported or had been diagnosed with significant pre-defined complications during the pregnancy with the case or control. We included the common pregnancy complications in South-East Asia region as follows: 3 high blood pressure, preterm delivery, and maternal infections during pregnancy. For maternal infections, we classified upper respiratory infection, lower respiratory infection, gastrointestinal infection (including typhoid fever), genitourinary tract infections, dengue fever, malaria, varicella, measles, and unspecified infections (defined as fever of unknown cause for ≥3 days or requiring hospitalization). Reliable medical records in hospital and primary healthcare in Indonesia did not exist at the time of pregnancy. Therefore data on pregnancy complications was obtained using take- home questionnaires filled by participants (cases and controls), enabling information to be sourced from their mothers or other family members who were present throughout the pregnancy. We collected the questionnaire by visiting participant’s houses. We subsequently verified the data by a further interview to minimize missing data and resolve ambiguities.

Confounding variables and regression models There are several possible confounders that may be relevant to analysis of an association between pregnancy complications and premature ACS in adult offspring. The following variables were therefore included in the regression analyses: adulthood lifestyle (current smoking status); dietary pattern (high salty food and mono-sodium glutamate (MSG) intake, and high fatty food intake); socio-economic status (monthly income and college education); parental history of CVD; childhood infections,20,21 and adulthood cardiovascular risk factors (hypertension, raised fasting plasma glucose (≥6.1 mmol/L), low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, and body mass index (BMI)).

In the present study, we included childhood infections (yes/no) as a confounding variable, as we20 and others21 have reported that childhood infection is independently associated with an early CVD hospitalization in adult life. We defined exposure to childhood infections if participants had experienced at least one severe infection during early childhood (0-5 years of age), as previously reported.20

The selection of confounders in this study is crucial. As pregnancy complication is a broad categorization encompassing various conditions during pregnancy, there are several extraneous factors that potentially act either as a confounding or as an intermediate variable. Maternal infections during pregnancy may be related with offspring childhood infections, while maternal high blood pressure in pregnancy is related with the offspring hypertension in adult life.3 There is considerable evidence of association between pregnancy complications and the development of cardiovascular risk factors in adulthood.5,6 For that reason, we assumed that several adulthood cardiovascular risk factors (e.g. hypertension, diabetes, and metabolic syndrome) plausibly are intermediate variables that may affect the true association between maternal pregnancy complications and premature CVD in the offspring and hence lie on the causal pathway between pregnancy complications and adult CVD. Therefore to investigate whether these confounding and/or intermediate variables affected the associations, we performed stepwise analyses in four regression models as follows:

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Crude = Univariable (matched for age and sex) Model 1 = Crude + adulthood lifestyle + dietary pattern + socio-economic status Model 2 = Model 1 + parental history of CVD Model 3 = Model 2 + childhood infections Model 4 = Model 3 + adulthood cardiovascular risk factors

Data Analysis Baseline characteristics of cases and controls were first tabulated for descriptive purposes and confounder assessment. To assess group differences, paired t-tests were performed with normal distributions and non-parametric Wilcoxon signed-rank tests for skewed distributions. For categorical variables, McNemar’s chi-square tests were applied. We reported median and interquartile range (IQR) for skewed data. Main results were expressed as crude and adjusted odds ratios (OR) from uni- and multivariable conditional logistic regression, with their 95% confidence interval (CI), corresponding to 2-sided p-values <0.05.

We initially performed the overall analyses dichotomizing the presence of pregnancy complications as the exposure. We then performed complication-specific analyses for 2 subgroups: (1) high blood pressure, and (2) maternal infections. We did not apply further sub-group analyses for preterm delivery as this complication showed very low numbers amongst cases and controls. In subgroup analyses, we restricted the analyses to the subset group of interest as ‘exposed’ group, while other pregnancy complications and those without any pregnancy complications were classified as ‘unexposed’ group. Statistical analyses were performed with IBM SPSS 23.0.

RESULTS

Baseline characteristics of cases and controls are shown in table 1. The mean (SD) age was 47 (6.3) years (range 28-55 years) and 81.7% were male. Compared to controls, cases were more likely to have a higher fasting plasma glucose, a lower HDL-cholesterol level, a lower LDL-cholesterol level, metabolic syndrome, to report hypertension and/or diabetes, to have had college education, to be a current smoker, to consume more salty food and MSG, and more fatty food. Cases and controls had approximately equal monthly income and similar BMI (table 1).

36 Pregnancy-related conditions and premature CAD in adult offspring

Table 1. Baseline characteristics of cases and controls (adult offspring)

Case Control 3 Variables p-value (n= 153) (n= 153) Male 125 (81.7) 125 (81.7) 1.000 Age (years) 47.1 6.2 46.9 6.4 0.121 Systolic BP (mmHg) 120.7 21.2 120.3 21.6 0.867 Diastolic BP (mmHg) 78.2 13.7 80.2 14.1 0.221 Fasting plasma glucose (mmol/L)a 6.9 (5.7-9.6) 4.8 (4.3-5.6) <0.001 Raised plasma glucoseb 103 (67.3) 25 (16.3) <0.001 Total cholesterol (mmol/L)a 5.1 (4.4-5.9) 5.3 (4.8-5.9) 0.541 Triglycerides (mmol/L)a 1.6 (1.1-2.4) 1.5 (1.2-2.3) 0.287 HDL-chol (mmol/L) 0.9 0.2 1.2 0.3 <0.001 LDL-chol (mmol/L) 3.5 1.3 3.9 0.9 0.002 Body mass index (kg/m2) 24.4 3.1 24.4 4.1 0.962 Waist circumference (cm) 86.3 7.8 88.7 10.2 0.013 Metabolic syndrome 92 (60.1) 30 (19.6) <0.001 History of hypertension 99 (64.7) 60 (39.2) <0.001 History of diabetes mellitus 44 (28.8) 17 (11.1) <0.001 Maternal history of CVDc 21 (13.7) 27 (17.6) 0.430 Paternal history of CVDd 22 (14.4) 25 (16.3) 0.755 Monthly income (≥ Rp.1,810,000)e 82 (53.6) 68 (44.4) 0.146 College education 67 (43.8) 48 (31.4) 0.034 High salty food and MSG intake 73 (47.7) 47 (30.7) 0.002 High fatty food intake 31 (20.3) 9 (5.9) <0.001 Less fiber 9 (5.9) 11 (7.2) 0.824 Current smoker 70 (45.8) 49 (32.0) 0.015 Former smoker 36 (23.5) 46 (30.1) 0.203 Physical inactivity 101 (66.0) 117 (76.5) 0.060 Values are n (%) or means ± SD, unless otherwise stated. Comparison of baseline characteristics between cases and controls (adult offspring) was performed using paired-samples t-test for continuous variables and McNemar’s Chi-square test for categorical variables. aValues are medians (Q1-Q3). Comparison was performed using Wilcoxon sign-rank test for paired samples. bDefined as fasting plasma glucose ≥6.1 mmol/L. cDefined as mother had CVD at age <65 years. dDefined as father had CVD at age <55 years. eThe cut-off point based on the national average of minimum wages for decent living in Indonesia in 2015. BP: blood pressure; HDL-chol: high density lipoprotein-cholesterol; LDL-chol: low density lipoprotein-cholesterol; BMI: body mass index; CVD: cardiovascular disease; MSG: monosodium glutamate.

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Table 2 lists the detail of pregnancy complications of the participants. Thirty (19.6%) of mothers of cases had a complication during pregnancy, compared with 11 (7.2%) mothers of controls (p=0.003).

Table 2. Pregnancy-related conditions sustained by mothers of cases and controls

Cases Controls Pregnancy complications p-value (n = 153) (n = 153)

Maternal high blood pressure 9 (5.9) 3 (2.0) 0.146 Preterm deliverya 1 (0.7) 1 (0.7) 1.0 Maternal infections 20 (13.1) 7 (4.6) 0.015 Upper respiratory infectionb 5 (3.3) 2 (1.3) 0.453 Lower respiratory infectionc 2 (1.3) 0 (0.0) 0.157 Gastrointestinal infectiond 4 (2.6) 0 (0.0) 0.046 Unspecified infectionse 9 (5.9) 5 (3.3) 0.388 Total Complications 30 (19.6) 11 (7.2) 0.003 Values are n (%). Comparison was made using Exact McNemar’s Chi-square test. aDefined as babies born alive before 37 weeks of gestational age.6 bConsisted of influenza, tonsillitis, pharyngitis, laryngitis, sinusitis, or otitis media. cConsisted of bronchitis, pneumonia, and tuberculosis. dConsisted of diarrhea and typhoid fever. eDefined as fever of unknown cause for ≥3 days or requiring hospitalization.

Table 3 shows the results of univariable and multivariable regressions as the main analyses. In univariable analysis, participants whose mothers had a pregnancy complication had an almost 3-fold increased odds of acquiring premature ACS in adulthood compared to those whose mothers had no complication. For overall pregnancy complications, these associations remained statistically significant in multivariable analyses (ORadjusted 4.5, 95% CI 1.1–18.1, p=0.036). In subgroup analyses, maternal high blood pressure (ORadjusted 5.0, 1.0–24.7, p=0.050) and maternal infections (ORadjusted 5.2, 1.1–24.2, p=0.035) during pregnancy were related with offspring premature ACS.

DISCUSSION

In this case-control study of Indonesian adults, complications during pregnancy were associated with premature ACS in adult offspring. These associations were independent of adulthood cardiovascular risk factors, dietary pattern, socio-economic status, parental history of CVD, and childhood infections. In subgroup analyses, those born following pregnancies complicated by infection were significantly at increased risk of premature ACS. To the best of our knowledge, this is the first report of an association between maternal infections in pregnancy and CVD in the offspring.

Although CVD risk factors burden has transited from rich to poor populations in Indonesia,22 this risk burden is still more marked in the rich people. Apparently, in our study population, the cases – of which most of them came from middle to high socio-economic level – had more traditional CVD risk factors, had higher education attainment, were often smokers, and consumed more salty/MSG and fatty food compared to controls.

38 Pregnancy-related conditions and premature CAD in adult offspring

Table 3. Odds ratios for maternal pregnancy complications

Pregnancy complications OR (95% CI) p-value Overall pregnancy complications 3 Crudea 2.90 (1.41-5.95) 0.004 Model 1b 3.16 (1.42-7.08) 0.005 Model 2c 4.06 (1.68-9.79) 0.002 Model 3d 3.25 (1.27-8.28) 0.014 Model 4e 4.47 (1.10-18.13) 0.036 Maternal high blood pressure Crudea 3.00 (0.81-11.08) 0.099 Model 1b 5.18 (1.02-26.33) 0.048 Model 2c 4.80 (1.03-22.48) 0.046 Model 3d 4.83 (0.81-28.68)# 0.083# Model 4f 4.96 (1.00-24.66) 0.050 Maternal infections Crudea 3.17 (1.27-7.93) 0.014 Model 1b 3.00 (1.14-7.90) 0.026 Model 2c 3.66 (1.30-10.26) 0.014 Model 3d 2.81 (0.94-8.37)# 0.064# Model 4e 5.21 (1.13-24.20) 0.035

Univariable and multivariable analyses were performed using conditional logistic regression for matched data. aCrude was univariable analysis. bModel 1 was adjusted for current smoking status, high salty food and MSG intake, high fatty food intake, monthly income and college education. cModel 2 was Model 1 plus adjusted for parental history of CVD. dModel 3 was Model 2 plus adjusted for childhood infections. eModel 4 was Model 3 plus adjusted for adulthood cardiovascular risk factors (hypertension, raised fasting plasma glucose, LDL-cholesterol, HDL-cholesterol, and BMI). fModel 4 was not adjusted for offspring adulthood hypertension and childhood infections because of strong collinearity among these variables. # Multicollinearity was assumed

It is generally accepted that maternal problems such as hypertension and infections during pregnancy, and preterm delivery may directly affect birth outcomes in the newborns. There is also increasing evidence relating these exposures to later outcomes in childhood2,4,10 and adulthood.6 Several studies have shown that offspring from pregnancies complicated by preeclampsia or gestational hypertension have higher blood pressure, BMI, and cholesterol during childhood10 and adolescence.2,4 Furthermore, in a recent meta-analysis, preterm delivery was associated with higher blood pressure and increased plasma LDL in adulthood.6 Delivery prior to 34 weeks gestational age has also been associated with all-cause mortality between 15 and 45 years of age in adult offspring.23

This is the first study to address the relationship between maternal infections during pregnancy and clinical CVD in adult offspring. The mechanisms are unclear, as the absolute number of mothers

39 Chapter 3 reporting infection in pregnancy is modest, the diagnoses were by maternal recall, and antibiotic and other treatments are largely unknown. Further longitudinal studies are warranted to confirm this finding, interrogate mechanisms and provide a platform for translation. Previous studies and meta-analyses on pregnancies complicated by maternal infection have reported increased risk of adverse neurodevelopmental outcomes in the offspring, including autism spectrum disorder,24 schizophrenia,25 and brain damage26. Another study reported the increased risk of congenital heart defects in the newborns after pregnancy complicated by maternal febrile illness.27

Mounting evidence suggests that impaired fetal growth is associated with increased risk of adult CHD.9 Although the exact mechanisms are unknown, pregnancy-related morbidity may induce an adverse intrauterine environment and compromise fetal nutrition,28 consequently impairing the fetal growth. During fetal development, a range of disruptions in pregnancy may act through common pathways,7 induced early metabolic8 and arterial9 changes, and program a predisposition to atherosclerosis.9 Impaired in utero growth is associated with changes to both arterial function (endothelial dysfunction) and structure (increased wall thickness).9 This is in keeping in animal models, which report that exposure to cardiovascular risk factors such as hypercholesterolemia during pregnancy may contribute to later atherosclerosis development.29 These recent findings indicate that intrauterine factors, in tandem with genetic predisposition and postnatal environmental exposures might contribute to a precocious atherosclerosis,9 and increase the risk of later CVD.

The longitudinal Helsinki birth cohort study reported a relationship between preeclampsia and pregnancy hypertension with the occurrence of stroke in adult offspring, but not with CHD.30 However our study is among the first investigated the association between the common complications of pregnancy with premature CHD in adult offspring in a low- and middle- income population in South-East Asia, where differences in both heritable and environmental factors may lead to divergent causal pathways. Our study adds to the existing knowledge on maternal pregnancy complications and cardiovascular risk factors, notably that such exposures may partly contribute to premature CVD in these settings.

Interpretation of these novel but preliminary data should be considered within the limitations of longitudinal data in this setting. The potential mechanisms that underlie the association between pregnancy complications and premature ACS in adult offspring may involve fetal growth impairment,8,9,31 for which birth weight is a proxy. Unfortunately, we could not obtain accurate data on birth weight because at the time of birth of participants no reliable hospital or primary healthcare records were kept on birth, newborn characteristics, maternal profiles, or complications during pregnancy in Indonesia. Although recent studies and meta-analysis have shown that low birth weight is an independent predictor for adulthood CVD,32 other studies suggest that birth weight is not causal, but rather a surrogate marker of risk for adult CVD.1 In this study we obtained data directly from subjects and parental recall. We are confident that the treating midwives, physicians, or obstetricians of participants’ mother adopted the standardized and widely accepted definitions of common pregnancy complications. However, we acknowledge the possibility of recall bias, particularly differential recall of past maternal pregnancy complications because of current disease status (ACS or not). In an attempt to avoid this recall bias, during home visits, we directly verified data on pregnancy complications from the cases and controls with the parents, siblings, or other

40 Pregnancy-related conditions and premature CAD in adult offspring closest family members who were present during the pregnancy. Participants and their family members were only informed about the general overall research interest, the possible influence of early life factors on ACS. The pregnancy data pertaining to this study were drawn from an extensive questionnaire, and as this association is not widely considered, it is unlikely that patients or controls 3 and their family have been reporting differentially about the pregnancy complications. Nevertheless, we cannot definitively exclude the possibility of recall bias.

Finally, we could not consistently detect the association between maternal high blood pressure and offspring CHD. The associations were unstable, but the odds ratios were increased, and therefore this may reflect limited power from our sample size to perform sub-group analysis. Our study was a formal and planned case-control study as apparent from prospective (new) ACS cases collection and incidence density sampling of controls. We did not perform a pre-hoc power calculation. Instead, we planned for inclusion of as many cases as possible within a reasonable time-frame and managed to include one control for every included case, as described. Notably, ours is one of the biggest case- control studies performed on this subject, certainly in Indonesia. We did attempt to avoid overfitting our models, and therefore we carefully performed stepwise analyses in 4 adjustment models. Although clear rules of thumb for multivariable (conditional) logistic regression are currently not available,33 we did have 10-15 outcome observations (cases) per predictor/variable in our analysis. We believe that our findings do approximate real rate ratios because we only enrolled incident cases (newly-diagnosed ACS patients), and we randomly selected age- and sex-matched controls from the same neighborhoods that the cases came from, at the same time with cases inclusion.

Our findings contribute to the understanding of the relationship between pregnancy complications and the clinically manifest CVD in adult offspring. However, further studies – ideally larger, prospective, and longitudinal – are required to confirm the specific associations and to investigate the underlying mechanisms. In terms of clinical implications, optimizing maternal health and nutrition during pregnancy may reduce or delay the development of CVD in the offspring. Vaccination and adequate treatment of pregnant women with infectious diseases is of importance, especially in settings where the burden of infection is high. In addition, the necessity of standardized data and management of pregnancy complications is essential, particularly in low- and middle-income countries in South-East Asia where the infrastructure, financial, and human resources are limited.

In conclusion, offspring of mothers with complicated pregnancies are at increased risk of premature ACS in young adulthood. Our finding may be of particular relevance in populations with epidemiological transition, where the incidence of both pregnancy-related morbidity and CVD are high.

41 Chapter 3

NOTES

Acknowledgements The authors thank all participants who enrolled in this study, and their mothers and family members for the cooperation. The authors also thank the staff of Cardiovascular Care Unit (CVCU) Wahidin Sudirohusodo Hospital Makassar for their hospitality, care, and help; cadres of Community Healthcare Center (Puskesmas) Batua Makassar for their dedicated assistance; the staff of Prodia Clinical Laboratory Makassar for their assistance in blood sampling, and all research assistants for the data collection and data management.

Information The abstract of this paper has been presented in European Society of Cardiology (ESC) congress, 27-31 of August 2016, in Rome, Italy, and published in the abstract supplement of European Heart Journal, volume 37, Issue suppl_1, August 2016.

Funding This work was supported by a grant from Direktorat Jenderal Pendidikan Tinggi/Directorate General of Higher Education (DGHE), Ministry of National Education Republic of Indonesia, based on letter No. 600/E4.4/K/2011, dated 12 July 2011. D.P.B reports grant by National Health and Medical Research Council (Australia) Fellowship [APP1064629] and an Honorary Future Leader Fellowship of the National Heart Foundation of Australia (#100369).

Competing interests None declared.

42 Pregnancy-related conditions and premature CAD in adult offspring

Key Messages What is already known about this subject? • Registry data on cardiovascular diseases and deaths in the low- and middle-income countries 3 are lacking. • Previous studies have suggested that traditional risk factors and adverse clinical presentation at admission were all independent predictors of cardiovascular death. • Evidence showed that well-established traditional risk factors in western and high-income countries play a similar role in cardiovascular mortality in the South-East Asian region.

What does this study add? • Mortality both during and after hospitalization is unacceptably high in patients with CAD in Indonesia. After the total follow-up (median 18 (IQR 6 – 36) months), 32.3% patients died. • In-hospital and total medium-term mortality differed between underlying disease (higher in NSTEMI than other diagnosis groups) with p=0.002 and p=0.007, respectively. • The initial severity of disease, lack access to guidelines-recommended therapy and poor adherence to after-discharge medications are the main drivers for excess medium-term mortality. • Poor adherence to medications predicted after discharge mortality, and did so irrespective of underlying CAD diagnosis (p-interaction = 0.88).

How might this impact on clinical practice? • This study provides a general picture of risk stratification for clinical practitioners to recognize CAD patients with poor prognosis in a resource-limited South-East Asian setting, particularly in Indonesia. • Hospitalization is an important window of opportunity to address both in-hospital and, largely as a consequence, longer term survival in CAD patients. • Optimizing medication adherence and life-style adjustment, irrespective of underlying CAD diagnosis will likely help reduce excess CAD mortality.

43 Chapter 3

REFERENCES 1. Ryckman KK, Borowski KS, Parikh NI, Saftlas AF. Pregnancy Complications and the Risk of Metabolic Syndrome for the Offspring. Curr Cardiovasc Risk Rep 2013; 7: 217-223. 2. Miettola S, Hartikainen AL, Vaarasmaki M, Bloigu A, Ruokonen A, Jarvelin MR, et al. Offspring’s blood pressure and metabolic phenotype after exposure to gestational hypertension in utero. Eur J Epidemiol 2013; 28: 87-98. 3. Davis EF, Lewandowski AJ, Aye C, Williamson W, Boardman H, Huang RC, et al. Clinical cardiovascular risk during young adulthood in offspring of hypertensive pregnancies: insights from a 20-year prospective follow-up birth cohort. BMJ Open 2015; 5: e008136. 4. Vatten L. Intrauterine exposure to preeclampsia and adolescent blood pressure, body size, and age at menarche in female offspring.Obstetrics & Gynecology 2003; 101: 529- 533. 5. Davis EF, Lazdam M, Lewandowski AJ, Worton SA, Kelly B, Kenworthy Y, et al. Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review. Pediatrics 2012; 129: e1552-1561. 6. Parkinson JRC, Hyde MJ, Gale C, Santhakumaran S, Modi N. Preterm birth and the metabolic syndrome in adult life: a systematic review and meta-analysis. Pediatrics 2013; 131: e1240-e1263. 7. Visentin S, Grumolato F, Nardelli GB, Di Camillo B, Grisan E, Cosmi E. Early origins of adult disease: low birth weight and vascular remodeling. Atherosclerosis 2014; 237: 391-399. 8. Thompson JA, Regnault TR. In Utero Origins of Adult Insulin Resistance and Vascular Dysfunction. Semin Reprod Med 2011; 29: 211-224. 9. Skilton MR. Intrauterine risk factors for precocious atherosclerosis. Pediatrics 2008; 121: 570-574. 10. Tenhola S, Rahiala E, Halonen P, Vanninen E, Voutilainen R. Maternal preeclampsia predicts elevated blood pressure in 12-year-old children: evaluation by ambulatory blood pressure monitoring. Pediatr Res 2006; 59: 320-324. 11. World Health Organization. Media centre: Maternal mortality. Fact sheet No. 348 http:// www.who.int/mediacentre/factsheets/fs348/en/ (25 March 2016). 12. World Health Organization. Media centre: Cardiovascular diseases (CVDs). Fact sheet No. 317 http://www.who.int/mediacentre/factsheets/fs317/en/ (22 January 2015). 13. Ohira T, Iso H. Cardiovascular disease epidemiology in Asia: an overview. Circ J 2013; 77: 1646-1652. 14. Lam CSP. Heart failure in Southeast Asia: facts and numbers. ESC Heart Failure 2015; 2: 46-49. 15. World Health Organization: Regional Office for South-East Asia. Noncommunicable Diseases in the South-East Asia Region: 2011 Situation and Response. New delhi, 2011. 16. Krishnan MN. Coronary heart disease and risk factors in India - on the brink of an epidemic? Indian Heart J 2012; 64: 364-367. 17. Kumar A, Cannon CP. Acute Coronary Syndromes: Diagnosis and Management, Part I. Mayo Clin 2009; 84: 917-938. 18. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016; 37: 267-315. 19. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. Circulation 2012; 126: 2020-2035.

44 Pregnancy-related conditions and premature CAD in adult offspring

20. Qanitha A, de Mol BA, Pabittei DR, Mappangara I, van der Graaf Y, Dalmeijer GW, et al. Infections in early life and premature acute coronary syndrome: A case-control study. Eur J Prev Cardiol 2016; 23: 1640-1648. 3 21. Burgner DP, Cooper MN, Moore HC, Stanley FJ, Thompson PL, de Klerk NH, et al. Childhood hospitalisation with infection and cardiovascular disease in early-mid adulthood: a longitudinal population-based study. PLoS One 2015; 10: e0125342. 22. Ng N, Stenlund H, Bonita R, Hakimi M, Wall S, Weinehall L. Preventable risk factors for noncommunicable diseases in rural Indonesia: prevalence study using WHO STEPS approach. Bulletin of the World Health Organization 2006; 84: 305-313. 23. Risnes KR, Pape K, Bjorngaard JH, Moster D, Bracken MB, Romundstad PR. Premature Adult Death in Individuals Born Preterm: A Sibling Comparison in a Prospective Nationwide Follow-Up Study. PLoS One 2016; 11: e0165051. 24. Jiang HY, Xu LL, Shao L, Xia RM, Yu ZH, Ling ZX, et al. Maternal infection during pregnancy and risk of autism spectrum disorders: A systematic review and meta-analysis. Brain Behav Immun 2016. 25. Moreno JL, Kurita M, Holloway T, Lopez J, Cadagan R, Martinez-Sobrido L, et al. Maternal Influenza Viral Infection Causes Schizophrenia- Like Alterations of 5-HT2A and mGlu2 Receptors in the Adult Offspring. The Journal of Neuroscience 2011; 31: 1863-1872. 26. Huleihel M, Golan H, Hallak M. Intrauterine infection/inflammation during pregnancy and offspring brain damages: Possible mechanisms involved. Reproductive Biology and Endocrinology 2004; 2: 1-8. 27. Botto LD, Panichello JD, Browne ML, Krikov S, Feldkamp ML, Lammer E, et al. Congenital heart defects after maternal fever. Am J Obstet Gynecol 2014; 210: 359 e351-359 e311. 28. Szitanyi P, Janda J, Poledne R. Intrauterine Undernitrition and Programming as a New Risk of Cardiovascular Disease in Later Life. Physiol. Res. 2003; 52: 389-395. 29. Alkemade FE, Gittenberger-de Groot AC, Schiel AE, VanMunsteren JC, Hogers B, van Vliet LS, et al. Intrauterine exposure to maternal atherosclerotic risk factors increases the susceptibility to atherosclerosis in adult life. Arterioscler Thromb Vasc Biol 2007; 27: 2228- 2235. 30. Kajantie E, Eriksson JG, Osmond C, Thornburg K, Barker DJ. Pre-eclampsia is associated with increased risk of stroke in the adult offspring: the Helsinki birth cohort study. Stroke 2009; 40: 1176-1180. 31. Zoller B, Sundquist J, Sundquist K, Crump C. Perinatal risk factors for premature ischaemic heart disease in a Swedish national cohort. BMJ Open 2015; 5: e007308. 32. Wang SF, Shu L, Sheng J, Mu M, Wang S, Tao XY, et al. Birth weight and risk of coronary heart disease in adults: a meta-analysis of prospective cohort studies. J Dev Orig Health Dis 2014; 5: 408-419. 33. van Smeden M, de Groot JA, Moons KG, Collins GS, Altman DG, Eijkemans MJ, et al. No rationale for 1 variable per 10 events criterion for binary logistic regression analysis. BMC Med Res Methodol 2016; 16: 163.

45 Chapter 3

SUPPLEMENT

Supplementary Methods We developed a simple questionnaire on dietary pattern by adopting and modifying the National Health and Nutrition Examination Survey (NHANES) food frequency questionnaire. We applied questions on food frequencies and dietary habit corresponding to the local circumstance of Makassar population. We defined high salty food intake as a consumption of salt and MSG in daily food of ≥1 teaspoon/day and/or consumption of local salty/MSG food (i.e. salty fish, bakso, coto, pallubasa, or instant/dried noodle) for ≥3 times/week. High fatty food intake was defined as consumption of local fatty food (i.e. coto, pallubasa, karee, or other traditional meat (beef, buffalo, lamb) dietary) and/or seafood (i.e. crab, prawn, squid, or mussles) for ≥3 times/week. Less fiber was defined as consumption of a serving of fruit, juices, or vegetables for <3 times/week.

Furthermore, we adopted physical activity recommendation from the American Heart Association. We defined physical inactivity as never or doing moderate-intensity aerobic activities (i.e. walking, climbing stairs, gardening, yard work, moderate-heavy house work, dancing, or home exercise) for <150 minutes/week, or doing at least 20 minutes of vigorous aerobic exercises (i.e. brisk walking, jogging, swimming, bicycling, or jumping rope) for <3 times/week.1 For smoking status, we combined the standard National Health Interview Survey (NHIS) and the standard National Survey on Drug Use and Health (NSDUH-S) to differentiate current and former smoker. Current smoker was defined as participant who has smoked at least 100 cigarettes in their lifetime and has smoked in the last 30 days, while former smoker was defined as those who smoked at least 100 cigarettes in their lifetime and has not smoked at all in the last 30 days.2 A positive family history of CVD was defined as ≥1 first degree and/or ≥2 second degrees family members with CVD before the age of 55 years in men and 65 years in women.3-5 Parental history of diabetes mellitus (DM) was positive if participant have mother or father with type 2 DM. Family history of premature sudden cardiac death was positive if ≥1 first-degree and/or ≥2 second-degree family members have died at age <60 years due to CVD.6 Positive history of hypertension was defined as a known hypertension (systolic blood pressure (BP) ≥140 mmHg and/or diastolic BP ≥90 mmHg7), or on medication for hypertension. History of type 2 diabetes mellitus (DM) was defined positive if participant had a known type 2 DM (fasting plasma glucose ≥7.0 mmol/L or 2-hour plasma glucose ≥11.1 mmol/L),8 or on medication for type 2 DM. Lastly, for current monthly income, we used the cut-off point of ≥Rp.1,810,000,- as the national average of minimum wages for decent living in Indonesia in 2015.9

46 Pregnancy-related conditions and premature CAD in adult offspring

References 1. Haskell WL, Lee IM, Pate RR, Powell KE, Blair SN, Franklin BA, et al. Physical activity and public health: Updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Circulation 2007; 116: 1081-1093. 2. Ryan H, Trosclair A, Gfroerer J. Adult current smoking: differences in definitions and prevalence 3 estimates-NHIS and NSDUH, 2008. J Environ Public Health 2012; 2012: 918368. 3. Mulders TA, Meyer Z, van der Donk C, Kroon AA, Ferreira I, Stehouwer CD, et al. Patients with premature cardiovascular disease and a positive family history for cardiovascular disease are prone to recurrent events. Int J Cardiol 2011; 153: 64-67. 4. Lloyd-Jones DM, Nam B, D’Agostino RB, Levy D, Murabito JM, Wang TJ, et al. Parental Cardiovascular Disease as a Risk Factor for Cardiovascular Disease in Middle-aged Adults: A Prospective Study of Parents and Offspring. JAMA 2004; 291: 2204-2211. 5. Nasir K, Budoff MJ, Wong ND, Scheuner M, Herrington D, Arnett DK, et al. Family history of premature coronary heart disease and coronary artery calcification: Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2007; 116: 619-626. 6. Ranthe MF, Carstensen L, Oyen N, Tfelt-Hansen J, Christiansen M, McKenna WJ, et al. Family history of premature death and risk of early onset cardiovascular disease. J Am Coll Cardiol 2012; 60: 814-821. 7. Narkiewwicz K, Redon J, Zanchetti A, The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). ESC Essential Mesages. 2013 ESH/ESC Guidlines for the management of arterial hypertension. Eur Heart J 2013; 34: 2159-2219. 8. World Health Organization-International Diabetes Federation. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia : report of a WHO/IDF consultation. Geneva, Switzerland, 2006. 9. Pemerintah.net. Daftar Lengkap UMP 2015. Informasi Nasional, Kebijakan. http://pemerintah.net/ daftar-lengkap-ump-2015/ (02 February 2015).

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49 50 51 Chapter 4

ABSTRACT

Objective To provide a detailed description of characteristics at hospital admission and clinical outcomes at 30-day and 6-month follow-up in patients hospitalized with coronary artery disease (CAD) in a poor South-East Asian setting.

Design Prospective observational cohort study.

Setting From February 2013 to December 2014, in Makassar Cardiac Center, Indonesia.

Participants 477 patients with CAD (acute coronary syndrome and stable CAD).

Outcome measures All-cause mortality and major adverse cardiovascular events (MACE).

Results Out of 477 patients with CAD, the proportion of young age (<60 years) was 53.9% and 72.7% were male. At admission, 44.2% of patients were diagnosed with ST-segment elevation myocardial infarction (STEMI), 38.6% with diagnosis or signs of heart failure, and 75.1% had previous hypertension. Out of 211 STEMI patients, only 4.7% had been treated with primary percutaneous coronary intervention (PCI) and 6.2% received thrombolysis. The time lapse from symptom onset to hospital admission was 26.8 (IQR 10.0–48.0) hours, and 19.1% of all patients had undergone either PCI or coronary artery bypass graft. The survival rate at 6 months was 78.9%. The rates of all-cause mortality at 30 days and 6 months were 13.4% and 7.3%, respectively; the rate of composite MACE at 30 days was 26.2% and 18.0% at 6 months.

Conclusions Patients with CAD from a poor South-East Asian setting present themselves with predominantly unstable conditions of premature CAD. These patients show relatively severe illness, have significant time delay from symptom onset to admission or intervention, and most do not receive the guidelines- recommended treatment. Awareness of symptoms, prompt initial management of acute CVD, well- established infrastructures and resources both in primary and secondary hospital for CVD should be improved to reduce the high rates of 30-day and 6-month mortality and adverse outcomes in this population.

Keywords Cardiovascular outcomes; mortality rate; major adverse cardiac event; coronary artery disease; poor setting.

52 Characteristics and the short-term outcomes of CAD patients

INTRODUCTION

The South-East Asia region, which accounts for one-quarter of the world’s population and 40% of the global poor, is facing a rapid epidemiologic transition.1 This leads to the high rates of premature 4 death from non-communicable diseases (NCD), primarily from cardiovascular disease (CVD).2 Of the 7.9 million annual NCD in this region, 34% occur before the age of 60 years compared with 16% in the European region and 23% in the rest of the world.2 Half of the world’s cardiovascular burden is estimated to occur in Asia,3 and the prevalence of symptomatic heart failure appears to be higher in South-East Asia countries compared with the rest of the world.4 Despite the high burden of CVD in South-East Asia, little is known about characteristics at admission and clinical outcomes in patients with coronary artery disease (CAD), especially acute coronary syndrome (ACS).

Recent studies indicate the insufficient access to evidence-based interventions for combating CVD in low- and middle-income countries.5,6 Particularly in Indonesia, the population of 260 million and a unique demographic situation (consisting of 17,508 islands, over 6,000 are inhabited) aggravate the inequity in the access to healthcare services, not only between the the rich and the poor, but also between rural and urban population within the country. Logistics and financial shortcomings7, as well as the low awareness of the symptoms6 associated with CVD in these populations – resulted in delayed diagnosis and a younger age of death from CVD compared with the Western world.8 In Indonesia, there were approximately 760 cardiologists9 and only 70 certified interventional cardiologists10 available to serve 883,447 patients diagnosed with CAD and approximately 2,650,340 patients suspected with CAD in 2013.11 However, half of these cardiologists work on Java island and in the big cities, leaving other regions even less well served.9

Beside the centralization of healthcare facilities and the lack of healthcare professionals, 94.1% of households in 18 provinces in Indonesia are located more than 5 km from any primary healthcare center or hospital12 with very minimal means of transportation and infrastructure. In addition, 28.6 million people (11.2% of total population) are living at poor socio-economic levels,13 and the majority were insufficiently health insured until 2013.7 Despite the fact that CVD ranks as the top cause of mortality in Indonesia, any follow-up studies of hospitalized patients with CAD (ACS and stable CAD) are rare.

Thus, in Indonesia there is clearly a general problem with access to care, but possibly also with the quality of care. It is suspected that many hospitalized patients who should be considered for early invasive strategy actually encounter delayed or overly conservative approaches. We studied the characteristics and clinical profiles of CAD patients presenting at the Makassar Cardiac Center, Indonesia. These patient outcomes were evaluated in hospital, at 30 days, and at 6 months.

METHODS

Study population This was an observational cohort study of 477 consecutive patients who presented between February 2013 and December 2014 with a diagnosis of CAD at the Makassar Cardiac Center, Wahidin Sudirohusodo Hospital, one of the two public cardiac referral centers in East Indonesia. The cardiac center with seven cardiologists mainly serves the 9.5 million South Sulawesi population, and also

53 Chapter 4 other regions inside and outside Sulawesi island. The study protocol was approved by the Ethics Committee and Institutional Review Board of the Faculty of Medicine, University of Hasanuddin Makassar, Indonesia.

Patients were included if they had confirmed CAD, defined as acute coronary syndrome (ACS) and stable coronary artery disease (SCAD). ACS was defined as a spectrum of clinical presentations consistent with acute cardiac ischemia within 24 hours of hospital presentation, including unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI).14,15 SCAD was defined as at least one of the following criteria: stable angina, history of unstable angina, prior myocardial infarction (MI), prior coronary revascularization (PCI and/or CABG), or multivessel CAD without revascularization.16 All eligible patients signed written informed consent before the first interview. We excluded all fatal patients who immediately died at the emergency department or intensive cardiovascular care (ICCU) unit before being able to give informed consent, and all suspected patients with normal coronary angiography (defined as 0% lumen stenosis in all coronary vessels).17 The flowchart of the study population is presented infigure 1.

Figure 1. Flowchart of the study population CVD: cardiovascular disease; RSWS: Rumah Sakit Wahidin Sudirohusodo (Wahidin Sudirohusodo hospital); ACS: acute coronary syndrome, CAD: coronary artery disease; HF: heart failure; CHF: congestive heart failure.

54 Characteristics and the short-term outcomes of CAD patients

Data collection and follow-up At hospital admission, we obtained baseline data from medical records and questionnaire interviews. Data on socio-demographic characteristics included age, gender, occupation, living area, monthly income, and educational level; lifestyle included smoking status, dietary pattern, and physical activity; 4 family history of CVD included family history of premature sudden death at age <60 years18; clinical profiles included characteristics and onset of chest pain, previous medications, as well as history of previous diseases (i.e. hypertension, type 2 diabetes mellitus, MI, stroke, and kidney disease). Detailed methods were presented as supplementary material.

Clinical data were collected prospectively at the time of hospital admission based on physical examination including vital signs, anthropometric measurements (i.e. height, weight, and waist circumference), electrocardiography, echocardiography including left ventricular ejection fraction (LVEF), coronary angiography (CAG), laboratory tests including cardiac enzymes and estimated glomerular filtration rate. In-hospital managements and at-discharge medications were also recorded. Plasma glucose, lipid profiles, uric acid, renal and liver functions were measured within 24 hours of hospital admission following a minimum 8 hours fast for all patients hospitalized at Wahidin Sudirohusodo Hospital. While, for patients who were referred from other hospitals or clinics (n = 70), we obtained baseline and laboratory data from their medical records. All blood samples analyses were generated with standardized methods at the hospital laboratory.

Furthermore, data on mortality and major adverse cardiovascular events (MACE) were obtained during hospitalization, at 30 days, and at 6 months after hospital admission. For referred patients, we obtained data on in-hospital mortality from their family members and this was confirmed with hospital medical records from where the patients were admitted (n = 1). We actively performed the follow-up by visiting patient’s houses or by an interview via telephone. The nurses asked a detailed questionnaire about patient’s current condition, cardiovascular complaints, re-hospitalization, deaths and other CVD-related events from the patients, family members, or their relatives. Subsequently, we verified their answers with the medical records in hospital, or with the patient’s documentation at home.

Study Outcomes The primary endpoint of our study were the rates of in-hospital, 30-day and 6-month all-cause mortality and composite MACE. The composite MACE counting for cardiac and non-cardiac death, MI re-hospitalization, heart failure requiring hospitalization, re-hospitalization due to stroke, (emergency) CABG, stent thrombosis, repeat PCI, repeat CAG, first PCI, and first CAG.

Statistical analysis Continuous variables were presented as mean ± SD, and categorical variables as number (percentage). Skewed data were provided as median (Q1-Q3). Baseline characteristics, clinical profiles, and managements during hosptalization were divided into acute (ACS) and non-acute (SCAD) groups. The rates of mortality and composite MACE in hospital, at 30 days, and at 6 months after hospital admission were calculated. Kaplan-Meier curves were used to describe the cumulative survival during 6-month follow-up. Log rank statistics were used to assess the difference between guideline-treated and non-guideline-treated groups. A 95% confidence interval not including one,

55 Chapter 4 corresponding to a two-sided p<0.05 was considered statistically significant. All statistical analyses were performed using SPSS V.23.0.

Patient involvement Patients were not involved in the design and development of the research questions. The results of this study are used to provide information for the stakeholders and health-policy makers to improve healthcare services in Indonesia. Therefore, the findings of our study were not disseminated directly to all participants.

RESULTS

Among 477 patients hospitalized with CAD, 257 (53.9%) were at young age (<60 years),19 and 347 (72.7%) were male.

Table 1 shows the baseline characteristics of CAD patients. As presented, CAD patients in Indonesia had high levels of systolic blood pressures, fasting plasma glucose, and LDL-cholesterol, and low level of HDL-cholesterol. More than half of these patients had metabolic syndrome but did not have central obesity. Most came from rural areas and from low and middle socio-economic status, more often were current or former smokers, had poor dietary habits with high consumption of sugar and deep fried food, and had low physical activity.

The clinical profiles at hospital admission are presented intable 2. Of all patients, 75.1% had previous hypertension, 34.4% had previous MI, and 7.5% had a previous stroke. Patients diagnosed with STEMI, NSTEMI, UA, and SCAD were 44.2%, 17.8%, 14.3%, and 23.7%, respectively. At hospital admission, 30.8% of patients had diabetes mellitus, 38.6% were diagnosed or presented with heart failure signs, and 31.2% had reduced renal function. Out of 273 patients with CAG, 169 (61.9%) had multi-vessel disease. Amongst 262 (54.9%) patients who underwent echocardiography, 24.0% had an LVEF ≤35%.

Table 3 summarizes invasive and pharmaco-therapy managements during hospitalization. Of 211 STEMI patients, only 10 (4.7%) underwent primary PCI and 13 (6.2%) received thrombolysis for early reperfusion. Meanwhile, of 477 patients, 42.8% had no exploration of coronary angiography, and 19.1% underwent either PCI or CABG for revascularization. Overall, there was a 24 to 36 hours time lapse between angina onset and hospital admission in ACS and SCAD groups, respectively (p=0.002). Patients with stable disease (SCAD) stayed shorter in hospital compared with ACS patients (p<0.001). insert table 3

Figure 2 describes the clinical outcomes at 30-day and 6-month follow-up. More ACS patients died during hospitalization compared to SCAD (12.6% vs. 5.3%, p=0.029). However, these SCAD group experienced 6-month adverse cardiovascular events more frequently compared with ACS group (25.7% vs. 15.7%, p=0.043). The rates of all-cause mortality in hospital, at 30 days, and at 6 months were 10.9%, 2.5%, and 7.3%, respectively. In total, 189 (39.6%) participants experienced at least one adverse event during the study period. A detailed description of MACE at 30 days and 6 months of these CAD patients is presented in table 4.

56 Characteristics and the short-term outcomes of CAD patients

Table 1. Baseline characteristics at hospital admission

ACS SCAD Total Variables p-value (n = 364) (n = 113) (n = 477) 4 Age (years) 57.5 ± 11.2 60.6 ± 8.8 58.2 ± 10.8 0.007 Male 260 (71.4) 87 (77.0) 347 (72.7) 0.246 Systolic BP (mmHg) 130.0 ± 27.6 127.3 ± 20.4 129.4 ± 26.1 0.336 Diastolic BP (mmHg) 82.7 ± 16.1 80.8 ± 10.3 82.2 ± 14.9 0.228 Fasting plasma glucose (mmol/L)a 7.3 (5.8-9.6) 5.9 (5.1-8.2) 7.0 (5.7-9.1) <0.001 Total cholesterol (mmol/L)a 5.0 (4.2-5.7) 5.1 (3.7-5.6) 5.0 (4.1-5.7) 0.233 Triglyserides (mmol/L)a 1.4 (1.1-1.9) 1.5 (1.0-1.9) 1.5 (1.1-1.9) 0.654 HDL-chol (mmol/L) 0.95 ± 0.31 0.92 ± 0.35 0.94 ± 0.32 0.456 LDL-chol (mmol/L)a 3.3 (2.6-4.0) 3.2 (2.3-3.7) 3.3 (2.6-3.9) 0.032 Waist circumference (cm) 84.6 ± 7.4 84.9 ± 6.1 84.6 ± 7.1 0.666 Obese (BMI ≥25 kg/m2) 119 (32.7) 46 (40.7) 165 (34.6) 0.118 Metabolic syndromeb 208 (57.1) 56 (49.6) 264 (55.3) 0.157 Parental history of CVDc 95 (26.1) 27 (23.9) 122 (25.6) 0.639 Monthly income ≥Rp.1,810,000d 155 (42.6) 74 (65.5) 229 (48.0) <0.001 College education 134 (36.8) 55 (48.7) 189 (39.6) 0.024 Living >20 km from hospital (rural) 193 (53.0) 54 (47.8) 247 (51.8) 0.331 Funding/insurance Private fund (high-income) 30 (8.2) 6 (5.3) 36 (7.5) 0.303 Jamsostek (company)e 10 (2.7) 0 (0.0) 10 (2.1) 0.127 Askes (mid-income) 144 (39.6) 97 (85.8) 241 (50.5) <0.001 Jamkesmas/Jamkesda (low-income) 107 (29.4) 8 (7.1) 115 (24.1) <0.001 BPJS (national)f 73 (20.1) 2 (1.8) 75 (15.7) <0.001 Current smoker 103 (28.3) 20 (17.7) 123 (25.8) 0.024 Former smoker 118 (32.4) 56 (49.6) 174 (36.5) 0.001 Physical inactivity 218 (59.9) 59 (52.2) 277 (58.1) 0.148 High sugar intake 202 (55.5) 46(40.7) 248 (52.0) 0.006 High salty food and MSG intake 148 (40.7) 33 (29.2) 181 (37.9) 0.028 High fried food intake 221 (60.7) 68 (60.2) 289 (60.6) 0.919 Often re-use cooking oil 190 (52.2) 29 (25.7) 219 (45.9) <0.001

Values are n (%) or means ± SD, unless otherwise stated. Comparison of baseline characteristics was per- formed using independent-samples t-test for continuous variables and Pearson chi-square test for categorical variables. aValues are medians (Q1-Q3). Comparison was performed using Mann-Whitney U test. bMetabolic sydrome was defined using National Cholesterol Education Program (NCEP) – Adult Treatment Panel III (ATP III) classification. cParental history of CVD was positive, if patients have had either mother with CVD at the age under 65 years old, or father with CVD at the age under 55 years old, or 2nd degree of family with history of premature sudden cardiac death. dUS$ 1= Rp.13,500 (Indonesian Rupiah). The cut point based on the national average of decent-living minimum income in 2015.

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eComparison was done using Fisher’s Exact test. fAs a national health insurance, BPJS has been started since 1 January 2014. ACS: acute coronary syndrome; SCAD: stable coronary artery disease; BP: blood pressure; HDL-chol: high density lipoprotein-cholesterol; LDL-chol: low density lipoprotein-cholesterol; BMI: body mass index; CVD: cardiovascular disease; Jamsostek: jaminan sosial tenaga kerja (company insurance); Askes: asuransi kesehatan (civil servant insurance); Jamkesmas: jaminan kesehatan masyarakat (national insurance for poor people); Jamkesda: jaminan kesehatan daerah (local insurance for poor people); BPJS: badan penyelanggara jaminan sosial (national insurance); MSG: mono-sodium glutamate.

Table 2. Clinical presentation at hospital admission

ACS SCAD Total Variables p-value (n = 364) (n = 113) (n = 477) Pre hospital Previous hypertension 268 (73.6) 90 (79.6) 358 (75.1) 0.196 On medication of hypertension 156 (42.9) 55 (48.7) 211 (44.2) 0.277 Previous MI 126 (34.6) 38 (33.6) 164 (34.4) 0.847 Previous stroke 27 (7.4) 9 (8.0) 36 (7.5) 0.848 Previous CAG 48 (13.2) 21 (18.6) 69 (14.5) 0.154 Previous PCI 14 (3.8) 13 (11.5) 27 (5.7) 0.002 In hospital STEMI 211 (58.0) N/A 211 (44.2) N/A NSTE-ACS 153 (42.0) N/A 153 (32.1) N/A Diabetes Mellitus 112 (30.8) 35 (31.0) 147 (30.8) 0.967 With HF diagnosis/signs 150 (41.2) 34 (30.1) 184 (38.6) 0.034 Atrial fibrillationa 9 (2.5) 3 (2.7) 12 (2.5) 1.000 Left ventricle hypertrophy 124 (34.1) 21 (18.6) 145 (30.4) 0.002 Echocardiography assessed 210 (57.7) 52 (46.0) 262 (54.9) 0.029 LVEF (%) 45.0 ± 13.2 49.3 ± 17.4 45.8 ± 14.2 0.049 Troponin T (μg/L)b 0.42 (0.10-1.58) 0.00 (0.00-0.02) 0.20 (0.02-1.00) <0.001 Haemoglobin (g/dL) 13.6 ± 2.1 13.5 ± 2.1 13.6 ± 2.1 0.610 Haematocrit 0.40 ± 0.06 0.41 ± 0.14 0.40 ± 0.09 0.296 Creatinine (µmol/L)b 88.4 (79.6-114.9) 88.4 (77.8-114.9) 88.4 (79.6-114.9) 0.869 eGFR <60 mL/min 108 (29.7) 41 (36.3) 149 (31.2) 0.185 Co-morbidities Concomitant strokea 18 (4.9) 3 (2.7) 21 (4.4) 0.300 With cardiogenic shocka 17 (4.7) 0 (0.0) 17 (3.6) 0.017 Concomitant pneumonia 37 (10.2) 5 (4.4) 42 (8.8) 0.060 Vessel disease Non significant 1-2 VDc 27 (7.4) 12 (10.6) 39 (8.2) 0.666 1 VD 45 (12.4) 20 (17.7) 65 (13.6) 0.738 2 VD 30 (8.2) 15 (13.3) 45 (9.4) 0.954 3 VD 53 (14.6) 41 (36.3) 94 (19.7) 0.007 >3 VD† 28 (7.7) 2 (1.8) 30 (6.3) 0.001

58 Characteristics and the short-term outcomes of CAD patients

Values are n (%) or means ± SD, unless otherwise stated. Comparison was performed using independent-sam- ples t-test for continuous variables and Pearson Chi-square test for categorical variables. aComparison was done using Fisher’s Exact test. bValues are medians (Q1-Q3). Comparison was done using Mann-Whitney U test. 4 cDefined as 1-49% lumen stenosis in at least 1 coronary vessel.17 ACS: acute coronary syndrome; SCAD: stable coronary artery disease; MI: myocardial infarction; CAG: coronary angiography; PCI: percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction; NSTE-ACS: Non ST-segment elevation acute coronary syndrome; HF: heart failure; LVH: Left ventricle hypertro- phy; LVEF: left ventricular ejection fraction; eGFR: estimated glomerular filtration rate; CABG: coronary artery bypass graft; ASA: acetylsalicylic acid; VD: vessel disease; N/A: Not applicable.

Table 3. Managements in hospital from admission to 6 months

ACS SCAD Total Variables p-value (n = 364) (n = 113) (n = 477) Onset to admission (hours) 24 (9-48) 36 (16.3-72) 26.8 (10-48) 0.002 Length of hospitalization (days) 7 (5-10) 1 (0-7) 6 (4-9) <0.001 Admission to intervention (hours) 120 (8-168) 8 (4-149.6) 96 (8-149.6) <0.001 Invasive treatment Thrombolysis 13 (3.6) N/A 13 (2.7) N/A Primary PCI 10 (2.7) N/A 10 (2.1) N/A Elective PCI 47 (12.9) 32 (28.3) 79 (16.6) 0.003 CABG + PCIa 2 (0.5) 0 (0.0) 2 (0.4) 1.000 CAG only 124 (34.1) 58 (51.3) 182 (38.2) 0.001 No-exploration 181 (49.7) 23 (20.4) 204 (42.8) <0.001 Pharmacotherapy Anti-coagulant 168 (46.2) 16 (14.2) 184 (38.6) <0.001 ASA 320 (87.9) 74 (65.5) 394 (82.6) <0.001 Clopidogrel 308 (84.6) 58 (51.3) 366 (76.7) <0.001 Statin 271 (74.5) 54 (47.8) 325 (68.1) <0.001 Hypertension medication 263 (72.3) 80 (70.8) 343 (71.9) 0.123

Values are n (%) and medians (Q1-Q3). Comparison was done using Mann-Whitney U test for continous vari- ables and Pearson Chi-square test for categorical variables. aComparison was done using Fisher’s Exact test. ACS: acute coronary syndrome; SCAD: stable coronary artery disease; PCI: percutaneous coronary intervention; CAG: coronary angiography; CABG: coronary artery bypass graft; ASA: acetylsalicylic acid; N/A: Not applicable.

Seven (1.5%) participants were lost to follow-up. At 6 months, the survival rate was 78.9%. The Kaplan-Meier curves showed significantly better survival in patients with statin (p=0.002), clopidogrel (p<0.001), and revascularization (PCI/CABG) groups (p=0.001) compared with the respective counterparts. In subgroup analysis, ACS and SCAD patients without PCI/CABG had the worst survival rates compared to those with revascularization (p=0.002) (figure 3). Description of the most notable complaints or symptoms reported by all survivors is provided as supplement.

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Figure 2. Clinical outcomes at 30-day and 6-month follow-up ACS: acute cvoronary syndrome; SCAD: stable coronary artery disease; MACE: major adverse cardiovascular events.

DISCUSSION

The present study shows that CAD patients in Indonesia are predominantly young males with high prevalence of cardiovascular risk factors. More than half of this cohort had metabolic syndrome and prior hypertension; and approximately one-third had prior MI and diabetes mellitus. The majority came from rural areas with a low or middle socio-economic status, and had a history of smoking. These CAD patients showed relatively severe illness, had significant time delay from angina onset to admission or intervention, and rarely received the guidelines-recommended treatment.

60 Characteristics and the short-term outcomes of CAD patients

Table 4. Major adverse cardiovascular events (MACE) during follow-up

At 30 days At 6 months Total Composite MACE (n = 477) (n = 477) (n = 477) 4 All-cause mortality 64 (13.4) 35 (7.3) 99 (20.8) MI re-hospitalization 14 (2.9) 23 (4.8) 37 (7.8) HF re-hospitalization 1 (0.2) 6 (1.3) 7 (1.5) Stroke 2 (0.4) 4 (0.8) 6 (1.3) Emergency CABG 1 (0.2) 1 (0.2) 2 (0.4) Repeat PCI 5 (1.0) 3 (0.6) 8 (1.7) Repeat CAG 3 (0.6) 5 (1.0) 8 (1.7) First PCI post-discharge 23 (4.8) 3 (0.6) 26 (5.5) First CAG post-discharge 11 (2.3) 6 (1.3) 17 (3.6) Stent thrombosis 1 (0.2) 0 (0.0) 1 (0.2) Total MACE 125 (26.2) 35 (7.3) 211 (44.2)

Values are n (%). MACE: major adverse cardiovascular events; MI: myocardial infarction; HF: heart failure; CABG: coronary artery bypass graft; PCI: percutaneous coronary intervention; CAG: coronary angiography.

At baseline, compared to SCAD, patients with ACS were younger, had higher plasma glucose and LDL-cholesterol, had lower income and educational level, were more often current smoker, and had poorer dietary habits. Further, we observed considerably more ACS patients with diagnosis/signs of heart failure, with left ventricle hypertrophy (LVH), and with lower LVEF than SCAD patients. Likely as a result, those with ACS had poorer clinical outcomes mainly during hospitalization and at 30-day follow-up compared to those with SCAD.

In contrast, at 6-month follow-up, more patients with SCAD had adverse cardiac events compared to ACS (p=0.043). The most likely explanation is that these SCAD patients were undertreated for secondary prevention and aftercare management. Out of 113 SCAD patients, 34 (30.1%) were admitted for congestive heart failure (CHF); and of 90 SCAD patients with cardiac catheterization, 58 (64.4%) had multivessel CAD. Of those, only 32 (55.2%) underwent elective PCI. Therefore, the lack access or adherence to the guidelines-recommended treatment (i.e. elective PCI or CABG) and the lack of engagement to the long-term cardiovascular medications might largely contribute to these poorer outcomes. Meanwhile, in ACS, low access to an early invasive strategy was more likely to be associated with the high incidence of short-term death, chiefly in the first 30 days since admission.

In this study, we found that ACS patients in Indonesia (mean age 57.5 years) were younger than ACS patients in Japan (66.4 years)20 and in the Global Registry of Acute Coronary Events (GRACE) from 14 countries (65 years),21 but equally young with ACS patients in Malaysia (58.1 years).22 In these previous studies, the majority of patients were male (>65%).20-22

Hypertension, diabetes, and smoking are the top three risk factors responsible for 3.5 million deaths in South-East Asia every year, and particularly afflicting the young population.2,4 In our ACS group, the proportions of hypertension (73.6% vs. 47.1%) and diabetes mellitus (30.8% vs.15.6%) were higher than in a similar multicenter study of acute MI patients in France.23 The smoking-experience

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Figure 3. Kaplan-Meier curves for cumulative 6-month survival, comparing the guideline- treated vs. non-guideline-treated groups in all participants and between diagnosis groups Comparison was performed using Log Rank (Mantel-Cox) test. LR: log rank; PCI: percutaneous coronary intervention; CABG: coronary artery bypass graft; ACS: acute coronary syndrome; SCAD: stable coronary artery disease. rate of CAD patients in Indonesia (62.3%) was strikingly higher than in Japan (57.0%),20 UK (53.4%),19 and Malaysia (47.0%).22 This finding is compatible with the World Health Organization Global Status Report in 2014.4

Asian populations are less obese than western populations.4,24 Despite a much lower prevalence of overweight or obesity (22-26% in South-East Asia vs. 67% in UK and 70% in USA), raised blood glucose/diabetes mellitus is a pivotal risk factor in South-East Asia, reaching similarly high prevalence with the UK and USA.4 In contrast to the western populations where diabetes is strongly associated with obesity, South-East Asia populations have a unique ‘lean diabetic’ phenotype.4 In terms of lifestyles, patients with CAD in Indonesia have a poor dietary pattern as reflected by high intakes of sugar and deep fried foods. Our cohort showed physical inactivity levels (58.1%) higher than the

62 Characteristics and the short-term outcomes of CAD patients open population reported in Malaysia (51.6%), UK (40.0%), and USA (35.0%).4

Overall at hospital admission, these CAD patients showed relatively severe clinical features, with more renal insufficiency and heart failure. Our findings are in line with a previous report that, compared 4 to the Netherlands, patients with STEMI in Indonesia more often presented with severe illness with heart failure signs and had a longer time delay between symptom onset and hospital admission.7 We found that the time lapse between symptom onset and admission was 24 (IQR 9-48) hours in ACS patients. This was much longer compared to the GRACE study from 95 hospitals of 14 countries for STEMI patients (139 (73-313) minutes), NSTEMI (190 (90-510) minutes), or for UA (180 (90-435) minutes).21

The time lapse from admission to intervention and length of stays were remarkably shorter in SCAD than in ACS group, because in our study the majority of referred patients (n=50, 71.4%) were classified as SCAD. These patients underwent an elective cardiac catheterization and/or PCI and were then immediately returned to the referring hospitals. We did not track and record the duration of stay in the original hospitals. However, we assumed hospital stay duration in the referring hospitals to be relatively short because these patients usually underwent elective interventions for stable coronary artery disease.

Longer time delay from the symptom onset to hospital admission remains one of the most crucial issues in cardiovascular services in the low- and middle-income countries,25 particularly in Indonesia. The prominent problems appeared from the patients side were the lack of awareness of precursor symptoms,25,26 the negative perception and apprehension to the hospital, and financial problems.26 On the other hand, clinicians delay in making an early diagnosis and treatment in primary hospital or clinic, lack of collaboration between hospitals and doctors, administrative barriers, transportation problems, and lack of ambulance organisation26 were also the influential factors for this extensive delay. Those who live in very remote areas, tend to manage their complaints with a visit to the local/ traditional healer or non-traditional healthcare provider. As a result, there was a very low frequency of primary PCI and thrombolysis procedures conducted in our center considering the ‘golden time’ period for effective reperfusion. A previous study reported that in the real-world practice, primary PCI as recommended by the guidelines is very difficult to perform in STEMI patients in Indonesia; time delay is a critical issue for decision making in choosing reperfusion strategy (primary PCI, fibrinolytic, or the combination).26

We believed there are many unrecorded deaths due to CVD in this population because patients with more severe disease are likely to die before reaching the hospital and are not reported. This indicated that those with more stable and stronger physical endurance will have a chance to turn up alive in the hospital. We conclude that in general, hemodynamically unstable patients – for logistic reasons (ie. the lack of transportation, interventional cardiologist, and cath lab capacity) – first had to be stabilized prior to a rather planned intervention. Evidently, the infrastructure and resources were not sufficient to deal with emergency CAG followed by rescue PCI to treat the patients with acute CVD.

From hospital admission to 6 months, 59 (16.2%) ACS patients underwent primary or elective PCI. This is comparable with PCI following ACS in Malaysia (13-17%),27 but much lower than Japan (74%) and USA (71-87%).27 The total mortality rate at 30 days was 15.7% in ACS patients (figure 2),

63 Chapter 4 which is incredibly higher compared with patients in Japan (3.4%),20 and in the US patients after PCI intervention (1.0%).28 Meanwhile, 24 (6.6%) ACS patients died between discharge and 6-month follow-up, and therefore higher than in the GRACE registry study (4.7%).29

Previous studies suggested that optimal revascularization could prevent ~32% of deaths by 6 months,27,29 and better 6-month survival was associated with the use of clopidogrel, statin, and timely PCI or CABG.27,30 Our data showed similar findings: the survival was significantly better in patients with statin, clopidogrel, and revascularization (PCI/CABG) compared with the non-guidelines-treated groups (see figure 3).

Patients undergoing PCI for ACS have higher short- and long-term mortality rates compared to those with SCAD undergoing elective PCI.31 In our study, patients with revascularization (PCI or CABG) in ACS and SCAD groups were not significantly different in terms of survival (p=0.236). However, when we compared the 6-month survival between patients with vs. without revascularization, there was an explicitly lower survival in those who did not undergo a revascularization, both in ACS and SCAD groups (p=0.002) (figure 3).

Despite the fact that over 80% of mortality from CVD occurs in low- and middle-income countries,32 these countries often do not have integrated primary healthcare programs for early detection and treatments for cardiovascular risk factors to meet that challenge. In Indonesia, the poorest and very remote people are affected the most. Before the national health insurance era started in 2014, 80% of Indonesian people were uncovered by a sufficient health insurance.7 Although the existing insurance schemes (Askes, Jamsostek, Jamkesmas, and Jamkesda) conferred a large positive impact on access to healthcare facilities – notably for people from the low and middle socio-economic level33– still, the provided access to specific “elitary treatments” were limited.34

Moreover, people who already suffered from CVD have also less access to an effective secondary prevention.8 Geographical and regional distances, low awareness and support from family members, and financial constraints were most likely responsible for the lack of access to this aftercare rehabilitation. According to the guidelines also adopted in Indonesia, most of these patients were not appropriately treated. Therefore, the stakeholders in Indonesia should focus on the improvement of primary and secondary prevention. Promotion of healthy lifestyles should be well-established in order to reduce the prevalence of cardiovascular risk factors. The dissemination of first-aid management for acute CVD as well as a rapid and standardized in-hospital response has to be established.

Strengths and Limitations There are some strengths and limitations in the present study: • We had to exclude all patients who immediately died at emergency department and intensive cardiovascular care unit because we could not obtain a written informed consent from this group with the most critically ill conditions. • The majority of our patients (51.8%) were living in rural, often very-remote areas. Hence, it was not possible to interview all patients by means of a face-to-face interview for follow-up. In 239 (50.1%) patients, phone-calls were used, which may have led to less accurate data than obtained by direct questionnaire-interview. However, we always verified the answers at the next visits or phone-calls with a different interviewer to reduce inaccuracies.

64 Characteristics and the short-term outcomes of CAD patients

• We excluded all patients with normal coronary angiography, which were mostly females. Thus, our study may have overlooked the minor group of myocardial infarction with no obstructive coronary atherosclerosis (MINOCA). • Our study is, to our knowledge, the first in Indonesia with regard to clinical outcomes of 4 hospitalized CAD patients. Thus, we consider our study a quite unique effort to properly report on characteristics at admission and on short- and mid-term outcomes in an attempt to identify opportunities to improve care.

CONCLUSIONS

Patients with CAD from a poor South-East Asian setting present themselves with predominantly unstable conditions of premature CAD. These patients show relatively severe illness, have significant time delay from symptom onset to admission or intervention, and most do not receive the guidelines- recommended treatment. Awareness of symptoms, prompt initial management of acute CVD, well- established infrastructures, and resources both in primary and secondary hospital for CVD should be improved to reduce the high rates of 30-day and 6-month mortality and adverse outcomes in this population.

NOTES

Acknowledgements The authors gratefully acknowledge all participants who enrolled in this cohort study. Patients’ family members and advisers are also acknowledged for their support and cooperation. We thank the staff of cardiovascular care unit (CVCU) Wahidin Sudirohusodo Hospital, Makassar for their contributions to the success of this research project and all research assistants for the data collection and data management. Special thanks for Mrs. Fithriany Harry S.Farm, Apt., all nurses, and nursing students in Puskesmas Batua (Batua Primary Healthcare Center) Makassar for their dedication to complete the continuation of the follow-up.

Information The abstract of this manuscript has been presented in the American Heart Association (AHA) scientific event 2017, 11-15 November 2017, in Anaheim, California, US, and published in Circulation, November 14, 2017 – Volume 136, Issue Suppl 1: A20914.

Funding This work was supported by Directorate General of Higher Education/Direktorat Jenderal Pendidikan Tinggi (DIKTI), Ministry of National Education Republic of Indonesia [grant number 600/E4.4/K/2011, 2011]. The study sponsor had no influence on the design of the study, analysis of data, interpretation of results or the decision to submit the manuscript for publication.

Competing interests None.

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Strengths and limitations of this study: • This is the first study that fully reports on characteristics at admission as well as the short- and mid-term outcomes of patients with coronary artery disease (CAD) in Indonesia. • We completed, to the best of our ability, the follow-up of this study by actively visiting patients’ houses or contacting their family members to obtain outcomes data. • Diversity on places of origin in our cohort represents the population in East Indonesia, and generally the South-East Asia population with limited resources. • Due to geographical and distance constraints, follow up was completed by telephone in half of this cohort. • We excluded all patients with normal coronary angiography, and therefore our study might overlook the minor group of non-obstructive CAD.

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REFERENCES 1. Dhillon PK, Jeemon P, Arora NK, et al. Status of epidemiology in the WHO South-East Asia region: burden of disease, determinants of health and epidemiological research, workforce and training capacity. Int J Epidemiol 2012; 41: 847-60. 4 2. World Health Organization: Regional Office for South-East Asia. Noncommunicable Diseases in the South-East Asia Region: 2011 Situation and Response. New delhi, 2011. 3. Ohira T, Iso H. Cardiovascular disease epidemiology in Asia: an overview. Circ J 2013; 77: 1646-52. 4. Lam CSP. Heart failure in Southeast Asia: facts and numbers. ESC Heart Failure 2015; 2: 46-49. 5. Bowry AD, Lewey J, Dugani SB, et al. The Burden of Cardiovascular Disease in Low- and Middle-Income Countries: Epidemiology and Management. Can J Cardiol 2015; 31: 1151- 9. 6. Seligman B, Vedanthan R, Fuster V. Acute coronary syndromes in low- and middle- income countries: Moving forward. Int J Cardiol 2016; 217 Suppl: S10-12. 7. Juwana YB, Wirianta J, Ottervanger JP, et al. Primary coronary intervention for ST-segment elevation myocardial infarction in Indonesia and the Netherlands: a comparison. Neth Heart J 2009; 17: 418-21. 8. World Health Organization. Media centre: Cardiovascular diseases (CVDs). Fact sheet No. 317. http://www.who.int/mediacentre/factsheets/fs317/en/ (20 March 2015). 9. Firman D. Use of coronary interventions in Indonesia. AsiaPCR/SingLIVE 2016. Singapore, 2016, p. 22-23. 10. Munawar M. Bifurcatio stenting in Indonesia. In: AsiaPCR. AsiaPCR/SingLIVE. Singapore, 2015. 11. Pusat Data dan Informasi Kementerian Kesehatan Republik Indonesia. Situasi Kesehatan Jantung-Info DATIN. 2014. 12. Telemedicine: sharing experiences and a way forward. Report of a regional consultation, Pyongyang, Democratic People’s Republic of Korea, 30 July-1 August 2013. Report, 2013. 13. Badan Pusat Statistik Republik Indonesia. Berita Resmi Statistik: Persentase Penduduk Miskin Maret 2015 Mencapai 11,22 Persen. https://www.bps.go.id/index.php/brs/1158 (30 April 2016). 14. Kumar A, Cannon CP. Acute Coronary Syndromes: Diagnosis and Management, Part I. Mayo Clin 2009; 84: 917-38. 15. Grech ED, Ramsdale DR. ABC of interventional cardiology, Acute coronary syndrome: unstable angina and non-ST segment elevation myocardial infarction. BMJ 2003; 326: 1259-61. 16. Elbez Y, Cheong AP, Fassa A-A, et al. Clinical outcomes in patients with stable coronary artery disease with vs. without a history of myocardial revascularization. Eur Heart J Qual Care Clin Outcomes 2016; 2 (1): 23-32. 17. Pizzi C, Xhyheri B, Costa GM, et al. Nonobstructive Versus Obstructive Coronary Artery Disease in Acute Coronary Syndrome: A Meta-Analysis. J Am Heart Assoc 2016; 5: 1-14. 18. Ranthe MF, Carstensen L, Oyen N, et al. Family history of premature death and risk of early onset cardiovascular disease. J Am Coll Cardiol 2012; 60: 814-21. 19. Rathod KS, Jones DA, Gallagher S, et al. Atypical risk factor profile and excellent long-term outcomes of young patients treated with primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Eur Heart J Acute Cardiovasc Care 2016; 5: 23-32. 20. Nakamura M, Yamashita T, Yajima J, et al. Clinical outcome after acute coronary syndrome in Japanese patients: an observational cohort study. J Cardiol 2010; 55: 69-76.

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21. Fox K. Management of acute coronary syndromes. Variations in practice and outcome. Findings from the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2002; 23: 1177-89. 22. Ahmad WAW, Ramesh SV, Zambahari R. Malaysia-ACute CORonary syndromes Descriptive study (ACCORD): evaluation of compliance with existing guidelines in patients with acute coronary syndrome. Singapore Med J 2011; 52: 508-11. 23. Montalescot G, Dallongeville J, Van Belle E, et al. STEMI and NSTEMI: are they so different? 1 year outcomes in acute myocardial infarction as defined by the ESC/ACC definition (the OPERA registry). Eur Heart J 2006; 28: 1409-17. 24. Ueshima H, Sekikawa A, Miura K, et al. Cardiovascular disease and risk factors in Asia: a selected review. Circulation 2008; 118: 2702-9. 25. Reboldi G, Lee ES, Vedanthan R, et al. Quality Improvement for Cardiovascular Disease Care in Low- and Middle-Income Countries: A Systematic Review. Plos One 2016; 11: e0157036. 26. Dharma S, Juzar DA, Firdaus I, et al. Acute myocardial infarction system of care in the third world. Neth Heart J 2012; 20: 254-9. 27. Chan MY, Du X, Eccleston D, et al. Acute coronary syndrome in the Asia-Pacific region. Int J Cardiol 2016; 202: 861-9. 28. Hannan EL, Farrell LS, Walford G, et al. The New York State risk score for predicting in-hospital/30-day mortality following percutaneous coronary intervention. JACC Cardiovasc Interv 2013; 6: 614-22. 29. Fox KA, Dabbous OH, Goldberg RJ, et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). BMJ 2006; 333: 1091. 30. Chew DP, Anderson FA, Avezum A, et al. Six-month survival benefits associated with clinical guideline recommendations in acute coronary syndromes. Heart 2010; 96: 1201- 6. 31. Alcock RF, Yong AS, Ng AC, et al. Acute coronary syndrome and stable coronary artery disease: are they so different? Long-term outcomes in a contemporary PCI cohort.Int J Cardiol 2013; 167: 1343-6. 32. Yusuf S, Rangarajan S, Teo K, et al. Cardiovascular risk and events in 17 low-, middle-, and high-income countries. N Engl J Med 2014; 371: 818-27. 33. Hidayat B. The effects of mandatory health insurance on equity in access to outpatient care in Indonesia. Health Policy and Planning 2004; 19: 322-35. 34. Thabrany H. Social Health Insurance in Indonesia: Current Status and the Proposed National Health Insurance. Presented in Social Health Insurance Workshop WHO SEARO, New Delhi, March 13-15, 2003. In: Center for Health Economic Studies. University of Indonesia, 2003.

68 Characteristics and the short-term outcomes of CAD patients

SUPPLEMENTS

Supplementary Method We developed a simple questionnaire on dietary pattern by adopting and modifying the National 4 Health and Nutrition Examination Survey (NHANES) food frequency questionnaire. We applied questions on food frequencies and dietary habits corresponding to the local circumstances of the Makassar population. We defined high sugar intake as a consumption of sugar >3 spoons per day and/or consumption of soda drinks >1.5 litres/week. High salty food intake was defined as a consumption of salt and monosodium glutamate (MSG) in daily food of ≥1 teaspoon (2,300 mg)1 per day and/or consumption of local salty/MSG food (i.e. salty fish, bakso, coto, pallubasa, or instant/ dried noodle) for ≥3 times/week. High fried food intake was defined as consumption of fried food ≥3 times/week. Often re-used cooking oil defined as everyday or ≥5 days/week using re-used oil for daily food.

We adopted the physical activity recommendation from the American Heart Association. We defined physical inactivity as never, or doing moderate-intensity aerobic activities (i.e. walking, climbing stairs, gardening, yard work, moderate-heavy house work, dancing, or home exercise) for <150 minutes/week, or doing at least 20 minutes of vigorous aerobic exercises (i.e. brisk walking, jogging, swimming, bicycling, or jumping rope) for <3 times/week.2 For smoking status, we combined the standard National Health Interview Survey (NHIS) and the standard National Survey on Drug Use and Health (NSDUH-S) to differentiate current and former smoker. Current smoking was defined as a participant who had smoked at least 100 cigarettes in their lifetime and had smoked in the last 30 days, while a former smoker was defined as a participant who smoked at least 100 cigarettes in lifetime and had not smoked at all in the last 30 days.3 A positive family history of CVD was defined as ≥1 first degree and/or ≥2 second degree family members with CVD before the age of 55 years in men and 65 years in women.4-6 Family history of premature sudden cardiac death was positive if ≥1 first degree and/or ≥2 second degree family members had died at age <60 years due to CVD.7

Positive history of hypertension was defined as a known hypertension (systolic blood pressure (BP) ≥140 mmHg and/or diastolic BP ≥90 mmHg8), or being on medication for hypertension. Type 2 diabetes mellitus (DM) was defined positive if participant had a known type 2 DM, fasting plasma glucose ≥7.0 mmol/L or 2-hour plasma glucose ≥11.1 mmol/L,9 or was on medication for type 2 DM. Lastly, for current monthly income, we used the cut-off point of ≥Rp.1,810,000,- as the national average of minimum wages for decent living in Indonesia in 2015.10

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Supplementary Tables

Table S1. Major adverse cardiovascular events (MACE) during follow-up

At 30 days At 6 months Total Composite MACE (n = 477) (n = 477) (n = 477) All-cause mortality 64 (13.4) 35 (7.3) 99 (20.8) MI re-hospitalization 14 (2.9) 23 (4.8) 37 (7.8) HF re-hospitalization 1 (0.2) 6 (1.3) 7 (1.5) Stroke 2 (0.4) 4 (0.8) 6 (1.3) Emergency CABG 1 (0.2) 1 (0.2) 2 (0.4) Repeat PCI 5 (1.0) 3 (0.6) 8 (1.7) Repeat CAG 3 (0.6) 5 (1.0) 8 (1.7) First PCI post-discharge 23 (4.8) 3 (0.6) 26 (5.5) First CAG post-discharge 11 (2.3) 6 (1.3) 17 (3.6) Stent thrombosis 1 (0.2) 0 (0.0) 1 (0.2) Total MACE 125 (26.2) 86 (18.0) 211 (44.2) Values are n (%). MACE: major adverse cardiovascular events; MI: myocardial infarction; HF: heart failure; CABG: coronary artery bypass graft; PCI: percutaneous coronary intervention; CAG: coronary angiography.

Table S2. Chief complaints or symptoms of all survivors

30-day 6-month Chief complaints/symptoms (n = 406) (n = 371) Chest pain 104 (25.6) 84 (22.6) Dyspnea 23 (5.7) 22 (5.9) Palpitation 31 (7.6) 17 (4.6) Hemi-paresis 3 (0.7) 2 (0.5) Weakness 6 (1.5) 7 (1.9) Cough 4 (1.0) 3 (0.8) Swelling on inferior extremities 1 (0.2) 1 (0.3) Epigastric pain 11 (2.7) 22 (5.9) Dizziness and sweating 17 (4.2) 41 (11.1) Sleeping disorder 4 (1.0) 2 (0.5) Muscle cramps 3 (0.7) 4 (1.1) Anxiousness 2 (0.5) 0(0.0) Others 11 (2.7) 4 (1.1) Values are n (%). MACE: major adverse cardiovascular events; MI: myocardial infarction; HF: heart failure; CABG: coronary artery bypass graft; PCI: percutaneous coronary intervention; CAG: coronary angiography.

70 Characteristics and the short-term outcomes of CAD patients

References 1. American Heart Association. ANSWERS by heart, Lifestyle + Risk Reduction: High Blood Pressure. Why Should I Limit Sodium? http://www.heart.org/idc/groups/heartpublic/@wcm/@hcm/documents/ downloadable/ucm_300625.pdf (22 September 2017). 2. Haskell WL, Lee IM, Pate RR, Powell KE, Blair SN, Franklin BA, et al. Physical activity and public health: 4 Updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Circulation 2007; 116: 1081-1093. 3. Ryan H, Trosclair A, Gfroerer J. Adult current smoking: differences in definitions and prevalence estimates-NHIS and NSDUH, 2008. J Environ Public Health 2012; 2012: 918368. 4. Mulders TA, Meyer Z, van der Donk C, Kroon AA, Ferreira I, Stehouwer CD, et al. Patients with premature cardiovascular disease and a positive family history for cardiovascular disease are prone to recurrent events. Int J Cardiol 2011; 153: 64-67. 5. Lloyd-Jones DM, Nam B, D’Agostino RB, Levy D, Murabito JM, Wang TJ, et al. Parental Cardiovascular Disease as a Risk Factor for Cardiovascular Disease in Middle-aged Adults: A Prospective Study of Parents and Offspring. JAMA 2004; 291: 2204-2211. 6. Nasir K, Budoff MJ, Wong ND, Scheuner M, Herrington D, Arnett DK, et al. Family history of premature coronary heart disease and coronary artery calcification: Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2007; 116: 619-626. 7. Ranthe MF, Carstensen L, Oyen N, Tfelt-Hansen J, Christiansen M, McKenna WJ, et al. Family history of premature death and risk of early onset cardiovascular disease. J Am Coll Cardiol 2012; 60: 814-821. 8. Narkiewwicz K, Redon J, Zanchetti A, The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). ESC Essential Mesages. 2013 ESH/ESC Guidlines for the management of arterial hypertension. Eur Heart J 2013; 34: 2159-2219. 9. World Health Organization-International Diabetes Federation. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia : report of a WHO/IDF consultation. Geneva, Switzerland, 2006. 10. Pemerintah.net. Daftar Lengkap UMP 2015. Informasi Nasional, Kebijakan. http://pemerintah.net/ daftar-lengkap-ump-2015/ (02 February 2015).

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ABSTRACT

Objective To measure medium-term outcomes and determine the predictors of mortality in patients with coronary artery disease (CAD) both during and after hospitalization in a resource-limited South-East Asian setting.

Methods From February 2013 to December 2014, we conducted a prospective observational cohort study of 477 patients admitted to Makassar Cardiac Center, Indonesia with acute coronary syndrome and stable CAD. We actively obtained data on clinical outcomes and after-discharge management until April 2017. Multivariable Cox-proportional hazard analysis was performed to examine predictors for our primary outcome, all-cause mortality.

Results From hospital admission, patients were followed over a median 18 (IQR 6–36) months; in total 154 (32.3%) patients died. More patients with acute myocardial infarction died in hospital compared with unstable and stable angina (p=0.002). Over total follow-up, there was a difference in mortality between NSTEMI (n=41, 48.2%), STEMI (n=65, 30.8%), UA (n=18, 26.5%), and SCAD (n=30, 26.5%) groups (p=0.007). Independent predictors of all-cause mortality were: hyperglycemia on admission (HR 1.55 (95% CI 1.12-2.14), p=0.008), heart failure/Killip class ≥2 (HR 2.50 (1.76-3.56), p<0.001), eGFR <60 mL/min (HR 1.77 (1.26-2.50), p=0.001), no revascularization (PCI/CABG) (HR 2.38 (1.31-4.33), p=0.005), and poor adherence to after-discharge medications (HR 10.28 (5.52-19.16), p<0.001). Poor medication adherence predicted post-discharge mortality, and did so irrespective of underlying CAD diagnosis (p-interaction = 0.88).

Conclusions CAD patients in a poor South-East Asian setting experience high in-hospital and medium-term mortality. The initial severity of disease, lack access to guidelines-recommended therapy, and poor adherence to after-discharge medications are the main drivers for excess mortality. Improved access to early and late hospital care, and patient education should be prioritized for better survival.

Keywords Coronary artery disease; risk factors; all-cause mortality; quality of care and outcomes; adherence to medications.

74 Predictors of mid-term mortality of CAD patients

INTRODUCTION

The rate of cardiovascular disease and death is substantially higher in low- and middle-income countries (LMICs) than in high-income countries.1 It is estimated that globally, more than 80% of 5 cardiovascular deaths occur in LMICs.1 Half of the world’s cardiovascular disease (CVD) burden is expected to occur in Asia.2 Also, the prevalence of heart failure is higher in South-East Asian countries than in the rest of the world.3 The World Health Organization (WHO) reported that in South-East Asian populations, the prevalence of CVD risk factors in young adults is high as is the rate of premature death (age <60 years).4 Despite the alarming increase of cardiovascular deaths in these regions, identification of risk factors associated with medium-term mortality in patients with coronary artery disease in the resource-limited South-East Asian countries is poorly documented. This is particularly true for Indonesia with its 260 million inhabitants, which has a poor healthcare infrastructure resulting in a lack of registration of cardiovascular disease and death.

Epidemiological studies have shown that risk factors for recurrent non-fatal and fatal coronary artery disease (CAD) resemble risk factors for primary events.5 Several studies have suggested that the unmodifiable or uncontrollable traditional CVD risk factors (e.g. older age,6 diabetes mellitus5,6 or hyperglycemia,7 smoking,5 and systolic blood pressure8), as well as adverse clinical profiles at hospital admission6,8 were all independent predictors of CVD deaths. Yet, these previous studies were conducted in Western populations with supposedly optimal follow-up treatment and disease management. There is substantial evidence to assume that traditional risk factors that are well- established in high income countries play a similar role in CVD mortality in the South-East Asian region. However, both different levels of exposure to such risk factors and additional other factors may explain local excess mortality. Therefore, we questioned if predictors of mortality, particularly modifiable factors, in patients admitted to hospital for CAD are different in the South-East Asian setting. This is the first study to fully report on medium-term mortality after hospital discharge in Indonesia. We conducted a prospective cohort study of CAD patients in Makassar to evaluate medium-term clinical outcomes and to investigate what factors particularly impact on all-cause mortality in CAD patients during and after hospitalization, in a country with limited infrastructural, financial, and human resources.

METHODS

Study population In this prospective observational cohort study, we included 477 consecutive CAD patients who presented between February 2013 and December 2014, at the Makassar Cardiac Center, Wahidin Sudirohusodo Hospital, one of the two public cardiac referral centers in East Indonesia. This cardiac center mainly serves the 9.5 million South Sulawesi population, and also other regions inside and outside Sulawesi island. The catchment area of Makassar Cardiac Center is shown in figure 1.

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Figure 1. Province of South Sulawesi (46,717 km2) with its cities and regencies – catchment area of Makassar cardiac center, RS Wahidin Sudirohusodo

Patients were included if they had been clinically diagnosed with CAD, defined as acute coronary syndrome (ACS) or stable coronary artery disease (SCAD). ACS was defined as unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), or ST-segment elevation myocardial infarction (STEMI).9,10 SCAD or stable angina included prior ACS, prior coronary revascularization or known significant CAD on angiography without revascularization.11 To enroll as a participant, all eligible patients signed written informed consent. We excluded all fatal patients who immediately died at the emergency department or intensive cardiovascular care unit (ICCU) before giving informed consent and all patients with normal coronary angiography (defined as 0% lumen stenosis in all coronary vessels).12 The flowchart of the study population is presented in figure 2.

76 Predictors of mid-term mortality of CAD patients

5

Figure 2. Overview of the study population RSWS: Rumah Sakit Wahidin Sudirohusodo (Wahidin Sudirohusodo hospital); ACS: acute coronary syndrome, CAD: coronary artery disease; HF: heart failure; CHF: congestive heart failure; CVD: cardiovascular disease.

Data collection and follow-up At hospital admission, we obtained baseline clinical data from medical records and questionnaire interviews. Data on socio-demographic characteristics, lifestyle, dietary pattern, family history of CVD and premature sudden death at age <60 years,13 and clinical profiles were all obtained.

Prospectively collected clinical data at physical examination covered electrocardiography, echocardiography, coronary angiography (CAG), and laboratory tests including cardiac enzymes. In-hospital management and at-discharge medications were also recorded. Plasma glucose, lipid profiles, uric acid, renal and liver functions were measured within 24 hours of hospital admission following a minimum 8-hour fast in all participants. All blood samples were analyzed in the hospital laboratory using standardized methods. Hyperglycemia on admission was defined as fasting plasma glucose >7.7 mmol/L on hospital admission.7

The endpoint in this study was all-cause mortality. We actively collected this data during hospitalization, at 30 days, 6 months, and 12 months, and yearly up to 3 years or the end of follow-up period on 30 April 2017. During home visits or phone call interviews, research nurses recorded the

77 Chapter 5 dates and causes of participants’ deaths. However, cause of death was not specified, largely due to the lack of proper death records in Indonesia with most of the deaths occurring suddenly at home.

We obtained self-reported data on post-discharge management, including adherence to medications (yes/no), names or types of medications, as well as lifestyle modifications. This included smoking cessation (yes/no) and dietary habit improvement, i.e. restriction from salt/monosodium glutamate (MSG)-containing food and fatty/deep-fried food (yes/no). At 30-day follow-up, we collected data on medications from all survivors (n = 406) and smoking status of active smokers at baseline (n = 108). Meanwhile, data on dietary changes were collected at 3 years or at the end of study follow-up (n = 316).

Statistical analysis Categorical variables were expressed as numbers (percentage), and continuous variables as mean ± SD. Skewed data were presented as median (Q1-Q3). Baseline characteristics, clinical presentations, and management in hospital and after discharge were tabulated by ACS (STEMI, NSTEMI, and UA) and non-ACS (SCAD).

We constructed a Kaplan-Meier curve to depict the cumulative incidence of all-cause mortality amongst CAD patients. Follow-up time was defined as the time from date of hospital admission to death or censoring, until the end of study follow-up. The survival times of participants who had moved, who had given an incorrect address, and who, for other reasons, were unreachable via telephone or home visit were censored at the last date that they were known to be still alive. Survival times of participants who were still alive at the end of follow-up were censored on 30 April 2017.

Multivariable Cox regression analysis was performed to estimate hazard ratios (HRs) for all selected predictors of medium-term all-cause mortality amongst CAD patients. A 95% confidence interval not including one, corresponding to a 2-sided p-value <0.05 was considered statistically significant. We performed all statistical analyses with SPSS version 23.0.

RESULTS

Amongst 477 patients hospitalized with CAD, a total of 347 (72.7%) were male and mean age was 58.2 ± 10.8 years.

Table 1 shows the baseline characteristics of ACS (STEMI, NSTEMI, and UA), and SCAD patients. Patients with ACS were relatively younger, had higher plasma glucose, lower income and educational attainment levels, and were more often current smokers compared with SCAD patients. More than half (51.2%) of our patients were coming from outside Makassar city: 121 (25.4%) patients lived between 20 – 100 kms from the hospital; 48 (10.1%) between 100 – 200 kms; and 75 (15.7%) more than 200 kms.

78 Predictors of mid-term mortality of CAD patients

Table 1. Baseline characteristics of all patients according to diagnosis

STEMI NSTEMI UA SCAD Total Variables (n = 211) (n = 85 ) (n = 68) (n = 113) (n = 477) p-value 5 Male sex 161 (76.3) 51 (60.0) 48 (70.6) 87 (77.0) 347 (72.7) 0.023 Age (years) 56.6 ± 11.8 58.6 ± 10.5 58.7± 10.2 60.6 ± 8.8 58.2 ± 10.8 0.016 Previous hypertension 142 (67.3) 71 (83.5) 55 (80.9) 90 (79.6) 358 (75.1) 0.006 Previous MI 61 (28.9) 35 (41.2) 30 (44.1) 38 (33.6) 164 (34.4) 0.060 Diabetes mellitus 62 (29.4) 35 (41.2) 15 (22.1) 35 (31.0) 147 (30.8) 0.074 Waist circumference (cm) 84.9 ± 6.1 83.7 ± 10.9 84.8 ± 5.6 84.9 ± 6.1 84.6 ± 7.1 0.575 Obese (BMI ≥25 kg/m2) 66 (31.3) 32 (37.6) 21 (30.9) 46 (40.7) 165 (34.6) 0.301 Metabolic syndromea 118 (55.9) 56 (65.9) 34 (50.0) 56 (49.6) 264 (55.3) 0.104 Current smoker 72 (34.1) 18 (21.2) 13 (19.1) 20 (17.7) 123 (25.8) 0.003 Former smoker 62 (29.4) 27 (31.8) 29 (42.6) 56 (49.6) 174 (36.5) 0.002 Parental history of CVD 42 (19.9) 26 (30.6) 27 (39.7) 27 (23.9) 122 (25.6) 0.007 Physical inactivity 129 (61.1) 46 (54.1) 43 (63.2) 59 (52.2) 277 (58.1) 0.296 >20 km from hospital 124 (58.8) 40 (47.1) 29 (42.6) 54 (47.8) 247 (51.8) 0.049 Low monthly incomeb 116 (55.0) 60 (70.6) 33 (48.5) 39 (34.5) 248 (52.0) <0.001 Low educationc 71 (33.6) 31 (36.5) 18 (26.5) 18 (15.9) 138 (28.9) 0.003

Values are n (%) or means ± SD. Comparison was done by using One-way ANOVA test for continuous variables and Pearson Chi-square test for categorical variables. aDefined using National Cholesterol Education Program (NCEP) – Adult Treatment Panel III (ATP III) classification. bDefined as monthly income <1,810,000,- Indonesian Rupiah (IDR; 1 USD = 13,500,- IDR). The cut point based on the national average of minimum income for proper life in 2015. cDefined as the highest formal education was junior high/elementary school, never school, or illiterate. STEMI: ST-segment elevation myocardial infarction; NSTEMI: non-ST-segment elevation myocardial infarction; UA: unstable angina; SCAD: stable coronary artery disease; MI: myocardial infarction; BMI: body mass index; CVD: cardiovascular disease.

The clinical profiles and in-hospital treatments per diagnosis are presented intable 2. A total of 358 patients (75.1%) had a history of hypertension, particularly the NSTEMI and UA groups. The STEMI group had the shortest time interval between angina onset and hospital admission (24 (IQR 7-48) hours), compared with the other groups. Duration of hospitalization and time from admission to intervention were significantly shorter in the SCAD group than in the ACS groups. Of 211 STEMI patients, only 10 (4.7%) underwent primary PCI and 13 (6.2%) received thrombolysis for early reperfusion, and 30 (14.2%) underwent elective PCI or CABG.

Adherence to medications and lifestyle adjustments after hospital discharge in all survivors are cross- tabulated in table 3. Of 406 survivors in the first 30 days, only 44.1% then adhered to after-discharge medications. At 30-days follow-up, more than half of survivors had improved their lifestyles by quitting from smoking, and implementing low-cholesterol and low-sodium diet.

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Table 2. Clinical profiles and treatments of all patients according to diagnosis

STEMI NSTEMI UA Variables (n = 211) (n = 85) (n = 68) Systolic BP (mmHg) 127.7 ± 25.1 131± 33.1 136.1 ± 27.0 Diastolic BP (mmHg) 82.0 ± 15.3 82.0 ± 18.6 85.9 ± 14.7 Plasma glucose (mmol/L)a 7.4 (6.2-9.9) 7.8 (6.0-9.8) 6.2 (5.3-8.4) Total cholesterol (mmol/L)a 5.0 (4.2-5.8) 4.9 (4.2-5.5) 4.9 (4.2-5.6) Triglycerides (mmol/L)a 1.4 (1.0-1.8) 1.6 (1.1-1.9) 1.4 (1.0-2.2) HDL-chol (mmol/L) 0.95 ± 0.29 0.91± 0.35 0.97± 0.31 LDL-chol (mmol/L)a 3.4 (2.6-4.0) 3.2 (2.6-4.1) 3.1 (2.6-3.9) LVEF ≤35% 30 (23.8) 12 (26.1) 7 (18.4) Atrial fibrillation 2 (0.9) 4 (4.7) 3 (4.4) Left ventricle hypertrophy 65 (30.8) 35 (41.2) 24 (35.3) Troponin T (μg/L)a 0.86 (0.20-2.00) 0.35 (0.15-0.78) 0.02 (0.02-0.24) eGFR <60 mil/min 59 (28.0) 36 (42.4) 13 (19.1) With HF or Killip class ≥2 80 (37.9) 48 (56.5) 22 (32.4) With concomitant strokeb 9 (4.3) 9 (10.6) 0 (0.0) With cardiogenic shockb 14 (6.6) 3 (3.5) 0 (0.0) Multivessel diseasec 63 (29.9) 18 (21.2) 30 (44.1) Onset to admission (hours) 24.0 (7.0-48.0) 30.0 (14.3-83.0) 32.0 (9.0-57.0) Length of stay (days)a 7.0 (5.0-9.0) 6.0 (4.5-10.0) 7.0 (5.0-10.0) Admission to intervention (hours)a 120.0 (6.5-163.4) 149.6 (120.0 -192.0) 144.0 (24.0-168.0) Primary PCI 10 (4.7) N/A N/A Thrombolysis/fibrinolysis 13 (6.2) N/A N/A CAG performed 112 (53.1) 27 (31.8) 44 (64.7) Elective PCI/CABG 30 (14.2) 10 (11.8) 11 (16.2)

Table 3. Adherence to medication and lifestyle adjustments after

STEMI NSTEMI UA SCAD At 30-day follow-up (n = 178) (n = 62) (n = 62) (n = 104) Adherence to medications 76 (42.7) 18 (29.0) 31 (50.0) 54 (51.9) STEMI NSTEMI UA SCAD At 30-day follow-upa (n = 63) (n = 14) (n = 12) (n = 19) Smoking cessation 40 (63.5) 5 (35.7) 7 (58.3) 12 (63.2) At 3-year/ STEMI NSTEMI UA SCAD the end of follow-up (n = 145) (n = 41) (n = 49) (n = 81) Reduced cholesterol dietb 80 (55.2) 20 (48.8) 28 (57.1) 51 (63.0) Reduced sodium/MSG dietc 76 (52.4) 20 (48.8) 28 (57.1) 51 (63.0)

80 Predictors of mid-term mortality of CAD patients

Values are n (%) or means ± SD, unless otherwise stated. Comparison of clinical profiles was performed using One-way ANOVA test for continuous SCAD variables and Pearson Chi-square test for categorical variables. p-value (n = 113) aValues are medians (Q1-Q3). Comparison was done using Kruskal-Wallis test. 5 127.3 ± 20.4 0.089 bComparison was performed using exact Chi-square test. 80.8 ± 10.3 0.152 cDefined as angiographic 2- or 3-vessel disease (stenoses ≥50% in at least 5.9 (5.1-8.2) <0.001 two of the three major epicardial coronary arteries), which the cardiologist 5.1 (3.7-5.6) 0.633 considered for stenting.27 1.5 (1.0-1.9) 0.864 STEMI: ST-segment elevation myocardial infarction; NSTEMI: non-ST- 0.92 ± 0.35 0.562 segment elevation myocardial infarction; UA: unstable angina; SCAD: stable coronary artery disease; BP: blood pressure; HDL-chol: high density 3.2 (2.3-3.7) 0.157 lipoprotein-cholesterol; LDL-chol: low density lipoprotein-cholesterol; 14 (26.9) 0.801 LVEF: left ventricular ejection fraction; eGFR: estimated glomerular 3 (2.7) 0.188 filtration rate; HF: heart failure; PCI: percutaneous coronary intervention; 21 (18.6) 0.005 N/A: not applicable; CAG = coronary angiography; CABG: coronary artery bypass grafting. 0.00 (0.00-0.02) <0.001 41 (36.3) 0.008 34 (30.1) 0.001 3 (2.7) 0.008 0 (0.0) 0.005 58 (51.3) <0.001 36.0 (16.3-72.0) <0.001 1.0 (0.0-7.0) <0.001 8.0 (4.0-149.6) <0.001 N/A N/A N/A N/A 90 (79.6) <0.001 35 (31.0) 0.001

Values are n (%). Comparison was performed using Pearson Chi-square test. Total aComparison was performed using exact Chi-square test. For active smok- p-value (n = 406) ers at baseline. bDefined as none to <3 times per week consumption of deep-fried/fatty 179 (44.1) 0.025 food and/or high-cholesterol seafood. Total cDefined as none to <¼ teaspoon (<1,500 mg) per day consumption of p-value (n = 108) salt/MSG in daily food28 and/or none to <3 times per month consump- tion of local salty/MSG food. 64 (59.3) 0.291 STEMI: ST-segment elevation myocardial infarction; NSTEMI: non-ST-seg- Total p-value ment elevation myocardial infarction; UA: unstable angina; SCAD: stable (n = 316) coronary artery disease; MSG: mono-sodium glutamate. 179 (56.6) 0.479 175 (55.4) 0.364

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In table 4, we estimated the fully adjusted cox-regression models for medication adherence as predictor of mortality, both within subgroups of types of diagnosed CAD and for separate sections of follow-up. Adherence was significantly associated with mortality in all CAD subgroups, and both for total follow-up and for follow-up after hospital discharge. Formal testing with an interaction term medication adherence*type of CAD diagnosis in a fully adjusted model with all patients showed not statistically significant interaction (p=0.88).

Table 4. Adherence to medication and total mortality within disease subgroups and by sections of follow-up duration

HR 95% CI p-value Analyses within patient subgroupsa NSTEMI 5.77 1.61-20.63 0.007 STEMI 11.37 3.46-37.36 <0.001 UA 49.60 5.59-440.39 <0.001 SCAD 12.31 3.37-44.97 <0.001 Analyses in all patientsb Total follow-up 10.28 5.51-19.18 <0.001 Follow-up only post-discharge 9.74 5.04-18.85 <0.001 aModels were adjusted for age, sex, hypertension, hyperglycaemia, Killip class, eGFR, PCI/ CABG, thrombolysis/anticoagulants, onset to admission, hospital stay, and re-hospitalization for MI, stroke, or heart faillure. bModels were adjusted for age, sex, hypertension, hyperglycaemia, Killip class, cardiac biomarkers, ST-segment elevation, eGFR, PCI/CABG, thrombolysis/anticoagulants, onset to admission, hospital stay, re-hospitalization for MI, stroke, or heart faillure, socio-economic status, and residence distance from hospital. HR: hazard ratio; CI: confidence interval; NSTEMI: non-ST-segment elevation myocardial infarction; STEMI: ST-segment elevation myocardial infarction; UA: unstable angina; SCAD: stable coronary artery disease.

Over the whole follow-up period, a total of 154 (32.3%) participants had died. The mean age of the deceased patients was 60.8 years. Cumulative mortality differed between the categories; NSTEMI (48.2%), STEMI (30.8%), UA (26.5%), and SCAD (26.5%) (figure 3).

Figure 4 shows Kaplan-Meier curves for short- and medium-term mortality with considerably higher rates in NSTEMI patients compared with other CAD diagnoses (p=0.001 and p=0.037, respectively).

The forest plot of multivariable hazard ratios for medium-term mortality amongst CAD patients is shown in figure 5. Independent predictors of medium-term all-cause mortality of CAD patients were: hyperglycemia on admission (HR) 1.55 (95% CI 1.12-2.14), p=0.008), concomitant heart failure or Killip class ≥2 (HR 2.50 (1.76-3.56), p<0.001), reduced renal function (eGFR<60 ml/min) (HR 1.77 (1.26-2.50), p=0.001), absence of revascularization (PCI or CABG) (HR 2.38 (1.31-4.33), p=0.005), and poor adherence to medications (HR 10.28 (5.52-19.16), p<0.001).

Seven (1.5%) participants were lost to follow-up. The median of total follow-up was 18 (IQR 6–36) months.

82 Predictors of mid-term mortality of CAD patients

5

Figure 3. Rates of all-cause mortality amongst coronary artery disease patients during the study period STEMI: ST-segment elevation myocardial infarction; NSTEMI: non-ST-segment elevation myocardial infarction; UA: unstable angina; SCAD: stable coronary artery disease.

DISCUSSION

The main finding of our unique cohort is that mortality both during hospitalization and after hospital discharge in Indonesia is high in CAD patients. During the whole follow-up period (median 18 (IQR 6–36) months), 154 (32.3%) patients died. Many patients presented with poor clinical conditions (i.e. hyperglycemia, concomitant heart failure/Killip class ≥2, and reduced renal function), and had difficult access to guidelines-recommended therapy (i.e. untreated with early thrombolysis or primary PCI for ACS) during admission. Poor adherence to medications plays a significant role in mortality irrespective of underlying CAD diagnosis, particularly after hospital discharge. Although not formally tested, the same probably holds for lack of life-style adjustments.

The rates of mid-term mortality of acute and non-acute CAD in a low-to-middle income Indonesian population were substantially higher compared with high-income or Western populations. For example 30.8% of STEMI patients from our study vs. 7.1% from a 3-year follow-up study of STEMI patients in UK.6 Another study from Australia with 4-year mean follow-up observed an overall 10% all-cause mortality from ACS and SCAD patients treated with PCI.14 Studies from the Western world usually focus on the more traditional risk factors such as age,6 diabetes mellitus,5,6 systolic blood pressure,8 as well as adverse clinical profiles such as higher Killip class.6,8 It is established that the

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Figure 4. Kaplan-Meier curve presenting the cumulative incidence of all-cause mortality of CAD patients over the follow-up period Comparison was performed using Log Rank (Mantel-Cox) test. NSTEMI: non-ST-segment-elevation myocardial infarction; STEMI: ST-segment-elevation myocardial infarction; UA: unstable angina; SCAD: stable coronary artery disease; LR-test: Log Rank-test. presence of hyperglycemia at admission in non-diabetic patients was associated with an increased risk of 1-year mortality, similar to those with diabetes, even after correction for the use of guidelines- recommended treatment.7 Higher Killip class is an independent predictor of in-hospital mortality in patients with STEMI and non-ST-segment-elevation acute coronary syndrome (NST-ACS).15 A meta- analysis16 and 16-year follow-up study in the United States17 suggests that renal insufficiency (eGFR <60 ml/min) is a significant predictor of all-cause mortality and cardiovascular mortality in general populations, including increased mortality after ACS18 or PCI19.

This explains the increased of immediate mortality during hospitalization observed in this cohort, independent from the lack of revascularization. Unsurprisingly, in our study, NSTEMI patients with poorer clinical profiles, greater prevalence of co-morbidities, longer time intervals from admission to intervention, poorer adherence to after-discharge medications, and less likely to undergo diagnostic CAG and elective PCI/CABG had the worst outcomes and considerably higher mortality rate compared to STEMI, UA, and SCAD patients (figure 4). A previous study also confirmed that cardiac mortality and outcomes were independently worse in NSTEMI patients treated with PCI compared to those with stable angina; whilst the long-term outcomes of patients following PCI for STEMI were favorable, with similar outcomes as those with stable angina.20 Patients presenting with NSTEMI often have a higher prevalence of cardiovascular and non-cardiovascular co-morbidities compared with STEMI patients,20-22 and therefore the presence of such unmeasured confounders has been suggested to contribute to the adverse outcomes of NSTEMI group.

84 Predictors of mid-term mortality of CAD patients

5

Figure 5. Forest plot presenting multivariable hazard ratios (HRs) for all-cause mortality during the study period CI: confidence interval; HF: heart failure; eGFR: estimated glomerular filtration rate; PCI: percutaneous coronary intervention; CABG: coronary artery by pass graft; MI: myocardial infarction. *p<0.05

We found that disease- and patient-related predictors of all-cause mortality of CAD patients in Indonesia were comparable with the predictors in high-income or Western populations. This study emphasizes the difference in disease management due to lack of access to guidelines-recommended therapies and poor compliance to medication and life-style corrections. Particularly in Indonesia, financial and administrative barriers, transport difficulties, poor education, and low awareness of the symptoms do play a role in delaying patients to get immediate reperfusion, as well as after-discharge medications for secondary prevention.

Due to local circumstances, transfer and admission of patients from remote areas to cardiac centers or hospitals with cardiac facilities in the city of Makassar is difficult. These situations most likely also exist in other traffic clogged metropolitan areas in Indonesia. Apart from delayed access making a primary intervention futile, there was a considerably longer time lapse than the timeline for early reperfusion of <120 minutes recommended by guidelines;23 an average of 24 hours for STEMI and 30 hours for NSTEMI (see table 2). Nevertheless, we found that the prolonged delays from first onset to hospital admission was insignificantly associated with higher medium-term all-cause mortality in Indonesia (see figure 5). The plausible reason is that longer time delay from onset to admission and intervention was mostly associated with immediate in-hospital mortality, primarily in patients with acute myocardial infarction, i.e. STEMI and NSTEMI (figure 3). Accordingly, the rate of in-hospital

85 Chapter 5 mortality of ACS patients in our study (12.6%) was also higher than that of the global registry of acute coronary events (GRACE) study from 94 hospitals in 14 countries in Europe, North and South America, Australia, and New Zealand (4.9%).8

Patients undergoing PCI for ACS are known to have poorer short-term outcomes compared with stable CAD undergoing elective PCI.14 This is in line with our finding that 12.6% of ACS and 5.3% of SCAD patients died immediately after admission (p=0.029). A study from a high-income country also showed higher rates of in-hospital and medium-term all-cause mortality in patients with ACS compared to SCAD (3% vs. 0% and 13% vs. 7%, respectively).14 However, a recent systematic review and meta-analysis of randomized clinical trials has highlighted that when compared with optimal medical therapy, PCI treatment did not reduce the risk of all-cause mortality, cardiovascular death, non-fatal myocardial infarction, or repeat revascularization in patients with stable CAD.24

At our cardiac center, patients with ACS rarely underwent early invasive (i.e. diagnostic angiography with intent to perform revascularization) and ischemia-guided strategies, while the majority of patients with stable CAD underwent elective PCI. Although an investment in infrastructure for early invasive and ischemia-guided strategies seems expensive and cumbersome, improved adherence to guidelines for early intervention may result in a quick win of improved in-hospital and 30-day survival.

In this study, we found that adherence to medications of all survivors was lower compared with a large systematic review in resource-limited settings (44.1% vs. 57.5%).25 The factors that were considered to attribute to poor adherence to cardiovascular medications in these resources-limited settings were: lack of access, poor knowledge and negative perception of medications, side effects, high costs, change in symptoms, chronicity, comorbidities, complex treatment regimes, age, and family.25 We considered that all these factors were also applicable to our population in Indonesia. Additionally, in our study, geographical and regional distances were most likely responsible for the lack access for after-care rehabilitation and secondary prevention. Hence, improved patients knowledge through population-based seminar or using popular media, and improved performance of primary health care services in rural area may have an immediate effect on compliance and survival.

The present study has several limitations. All patients were required to sign a written informed consent form, which entailed excluding all CAD patients who immediately died at the emergency department and ICCU. A face-to-face interview was not possible in all patients, as the majority (51.2%) of patients live in rural, often very remote areas. In 239 (50.1%) patients, interviews were carried out by telephone, of which may have led to less accurate data than could have been obtained by direct questionnaire interview. However, we always verified the answers at the next visit or by an extra telephone call using a different interviewer to reduce inaccuracies. In this study, we also used self-reported data from the survivors or family members to measure the clinical outcomes and after- discharge managements that may be introducing reporting bias. To minimize this bias, we verified the answers with the hospitals’ medical records or family members’ report. Finally, we excluded all suspected patients with normal CAG findings, which were mostly females. Thus, our study may have overlooked the minor group of myocardial infarction with no obstructive coronary atherosclerosis.

86 Predictors of mid-term mortality of CAD patients

To our knowledge, this is the first study identifying predictors of medium-term mortality amongst CAD patients in a resources-limited Indonesian population, and thus provides a general picture of risk stratification for clinical practitioners to recognize CAD patients with poor prognosis. Rapid diagnosis and early risk stratification of patients with acute myocardial infarction (STEMI and NSTEMI) are mostly 5 important to identify patients in whom early interventions can improve the clinical outcomes and reduce mortality risk. The increased burden of cardiovascular risk factors26 and high mortality rate after hospital discharge in Indonesia implies that both primary and secondary prevention of CVD are still underperforming in this low-to-middle income country. Therefore, improvement of primary and secondary prevention on CVD in Indonesia is urgently required. Lastly, this study shows that generally in Indonesian CVD patients, proper risk stratification and targeted-treatment policies can help clinicians improve patient outcomes. Improving patient access to proper facilities, optimizing medication adherence and life-style adjustment will likely help reduce excess CAD mortality.

In conclusion, CAD patients in Makassar, Indonesia of which represent a poor South-East Asian setting, have unacceptably high short- and medium-term mortality rates. Both health policy-makers and clinicians should help improve Indonesian CVD patients’ survival by organizing compliance to guidelines-recommended therapy and improving adherence to medication and life-style corrections.

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NOTES

Ethics approval The study protocol was approved by the Ethics Committee and Institutional Review Board of the Faculty of Medicine, University of Hasanuddin Makassar, Indonesia (letter number 030/H4.8.4.5.31/ PP 36-KOMETIK/2013).

Acknowledgements The authors gratefully acknowledge all participants, the family members, and advisers for all support and contribution to this study. The staff of the Cardiovascular Care Unit (CVCU) RS. Wahidin Sudirohusodo, Makassar is acknowledged for their contributions to the success of this research project and all research assistants for the data collection and data management. Thanks to Dian Sidik Arsyad, SKM, MKM for providing figure 1 in this manuscript. Special thanks for Mrs. Fithriany Harry S.Farm, Apt, all research nurses, and nursing students in Puskesmas Batua (Batua Primary Healthcare Center) Makassar for their dedication to complete the continuation of the follow-up.

Information The abstract of this paper has been presented in the 21st Asian Pacific Society of Cardiology (APSC) Congress, 13-15 July 2017, in Singapore.

Funding This work was supported by Directorate General of Higher Education/Direktorat Jenderal Pendidikan Tinggi (DIKTI), Ministry of National Education Republic of Indonesia [grant number 600/E4.4/K/2011, 2011].

Competing interests None declared

88 Predictors of mid-term mortality of CAD patients

Key Messages

What is already known about this subject? 5 • Registry data on cardiovascular diseases and deaths in the low- and middle-income countries are lacking. • Previous studies have suggested that traditional risk factors and adverse clinical presentation on admission were all independent predictors of cardiovascular death. • Evidence showed that well-established traditional risk factors in Western and high-income countries play a similar role in cardiovascular mortality in the South-East Asian region.

What does this study add? • Mortality both during and after hospitalization is unacceptably high in patients with coronary artery disease (CAD) in Indonesia. After the total follow-up (median 18 (IQR 6 – 36) months), 32.3% of patients died. • In-hospital and total medium-term mortality differed between underlying disease (higher in non-ST-segment elevation myocardial infarction (NSTEMI) than other diagnosis groups), with p=0.002 and p=0.007, respectively. • The initial severity of disease, lack access to guidelines-recommended therapy and poor adherence to after-discharge medications are the main drivers for excess medium-term mortality. • Poor adherence to medications predicted after discharge mortality, and did so irrespective of underlying CAD diagnosis (p-interaction = 0.88).

How might this impact on clinical practice? • This study provides a general picture of risk stratification for clinical practitioners to recognize CAD patients with poor prognosis in a resource-limited South-East Asian setting, particularly in Indonesia. • Hospitalization is an important window of opportunity to address both in-hospital and, largely as a consequence, longer term survival in CAD patients. • Optimizing medication adherence and lifestyle adjustment, irrespective of underlying CAD diagnosis will likely help reduce excess CAD mortality.

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REFERENCES 1. Yusuf S, Rangarajan S, Teo K, Islam S, Li W, Liu L, et al. Cardiovascular risk and events in 17 low-, middle-, and high-income countries. N Engl J Med 2014; 371: 818-827. 2. Ohira T, Iso H. Cardiovascular disease epidemiology in Asia: an overview. Circulation 2013; 77: 1646-1652. 3. Lam CSP. Heart failure in Southeast Asia: facts and numbers. ESC Heart Failure 2015; 2: 46-49. 4. World Health Organization: Regional Office for South-East Asia. Noncommunicable Diseases in the South-East Asia Region: 2011 Situation and Response. New delhi, 2011. 5. Prugger C, Wellmann J, Heidrich J, Brand-Herrmann S, Keil U. Cardiovascular Risk Factors and Mortality in Patients with Coronary Heart Disease. Eur J Epidemiol 2008; 23: 731-737. 6. Rathod KS, Jones DA, Gallagher S, Rathod VS, Weerackody R, Jain AK, et al. Atypical risk factor profile and excellent long-term outcomes of young patients treated with primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction. Eur Heart J Acute Cardiovasc Care 2016; 5: 23-32. 7. Schiele F, Descotes-Genon V, Seronde MF, Blonde MC, Legalery P, Meneveau N, et al. Predictive value of admission hyperglycaemia on mortality in patients with acute myocardial infarction. Diabetic Medicine 2006; 23: 1370-1376. 8. Fox KA, Dabbous OH, Goldberg RJ, Pieper KS, Eagle KA, Van de Werf F, et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). BMJ 2006; 333: 1091. 9. Kumar A, Cannon CP. Acute Coronary Syndromes: Diagnosis and Management, Part I. Mayo Clin 2009; 84: 917-938. 10. Grech ED, Ramsdale DR. ABC of interventional cardiology, Acute coronary syndrome: unstable angina and non-ST segment elevation myocardial infarction. BMJ 2003; 326: 1259-1261. 11. Elbez Y, Cheong AP, Fassa A-A, Cohen E, Reid CM, Babarskiene R, et al. Clinical outcomes in patients with stable coronary artery disease with vs. without a history of myocardial revascularization. Eur Heart J Qual Care Clin Outcomes 2016; 2 (1): 23-32. 12. Pizzi C, Xhyheri B, Costa GM, Faustino M, Flacco ME, Gualano MR, et al. Nonobstructive Versus Obstructive Coronary Artery Disease in Acute Coronary Syndrome: A Meta- Analysis. J Am Heart Assoc 2016; 5. 13. Ranthe MF, Carstensen L, Oyen N, Tfelt-Hansen J, Christiansen M, McKenna WJ, et al. Family history of premature death and risk of early onset cardiovascular disease. J Am Coll Cardiol 2012; 60: 814-821. 14. Alcock RF, Yong AS, Ng AC, Chow V, Cheruvu C, Aliprandi-Costa B, et al. Acute coronary syndrome and stable coronary artery disease: are they so different? Long-term outcomes in a contemporary PCI cohort. Int J Cardiol 2013; 167: 1343-1346. 15. El-Menyar A, Zubaid M, AlMahmeed W, K. S, AlNabti A, Singh R, et al. Killip classification in patients with acute coronary syndrome: insight from a multicenter registry. Am J Emerg Med 2012; 30: 97-103. 16. Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010; 375: 2073-2081. 17. Muntner P, He J, Hamm L, Loria C, Whelton PK. Renal Insufficiency and Subsequent Death Resulting from Cardiovascular Disease in the United States. J Am Soc Nephrol 2002; 13: 745-753.

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18. Gibson CM, Pinto DS, Murphy SA, Morrow DA, Hobbach H-P, Wiviott SD, et al. Association of creatinine and creatinine clearance on presentation in acute myocardial infarction with subsequent mortality. J Am Coll Cardiol 2003; 42: 1535-1543. 19. Best PJM, Lennon R, Ting HH, Bell MR, Rihal CS, Holmes DR, et al. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary 5 interventions. J Am Coll Cardiol 2002; 39: 1113-1119. 20. Fath-Ordoubadi F, Spaepen E, El-Omar M, Fraser DG, Khan MA, Neyses L, et al. Outcomes in patients with acute and stable coronary syndromes; insights from the prospective NOBORI-2 study. PLoS One 2014; 9: e88577. 21. Montalescot G, Dallongeville J, Van Belle E, Rouanet S, Baulac C, Degrandsart A, et al. STEMI and NSTEMI: are they so different? 1 year outcomes in acute myocardial infarction as defined by the ESC/ACC definition (the OPERA registry). Eur Heart J 2006; 28: 1409-1417. 22. Balzi D, Di Bari M, Barchielli A, Ballo P, Carrabba N, Cordisco A, et al. Should we improve the management of NSTEMI? Results from the population-based “acute myocardial infarction in Florence 2” (AMI-Florence 2) registry. Intern Emerg Med 2013; 8: 725-733. 23. Kolh P, Windecker S, Alfonso F, Collet JP, Cremer J, Falk V, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur J Cardiothorac Surg 2014; 46: 517-592. 24. Pursnani S, Korley F, Gopaul R, Kanade P, Chandra N, Shaw RE, et al. Percutaneous coronary intervention versus optimal medical therapy in stable coronary artery disease: a systematic review and meta-analysis of randomized clinical trials. Circ Cardiovasc Interv 2012; 5: 476-490. 25. Bowry AD, Shrank WH, Lee JL, Stedman M, Choudhry NK. A systematic review of adherence to cardiovascular medications in resource-limited settings. J Gen Intern Med 2011; 26: 1479-1491. 26. Hussain MA, Al Mamun A, Peters SA, Woodward M, Huxley RR. The Burden of Cardiovascular Disease Attributable to Major Modifiable Risk Factors in Indonesia.J Epidemiol 2016; 26: 515-521. 27. Tonino PA, Fearon WF, De Bruyne B, Oldroyd KG, Leesar MA, Ver Lee PN, et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation. J Am Coll Cardiol 2010; 55: 2816-2821. 28. American Heart Association. ANSWERS by heart, Lifestyle + Risk Reduction: High Blood Pressure. Why Should I Limit Sodium? http://www.heart.org/idc/groups/heart-public/@ wcm/@hcm/documents/downloadable/ucm_300625.pdf (22 September 2017).

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ABSTRACT

Background Timely coronary angiography (CAG) is pivotal in treating coronary artery disease (CAD). In South-East Asian populations and particularly in Indonesia, access to CAG is limited. We investigated if, once admitted to a hospital with CAG facilities, patients were treated according to accepted guidelines for undergoing CAG. Secondly, we examined whether or not undergoing CAG would have an impact on medium-term mortality and morbidity.

Methods The study consecutively enrolled 477 patients with acute coronary syndrome (ACS) and stable CAD at Makassar Cardiac Center, Indonesia from February 2013 to December 2014. Patients were grouped according to CAG assessment (yes/no). Patients with CAG were classified based on the SYNTAX score: low (≤18), intermediate (>18-27), and high (>27) groups. Follow-up was conducted until January 2018 with primary endpoints being all-cause mortality and major adverse cardiovascular events (MACE). Kaplan-Meier curves and multivariable Cox-proportional hazard analyses were used to compare the short and medium-term outcomes between the groups.

Results Based on the guidelines, 474 (99.4%) patients were eligible for CAG, of whom only 273 (57.6%) underwent the procedure. Factors for not undergoing CAG were: older age, female gender, low educational and socio-economic status, and insurance type. During follow-up (median 19.0 (IQR 5.5– 39.0) months), 157 (32.9%) patients died, and 261 (54.7%) experienced at least one adverse event. Undergoing CAG was associated with lower all-cause mortality, even after adjustment for potential confounders (Hazard ratio (HR) 0.62 (95% CI 0.41–0.93, p=0.020). Reasons for patients refusing CAG and subsequent intervention included fear, symptoms reduction, and lack of trust concerning the benefit of the procedure. In patients with CAG, higher SYNTAX scores independently predicted a higher risk of all-cause mortality (HRadjusted 1.58 (1.15–2.18), p=0.005) and MACE (HRadjusted 1.26 (1.03– 1.55), p=0.028).

Conclusions Adherence to CAG recommendation in poor South-East Asian setting is low. Undergoing CAG is associated with a significantly lower risk of short- and medium-term all-cause mortality.

Keywords Coronary angiography; SYNTAX score; adherence to guidelines recommendation; coronary artery disease; mortality; South-East Asia.

94 Adherence to coronary angiography recommendations and its impacts

INTRODUCTION

Coronary angiography (CAG) is the diagnostic test used to detect and quantify the presence and extent of atherosclerotic coronary artery disease (CAD).1 CAG should be available to patients with 6 acute coronary syndrome (ACS) and stable CAD for several purposes: (1) recognition and treatment of acute myocardial infarction – urgent invasive strategy (<2 hours of admission); (2) early invasive strategy (<24 hours), or delayed invasive strategy (<25–72 hours); and (3) risk stratification (elective diagnostic CAG).2-4

Patient with angiographically proven coronary artery disease may undergo revascularization, either by PCI or CABG.5 The SYNTAX score is an angiographic tool developed to grade the complexity and severity of coronary artery lesions.5,6 This score assists clinicians to select the optimal revascularization strategy.5,6 A higher SYNTAX score indicates a more complex condition and a worse prognosis in patients undergoing revascularization, especially PCI.5

This cohort study is the first to measure the adherence to the guidelines recommendation to perform CAG in a setting with limited resources. The study also intends to demonstrate the short- and medium-term prognostic consequences of the adherence to these guidelines.

METHODS

Study population This study was based on a prospective cohort of 477 patients who were diagnosed with CAD at the Makassar Cardiac Center, Wahidin Sudirohusodo Hospital, between February 2013 and December 2014. This cardiac center is the biggest in Eastern Indonesia, serving the population of South Sulawesi as well as the populations from other regions in Sulawesi and beyond.

All patients were recruited from either the cardiovascular care unit (including intensive care and catheterization lab) or the regular ward. Patients were included if they had been diagnosed with CAD, defined as acute coronary syndrome (ACS) or stable coronary artery disease (SCAD). ACS was defined as unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), or ST-segment elevation myocardial infarction (STEMI).7,8 SCAD was defined as stable angina, including prior ACS, prior coronary revascularization or known significant CAD on angiography without revascularization.9 All eligible patients gave written informed consent before being enrolled. We excluded all patients who immediately died in the emergency department or intensive cardiovascular care unit before giving informed consent, and all patients in whom coronary angiography had been confirmed as normal (defined as 0% lumen stenosis in all coronary vessels).10 Detailed description and flowchart of the study population has been previously reported.11

Data collection Socio-demographic data, lifestyle, dietary pattern, family history of cardiovascular disease (CVD) and clinical profiles were all collected from medical records and questionnaire interviews. We also recorded clinical data from electrocardiography and echocardiography examinations. In patients with symptomatic angina, cardiac enzymes were immediately tested to confirm the clinical diagnosis. Laboratory tests including plasma glucose, lipid profiles, uric acid, and renal and liver function

95 Chapter 6 markers were measured within 24 hours of hospital admission. An overnight 8-hour fasting blood sample was taken via venipuncture. All blood samples were analyzed in the hospital laboratory using standardized methods.

In-hospital and after-discharge management Management strategies before, during, and after hospitalization including medications, fibrinolysis/ thrombolysis, primary and elective PCI, and elective CABG were all recorded. Thirty days from admission, we followed up the adherence to after-discharge and secondary prevention medications in all survivors (n = 406).

Coronary angiography As our main determinant we collected all data on coronary angiography including date and time of hospital admission, indications, contraindications, procedures, findings, and SYNTAX scores.

The recommendation to perform CAG in clinically indicated patients was based on the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for coronary angiography (1999).2,3 Detailed descriptions of the classes of recommendation (COR) and level of evidence (LOE) for CAG procedure are given as supplement (table S1).2-4,12 In the present study, we measured the adherence to the guideline recommendation to perform a coronary angiography as the initial diagnostic tool or as a precondition of an urgent/early invasive treatment, and for the risk stratification purposes, both from patients’ and clinicians’ sides. We marked the recommendation as classes IA and IB (table S2 in supplement).

We also quantified the recommendation not to perform the procedure, i.e. where the patients were not candidates for this or if they had refused revascularization regardless of the coronary findings; this was designated as class IIIC. Patients who did not consent to undergo CAG were asked about the motivation for their decision. A trained and experienced catheterization laboratory analyst (SS) and a cardiologist read all video recordings of the coronary angiograms (IM) and analyzed the SYNTAX scores.

Significant or obstructive vessel disease was defined as a lesion in a coronary vessel (diameter ≥1.5 mm) with ≥50% reduction in luminal diameter on angiographic assessment.5 In this study, the SYNTAX scores of the non-significant lesions were also quantified.

Definitions The Canadian Cardiology Society (CCS) grading of angina pectoris was used to classify patients with stable angina. We also used the New York Heart Association (NYHA) Functional Classification system to grade heart failure according to the severity of symptoms.

In patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS), diagnostic angiography within 24 hours of admission with intent to perform revascularization based on the coronary anatomy findings was defined as the appropriate early invasive strategy.3 Increased risk for clinical events was defined if one or more of the following features were present: prolonged ongoing pain at rest (>20 minutes), angina at rest with dynamic ST changes ≥1 mm, pulmonary edema, angina with new or worsening mitral regurgitation (MR) murmur, angina with S3 or new/worsening rales, or angina with hypotension.2 Patients with prior revascularization, congestive heart failure (CHF), LVEF

96 Adherence to coronary angiography recommendations and its impacts

<50%, ventricular arrhythmia, or persistent/recurrent ischemic angina who had an indication for CAG, were considered at high-risk for peri-operative complications.2 The Killip classification was used to stratify the risk of mortality in acute myocardial infarction (STEMI 6 and NSTEMI) patients.

Follow-up The endpoints of this study were all-cause mortality and the composite outcome of major adverse cardiovascular events (MACE). We actively collected outcomes data during hospitalization, at 30 days, 6 months, and 12 months, and yearly until the end of study period in January 2018. At home visits or phone call interviews, nurses recorded the dates on which patients had experienced adverse events. These included: cardiovascular and non-cardiovascular mortality, re-hospitalization due to MI or heart failure, stroke, PCI, CABG, repeat PCI, and non-CVD hospitalization. However, the cause of mortality was largely based on reports from family members. We considered such a report to be cardiovascular death if patients died suddenly at home, or on the way to hospital, or during hospitalization for a cardiovascular cause or having shown a CVD symptom resulting in death.

Statistical analysis Means ± standard deviations (SD) were calculated for continuous variables. Data with skewed distribution were presented as median (Q1-Q3). For categorical variables, we calculated numbers (proportions). Differences in continuous variables were estimated using independent t-test or 1-way ANOVA test, while differences in proportions were compared using Pearson’s Chi-square or exact Chi-square test. For skewed continuous data, differences were estimated using Mann-Whitney U test or Kruskal-Wallis test.

Patients were divided according to whether or not they underwent CAG. Subsequently, patients with CAG were grouped based on their SYNTAX score (SS): low (≤18), intermediate (>18-27), and high (>27). Baseline characteristics, clinical profiles, and clinical outcomes were firstly tabulated based on CAG assessment (yes/no), and then presented amongst SYNTAX score tertile groups.

Kaplan-Meier curves were constructed to present the cumulative incidence of all-cause mortality. The log-rank test was used to estimate the difference between CAG and non-CAG groups, and subsequently we estimated the differences between non-CAG, low SS, intermediate SS, and high SS groups. Follow-up time was defined as the time from hospital admission to mortality or censoring, until the end of study period. The survival times of participants who had moved, given an incorrect address or who, for whatever reason, were unreachable via telephone or home visit were censored at the last date that they were known to be still alive. Survival times of participants who were still alive at the end of follow-up were censored on January 5, 2018.

We applied multivariable Cox regression analyses to estimate the hazard ratios (HRs) for all-cause mortality and composite MACE between non-CAG and CAG groups, and then between the SYNTAX score tertile groups. We considered a 95% confidence interval not including one, with p-value <0.05 as statistically significant. All statistical analyses were performed with SPSS version 23.0 for Mac.

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RESULTS

A total of 477 patients with coronary artery disease were included in our analysis: 364 (76.3%) patients admitted for ACS, and 113 (23.7%) for stable CAD. Out of 113 patients with stable CAD, 19 (16.8%) were hospitalized for stable angina, 34 (30.1%) for CHF, and 60 (53.1%) were recruited from the catheterization laboratory. The majority of patients (72.7%) were male with a mean age of 58.2 ± 10.8 years. Based on the symptoms and disease, guidelines would have recommended CAG in 474 (99.4%) patients. Eventually, 273 (57.6%) patients underwent the procedure: 93 (34.1%) were performed as an early invasive strategy (<24 hours of admission), and the remaining 180 (65.9%) as an elective CAG.

Table 1 presents the baseline characteristics and clinical profiles of the cohort according to CAG assessment (yes/no). When compared with the CAG group, patients who did not undergo the procedure were older, more were female, with a lower educational level and lower socio-economic status. With respect to clinical presentation, the non-CAG patients had less history of prior MI, PCI, and parents with CVD, more often had diabetes, reduced renal function, and heart failure with NYHA class III and IV, were less often current/former smokers, stayed longer in hospital, and more were diagnosed with NSTEMI compared to the CAG group.

We describe in detail the strict indications to perform (class IA and IB) and not to perform (class IIIC) diagnostic coronary angiography as supplement (table S2). A total of 204 patients did not undergo the procedure; n=23 (11.3%) in SCAD, n=82 (40.2%) in NSTE-ACS, and n=99 (48.5%) in STEMI patients. Of those, 152 (74.5%) participants deliberately refused CAG or coronary revascularization for various reasons. Detailed reasons and the motivation behind the decisions of patients not undergoing the CAG procedure are listed in table 2. Due to limited resources (i.e. poor transportation, complicated administration, or limited cardiologists), 49 (24.0%) ACS patients who should be treated with an urgent/early invasive strategy did not receive the recommended treatment: 30 NSTE-ACS patients with refractory angina, hemodynamic/ECG instability, or at high risk for adverse events; 16 STEMI patients should have had primary/rescue PCI, or with persistent angina; and three STEMI patients with cardiogenic shock. Meanwhile, three patients were not clinically indicated to undergo CAG due to severe comorbidities (table 2).

The median follow-up of the cohort was 19.0 (IQR 5.5–39.0) months. During the observation period, 157 (32.9%) patients died, 261 (54.7%) experienced MACE, and seven (1.5%) participants were lost to follow-up.

Table 3 lists in detail the clinical outcomes at short- (≤30 days) and medium-term (>30 days up to the end of study) follow-up across the CAG groups. At 30 days, there was a considerably higher cardiovascular mortality rate in the non-CAG (n=50, 24.5%) compared with the CAG group (n=14, 5.1%) (p<0.001). Over 30 days up to the end of follow-up period, we also observed that more patients without CAG died than those with the procedure (22.5% vs. 17.2%), although not statistically significant. Five (1.8%) patients with CAG have hospitalized for non-cardiovascular diseases over 6 months of follow-up.

98 Adherence to coronary angiography recommendations and its impacts

Table 1. Baseline characteristics and clinical profiles of the study population according to CAG procedure CAG NO CAG YES Total Variables p-value (n = 204) (n = 273) (n = 477) 6 Age (years) 59.7 ± 11.7 57.1 ± 10.0 58.2 ± 10.8 0.009 Male sex 127 (62.3) 220 (80.6) 347 (72.7) <0.001 Previous MI 56 (27.5) 108 (39.6) 164 (34.4) 0.006 Previous CAG 5 (2.5) 64 (23.4) 69 (14.5) <0.001 Previous PCI 1 (0.5) 26 (9.5) 27 (5.7) <0.001 Risk factors Hypertension 157 (77.0) 201 (73.6) 358 (75.1) 0.405 Diabetes mellitus 74 (36.3) 73 (26.7) 147 (30.8) 0.026 Dyslipidemia 151 (74.0) 219 (80.2) 370 (77.6) 0.108 Current/former smoker 112 (54.9) 185 (67.8) 297 (62.3) 0.004 Parents with CVD 42 (20.6) 80 (29.3) 122 (25.6) 0.031 BMI (kg/m2) 24.1 ± 3.5 24.4 ± 3.2 24.3 ± 3.4 0.142 Low educationa 95 (46.6) 43 (15.8) 138 (28.9) <0.001 Low socio-economic statusb 149 (73.0) 99 (36.3) 248 (52.0) <0.001 >20 km from hospital (rural) 107 (52.5) 140 (51.3) 247 (51.8) 0.800 Clinical presentation Stable angina 23 (11.3) 90 (33.0) 113 (23.7) <0.001 Unstable angina 24 (11.8) 44 (16.1) 68 (14.3) 0.179 Non-ST-segment elevation MI 58 (28.4) 27 (9.9) 85 (17.8) <0.001 ST-segment elevation MI 99 (48.5) 112 (41.0) 211 (44.2) 0.103 LVEF (%) 41.8 ± 13.2 48.4 ± 14.3 45.8 ± 14.2 <0.001 eGFR <60 mL/min 82 (40.2) 67 (24.5) 149 (31.2) <0.001 CHF/Killip class ≥2 114 (55.9) 70 (25.6) 184 (38.6) <0.001 NYHA Class II 11 (5.4) 9 (3.3) 20 (4.2) 0.259 Class III 46 (22.5) 27 (9.9) 73 (15.3) <0.001 Class IV 11 (5.4) 2 (0.7) 13 (2.7) 0.002 Onset to admission (hours)c 24.8 (10-48) 27.0 (9-48) 26.8 (10-48) 0.629 Length of stay (days)c 7(5-10) 6 (0-8) 6 (4-9) <0.001

Values are n (%) or means ± SD. Comparison was performed using independent t-test for continuous variables and Pearson Chi-square test for categorical variables. aDefined as the highest formal education was junior high/elementary school, no schooling, or illiterate. bDefined as monthly income

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Table 2. Results I: Reasons not to undergo diagnostic coronary angiography

Frequency Reasons/motivations (%) High costs without possibility to cover these expenses (no funds or insurance) 1 (0.5) Fear of side effects of the procedure that will be debilitating, cause disability, and 28 (13.7) life-threatening Fear that the procedure is a major/big surgical procedure and patient is not ready for all 22 (10.8) the potential risks Family’s refusal for the patient to undergo the procedure 5 (2.5) Reduced symptoms on current medication and patient is convinced that additional 46 (22.5) procedures or treatments are not necessary Denial of a heart disease (e.g. belief that symptoms are caused by other reasons) 1 (0.5) Personal uncertainty concerning the beneficial impact on clinical outcomes or quality 23 (11.3) of life Preference to the procedure at a larger tertiary center (the National Heart Center in 1 (0.5) Jakarta) Other reasons (e.g. older age; preference for traditional medications or natural healing; 15 (7.4) relatives/friends’ negative information, belief, etc.) Unknown or personal reasons 10 (4.9) Constrained by the condition (i.e. poor transportation, complicated administration, or 49 (24.0) limited cardiologists) By indication (clinically not recommended) 3 (1.5) Total 204 (100.0)

The Kaplan-Meier curve better illustrates that the cumulative incidence of mortality was higher in non-CAG patients than those with CAG, both at short- (p<0.001) and medium-term (p=0.001) follow- up (figure 1).

As shown by table 4, there were no differences of socio-demographic and clinical characteristics amongst the SYNTAX score tertile groups. Sixty-six (98.5%) patients with high SS had multivessel disease.

Overall in the CAG group, patients in the highest tertile showed considerably higher composite MACE compared with the intermediate and low SS groups over 30 days until the end of study period (p<0.001) (table 5). Detailed managements during and after hospitalization across the SYNTAX score groups are presented as supplement (table S3).

The scheme of insurance or funding of the study population is presented in table 6. We found that patients with the national health insurance for civil servant (middle to high income) were prone to undergo CAG (p<0.001), while those with the national or local insurance for lower income tended to not receive this invasive procedure (p<0.001).

We also estimated the hazard ratios by comparing non-CAG vs. CAG groups, and then specifically comparing the tertile SS groups (figure 2). We observed that undergoing CAG in patients with coronary artery disease – either immediately or later after hospital admission – was associated with

100 Adherence to coronary angiography recommendations and its impacts lower all-cause mortality (hazard ratio (HR) 0.38 (95% confidence interval (CI) 0.27– 0.52), p<0.001) and composite MACE (HR 0.77 (95% CI 0.60–0.98), p=0.033). After adjustment for some potential confounders, the hazard ratio for all-cause mortality attenuated, but was still significant (HR 0.62 (95%CI 0.41–0.93, p=0.020). 6

A high SYNTAX score independently predicted a higher risk of all-cause mortality (HRadjusted 1.58 (95%

CI 1.15–2.18), p=0.005) and adverse events (HRadjusted 1.26 (95% CI 1.03–1.55), p=0.028) compared with a low SYNTAX score (figure 2). Meanwhile, from our extra analysis, not undergoing CAG would have a similar hazard of death as the high SS patients (data not shown).

Table 3. Results II: Clinical outcomes in patients with and without CAG

CAG NO CAG YES Total Variables p-value (n = 204) (n = 273) (n = 477) ≤30 days Cardiovascular death 50 (24.5) 14 (5.1) 64 (13.4) <0.001 Re-hospitalization for MI or HF 4 (2.0) 12 (4.4) 16 (3.4) 0.144 Stroke 0 (0.0) 2 (0.7) 2 (0.4) 0.509 PCI 0 (0.0) 23 (8.4) 23 (4.8) <0.001 CABG 0 (0.0) 1 (0.4) 1 (0.2) 1.000 Re-PCI N/A 5 (1.8) 5 (1.0) N/A >30 daysa Cardiovascular death 45 (22.1) 46 (16.8) 91 (19.1) 0.152 Non-cardiovascular death 1 (0.5) 1 (0.4) 2 (0.4) 1.000 Re-hospitalization for MI or HF 12 (5.9) 26 (9.5) 38 (8.0) 0.146 Stroke 1 (0.5) 4 (1.5) 5 (1.0) 0.301 PCI 4 (2.0) 12 (4.4) 16 (3.4) 0.144 CABG 0 (0.0) 9 (6.7) 9 (1.9) 0.009 Re-PCI N/A 9 (3.3) 9 (1.9) N/A

Values are n (%). Differences were estimated using Pearson’s or exact Chi-square test. aUp to the end of study follow-up. CAG: coronary angiography; MI: myocardial infarction; HF: heart failure; PCI: percutaneous coronary inter- vention; CABG: coronary artery bypass graft; N/A: not applicable.

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Fig. 1. Kaplan-Meier curve describes the short- and medium-term all-cause death between patients with and without CAG The difference between groups was estimated using Log-rank test.

Table 4. Characteristics and clinical profiles of patients with CAG across the SYNTAX score tertile groups SYNTAX Characteristics Low Intermediate High p-value (n = 146) (n = 60) (n = 67) Age 54.9 ± 10.1 57.3 ± 9.8 61.7 ± 8.2 0.126 Male sex 115 (78.8) 51 (85.0) 54 (80.6) 0.590 Previous MI 51 (34.9) 24 (40.0) 33 (49.3) 0.139 Previous CAG 31 (21.2) 15 (25.0) 18 (26.9) 0.633 Previous PCI 13 (8.9) 4 (6.7) 9 (13.4) 0.402 Clinical presentation Stable angina 45 (30.8) 23 (38.3) 22 (32.8) 0.581 Unstable angina 20 (13.7) 9 (15.0) 15 (22.4) 0.268 Non-ST-elevation MI 12 (8.2) 9 (15.0) 6 (9.0) 0.320 ST-segment-elevation MI 69 (47.3) 19 (31.7) 24 (35.8) 0.072 SYNTAX score 9.9 ± 4.3 23.4 ± 2.8 37.7 ± 7.8 <0.001 Raised blood glucosea 81 (55.5) 38 (63.3) 42 (62.7) 0.452 Hypertension 105 (71.9) 43 (71.7) 53 (79.1) 0.503 eGFR <60 mL/min 33 (22.6) 12 (20.0) 22 (32.8) 0.178 CHF/Killip class ≥2 35 (24.0) 12 (20.0) 23 (34.3) 0.145

102 Adherence to coronary angiography recommendations and its impacts

Echocardiography assessed 83 (56.8) 35 (58.3) 41 (61.2) 0.837 LVEF (%) 49.6 ± 13.7 47.6 ± 14.5 46.7 ± 15.4 0.584 Multivessel CADb 50 (34.2) 53 (88.3) 66 (98.5) <0.001 6 Values are n (%) or means ± SD. Comparison was performed using 1-way ANOVA test for continuous vari- ables and Pearson Chi-square test for categorical variables. aDefined as fasting plasma glucose >7.7 mmol/L on hospital admission. bDefined as angiographic 2- or 3-vessel disease (stenoses ≥50% in at least two of the three major epicardial coronary arteries). CAG: coronary angiography; SYNTAX: SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery; MI: myocardial infarction; PCI: percutaneous coronary intervention; eGFR: estimated glomerular filtration rate; CHF: congestive heart failure; LVEF: left ventricular ejection fraction; CAD: coronary artery disease.

Table 5. Characteristics and clinical profiles of patients with CAG across the SYNTAX score tertile groups SYNTAX p-value Characteristics Low Intermediate High (n = 146) (n = 60) (n = 67) ≤30 days Cardiovascular death 7 (4.8) 3 (5.0) 4 (6.0) 0.934 Re-hospitalization for MI or HF 5 (3.4) 1 (1.7) 6 (9.0) 0.058 Stroke 0 (0.0) 0 (0.0) 2 (3.0) 0.107 PCI 15 (10.3) 5 (8.3) 3 (4.5) 0.379 CABG 0 (0.0) 0 (0.0) 1 (1.5) 0.465 Re-PCI 1 (0.7) 0 (0.0) 4 (6.0) 0.023 Total 28 (19.2) 9 (15.0) 20 (29.9) 0.092 >30 daysa Cardiovascular death 16 (11.0) 11 (18.3) 19 (28.4) 0.007 Non-cardiovascular death 1 (0.7) 0 (0.0) 0 (0.0) 1.000 Re-hospitalization for MI or HF 10 (6.8) 7 (11.7) 9 (13.4) 0.257 Stroke 3 (2.1) 0 (0.0) 1 (1.5) 0.537 PCI 6 (4.1) 2 (3.3) 4 (6.0) 0.747 CABG 2 (1.4) 4 (6.7) 3 (4.5) 0.127 Re-PCI 6 (4.1) 0 (0.0) 3 (4.5) 0.267 Total 44 (30.1) 24 (40.0) 39 (58.2) <0.001

Values are n (%). Differences were estimated using Pearson’s or exact Chi-square test. aUp to the end of study follow-up. SYNTAX: SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery; MI: myocardial infarction; HF: heart failure; PCI: percutaneous coronary intervention; CABG: coronary artery bypass graft.

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Table 6. Insurance/funding scheme of the cohort according to CAG assessment

CAG NO CAG YES Total Insurance or source of funding p-value (n = 204) (n = 273) (n = 477) Private 21 (10.3) 15 (5.5) 36 (7.5) 0.050 Company insurancea 2 (1.0) 8 (2.9) 10 (2.1) 0.141 National insurance for civil servant (middle to high income – Askes)a 68 (33.3) 173 (63.4) 241 (50.5) <0.001 National/local insurance for low income (Jamkes- mas/Jamkesda)a 84 (41.2) 31 (11.4) 115 (24.1) <0.001 National health insurance (BPJS)b 29 (14.2) 46 (16.8) 75 (15.7) 0.434

Values are n (%). Differences were estimated using Pearson’s or exact Chi-square test. aBefore the era of national health insurance. bStarted since January 2014, for all Indonesian citizens. CAG: coronary angiography; Askes: Asuransi Kesehatan; Jamkesmas: Jaminan Kesehatan Masyarakat; Jamkesda: Jaminan Kesehatan Daerah; BPJS: Badan Penyelenggara Jaminan Sosial.

DISCUSSION

This study showed a low level of compliance – 57.6% out of 99.4% – with recommendations from guidelines on performing CAG in real-world practice in an underprivileged South-East Asian setting. Patients who did not undergo the procedure were more often female and older, had a lower educational level and lower socio-economic status. Coronary angiography was associated with lower short- and medium-term mortality.

After adjustment for potential confounders, the hazard ratio for all-cause mortality attenuated, but remained statistically significant (HR 0.62 (95% CI 0.41–0.93, p=0.020). Severity of disease and delayed invasive treatment, therefore, remained the dominant factors. Early CAG provides earlier risk stratification, timely revascularization, and accelerates hospital discharge, but greater logistic demands on healthcare system are involved.3

A third of patients in our cohort who refused CAG were fearful of undergoing this invasive procedure and were overly concerned about the complications. As an invasive intervention, there are inherent risks and complications related to the procedure that depend on the condition of the patient and the skill of the operator. Patients need to be informed that major complications associated with this procedure are rare.1

Due to poor resources and lack of awareness of symptomatic CAD, we observed a considerable excess delay from symptom onset to an early invasive intervention in this cohort; 2–3 hours in STEMI12 and 12–24 hours in NSTE-ACS3 as the reference standard. The seriousness of the underlying disease and the extensive comorbidities were influential factors that defer the cardiologist to perform immediate CAG. Interestingly, previous studies also reported the benefit of deferred CAG.3 The underlined rationale of delayed or elective angiography is that revascularization may be safer when plaque has been previously stabilized with optimal antithrombotic and/or anti-ischemic agents.3

104 Adherence to coronary angiography recommendations and its impacts

6

Fig. 2. Hazard ratios between coronary angiography groups for: (a) All-cause death and (b) composite MACE All hazard ratios were adjusted for: age, gender, hypertension, raised fasting plasma glucose, recent MI, eGFR <60 mL/min, LVEF <35%, revascularization (PCI/CABG), adherence to cardiovascular medications, socio-economic status, and distance from hospital.

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Because of administrative barriers, some patients who were indicated with the national or local insurance for the low-income people needed to be re-admitted to receive a planned CAG. After discharge, there were 11 (2.3%) patients who received their first CAG and 3 (0.6%) underwent repeat CAG at 30-day follow-up. Meanwhile, after 30 days up to the end of follow-up, 7 (1.5%) patients received the first CAG and 8 (1.6%) have repeated the procedure. The inefficiency of the current clinical practice might partly explain the non-adherence to the guidelines recommendation and therefore contribute to the high rate of early deaths in non-CAG group.

Apparently, we also found that patients without CAG experienced more death within 30 days of admission compared to those with CAG (24.5% vs. 5.1%, p<0.001). The plausible explanations for this finding are: (1) the low rate of early invasive strategy for ACS patients is associated with the increased risk of early mortality; (2) in the absence of a CAG procedure, the cardiologists have less reliable guidance to choose the optimal treatment. The fact that these patients died in the first 14 days of admission (n=50, out of 157 total deaths) was reflecting the more severe and unstable conditions of their coronary disease. However, when we excluded in-hospital mortality in separate analysis, we still found that undergoing CAG was associated with lower incidence of after-discharge all-cause mortality (HR 0.46 (95% CI 0.31-0.68), p<0.001). The association was unchanged in multivariable analysis, although borderline significant (HR 0.63 (95% CI 0.39-1.01), p=0.055) figure( 2).

This study aimed to provide evidence that the guidelines for conducting CAG may contribute to equal access and optimal cost-effective treatment and may provide a framework for allocating resources as well investing in education of patients and professionals.

Catheterization labs have become the cornerstone in patients with symptomatic CAD. Naturally, a diagnosis found with CAG has to be followed by sensible treatment. Lucas et al. have underlined a linear and strong association between the rates of CAG and coronary revascularization, particularly for PCI. For CABG, the association was proved to be modest.13 Therefore, in the absence of on-site cardiac surgical facilities, a CAG and PCI program for CAD can still have a major impact.

In addition to our main questions to understand the effects (and potential barriers) of undergoing CAG on clinical outcomes, we also investigated the SYNTAX score in patients who underwent a CAG. The SYNTAX score is valuable for decision making and estimating prognosis depending on the treatment instigated: PCI,6,14-17 CABG,18 or optimal medical therapy (OMT).19 In our study, we found that patients who showed a high SYNTAX score were prone to higher rates of all-cause mortality and major adverse events compared with the lowest tertile group.

This study has some limitations. The sample size is relatively small. Despite this inherent limitation, we still detected a strong relation between CAG and patients’ outcomes both in uni- and multi- variable analyses. Second, we do realize that the SYNTAX score was primarily developed to rate the severity of CAD in view of eligibility for PCI or CABG. The follow-up methods are perhaps unusual by Western standards, but the best that can be achieved in an underprivileged area. However, this study shows the prognostic relevance of CAG and SYNTAX score, even in populations with poor resources. Last but not least, it could be considered unreasonable to focus on adherence to ACC/AHA or ESC (European Society of Cardiology) guidelines for CAG in Indonesia as these guidelines were developed

106 Adherence to coronary angiography recommendations and its impacts for application in generously-equipped healthcare systems. Once available, CAG facilities should be more often used to support disease management and decision-making.

CONCLUSIONS 6

In conclusion, adherence to guidelines on performing CAG in an underprivileged South-East Asian setting is still low. Undergoing CAG is associated with a significantly lower risk of short- and medium- term all-cause mortality. Older age, female gender, low educational level and low socio-economic status are associated with not undergoing CAG. Education for patients and their families, awareness of CVD symptoms, well-established teamwork amongst clinicians, and the infrastructure for invasive intervention should be improved to enhance the adherence to the guidelines standard.

NOTES

Ethics approval and consent to participate The study protocol has been approved by the Ethics Committee and Institutional Review Board of the Faculty of Medicine, University of Hasanuddin Makassar, Indonesia [Letter number 030/H4.8.4.5.31/ PP 36-KOMETIK/2013].

Acknowledgements The authors gratefully acknowledge all participants who enrolled in this cohort study. Patients’ family members and advisers are also acknowledged for their support and cooperation. We thank the staff of cardiovascular care unit (CVCU) Wahidin Sudirohusodo Hospital, Makassar for their contributions to the success of this research project and all research assistants for the data collection and data management. Special thanks for Mrs. Fithriany Harry S.Farm, Apt., all nurses, and nursing students in Puskesmas Batua (Batua Primary Healthcare Center) Makassar for their dedication to complete the study follow-up.

Funding This work was supported by Directorate General of Higher Education/Direktorat Jenderal Pendidikan Tinggi (DIKTI), Ministry of National Education Republic of Indonesia [grant number 600/E4.4/K/2011, 2011]. The study sponsor had no influence on the design of the study, analysis of data, interpretation of results or the decision to submit the manuscript for publication.

Competing interests The authors have no competing interests to declare.

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REFERENCES 1. Tavakol M, Ashraf S, Brener SJ. Risks and complications of coronary angiography: a comprehensive review. Glob J Health Sci 2012; 4: 65-93. 2. Scanlon PJ, Faxon DP, Audet A-M, Carabello B, Dehmer GJ, Eagle KA, et al. ACC/AHA Guidelines for Coronary Angiography: Executive Summary and Recommendations. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Coronary Angiography) Developed in collaboration with the Society for Cardiac Angiography and Interventions. Circulation 1999; 99: 2345- 2357. 3. Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Jr., Ganiats TG, Holmes DR, Jr., et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-segment Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 64: e139-228. 4. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016; 37: 267-315. 5. Sianos G, Morel MA, Kappetein AP, Morice MC, Colombo A, Dawkins K, et al. The SYNTAX Score: an angiographic tool grading the complexity of coronary artery disease. EuroInterv 2005; 1: 219-227. 6. Yıldız A, Yıldız C, Bağırtan B, Karakurt A. Prognostic value of anatomical SYNTAX score in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention for unprotected left main coronary artery. International Journal of the Cardiovascular Academy 2016; 2: 98-102. 7. Kumar A, Cannon CP. Acute Coronary Syndromes: Diagnosis and Management, Part I. Mayo Clin 2009; 84: 917-938. 8. Grech ED, Ramsdale DR. ABC of interventional cardiology, Acute coronary syndrome: unstable angina and non-ST segment elevation myocardial infarction. BMJ 2003; 326: 1259-1261. 9. Elbez Y, Cheong AP, Fassa A-A, Cohen E, Reid CM, Babarskiene R, et al. Clinical outcomes in patients with stable coronary artery disease with vs. without a history of myocardial revascularization. Eur Heart J Qual Care Clin Outcomes 2016; 2 (1): 23-32. 10. Pizzi C, Xhyheri B, Costa GM, Faustino M, Flacco ME, Gualano MR, et al. Nonobstructive Versus Obstructive Coronary Artery Disease in Acute Coronary Syndrome: A Meta- Analysis. J Am Heart Assoc 2016; 5. 11. Qanitha A, Uiterwaal CSPM, Henriques JPS, Alkatiri AH, Mappangara I, Mappahya AA, et al. Characteristics and the average 30-day and 6-month clinical outcomes of patients hospitalised with coronary artery disease in a poor South-East Asian setting: the first cohort from Makassar Cardiac Center, Indonesia. BMJ Open 2018; 8: e021996. 12. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35: 2541-2619. 13. Lucas FL, Siewers AE, Malenka DJ, Wennberg DE. Diagnostic-therapeutic cascade revisited: coronary angiography, coronary artery bypass graft surgery, and percutaneous coronary intervention in the modern era. Circulation 2008; 118: 2797-2802.

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14. Safarian H, Alidoosti M, Shafiee A, Salarifar M, Poorhosseini H, Nematipour E. The SYNTAX Score Can Predict Major Adverse Cardiac Events Following Percutaneous Coronary Intervention. Heart Views 2014; 15: 99-105. 15. Nozue T, Kamijima R, Iwaki T, Michishita I. Impact of SYNTAX score on 1-year clinical outcomes in patients undergoing percutaneous coronary intervention for unprotected 6 left main coronary artery. Am J Cardiovasc Dis 2012; 2: 216-222. 16. Girasis C, Garg S, Raber L, Sarno G, Morel MA, Garcia-Garcia HM, et al. SYNTAX score and Clinical SYNTAX score as predictors of very long-term clinical outcomes in patients undergoing percutaneous coronary interventions: a substudy of SIRolimus-eluting stent compared with pacliTAXel-eluting stent for coronary revascularization (SIRTAX) trial. Eur Heart J 2011; 32: 3115-3127. 17. Choudhary S. Association of syntax score with short-term outcomes among acute ST- segment elevation myocardial infarction patients undergoing primary PCI. Indian Heart J 2017; 69 Suppl 1: S20-S23. 18. Cho Y, Shimura S, Aki A, Furuya H, Okada K, Ueda T. The SYNTAX score is correlated with long-term outcomes of coronary artery bypass grafting for complex coronary artery lesions. Interact Cardiovasc Thorac Surg 2016; 23: 125-132. 19. Iqbal J, Zhang YJ, Holmes DR, Morice MC, Mack MJ, Kappetein AP, et al. Optimal medical therapy improves clinical outcomes in patients undergoing revascularization with percutaneous coronary intervention or coronary artery bypass grafting: insights from the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial at the 5-year follow-up. Circulation 2015; 131: 1269-1277.

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ABSTRACT

Objective After the first tele-ECG program had been initiated in East Indonesia, we aimed to assess the implementation of this program in primary care in a resource-poor setting and to investigate whether this tele-ECG consulting affects the short- and mid-term outcomes of the patients.

Methods Between January 2015 and February 2018, a total of 10,001 ECG recordings from primary care patients were transmitted to Makassar Cardiac Center, Hasanuddin University Hospital, Indonesia. For the purpose of this study, we prospectively collected data from January to June 2017 by sending a detailed questionnaire to the general practitioners (GPs) at primary care centers. A total of 505 patients with a cardiovascular symptom and/or risk factor, or for check-up purpose, were included in our study population. The follow-up was performed at 30 days after ECG assessment and at the end of study period, until October 2018. We tabulated the adverse outcomes (cardiovascular mortality and hospitalization) between referral (abnormal ECG) vs. non-referral (normal and abnormal ECG) groups.

Results Of the total ECG recordings (n=10,001), all (100%) ECGs were eligible for analysis, and ~73% showed normal findings. Ischemia presented in 13%, arrhythmia in 18%, and abnormalities compatible with structural changes in 5%. In our study population (n=505), factors that significantly associated with a normal ECG were: younger age, female gender, lower blood pressure and heart rate, and no history of previous cardiovascular disease or medications. More patients with abnormal ECG had a previous hypertension, known diabetes, and were current smokers (p<0.05). Half of the participants (n=254) had hypertension: 22% were unaware and 33% untreated. More female patients with angina showed a normal ECG (p=0.01), while men were prone to have an ischemic ECG (p<0.01). The majority (95%) of GPs were satisfied for each tele-ECG consultation. Of 88 patients who were advised for admission, 72 (81.8%) were referred to the hospital within 48 hours following the ECG consultation. Over the total follow-up (14 ± 6.6 months), seven (1.4%) patients died and 96 (19.0% - 72 due to advice) were hospitalized due to CVD. After 30 days, no significant differences on experiencing adverse cardiovascular events between referral and non-referral groups (4.5% vs. 4.1%) existed.

Conclusion Despite a shortage of cardiologists and resources, tele-ECG is helpful to support primary care GPs to make a quick decision for referring patients to the further specialized treatment. Tele-ECG consulting is associated with a higher rate of early hospitalization for indicated patients, but have no impact on medium-term mortality and admission.

Keywords Electrocardiogram, tele-ECG, low- and middle-income country, quality of care, cardiovascular deaths, adverse outcomes

114 Tele-ECG consulting and outcomes on primary care patients

INTRODUCTION

To date, telemedicine appears to be a popular tool to overcome geographical barriers and increase access to healthcare services. This particularly benefits the rural and underserved populations in 7 low- and middle-income countries (LMICs) – groups that traditionally suffer from lack of access to healthcare.1 WHO has defined telemedicine as delivery of healthcare services, where distance is a critical factor, using information and communication technologies (ICT) for the exchange of valid information for diagnosis, treatment, and prevention of disease, research, and evaluation.1

Indonesia is the worlds’ largest archipelago and the most populated nation in South-East Asia; consists of 17,508 islands with >260 million populations.2 More than half of Indonesian populations live in Java, with the rest distributed unevenly across ~6,000 islands.2,3 Of these populations, >10% live in poverty.4 Cardiovascular disease (CVD) is the leading cause of death in this lower middle-income country, responsible for ~37% of total deaths.4 Premature deaths from coronary artery disease (CAD), stroke, and diabetes are significantly higher in Indonesia compared with neighboring countries.4 The latest analyses of the Global Burden Disease (GBD) in 2016 reported that these diseases are also the top three causes of DALYs (disability-adjusted life-years) in Indonesia.2 Despite the high burden of CVD in this nation, only 1.5 cardiologists are available per 1,000,000 populations in 2016,4 and ~30 cardiac centers (half are located in Java) provided to serve >2.6 million prevalent cases of CAD in 2013.5,6

In view of the shortage of cardiologists and evident demand for expertise in cardiovascular care, Makassar Cardiac Center has initiated the first telemedicine project in eastern Indonesia – transferring the electrocardiogram (ECG) recordings from primary care facilities to an expertise center in Hasanuddin University Hospital. This project entails decision support for the primary care GPs when confronted with patients with CVD complaints or risk factors. Although the implementation of telemedicine program has been started in Indonesia in 2012, reporting on the performance and outcomes of the program remains less explored.

We aimed to study in detail the implementation of tele-ECG program in a South-East Asian population with low resources, and to assess the patients’ outcomes in relation with decision-making assisted by this tele-ECG consulting. To this end, we conducted a population-based cohort study in patients with CVD symptoms and/or risk factors at primary care centers in Makassar, Indonesia.

METHODS

In the initiation of this telemedicine program, Makassar Cardiac Center in collaboration with the local Government of Makassar City provided one digital ECG machine for each primary care center in 2015. At the initiation between August 2015 and February 2018, the 12-lead ECG recordings from 46 (100%) primary care centers and 2 private clinics were transmitted to Hasanuddin University Hospital. Distribution of all primary care centers in the city of Makassar participated in this tele-ECG program is depicted in figure 1.

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Figure 1. City of Makassar with its Districts (199.3 km2): Primary care centers (Puskesmas) covered by Makassar Telemedicine Service

Study population For the purpose of this study, we prospectively collected data by sending a detailed questionnaire to 46 primary care centers (known as Pusat Kesehatan Masyarakat or Puskesmas) from January to June 2017. The GPs completed the questionnaire based on the patient medical records and questionnaire interview. From thirty primary care centers, we included a total of 505 patients in our study population. We described the flowchart of this study population in figure 2.

Patients were eligible for ECG assessment if they presented at primary care facilities with a cardiovascular symptom and/or risk factor, or healthy subjects or patients with other disease who were willing to have an ECG examination. In case the GPs considered urgent referral or admission necessary, the patient was referred directly to the secondary/tertiary hospital without any delay, and therefore this group of patients excluded for the tele-ECG consulting. Informed consent was obtained from all participants. The Ethics Committee and Institutional Review Board of the Faculty of Medicine, University of Hasanuddin, Makassar approved the protocol of this study.

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7

Figure 2. Flowchart of the study population ECG: electrocardiogram; Puskesmas: Pusat Kesehatan Masyarakat; GP: General Practitioner.

Data collection and measurements A detailed questionnaire was designed to obtain data on socio-demographic, clinical profile (i.e. symptom, onset, prior disease, prior medication, anthropometric status, vital signs, and cardiovascular risk factors: hypertension, diabetes mellitus, current smoking, and family history of CVD), management and medications after tele-ECG, and GP’s reason and satisfaction for the tele-ECG consulting.

Vital signs (i.e. blood pressure, heart rate, respiration rate, and axillary temperature), anthropometric, standard physical examination, and ECG assessment were performed in all participants. During consultation, GP measured the blood pressure twice while participants were in seated position after 5 minutes of rest, using a manual mercury sphygmomanometer. The mean of these two readings was used in data analysis. Participants were advised to avoid cigarette smoking and exercise for at least 30 minutes before measurement. Body weight, height, and waist circumference were measured

117 Chapter 7 manually. Weight was measured in light indoor without shoes and heavy accessories. No laboratory measurements (e.g. fasting plasma glucose, lipid profiles, and creatinine) were performed, as these measurements are mostly not available at primary care level.

ECG examination was performed by the trained primary care nurses using an automated ECG machine, BTL-08 SD ECG (BTL Industries Ltd, Hertfordshire, United Kingdom). The ECG files were sent through the Internet to the analysis service center at Hasanuddin University Hospital, and saved in the hospital database. Two cardiologists reviewed and analyzed all the ECG recordings.

Definitions and classification CVD symptom was defined as mild-to-moderate chest pain (angina), short of breath (dyspnea), palpitation, heartburn (epigastric pain), lightheadedness (dizziness) or headache, and syncope. While hypertension, diabetes mellitus, current smoking, family history of CVD, and obesity were categorized as the risk factors. Obesity was defined as having a body mass index (BMI) ≥25 kg/m2 based on the cut-off for Asian populations. For smoking status, we combined the standard National Health Interview Survey (NHIS) and the standard National Survey on Drug Use and Health (NSDUH-S). Current smoking was defined as a participant who had smoked at least 100 cigarettes in their lifetime and had smoked in the last 30 days.7 A positive family history of CVD was defined as ≥1 first degree and/or ≥2 second-degree family members with CVD before the age of 55 years in men and 65 years in women.8-10

Hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg,11 or being on medication for hypertension. Type 2 diabetes mellitus (DM) was defined positive if participant had a known type 2 DM, or was on medication for type 2 DM. Lastly, participants were categorized into low-to-middle income socio-economic status, if they were unemployed or employed with monthly income ≤Rp.1,800,000 and use BPJS (the Healthcare and Social Security) insurance.

We classified the participants based on their ECG findings into normal and abnormal ECG. We used a hierarchical manner to determine the classification of the ECG patterns. The order of the categorization was: ischemia, arrhythmia, structural change, and others, respectively. Managements after tele-ECG were classified as: referral to the hospital, outpatient without any medications, and outpatient with cardiovascular medications for primary or secondary prevention.

ECG assessment and referral ECG sent to the service center were analyzed every day, and a diagnosis and advice was sent back to the GPs. The advice for referral was based on the ECG finding and the severity of the symptoms presented. Patients were referred if they had a marked CVD symptom and ECG showed an abnormal finding. Mainly, the primary care GPs and the cardiologists set the criteria for referral: patients with angina and ischemic ECG, patients with dyspnea and ischemic or structural-related ECG, and patients with palpitation/syncope/other symptoms with arrhythmic ECG. In case of criteria were met or doubt ECG, the advice was to refer the patient to the hospital with the cardiovascular care facilities. GPs made the final decision on the urgency of the referral based on their own assessment. Once referred, the patient came under the responsibility of the cardiologists for diagnostic work-up and treatment.

118 Tele-ECG consulting and outcomes on primary care patients

Follow-up and outcomes of the study population After ECG assessment, we followed the patients and measured the adverse outcomes (i.e. cardiovascular death and hospitalization) at 30 days and at the end of study period, until 30 October 2018. Primary care nurses, cadres, and research assistants performed the follow-up by obtaining data 7 from the primary care medical records, or through telephone calls or home visits. None of participants was lost-to-follow-up.

Statistical analysis For continuous variables, means ± standard deviations (SD) were calculated, while categorical variables were expressed as proportion (percentage). Median (Q1-Q3) was used for the skewed data. Differences in continuous variables were estimated using t-test for independent samples or Mann- Whitney U test. Proportions were compared using Pearson’s Chi square or Fisher’s Exact tests. Baseline and clinical profiles, CVD symptom and risk factors, management at primary care, and GP’s reason and satisfaction on tele-ECG were presented according to the ECG conclusion (normal vs. abnormal ECG). The rates of cardiovascular death and hospitalization at 30 days and >30 days until the end of follow-up were compared between referral (abnormal ECG) vs. non-referral (normal and abnormal ECG) groups. A two-tailed p-value <0.05 was considered statistically significant. Data management and statistical computation were performed with IBM SPSS Ver. 23 for Mac.

RESULTS

From 2015 to 2018, a total of 10,001 ECG recordings were received in the analysis center of the telemedicine program, Hasanuddin University Hospital. Of all ECG recordings, 100% were qualified for analysis. From the total ECG recordings, 72.6% were categorized as normal. After ECG classification, ischemia was found in 12.6%, arrhythmia in 18.4%, and abnormalities related to structural changes in 5.4%. Interpretation and distribution of the total ECG recordings from Makassar Telemedicine Program is shown in table 1.

In our study population (n = 505), the mean age of participants was 53.3 ± 13.6 years, and 203 (40.2%) were male. We classified and divided 253 (50.1%) participants in normal, and 252 (49.9%) in abnormal ECG groups. In table 2, we present the baseline and clinical profiles of the study population according to ECG classification. Patients with normal ECG were significantly younger, majority were female, had lower systolic and diastolic blood pressure, had lower heart rate, and less with prior CVD and cardiovascular medications compared to those with abnormal ECG. The majority (82.0%) of participants were coming from the low- and middle-socio-economic status. Men were prone to have an ischemic ECG compared to women (p<0.01); while older age (>55 years) was associated with an abnormal ECG, mainly showed an ischemic or arrhythmic pattern (p<0.05) (figure 3).

We show in detail the CVD symptoms and risk factors suffered by the participants intable 3. More female patients with chest pain had a normal ECG (p=0.01). Meanwhile, longer duration of angina and marked dyspnea was associated with an abnormal ECG (p<0.05). There were more patients with abnormal ECG had prior hypertension, known diabetes, and were current smokers (p<0.05). Half of the participants (254, 50.3%) had hypertension, and 171 (67.3%) were on medication. Of all participants, 42.4% were obese.

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Table 1. Total ECG recordings (n = 10,001) Interpretation of ECG recordings from Makassar Telemedicine Service

Total Classification ECG patterns* (n = 10,001)

Normal ECG Normal sinus rhythm 7265 (72.6) ST-elevation myocardial infarction 98 (1.0) Old myocardial infarction 548 (5.5) Ischemia ST and/or T wave changes suggestive for MI 509 (5.1) Non-specific ST and/or T wave changes 99 (1.0) Sinus bradycardia 892 (8.9) Sinus tachycardia 393 (3.9) Supraventricular tachycardia 11 (0.1) Atrial fibrillation 110 (1.1) Atrial flutter 9 (0.1) Arrhythmia Atrial premature complexes 94 (0.9) Ventricular premature complexes 105 (1.0) Sino-atrial block 6 (0.1) Atrio-ventricular block 49 (0.5) Right bundle branch block 160 (1.6) Left bundle branch block 21 (0.2) Left atrial enlargement 45 (0.5) Right atrial enlargement 48 (0.5) Structural change Left ventricular hypertrophy 418 (4.2) Right ventricular hypertrophy 23 (0.2) Early repolarization 72 (0.7) Left axis deviation 184 (1.8) Others Right axis deviation 128 (1.3) Hyper/hypokalemia 37 (0.4) Values are n (%). *More than one ECG diagnoses per patient are possible. ECG: electrocardiogram; MI: myocardial infarction.

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7 Table 2. Study population (n= 505) Baseline and clinical characteristics of the study population according to ECG findings

ECG Normal ECG Abnormal Total Variables p-value (n = 253) (n = 252) (n= 505) Age (years) 50.7 ± 14.1 6.0 ± 12.6 53.3 ± 13.6 <0.001 Male sex 85 (33.6) 118 (46.8) 203 (40.2) 0.002 Systolic BP (mmHg) 124.7 ±15.6 136.2 ± 22.2 130.4 ± 20.0 <0.001 Diastolic BP (mmHg) 79.5 ± 8.2 82.5 ± 9.4 81.0 ± 8.9 <0.001 Heart rate (bpm) 77.9 ± 9.5 83.5 ± 16.9 80.7 ± 14.0 <0.001 BMI (kg/m2)a 24.2 (21.8-26.7) 24.1 (21.4-27.2) 24.2 (21.6-26.9) 0.788 Low-to-middle SES 213 (84.2) 201 (79.8) 414 (82.0) 0.196 Previous Diseases: Cardiovascular diseaseb 2 (0.8) 8 (3.2) 10 (2.0) <0.001 COPDb 5 (2.0) 2 (0.8) 7 (1.4) 0.055 Previous Medications: Anti-hypertension 61 (24.1) 110 (43.7) 171 (33.9) <0.001 Anti-diabetic 14 (5.5) 29 (11.5) 43 (8.5) 0.016 Anti-cholesterol 9 (3.6) 19 (7.5) 28 (5.5) 0.051 Anti-platelet 1 (0.4) 11 (4.4) 12 (2.4) 0.003 Anti-arrhythmiab 0 (0.0) 2 (0.8) 2 (0.4) 0.249 Values are n (%) or means ± SD, unless otherwise stated. Comparison was performed using independent- samples t-test for continuous variables and Pearson Chi-square test for categorical variables. aValues are medians (Q1-Q3). Comparison was done using Mann-Whitney U test. bComparison was performed using Fisher’s Exact test. ECG: electrocardiogram; BP: blood pressure; bpm: beat per minute; BMI: body mass index; SES: socio- economic status; COPD: chronic obstructive pulmonary disease.

The profile of the study population and advice for referral according to ECG findings were described in table 4. Overall, 79 (15.6%) patients were categorized as ischemia, 119 (23.6%) as arrhythmia, and 26 (5.1%) was related to structural changes. Majority of participants (73.9%) presented at primary care with a CVD symptom and at least one risk factor, 95 (18.8%) presented with symptoms only, 24 (4.8%) were asymptomatic with at least one risk factor, and 13 (2.6%) had neither CVD symptom nor risk factor, purposely had an ECG assessment for a general check-up. Majority (79.5%) of patients who were advised for referral presented with an ischemic ECG (figure 3).

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Figure 3. Distribution of ECG findings in the study population, according to age, gender, and advised for referral *p<0.05; **p<0.01; ***p<0.001

122 Tele-ECG consulting and outcomes on primary care patients

Table 3. CVD symptoms and risk factors of the study population based on ECG findings

Variablesa ECG Normal ECG Abnormal Total p-value (n = 253) (n = 252) (n= 505) CVD Symptoms: 7 Chest pain 164 (64.8) 153 (60.7) 317 (62.8) 0.340 ≥15 minutes 17 (6.7) 30 (11.9) 47 (9.3) 0.045 Female sex 105 (64.0) 76 (49.7) 181 (57.1) 0.010 Heartburn 19 (7.5) 14 (5.6) 33 (6.5) 0.374 Dyspnea 27 (10.7) 54 (21.4) 81 (16.0) 0.001 Palpitation 24 (9.5) 38 (15.1) 62 (12.3) 0.055 Syncopeb 0 (0.0) 1 (0.4) 1 (0.2) 0.499 Dizziness/headache 20 (7.9) 24 (9.5) 44 (8.7) 0.519 Recurrent symptoms 64 (25.3) 78 (31.0) 142 (28.1) 0.157 CVD Risk Factors: Hypertension 99 (39.1) 155 (61.5) 254 (50.3) <0.001 Known diabetes 15 (5.9) 29 (11.5) 44 (8.7) 0.026 Current smoking 37 (14.6) 70 (27.8) 107 (21.2) <0.001 Sticks/day 10 ± 7 12 ± 6 11 ± 6 0.147 Family CVD 15 (5.9) 12 (4.8) 27 (5.3) 0.067 Obese (BMI ≥25) 106 (41.9) 108 (42.9) 214 (42.4) 0.827

Values are n (%) or means ± SD, unless otherwise stated. Comparison was performed using independent- samples t-test for continuous variables and Pearson Chi-square test for categorical variables. aMore than one symptoms and/or risk factors are possible. bComparison was performed using Fisher’s Exact test. ECG: electrocardiogram; CVD: cardiovascular disease.

Table 4. Patient profiles and advice for referral

ECG Abnormal* ECG Patient Advice for Normal Ischemia Arrhythmia Structure Others p-value profiles Referral (n = 253) (n = 79) (n = 119) (n = 26) (n = 28) (n = 88) Symptom only 55 (21.7) 21(26.6) 21 (17.6) 6 (23.1) 5 (17.9) 9 (10.2) 0.218 Symptom (+), 119 (47.0) 21 (26.6) 57 (47.9) 8 (30.8) 11 (39.3) 27 (30.7) 0.010 1 risk factor Symptom (+), 51 (20.2) 46 (58.2) 57 (47.9) 8 (30.8) 11 (39.3) 48 (54.5) <0.001 >1 risk factors Risk factors only 18 (7.1) 3 (3.8) 1 (0.8) 1 (3.8) 1 (3.6) 3 (3.4) 0.115 Check-up (no 10 (4.0) 1 (1.3) 1 (0.8) 0 (0.0) 1 (3.6) 1 (1.1) 0.322 symptom, no risk factors) Values are n (%). Comparison was performed using Pearson Chi-square test. *Categorization based on dominated pattern presented on ECG. ECG: electrocardiogram.

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Table 5 presents the GP reason, satisfaction, and management after tele-ECG consultation. Majority of the GPs made a consultation through tele-ECG for second opinion (58.6%) and because of the manifested (moderate) CVD symptoms (38.0%). Overall, 154 (30.5%) were observed for primary/ secondary prevention at primary care and received adequate medications; and 263 (52.1%) were sent home without any medications. Medications in normal and abnormal ECG groups are equal: 27.7% vs. 33.3%, respectively (p=0.167). Most (95%) of the GPs were satisfied for each tele-ECG consulting.

Table 5. Reason, management, and satisfaction on tele-ECG consulting

ECG ECG Total Variables Normal Abnormal p-value (n= 505) (n = 253) (n = 252) GP’s reason for tele-ECG: Manifested CVD symptoms 76 (30.0) 116 (46.0) 192 (38.0) <0.001 Unable to interpret the ECG 2 (0.8) 12 (4.8) 14 (2.8) 0.007 Second opinion 175 (69.2) 121 (48.0) 296 (58.6) <0.001 Othersa 0 (0.0) 3 (1.2) 3 (0.6) 0.124 Management after tele-ECG: Refer to hospital 0 (0.0) 88 (34.9) 88 (17.4) <0.001 Outpatient without medications 183 (72.3) 80 (31.7) 263 (52.1) <0.001 Outpatient with new/continued medications 70 (27.7) 84 (33.3) 154 (30.5) 0.167 Medications at primary care: Aspirin 2 (0.8) 49 (19.4) 51 (10.1) <0.001 Clopidogrela 0 (0.0) 8 (3.2) 8 (1.6) 0.004 Beta blockera 0 (0.0) 8 (3.2) 8 (1.6) 0.004 Calcium-channel blocker 53 (20.9) 95 (37.7) 148 (29.3) <0.001 ACE inhibitor 7 (2.8) 54 (21.4) 61 (12.1) <0.001 Angiotensin receptor blocker 4 (1.6) 10 (4.0) 14 (2.8) 0.102 Diuretic 0 (0.0) 17 (6.7) 17 (3.4) <0.001 Nitrate 13 (5.1) 47 (18.7) 60 (11.9) <0.001 Lipid-lowering agents 8 (3.2) 39 (15.5) 47 (9.3) <0.001 GP’s satisfaction for tele-ECG: Yes 232 (91.7) 247 (98.0) 479 (94.9) 0.001 Unknown or in doubt 18 (7.1) 5 (2.0) 23 (4.6) 0.006

Values are n (%). Comparison was performed using Pearson Chi-square test. aComparison using Fisher’s Exact test. ECG: electrocardiogram; CVD: cardiovascular disease.

124 Tele-ECG consulting and outcomes on primary care patients

Table 6. Major adverse cardiovascular events between normal vs. abnormal ECG groups

Referral with Non-referral Adverse Outcomes abnormal ECG Abnormal ECG Normal ECG p-value 7 (n = 88) (n = 164) (n = 253) ≤ 30 days CVD death 0 (0.0) 0 (0.0) 1 (0.4) 1.000 CVD hospitalization 75 (85.2) 6 (3.7) 0 (0.0) <0.001 48-hours admission 72 (81.8) 5 (3.0) 0 (0.0) <0.001 Total 75 (85.2) 6 (3.7) 1 (0.4) <0.001 > 30 days CVD death 2 (2.3) 3 (1.8) 1 (0.4) 0.245 CVD hospitalization 2 (2.3) 6 (3.7) 7 (2.8) 0.797 Total 4 (4.5) 9 (5.5) 8 (3.2) 0.499

Values are n (%) or means ± SD, unless otherwise stated. Comparison was performed using independent- samples t-test for continuous variables and Pearson Chi-square test for categorical variables. aMore than one symptoms and/or risk factors are possible. bComparison was performed using Fisher’s Exact test. ECG = electrocardiogram; CVD = cardiovascular disease; min. = minutes.

Over the whole follow-up (14 ± 6.6 months), seven (1.4%) patients died and 96 (19.0%) were admitted to hospital for CVD. Table 6 compares the adverse outcomes between referral (abnormal ECG) and non-referral (normal and abnormal ECG) groups. At the first 30 days, tele-ECG consulting was associated with the higher rate of an early hospital admission. Of 88 patients who were advised for referral, 72 (81.8%) were sent to the hospital within 48 hours after the consultation. Over the 30 days, there were no significant differences between the referral and non-referral groups in terms of the mid-term cardiovascular death and hospitalization. In the non-referral and normal ECG group, 9 (3.6%) adverse cardiovascular events occurred during the total study period.

DISCUSSION

This study shows that tele-ECG consulting was helpful to support the primary care GPs on making a quick decision for patients’ management. Of 10,001 ECG screenings transmitted to the analysis center, 100% were qualified for analysis. In our study population (n = 505), 88 (17.4%) participants were advised for referral based on their evident symptom and abnormal ECG. Of those, 72 (81.8%) had CVD hospitalization within 48 hours after the consultation. Most of the GPs (~95%) were satisfied for the each tele-ECG consulting. Despite the high-risk profile, 31% of patients received adequate medications and planned for long-term primary/secondary prevention. Over the total follow up (14 ± 6.6 months), seven (1.4%) patients died and 96 (19.0%) were hospitalized for CVD. Within 30 days, the tele-ECG consulting was associated with a higher rate of an early hospital admission (≤ 48 hours); while at >30 days, we found no significant differences between the referral and non-referral groups

125 Chapter 7 regarding the medium-term cardiovascular death and hospitalization. In the non-referral group, 7 (1.7%) adverse outcomes occurred within 30 days, and 17 (4.1%) occurred over 30 days after the ECG assessment.

From our analyses, we found that patients with normal ECG were predominantly female, younger, showed better clinical profiles, and with less CVD risk factors compared to those with abnormal ECG. Men were significantly prone to have an ischemic ECG compared to women; while older age was susceptible to have an ischemic or arrhythmic ECG compared with the younger ages. In this study, majority (80%) of our referral patients presented with moderate chest pain and suspected with ischemic heart disease.

Half of the participants in this study suffered from hypertension: 22% were unaware and 33% untreated. The National Survey 2013 reported that 62% of hypertension cases in Indonesian general population was undiagnosed.6 Previous review also reported that >50% of the study participants with hypertension in Indonesia were unaware and untreated.4 Our study population, the primary care patients with a manifested CVD symptom and/or risk factor, may explain the lower number of unaware and untreated cases. However, these numbers are still higher compared with the 16% unaware and 7% untreated hypertension cases in patients with stroke recently studied in China.12,13 Another report is that overtreatment appears to be detected in 0.1% population in Indonesia where medication privately consumed without diagnosis in healthcare facilities.6

A large proportion of the population in Indonesia is estimated to have undiagnosed diabetes; and often the first detection of diabetes is presented with secondary complications.4 Nevertheless, currently, the standard screening and detection for diabetes mellitus and dyslipidemia (i.e. fasting plasma glucose and lipid profiles) are mostly unavailable at primary care services in this country. In our study, there was ~9% of participants had known diabetes. We inferred that there were more undetected or undiagnosed diabetes cases in this study population, considering the high-risk profile. Standard screening for CVD risk factors should be always available and affordable at primary care level.

From the present study, we observed more female patients presented with chest pain, yet showed a normal ECG. Numerous evidence have indicated that women are more likely to present with the complaint of chest pain – often have recurrent symptom and re-admission – compared to men.14 However, CAD occurs more frequently in men.14 Another study also indicated that women scored the intensity of their chest pain significantly higher than men.15 Non-CAD related angina is commonly associated with persistent chest pain, causing poor function, quality of life, and re-admission.14 Therefore, one should keep in mind in women with normal ECG, is that, if the symptom was moderate and often recurrent, the angina should be not undervalued. Microvascular dysfunction, coronary artery spasm, coronary artery dissection, and myocardial bridging are the common causes of chest pain in women present in Emergency Department (ED).14 These underlying patho-mechanisms could be undetectable only with a one-time point resting ECG assessment. Women are more vulnerable to longer admission, slower diagnosis, and inadequate treatment.16 Previous studies suggested that coronary angiography is used less often in women, largely because their risk is underestimated.16 Women described an atypical clinical feature of chest pain significantly different with men. Often, women complain concomitant atypical symptoms (e.g. heartburn to epigastric pain, unusual fatigue,

126 Tele-ECG consulting and outcomes on primary care patients dizziness, feeling of doom, and generalized weakness),14 and make the direction to CVD is even more vague. Symptomatic patients with normal ECG findings, however, are often reassured with their diagnosis 7 and a favorable prognosis, but received no specific prevention management, although they have an increased risk for CVD events. Despite the high-risk profiles, 52% of our study population received no medications at all.

In total ECG recordings (n=10,001), 73% of ECG recordings were found to be normal. While the top three abnormalities were sinus bradycardia (9%), old myocardial infarction (6%) and ST-T wave changes suggestive for myocardial ischemia (5%). Our findings were comparable with a previous tele- ECG study in a rural Indian population.17 In their study, Singh et al. showed that ECG was interpreted as normal in 70% individuals; with left ventricle hypertrophy (9%) and old myocardial infarction (5%) were the common abnormalities. Patients’ satisfaction was ~95%; in our study, most of primary care GPs were found to be satisfied for the tele-ECG consulting in 95%.

In the present study, we focused on a qualitative interpretation of the tele-ECG performance, and conducted an in-depth case analyses of all deaths and hospitalizations observed at the first 30 days and >30 days after tele-ECG advice. Based on their risk profile and clinical history, we obtained a reasonable picture regarding the quality of care and the impact of the tele-ECG consulting. In the group with abnormal ECG and no advice for referral, six (3.7%) patients had been hospitalized for CVD within 30 days; while three (1.8%) patients died and 6 (3.7%) were admitted to hospital after the 30 days. In the normal ECG and non-referral group, two (0.8%) patients died due to uncontrolled diabetes and heart failure; while 7 (2.8%) were admitted to hospital over the total follow-up. This indicated that the criteria for referral should be revised, and patients with recurrent and marked cardiovascular symptoms should be treated with caution despite a normal ECG presentation.

In mid-term follow-up, there were no significant differences between patients with referral (abnormal ECG) and those with no advice for referral (abnormal and normal ECG) pertaining the cardiovascular death and admission. We can assume that: (1) the low rate of cardiovascular mortality in the abnormal ECG group indicated a favorable impact of the early hospitalization, based on the tele-ECG advice; (2) the higher rate of CVD hospitalization in the group of normal ECG, indicated that those patients could have undetectable and uncontrolled cardiovascular risk factors, particularly because of the standard screening for diabetes and dyslipidemia are mostly not available in primary care centers in Indonesia; and (3) the lower rate of mid-term CVD hospitalization implied the well-controlled or prevention of CVD risk factors in the referral group.

While low- and middle-income countries are more likely to consider resource barriers such as high costs, underdeveloped infrastructure, and lack of technical expertise to tackle telemedicine, high-income countries are more likely to consider legal issues surrounding patients privacy and confidentiality, competing health priorities, and perceived lack of demand to be barriers in telemedicine implementation.1 However, the succession of the Makassar Telemedicine Program has shown that implementation of telemedicine (e.g. tele-ECG) in a low resource setting is considerably feasible and beneficial in the context of patients’ detection and selection for referral.

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To our knowledge, the present study is among the first to explore the implementation of telemedicine program in Indonesia, and relate the programs’ performance with the patients’ outcomes. During the follow up, we had to challenge with the unorganized and incomplete patients’ data at primary care centers (Puskesmas). Follow-up should be far easier if all Puskesmas have standardized and reliable medical records. In the future, primary care records should be available as an electronic database to ease the integration and communication with the hospitals. Secondly, patient and doctor engagement and a long-term planning for primary or secondary prevention should be managed better. One patient should have one permanent record for all controls and consultations. Thirdly, patients who were eligible and willing to participate in a research study should provide a copy of an official ID card (e.g. residence permit or Kartu Tanda Penduduk (KTP) or driver license (Surat Ijin Mengemudi (SIM)), thus, follow-up and data acquisition from hospital could be performed efficiently. This study has some potential limitations. Firstly, due to low resources, we could not collect data and follow all participants in this cohort. In the large cohort, there were more healthy subjects with routine health check-up at primary care facilities (Puskesmas and laboratory clinics) were included. Considering our main purpose of studying the performance of tele-ECG consulting in patients, we randomly selected the participants only from Puskesmas. However, we believed that a sample of 505 participants representatively described the total cohort in this study. Distribution and comparison of characteristics of our study population (total cohort and sample) are tabulated as supplement (table S1). Secondly, we assumed there were more patients with diabetes remain undiagnosed and undetected in our study population, which might underestimate the rate of CVD risk factors in this study. The CVD risk profiles could even worse than we observed. This limitation, however, is unlikely to bias our main results. We suggest that Indonesian Government should be more serious in combating CVD risk factors burden in this country. Detection and screening of diabetes and dyslipidemia should be available and affordable at primary care level considering that atherosclerotic CVD and diabetes are the leading causes of mortality and morbidity in Indonesia.2,4 Thirdly, The effectiveness of the program can only be estimated, as data collection does not allow for reliable calculation of false- negative and false-positive ratios. Lastly, one has to be aware of the fact that healthcare resources are limited; and therefore, funding of study to monitor the effectiveness of the telemedicine program are also limited. Consequently, robust quantitative data collection and analysis can only be performed in limited manner.

In conclusion, in a less developed country, tele-ECG is indeed helpful for primary care GPs to make a quick decision in terms of patient management, based on the expertise advice. Tele-ECG consulting is associated with a higher rate of early hospitalization for indicated patients, but has no significant impact on medium-term mortality and hospitalization.

128 Tele-ECG consulting and outcomes on primary care patients

NOTES

Acknowledgements Idar Mappangara is the principal investigator of this Tele-ECG program (Makassar Telemedicine 7 Project). The authors gratefully acknowledge all participants in primary care centers in Makassar for their willingness to be participated in this cohort study. Patients’ family members and advisers are also acknowledged for their support and cooperation. We thank the local Government of Makassar City for their support on implementing Tele-ECG in Makassar. The staff and trainees of Makassar Cardiac Center (Pusat Jantung Terpadu Makassar) are also acknowledged for their contributions to the success of this telemedicine project. We thank all research assistants, primary care nurses, cadres and staff for the data collection and data management. Special thanks for Mrs. Fithriany Harry S.Farm, Apt. nurses, and nursing students in Puskesmas Batua (Batua Primary Healthcare Center) Makassar for their dedication to complete the study follow-up.

Conflict of interest None declared.

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REFERENCES 1. World Health Organization. Telemedicine - Opportunities and development in Member States: Report on the second global survey on eHealth (Global Observatory for eHealth series - Volume 2). Geneva2010. 2. Mboi N, Murty Surbakti I, Trihandini I, Elyazar I, Houston Smith K, Bahjuri Ali P, et al. On the road to universal health care in Indonesia, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet 2018; 392: 581-591. 3. R. Offline: Indonesia—unravelling the mystery of a nation. The Lancet 2016; 387: 830. 4. Cardiovascular Division & Health Services Research Center. Reducing the burden of CVD in Indonesia: Evidence Review. Newtown: The George Institute for Global Health, 2017. 5. Pusat Data dan Informasi Kementerian Kesehatan Republik Indonesia. Situasi Kesehatan Jantung-Info DATIN. 2014. 6. Ministry of Health of Republic of Indonesia. Basic Health Research - RISKESDAS 2013. In: National Institute of Health Research and Development. Jakarta,2013. 7. Ryan H, Trosclair A, Gfroerer J. Adult current smoking: differences in definitions and prevalence estimates-NHIS and NSDUH, 2008. J Environ Public Health 2012; 2012: 918368. 8. Mulders TA, Meyer Z, van der Donk C, Kroon AA, Ferreira I, Stehouwer CD, et al. Patients with premature cardiovascular disease and a positive family history for cardiovascular disease are prone to recurrent events. Int J Cardiol 2011; 153: 64-67. 9. Lloyd-Jones DM, Nam B, D’Agostino RB, Levy D, Murabito JM, Wang TJ, et al. Parental Cardiovascular Disease as a Risk Factor for Cardiovascular Disease in Middle-aged Adults: A Prospective Study of Parents and Offspring. JAMA 2004; 291: 2204-2211. 10. Nasir K, Budoff MJ, Wong ND, Scheuner M, Herrington D, Arnett DK, et al. Family history of premature coronary heart disease and coronary artery calcification: Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2007; 116: 619-626. 11. Narkiewwicz K, Redon J, Zanchetti A, The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). ESC Essential Mesages. 2013 ESH/ESC Guidlines for the management of arterial hypertension. Eur Heart J 2013; 34: 2159-2219. 12. Cao Q, Pei P, Zhang J, Naylor J, Fan X, Cai B, et al. Hypertension unawareness among Chinese patients with first-ever stroke. BMC Public Health 2016; 16: 170. 13. Han TS, Wang HH, Wei L, Pan Y, Ma Y, Wang Y, et al. Impacts of undetected and inadequately treated hypertension on incident stroke in China. BMJ Open 2017; 7: e016581. 14. Safdar B, D’Onofrio G. Women and Chest Pain: Recognizing the Different Faces of Angina in the Emergency Department. Yale Journal of Biology and Medicine 2016; 89: 227-238. 15. Granot M, Goldstein-Ferber S, Azzam ZS. Gender differences in the perception of chest pain. J Pain Symptom Manage 2004; 27: 149-155. 16. Mehta LS, Beckie TM, DeVon HA, Grines CL, Krumholz HM, Johnson MN, et al. Acute Myocardial Infarction in Women: A Scientific Statement From the American Heart Association. Circulation 2016; 133: 916-947. 17. Singh M, Agarwal A, Sinha V, Manoj Kumar R, Jaiswal N, Jindal I, et al. Application of Handheld Tele-ECG for Health Care Delivery in Rural India. Int J Telemed Appl 2014; 2014: 981806.

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SUPPLEMENT

Supplementary figures

Figure S1. Distribution of ECG abnormalities in all recordings (n = 10,001), based on gender and age *p<0.05

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(a)

(b) Figure S2. Implementation of tele-ECG consulting at primary care in Makassar (a); and ECG transmission through Makassar Medical System (MMS) service analysis (b)

132 Tele-ECG consulting and outcomes on primary care patients

Supplementary tables

Table S1. Characteristics of all ECG participants and study population

Variables Total ECG recordings Study population 7 (n = 10,001) (n =505) Age 53.6 ± 9.0 53.3 ± 13.6 Age ≤55 years 6,241 (62.4) 270 (53.5) Male sex 5,189 (51.9) 203 (40.2) ECG findings Normal ECG 7265 (72.6) 253 (50.1%) Abnormal ECG* Ischemia 1254 (12.5) 79 (15.6) Arrhythmia 1850 (18.5) 146 (28.9) Structural change 534 (5.3) 69 (13.7) Other 421 (4.2) 28 (5.5)

Values are n (%). *More than one ECG diagnoses per patient are possible.

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Table S2. List of primary care centers (pusat kesehatan masyarakat or Puskesmas) served by Makassar Telemedicine Service

ECG Patients Districts (Kecamatan) Primary care centers n (%) Ujung Tanah Puskesmas Pattingalloang* 22 (4.4) Puskesmas Barang Lompo* 0 (0.0) Puskesmas Tabaringan 0 (0.0) Puskesmas Kodingareng 0 (0.0) Bontoala Puskesmas Layang 0 (0.0) Puskesmas Malimongan Baru 8 (1.6) Wajo Puskesmas Tarakan 0 (0.0) Puskesmas Andalas 3 (0.6) Makassar Puskesmas Bara-barayya* 36 (7.1) Puskesmas Maccini Sawah 6 (1.2) Puskesmas Maradekaya 18 (3.6) Ujung Pandang Puskesmas Makkasau 15 (3.0) Mariso Puskesmas Dahlia 0 (0.0) Puskesmas Pertiwi 0 (0.0) Puskesmas Panambungan 16 (3.2) Mamajang Puskesmas Mamajang* 0 (0.0) Puskesmas Cenderawasih 7 (1.4) Tamalate Puskesmas Jongaya* 14 (2.8) Puskesmas Tamalate 15 (3.0) Puskesmas Barombong 30 (5.9) Rappocini Puskesmas Kassi-kassi* 53 (10.5) Puskesmas Minasa Upa* 15 (3.0) Puskesmas Mangasa 18 (3.6) Puskesmas Ballaparang 16 (3.2) Manggala Puskesmas Antang Perumnas* 19 (3.8) Puskesmas Antang 10 (2.0) Puskesmas Tamangapa 4 (0.8) Puskesmas Bangkala 0 (0.0) Puskesmas Maccini Sombala 0 (0.0) Panakkukang Puskesmas Batua* 12 (2.4) Puskesmas Pampang 20 (4.0) Puskesmas Tamamaung 30 (5.9) Puskesmas Karuwisi 42 (8.3) Puskesmas Toddopuli 3 (0.6)

134 Tele-ECG consulting and outcomes on primary care patients

Tamalanrea Puskesmas Tamalanrea 7 (1.4) Puskesmas Tamalanrea Jaya 0 (0.0) Puskesmas Bira 0 (0.0) 7 Puskesmas Antara 0 (0.0) Puskesmas Bulurokeng 0 (0.0) Puskesmas Paccerakkang 16 (3.2) Biringkanayya Puskesmas Kapasa 16 (3.2) Puskesmas Sudiang Raya 11 (2.2) Puskesmas Sudiang 7 (1.4) Tallo Puskesmas Jumpandang Baru* 0 (0.0) Puskesmas Rappokalling 0 (0.0) Puskesmas Kaluku Bodoa 16 (3.2) Total 505 (100.0) *Inpatient Puskesmas

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ABSTRACT

Although cardiovascular care has improved since the last decade in the low- and middle-income countries (LMICs) in South-East Asia Region, these countries are still encountering a number of challenges in providing standardized care and healthcare systems. This article aimed to highlight the current state of cardiology practices at primary and secondary care, including the novel cardiovascular risk factors, recommendations for improving quality of care, and future directions of cardiovascular research in a resource-poor South-East Asian setting. We also provided the most recent evidence by addressing our latest findings on cardiovascular research in East Indonesia, a region where infrastructure, human, and financial resources are largely limited. Improved healthcare policies and laws to reduce a nations’ exposure to CVD risk factors, providing affordable and accessible cardiovascular care both at primary and secondary levels, and capacity building for clinical research should be warranted in the LMICs in South-East Asia.

INTRODUCTION

Cardiovascular disease (CVD) remains a major cause of early death and chronic disability worldwide,1 responsible for >17 million premature deaths in 2016.2,3 WHO reported that an estimated 7.4 million people died due to coronary artery disease (CAD), and 6.7 million died from stroke in 2012.3 Although the CVD mortality rate has substantially declined in the developed world,1,4 it has increased in the low-to-middle-income populations, which includes most Asian countries.5 Compared with the western world, most Asian countries had higher age-standardized mortality from CVD, and a 2 to 5-fold higher mortality from stroke in 2004.6,7

The South-East Asia Region (SEAR) has a population of over 600 million people –the majority younger than 65 years.8 This region is predominantly populated by developing low- and middle- income countries (LMICs). With populations rising simultaneously with high poverty levels and rapid globalization, an epidemiological transition has been created. In SEAR, the burden of cardiovascular risk factors is growing rapidly,9 CVD is manifesting at a younger age,10-12 and premature CVD deaths are increasing at an alarming rate.8,9

Life expectancy in Indonesia has risen dramatically since the 1990s – an increase of 8.0 years (95% CI 7.3–8.8) – which has added to the burdens of ageing and chronic disease.13 The top three leading causes of disability-adjusted life-years (DALYs) in Indonesia in 2016 were non-communicable diseases, i.e. CAD, stroke, and diabetes.13

CVD RISK FACTORS IN LOW-TO-MIDDLE INCOME POPULATIONS

Of the well-established classical risk factors for CVD, hypertension, smoking and diabetes mellitus are the main risk factors in Asia.7,14 A meta-analysis showed that the risk factors for CVD are generally similar in western and Asian countries.15 The WHO Global Burden of Disease (GBD) 2013 study reports

138 General Discussion that although the prevalence of obesity and diabetes has increased in all observed countries, the prevalence of hypertension, high blood cholesterol, and tobacco smoking has increased in LMICs, while a decreased pattern was shown in high-income countries.16 For example in Indonesia, national 8 health surveys have shown that of the general population, more than 25% have hypertension, ~30% have high cholesterol and overweight, ~7% have diabetes, ~65% of men smoke, and ~23% are insufficiently physically active.17-19

Given the limited resources, it is generally understood that both primary and secondary prevention of CVD in LMICs are often unaffordable or unavailable,20 and inequality is a major issue.21 Along with the traditional CVD risk factors, recently a number of novel cardiovascular risk factors have been emerging in LMIC populations. Intra-uterine22 to early childhood factors,23 socio-economic status and dietary mediation,24 psychological distress,25 and air pollution2 have previously been reported as modifiable determinants associated with the established atherosclerotic CVD in adulthood in these settings. One systematic review suggests that living in a low socio-economic household during childhood has a significant association with the occurrence of CVD and its risk factors in adult life.26 Poor nutritional status and higher exposure to infections are believed to be intermediate factors that may induce inflammation in the atherosclerotic process, the underlying pathology in the development of CVD.26,27

CARDIOVASCULAR CARE AND PRACTICES IN LMICS

Currently, there is a wide gap between evidence-based recommendations and clinical practice in most of the less-affluent countries. Treatment of major CVD risk factors remains suboptimal, and only few patients who are treated achieve the target levels for blood pressure, glucose, and cholesterol.28 On the other hand, overtreatment can occur with the use of non-evidence-based protocols. Implementing standard treatment protocols could improve the quality of care, reduce clinical variability, and simplify treatment options.28

Previous research has shown that there is insufficient access to the guideline- recommended treatment for combating CVD in developing LMICs.29,30 In these countries the healthcare infrastructure is weak, the number of cardiologists is low, and access to quality and timely medical care is still a big challenge. For example in Indonesia, in 18 provinces 94.1% of households are located >5 km from any primary care centers or hospitals with only very minimal means of transportation.31 A previous study reported that almost 70% of the study population in Indonesia who were at moderate-to-high risk for CVD, failed to access cardiovascular care.32 Higher income, possession of health insurance, and residence in urban areas are significant predictors for the fulfilled needs of cardiovascular services in this LMIC.32 Patients have only limited options to access cardiac care facilities. Consequently, most of these patients are concentrated in urban secondary care or tertiary hospitals and this results in long waiting lists.17

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Most LMICs are striving to provide equal and standardized basic primary care services. However, in the majority of LMICs, primary care capacity is lacking, and the health outcomes are poor.33 Primary and secondary care tends to be delivered by a mix of public and private sector health care providers. Indeed, profit and non-profit private companies are becoming increasingly central to the high- quality secondary and tertiary care services.

To date, the main focus of CVD care in most LMICs is curation and hospital-centered. Therefore, the majority of people who are at high risk for CVD remain undetected, while those with established CVD or chronic risk factors (e.g. hypertension and diabetes) have only limited access to essential treatment at primary care level or even worse, cardiovascular services are not available at this level. The available secondary and tertiary care facilities can only accommodate a small proportion of the many patients.4

Most patients in LMICs have been shown to choose private rather than public hospitals where facilities are provided at the same level.34 It is widely accepted in these communities that services and facilities in private hospitals are far better than in the public hospitals. Particularly in SEAR, patients with better financial support tend to have CVD treatment abroad in the high-income countries, e.g. Singapore and Japan. The main reasons are the long waiting lists and the assumption that the medications, high-tech interventions, and services available abroad are superior to those in their home country. Non-communicable diseases (NCDs), in particular CVD, are strongly associated with poverty and level of development within a region or country.16 Countries in SEAR can be grouped based on their national economic status, i.e. developing, emerging, or advanced.35 This categorization also reflects the implementation of healthcare systems. In attempting to reduce the burden of CVD, developing LMICs encounter the challenges of limited healthcare budgets and infrastructures. Competing health priorities such as infectious diseases and maternal/child health problems – which often exhaust the already inadequate resources of these nations – aggravate this poor situation.16 In countries with emerging economies, these obstacles are still found, but to a lesser degree.35 From an economic perspective, developing CVD at a relatively young age means a less productive workforce and impoverished families. Even within the income distribution in LMICs, most CVD patients come from the lower end of the income level, and are often inappropriately insured, thus they have to bear high levels of debt for CVD treatment and comorbidities.36

In Indonesia, ~80% of the whole population had no health insurance until 2013,37 and these uninsured people had very limited or no access to secondary or tertiary referral hospitals.38 Starting on January 2014, the Indonesian Government launched the National Social Health Insurance scheme (known as the Jaminan Kesehatan National, or JKN), targeting the poor and near poor. Since the inception of this program, total enrollment has increased from 86.4 million people in 2014 to 111.6 million in November 2017 (with 92.2 million funded at national level and 19.4 million at local level).13 Medications for the primary and secondary prevention of CVD are available under the JKN scheme.

140 General Discussion

However, issues with coordination between levels of government and inadequate staffing have led to the inequality of access and availability across Indonesia.17 Health insurance in South-East Asian LMICs is differently regulated than equivalent insurance in the 8 high-income world. In most LMICs, healthcare coverage is still incomplete and, as a rule, budgets for healthcare are below what is truly needed.34 The insurance companies tend to spend substantial amounts of money on financing curative and rehabilitative treatments rather than on health promotion and preventive strategies.

In LMIC populations, patients are diagnosed at a late stage of their CVD and often present to hospitals with acute events or long-term complications.4 Based on our previous study, most CVD patients in Indonesia present at hospital at a relatively young age, predominantly with unstable CAD and severely ill. There is generally a significant time delay from onset to admission, and they have rarely received treatment recommended by the guidelines.39 As a consequence, if the CVD is at an advanced stage, expensive high-technology interventions may be necessary, e.g. coronary artery bypass graft (CABG).4 This condition makes the ‘out-of-pocket’ expenditure even higher, especially for those without health insurance.

The occurrence of acute CVD, such as acute coronary syndrome (ACS), is unpredictable and is often fatal.40,41 Good outcomes depend on timely management, requiring adequate and accessible healthcare facilities, a well-established transportation system, 24-hour services from professional providers, and patient awareness of the symptoms of CVD.41 In contrast, during a chronic phase of CVD, e.g. congestive heart failure (CHF), stable CAD, and stroke, screening for risk factors, systematic monitoring for complications, and engaged patient self-care and adherence to after-discharge medications are required. Our latest findings have shown that non-adherence to after-discharge medications is a strong predictor for medium-term mortality in patients with CAD in a poor South- East Asian setting.42

Many CVD patients in LMICs remain untreated or are incompletely treated with the standard oral medications for secondary prevention. WHO has reported that current LMIC health systems rarely meet the standard requirements for chronic care.4 Data from the Prospective Urban and Rural Epidemiology (PURE) study indicates significant gaps in the study population, where 50-75% of people with existing CVD, mostly in LMICs, received none of the recommended medicines for secondary prevention.20,28 This study also highlights that the use of CVD medications in women is lower than in men.1,43 Patients with CVD are often prescribed several long-term medications for primary or secondary prevention, making adherence to medications a key challenge in reducing the CVD burden in LMIC.41

Once known as a disease of the rich, mounting evidence has indicated that the poor are now at greater risk for CVD. The inverse relationship between socio-economic status and CVD incidence and

141 Chapter 8 mortality has been shown across several populations.16 Smoking, hypertension, dyslipidemia, heavy drinking, obesity, diabetes, and inflammatory markers are more prevalent amongst the poor, not only due to excessive exposure, but also to lack of physical activity and less opportunity to obtain healthier foods, and access preventive services or care.16 Regardless of location, the urban poor in LMICs also have higher rates of CVD. Rural areas are currently transforming to mirror this pattern; the modernization of agriculture, the increased used of motor vehicles, the global influence of TV and social media that promotes a modern lifestyle (e.g. consumption of fast food, fewer fruits and vegetables, increased sugar and salt and mono-sodium glutamate (MSG) intake, and less physical activity) are most likely responsible for this transition.16

Educational level and socio-economic status have always been closely associated. In general, in LMICs most people have a lower educational and socio-economic status compared with those from high-income societies. Roughly half of SEAR citizens only have a basic educational level (up to junior high school), and only a fifth of the population have the privilege of achieving university level.44 Only a basic education and limited information mean that patients in LMICs are rarely aware of the long- term consequences of the cardiovascular risk factors, nor do they understand the importance of primary and secondary prevention. Furthermore, traditional culture and beliefs still thrive in these populations. Besides educational and financial level, the opinions of family and relatives, religious beliefs, social values, local culture, and fear of hospital and interventions have always been influential factors, meaning that patients often end up being reluctant to accept treatment or interventions recommended by the guidelines, or rejecting them altogether.

SECONDARY CARDIAC CARE

Worldwide, there is increasing focus on secondary cardiac care in developing countries since the last decades. Improvements in infrastructures and healthcare policies have been implemented in SEAR.45,46 Globalization has allowed the easier exchange of knowledge between distant regions of the world. Internet has enabled easier access to the most recent information and developments, and has also warranted the continuity of efforts towards improvement. However, even though cardiovascular care has improved rapidly in LMICs compared with past decades, it is still lagging behind the high- income countries.47

In order to provide specialized CVD care, practical training of specific skills for care providers is required. However, the attempt to upgrade providers’ skills is hampered by some constraints. For instance, in Indonesia, training to consultant level of expertise, is only available in four centers on Java Island. The current large number of cardiologists has to be challenged with a long waiting list to get an avenue to do the fellowship training. To reduce the problem, more cardiac centers should be enabled to provide expertise training in other places outside Java.

142 General Discussion

Diagnostics are an important step in determining further treatment of disease. However, in many LMICs, basic tools for diagnosis are only available in secondary care hospitals.17 In order to detect people with CVD and those at high risk, trained health professionals able to perform clinical 8 examinations, and affordable tools such as simple laboratory equipment, ambulatory ECG, and cardiovascular risk assessment charts should be available at primary care level at least. Since atherosclerotic CVD is asymptomatic during the early stages, such tools are also rather important to avoid a delay in diagnosis and facilitate referral to hospital.4

The standard guidelines for cardiovascular care are not rarely found in South-East Asian countries, the majority are adopted from the western world, e.g. European Society of Cardiology (ESC) or American Heart Association (AHA), with adjustments for the available infrastructures and local settings. There are also guidelines and protocols that are derived from previous studies on each country. Unfortunately, in most LMICs, compliance to the guidelines and protocols in SEAR is lacking. The authority of medical doctors is still considered to be the main factor in disease management and decision-making. Based on our observation, we summarize the key problems of cardiovascular care practices in LMICs in table 1.

LESSONS FROM HIGH-INCOME COUNTRIES

In 2015, there were approximately 422 million prevalent cases of CVD worldwide, and the prevalence of CVD varied greatly between countries.1 In many regions, the big picture of CVD as a national health burden remains uncaptured, or only very limited data are available, particularly in underprivileged populations.

The Global Burden of Disease (GBD) 2015 study reported the association between sociodemographic changes and CVD variability in all regions worldwide. A significant decline in age-standardized CVD mortality occurred between 1990 and 2015 in all high-income and some middle-income countries, but no significant changes were detected for most of sub-Saharan Africa and multiple countries in Oceania and South-East Asia. Bangladesh and the Philippines had considerable increases in age- standardized mortality due to CVD.1 However, the unchanged pattern of CVD prevalence often reflects the lack, or unavailability, of data on CVD in these countries.1 Alongside sociodemographic changes, variation in exposure to modifiable risk factors and access to effective health care interventions are most likely associated with regional differences in CVD.1

Advancement of healthcare in the high-income world often emphasizes new technologies, including diagnostics and invasive interventions; and to date, this advancement continues to evolve rapidly. High-tech modalities and modern invasive methods have been implemented to achieve a more accurate diagnosis and advanced intervetions and therefore better clinical outcomes for patients. Data from WHO–Multinational MONItoring of Trends and Determinants of CArdiovascular Disease

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(MONICA) strongly propose that the reduction of CVD risk factors and mortality in high-income populations is due to effective population-wide primary prevention and individual healthcare interventions.4,48 Improved healthcare policies and laws to reduce a nations’ exposure to risk factors and providing affordable and accessible care and follow-up for high-risk and diagnosed individuals seem to be promising to be implemented in LMICs.

Table 1. Key problems of cardiovascular care in low- and middle-income countries, based on our observation Healthcare system • Low access to care • Healthcare facilities: inequality and distance (problems with transportation) • Unavailable or unaffordable CVD services in primary care • Lack of collaboration between hospitals and primary care doctors • Utilization of ambulance is underused, especially in rural areas • Immature health insurance coverage, or unaffordable health insurance • Lack of surveillance and disease monitoring in population • Primary care has insufficient capacity to diagnose, monitor and manage CVD burden, including hypertension and diabetes. Healthcare providers • Limited availability of health personnel, especially in remote areas • Lack of standardization among healthcare providers and experts in cardiology practice • Authority in decision-making, ignoring the guideline standards • Poor management of after-discharge care Patients • Low awareness of CVD symptoms and risk factors • Financial problems: high out-of-pocket expenditure or expensive cost of essential treatments, e.g. medicines for hypertension, diabetes, and cholesterol • Low adherence to medications for primary and secondary prevention • Low level of education of the patients and family, in the context of adherence to guideline recommendations

RECOMMENDATIONS FOR IMPROVING CARDIOVASCULAR CARE IN LMICS

Challenged with low healthcare budgets and poor infrastructure, it is far more difficult to improve the quality of care in LMICs than in high-income countries, in particular in the cardiovascular field. A sensible attempt to answer this challenge is to implement the most applicable and effective interventions adopted from the western world, rather than recommending unproven interventions.41 The program should be not expensive and should be easily applicable with respect to the limitations of the available resources. Although adopting clinical practice guidelines from high-income countries appears to be a great opportunity, adoption of guidelines and interventions should be adjusted to

144 General Discussion local settings and needs.41 Specifically in this context, we have proposed a framework to improve the quality of cardiovascular care in Indonesia, based on the local evidence acquired during our research (see table 2). 8 Currently, the question of whether to target populations on a wide scale, or focus on high-risk and diagnosed individuals to reduce the CVD burden is still a matter of debate. Individual-scale programs are appropriate for short-term purposes, while population-wide strategies are for long-term investment. Learning from the high-income world, a relatively new approach that may well be most effective is to combine population- and individual-level strategies.16

At population level, a reduction in sodium intake and tobacco control strategies with their focus on health education via mass media campaigns, product reformulation, and relabeling,49 have always been cost-saving.16 Based on the WHO Framework Convention on Tobacco Control (FCTC), the key components for intervention are: legislation to increase taxes for tobacco products, creation of smoke-free environments, provision of health information and warnings to the public, and banning the advertising, promotion and sponsorship of tobacco products. These strategies were estimated to have averted >5 million deaths in the 23 large LMICs between 2006 and 2016.16 Meanwhile, on an individual scale, the most feasible and cost-saving program is to treat people at high risk or with diagnosed CVD with polypills (i.e. a combination of fixed-dosed generic cardiovascular drugs), together with counseling on lifestyle improvement.16,49,50 In high-risk populations, blood pressure- lowering intervention was the most cost-effective option.49

Improved access to treatment for acute and chronic CVD is crucial. Timely interventions save lives and can reduce costs of disability and can be presented as examples of a successful policy. This approach is effective only once combined with primary and primordial prevention strategies. It may compensate for the fact that in most LMICs, screening strategies have not been well implemented.49 Simply replicating the prevention programs from high-income countries could become another challenge, and is not realistic considering the resource discrepancies. To this end, evidence-based prevention strategies that are applicable to the local setting are warranted, these include smoking cessation, improved physical activity, better dietary practice and infection control. Considering the competing priorities (maternal/child health problems and infectious diseases) in Indonesia, based on our findings, we suggest that optimizing maternal health and nutrition during pregnancy may reduce or delay the development of CVD in the offspring.22 Our previous study also confirms that higher levels of exposure to infection during childhood and adolescence is associated with the occurrence of early coronary heart disease in adult life, and may potentiate the effects of traditional CVD risk factors.23 Vaccination and adequate treatment for those who are vulnerable – pregnant women and young children with infectious disease – are of practical importance, especially in areas where the prevalence of infections is high.22 Nowadays, the Indonesian Government aggressively promotes and undertakes a vaccination program. All Indonesian children below the age of 15 years are obliged to

145 Chapter 8 be vaccinated in schools and primary care centers, known as ‘community healthcare center’ or ‘pusat kesehatan masyarakat’ (Puskesmas). In the context of CVD prevention, the prevention of outbreaks of infectious disease today could be a valuable long-term investment in the future.

A recent systematic review has shown that pharmacological interventions were predominantly assessed in the context of economic evaluation for primary and secondary prevention in LMICs.49

Table 2. Proposed conceptual framework for improving quality of cardiovascular care in Indonesia (based on the local needs and settings) Healthcare system • Reduce delay in hospital admission, especially for patients with acute CVD • Reduce administrative and insurance barriers in the hospital • Accessible and affordable cardiovascular care at Puskesmas (primary care centers), e.g. ambulatory ECG, basic/standard lab • Improve access to revascularization services • Implementing e-health program through SMS/phone calls to improve lifestyle and adherence to after-discharge medications • Tele-ECG monitoring and consulting at primary care level • Reliable patient registries should be available in computerized format • Improve data collection for healthcare utilization (i.e. population surveillance and death registry) • Preventive strategies: −− Adequate/complete vaccination for children, especially those living in rural areas and of low socio-economic status −− Optimizing health and nutrition in pregnant women (including vaccination prior to or during pregnancy and adequate treatment for maternal high blood pressure) −− Lifestyle improvement: reduce consumption of fatty/deep fried food, sugar, salty/MSG food, and fast food; promoting active lifestyle; smoking cessation −− Adequate treatment for hypertension and diabetes: accessible care/diagnostic tools and essential medicines in primary care Healthcare providers • Timely and standardized initial management of acute CVD • Implement clinical practice guidelines and improve adherence to the guideline recommendations • Improve hospital discharge planning and transition to chronic care • Update knowledge and skills Patients • Improve awareness of acute CVD symptoms • Improve home monitoring and awareness of CVD risk factors • Optimizing patients’ adherence and engagement with long-term medications • Improve lifestyle

146 General Discussion

Upcoming approaches should consider the non-pharmacological (i.e. behavioral and lifestyle) interventions, for example improvement of physical activity, dietary practices, and weight control. In Indonesia, recent evidence has shown that dietary risks were a leading contributor to the DALY burden, accounting for ~14% of total DALYs in 2016.13 8

Most LMICs will need efforts on a national scale to improve a healthy lifestyle in their population. For example, legislation to reduce trans-fat, salt and MSG in food, promotion of fruit and vegetable consumption, advertising on healthier food and the negative effects of fast food and excessive sugar in soft drinks, and urban and rural plans to create safe green spaces and separate paths for pedestrians to promote better physical activity.16 One important observation is that modernization is having a significant impact on the lifestyle of the populations in developing countries, particularly the upsurge in the use of smartphones and gadgets. Adolescents and young adults in particular may spend many hours every day with their gadgets, leading to an increase burden of physical inactivity in large populations. Advertising the importance of taking physical exercise and having an active lifestyle and should be stepped up.

Mobile phones and related technology are expected to become critical tools for improving access to healthcare, especially for the poor in LMICs.51 Evidence from high-income countries has shown that electronic health program (e-health) through SMS (short message service/text message) has improved disease management and prevention, is effective in changing lifestyle, and facilitates communication between patients and healthcare providers.52 One study from a low-income country has indicated that SMS intervention is effective in the better management of infectious disease (HIV), especially in improving adherence to medications.53 Polypills, mobile healthcare facilities, as well as educating patients and family are just some of the strategies that will perhaps increase patient engagement and adherence to medications.41

As the frontrunner for delivering healthcare services, primary care should be more active and involved in the execution of preventive strategies in LMICs. In Indonesia, a country with the largest archipelago in the world with over 260 million inhabitants,13 distance and infrastructures are the major issues where accessing care is concerned. Today, there are 9,825 primary care centers or Puskesmas (3,459 are inpatient) scattered throughout Indonesia.54 Puskesmas facilities and providers need to be improved in order to enable better health services. Promoting a healthy lifestyle, improving patient education, performing home-care visits, sending reminders for patient medications, and improving compliance to the guideline standards may result in better patient outcomes and population health level.

Telemedicine and e-health could deliver both standard and specialized care nearer to the patients. Implementing telemedicine, e.g. tele-electrocardiogram (ECG) at primary care level, could be a cost- effective strategy to detect CVD in high-risk patients and prevent overtreatment after a specialized cardiology consultation. Makassar Telemedicine Program is our first experience in implementing

147 Chapter 8 the tele-ECG consulting in East Indonesia. From January 2015 to February 2018, a total of 10,001 12-lead ECG recordings from 46 primary care centers in Makassar City were sent through internet to the analysis center in Hasanuddin University Hospital. All (100%) ECG recordings were eligible for analysis, and most (95%) of general practitioners (GPs) at primary care were satisfied with each tele-ECG consultation. Our findings suggest that despite a shortage of cardiologists and limited resources, tele-ECG is helpful to support primary care GPs to select and refer suspected CVD patients to secondary or tertiary care hospital for further specialized treatment. Figure 1 shows the routine healthcare services and implementation of tele-ECG program in one of primary care centers (Puskesmas) in Indonesia.

The ultimate responsibility for better nationwide health systems depends on governmental efforts, which should involve all sectors of society. In 2017, the Indonesian Government launched the Presidential Decree No. 1, to encourage a healthy lifestyle. This focused on physical activity, healthy diet, and early detection of health problems.13 Further legislation on supporting the reduction of cardiovascular risk factor burden is also warranted.

FUTURE DIRECTIONS

In terms of future research, building research capacity of local staff in the cardiovascular field by means of training courses, seminars, and workshops will empower local researchers to generate local evidence. Capacity-building is crucial in forging independence and sustainability of the conduct of health and clinical research in LMICs. Countries should consider further investment in CVD surveillance and population-based registries to benchmark their efforts in reducing CVD mortality and morbidity.

A major concern continues to be the challenge of conducting research in a resource-poor setting. Based on our experience, conducting clinical research in these settings is somehow rather ‘exhausting’. Working with the limited resources available for research means local researchers are forced to start everything from scratch. Unavailable standard system to perform follow-up for the patients or study participants in hospital and primary care centers required researchers to be more actively in reaching the patients or their family members to obtain the follow-up data. Figure 2 shows the primary care nurse performing the follow-up of CVD patients through home visits.

An interesting publication in The Lancet has highlighted that as the second most populous LMIC after India, in the global conversation in health and medical science the Indonesian voice is too quiet.55 The country has more of an oral than a written culture. The Indonesian researchers are unfamiliar with the scientific language of English and ignore the importance of international publishing. Research culture and allocation for health research should be encouraged.55 Increasing the number of health and clinical research modules in university curricula, good mentorship, knowledge-sharing events, and

148 General Discussion

8

Figure 1. Routine healthcare services and implementation of tele-ECG program in a primary care center (Puskesmas) in Indonesia

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Figure 2. Primary care nurse performing the follow-up of CVD patient through home visit access to free knowledge resources are several strategies to improve the research culture.56 Despite all the steps, personal motivation is also essential. Awareness of the importance of conducting clinical research and writing up the findings should be also encouraged.

Clinicians and practitioners in LMICs often undervalue the benefits of evidence-based medicine, probably it is erroneously perceived that standard guidelines could limit their autonomy in treating patients.56 Although clinical research is considered as a tool to measure and communicate the quality of care, most of these practitioners regard research as an academic pastime only, rather difficult, and always time-consuming. Naturally, an extremely heavy workload and other duties in hospitals limit their opportunity and willingness to undertake research. Research is often regarded as a side job that is needed to compete with private practice and other priorities.56 Non-faculty practitioners do not get any benefit of income or career development for doing research. Lack of resources and recognition in the public hospital system, negative attitudes and assumptions, and lack of peer support, all concurrently scrape the practitioners’ motivation to do research.56 We summarized the key challenges of conducting clinical research in low-to-middle-income settings, based on our own experience, in table 3.

Institutions should provide a supportive environment, allocate funding for research, and link research to career enhancement. International support and collaboration is is essential for capacity building and co-shaping infrastructure in many ways. For the international partners, the collaboration can be

150 General Discussion an innovative approaches for management of a disease that is considered ‘under control’ in their own countries. With the aforementioned examples of local evidence, we intend to show that similar to international collaboration projects to improve defence or economy, the local initiatives in the field 8 of medical research are beneficial to Indonesian patients and clinical science in general.

CONCLUSIONS

Although cardiovascular care has improved in the South-East Asian LMICs over past decades, these countries are still encountering a number of challenges in providing standardized and appropriate healthcare systems. Improved healthcare policies and laws to reduce a nations’ exposure to CVD risk factors, providing affordable and accessible cardiovascular care both at primary and secondary levels, and capacity building for cardiovascular research should be warranted in these nations.

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Table 3. Key challenges of conducting clinical/hospital-based research in low-to- middle income settings (learning from our experience) Patients • Negative attitude towards research: low participation rate, patients/family members’ mistrust and negative prejudice, rejection for follow-up • High rate of lost-to-follow-up, in particular for those from rural areas • Informed consent issues: difficulty on getting approval from patients and family members (especially if intervention needed), verbal informed consent for illiterates • Low education and social values are strong influencers (more comprehensive communications are needed for illiterates/low-educated participants) • Language barriers: some patients/participants only use their local/traditional language

System/environment • Lack or unavailable patient registries/computerized database • Limited and unreliable paper-based medical records • Limited or unavailable population surveillance • Unavailable/limited death registry • Inadequate research infrastructures: research devices/tools should be shared with routine services in the hospital • Less support from hospital environment (e.g. administrative barriers) • Lack of supportive facilities: poor internet connection, limited access to knowledge resources (e.g. international journals, webinars, ect.)

Researchers (academician and clinician) • Limited dedicated time for research, particularly if the investigators are clinicians • Lack of peer supports • High cost expenditures (e.g. hiring research assistant, laboratory expenses, rewards to patients/ participants, high publication costs) • Research community is less familiar with the scientific language of English • Low of ‘research and writing’ culture

152 General Discussion

Summary Box

• There is a wide gap between evidence-based recommendations and clinical practice in 8 most of the low- and middle-income countries (LMICs) in South-East Asia. Given the limited resources, both primary and secondary prevention of cardiovascular disease (CVD) in LMICs are often unaffordable or unavailable. • There is insufficient access to the guideline-recommended treatment for combating CVD in developing LMICs. In these countries, the healthcare infrastructure is weak, the number of cardiologists is low, and access to quality and timely medical care is still a big challenge. • The main focus of cardiovascular care in most LMICs is curation and hospital-centered. Therefore, the majority of people who are at high risk for CVD remain undetected, while those with established CVD or chronic risk factors have only limited or no access to essential treatment at primary care level. • Exploring the local evidence through capacity building and clinical research, implementation of the standard guidelines with adaptation to available resources, and involvement of the government and stake-holders are needed to reduce CVD burden in these resource-poor South-East Asian countries.

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REFERENCES 1. Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, Abyu G, et al. Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol 2017; 70: 1-25. 2. Hadley MB, Vedanthan R, Fuster V. Air pollution and cardiovascular disease: a window of opportunity. Nature Reviews Cardiology 2018; 15: 193-194. 3. World Health Organization. Media centre: Cardiovascular diseases (CVDs). Fact sheet No. 317. http://www.who.int/mediacentre/factsheets/fs317/en/ (20 March 2015). 4. World Health Organization. Improving health care: individual interventions. Global Status Report on Noncommunicable Diseases 2010. Geneva: WHO Press, 2011, p. 61-71. 5. Hong Y. Burden of Cardiovascular Disease in Asia: Big Challenges and Ample Opportunities for Action and Making a Differenc. Clinchem 2009; 55: 1450-1452. 6. Ohira T, Iso H. Cardiovascular disease epidemiology in Asia: an overview. Circ J 2013; 77: 1646-1652. 7. Ueshima H, Sekikawa A, Miura K, Turin TC, Takashima N, Kita Y, et al. Cardiovascular disease and risk factors in Asia: a selected review. Circulation 2008; 118: 2702-2709. 8. Lam CSP. Heart failure in Southeast Asia: facts and numbers. ESC Heart Failure 2015; 2: 46-49. 9. World Health Organization: Regional Office for South-East Asia. Noncommunicable Diseases in the South-East Asia Region: 2011 Situation and Response. New delhi, 2011. 10. WHO. Noncommunicable Diseases in th South East Asia Region: Situation and Response 2011. New delhi, India: World Health Organization. 2011. 11. WHO. Global Health Risks: Mortality and Burden of Disease Attributable to Selected Major Risks. Geneva: World Health Organization. 2009. 12. Dhillon PK, Jeemon P, Arora NK, Mathur P, Maskey M, Sukirna RD, et al. Status of epidemiology in the WHO South-East Asia region: burden of disease, determinants of health and epidemiological research, workforce and training capacity. Int J Epidemiol 2012; 41: 847-860. 13. Mboi N, Murty Surbakti I, Trihandini I, Elyazar I, Houston Smith K, Bahjuri Ali P, et al. On the road to universal health care in Indonesia, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet 2018; 392: 581-591. 14. Ueshima H. Explanation for the Japanese Paradox: Prevention of Increase in Coronary Heart Disease and Reduction in Stroke. J Atheroscler Thromb 2007; 14: 278-286. 15. Chen X, Zhou L, Zhang Y, Yi D, Liu L, Rao W, et al. Risk Factors of Stroke in Western and Asian Countries: A Systematic Review and Meta-analysis of Prospective Cohort Studies. BMC Public Health 2014; 14. 16. Yeates K, Lohfeld L, Sleeth J, Morales F, Rajkotia Y, Ogedegbe O. A Global Perspective on Cardiovascular Disease in Vulnerable Populations. Can J Cardiol 2015; 31: 1081-1093. 17. Cardiovascular Division & Health Services Research Center. Reducing the burden of CVD in Indonesia: Evidence Review. Newtown: The George Institute for Global Health, 2017. 18. World Health Organization. 11 Health Questions about 11 SEAR Countries. New Delhi, India: World Health Organization. 2007.

154 19. World Health Organization. Diabetes country profiles: Indonesia. 2016. 20. Khatib R, McKee M, Shannon H, Chow C, Rangarajan S, Teo K, et al. Availability and affordability of cardiovascular disease medicines and their effect on use in high- income, middle-income, and low-income countries: an analysis of the PURE study data. 8 The Lancet 2016; 387: 61-69. 21. Agyemang C, van den Born B-J. Limited access to CVD medicines in low-income and middle-income countries: poverty is at the heart of the matter. The Lancet Global Health 2018; 6: e234-e235. 22. Qanitha A, de Mol BAJM, Burgner DP, Kabo P, Pabittei DR, Yusuf I, et al. Pregnancy- related conditions and premature coronary heart disease in adult offspring.Heart Asia 2017; 9: 90-95. 23. Qanitha A, de Mol BA, Pabittei DR, Mappangara I, van der Graaf Y, Dalmeijer GW, et al. Infections in early life and premature acute coronary syndrome: A case-control study. Eur J Prev Cardiol 2016; 23: 1640-1648. 24. Psaltopoulou T, Hatzis G, Papageorgiou N, Androulakis E, Briasoulis A, Tousoulis D. Socioeconomic status and risk factors for cardiovascular disease: Impact of dietary mediators. Hellenic J Cardiol 2017; 58: 32-42. 25. Lazzarino AI, Hamer M, Stamatakis E, Steptoe A. Low Socioeconomic Status and Psychological Distress as Synergistic Predictors of Mortality From Stroke and Coronary Heart Disease. Psychosomatic Medicine 2013; 75: 311-316. 26. Galobardes B, Smith GD, Lynch JW. Systematic review of the influence of childhood socioeconomic circumstances on risk for cardiovascular disease in adulthood. Ann Epidemiol 2006; 16: 91-104. 27. Dratva J, Caviezel S, Schaffner E, Bettschart R, Kuenzli N, Schindler C, et al. Infectious diseases are associated with carotid intima media thickness in adolescence. Atherosclerosis 2015; 243: 609-615. 28. World Health Organization. HEARTS Technical package for cardiovascular disease management in primary health care: evidence-based treatments protocols. Geneva, 2018. 29. Seligman B, Vedanthan R, Fuster V. Acute coronary syndromes in low- and middle- income countries: Moving forward. Int J Cardiol 2016; 217 Suppl: S10-12. 30. Bowry AD, Lewey J, Dugani SB, Choudhry NK. The Burden of Cardiovascular Disease in Low- and Middle-Income Countries: Epidemiology and Management. Can J Cardiol 2015; 31: 1151-1159. 31. World Health Organization: Regional Office for South-East Asia. Telemedicine: sharing experiences and a way forward. Report of a regional consultation, Pyongyang, Democratic People’s Republic of Korea, 30 July-1 August 2013. Report, 2013. 32. Maharani A, Tampubolon G. Unmet needs for cardiovascular care in Indonesia. PLoS One 2014; 9: e105831. 33. Bitton A, Ratcliffe HL, Veillard JH, Kress DH, Barkley S, Kimball M, et al. Primary Health Care as a Foundation for Strengthening Health Systems in Low- and Middle-Income Countries. J Gen Intern Med 2017; 32: 566-571. 34. Chee G, Borowitz M, Barraclough A. Private sector health care in Indonesia. 2009. 35. Chomik R, Piggott J. Population ageing and social security in Asia. Asian Economic Policy Review 2015; 10: 199-222.

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36. Moran A, Vedanthan R. Cardiovascular disease prevention in South Asia: gathering the evidence. Glob Heart 2013; 8: 139-140. 37. Juwana YB, Wirianta J, Ottervanger JP, Dambrink J-HE, van ‘t Hof AJ, Gosselink ATM, et al. Primary coronary intervention for ST-elevation myocardial infarction in Indonesia and the Netherlands: a comparison. Neth Heart J 2009; 17: 418-421. 38. Thabrany H. Social Health Insurance in Indonesia: Current Status and the Proposed National Health Insurance. Presented in Social Health Insurance Workshop WHO SEARO, New Delhi, March 13-15, 2003. In: Center for Health Economic Studies. University of Indonesia, 2003. 39. Qanitha A, Uiterwaal CSPM, Henriques JPS, Alkatiri AH, Mappangara I, Mappahya AA, et al. Characteristics and the average 30-day and 6-month clinical outcomes of patients hospitalised with coronary artery disease in a poor South-East Asian setting: the first cohort from Makassar Cardiac Center, Indonesia. BMJ Open 2018; 8: e021996. 40. World Health Organization. Prevention of cardiovascular disease: pocket guidelines for assessment and management of cardiovascular risk (WHO/ISH cardiovascular risk prediction charts for the South-East Asia Region). Geneva: WHO Press, 2007. 41. Reboldi G, Lee ES, Vedanthan R, Jeemon P, Kamano JH, Kudesia P, et al. Quality Improvement for Cardiovascular Disease Care in Low- and Middle-Income Countries: A Systematic Review. PLoS One 2016; 11: e0157036. 42. Qanitha A, Uiterwaal CSPM, Henriques JPS, Mappangara I, Idris I, Amir M, et al. Predictors of medium-term mortality in patients hospitalised with coronary artery disease in a resource-limited South-East Asian setting. Open Heart 2018; 5: e000801. 43. Yusuf S, Islam S, Chow CK, Rangarajan S, Dagenais G, Diaz R, et al. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle- income, and low-income countries (the PURE Study): a prospective epidemiological survey. The Lancet 2011; 378: 1231-1243. 44. United Nations Educational SaCO. Education For All (EFA) Global Monitoring Report, Education for All by 2015 Will we make it? Regional Overview: East Asia. 2008, p. 1-14. 45. Dharma S, Siswanto BB, Firdaus I, Dakota I, Andriantoro H, Wardeh AJ, et al. Temporal trends of system of care for STEMI: insights from the Jakarta Cardiovascular Care Unit Network System. PLoS One 2014; 9: e86665. 46. Wan Ahmad WA. Annual Report of the NCVD - ACS Registry 2014 - 2015. National Cardiovascular Disease Database. Kuala Lumpur, Malaysia: National Heart Association of Malaysia (NHAM), 2017. 47. Chan MY, Du X, Eccleston D, Ma C, Mohanan PP, Ogita M, et al. Acute coronary syndrome in the Asia-Pacific region. Int J Cardiol 2016; 202: 861-869. 48. Tunstall-Pedoe H, Kuulasmaa K, Tolonen H, Davidson M, Mendis S, Project wocfTWM. MONICA Monograph and Multimedia Sourcebook - World’s largest study of heart disease, stroke, risk factors, and population trends 1979-2002. In: Tunstall-Pedoe H. Geneva2003. 49. Aminde LN, Takah NF, Zapata-Diomedi B, Veerman JL. Primary and secondary prevention interventions for cardiovascular disease in low-income and middle- income countries: a systematic review of economic evaluations. Cost Effectiveness and Resource Allocation 2018; 16. 50. Lonn E, Bosch J, Teo KK, Pais P, Xavier D, Yusuf S. The polypill in the prevention of cardiovascular diseases: key concepts, current status, challenges, and future directions. Circulation 2010; 122: 2078-2088.

156 51. Pop-Eleches C, Thirumurthy H, Habyarimana JP, Zivin JG, Goldstein MP, de Walque D, et al. Mobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders. AIDS 2011; 25: 825-834. 8 52. Cole-Lewis H, Kershaw T. Text messaging as a tool for behavior change in disease prevention and management. Epidemiol Rev 2010; 32: 56-69. 53. Lester RT, Ritvo P, Mills EJ, Kariri A, Karanja S, Chung MH, et al. Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. The Lancet 2010; 376: 1838-1845. 54. Kementerian Kesehatan Republik Indonesia (Ministry of Health Republic of Indonesia). Jumlah Puskesmas per Desember 2017. http://www.depkes.go.id/resources/ download/info-terkini/Jumlah PKM per Desember 2017.pdf (September 5, 2018). 55. Horton R. Offline: Indonesia—unravelling the mystery of a nation. The Lancet 2016; 387: 830. 56. Franzen SRP, Chandler C, Siribaddana S, Atashili J, Angus B, Lang T. Strategies for developing sustainable health research capacity in low and middle-income countries: a prospective, qualitative study investigating the barriers and enablers to locally led clinical trial conduct in Ethiopia, Cameroon and Sri Lanka. BMJ Open 2017; 7: e017246.

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SUMMARY AND FINAL REMARKS

Cardiovascular disease (CVD) is the leading cause of mortality in Indonesia, responsible for ~37% of total deaths nationally. Indonesia is one of the lower middle -income countries, in which the top three causes of premature death and disability are coronary artery disease (CAD), stroke, and diabetes. Cardiovascular risk factors affect the young population and manifest themselves at a younger age. In 2013, there were >2.6 million prevalent cases of CAD, and 67% of patients were aged under 55 years. Despite the high burden of cardiovascular disease and risk factors in this nation, its causes, characteristics, management, and outcomes have not been properly explored, particularly in East Indonesia, a region where the infrastructure, human, and financial resources are widely limited. This thesis describes the current state of coronary artery disease in Indonesia, based on investigation of the local evidence. We outline the description of this thesis in three parts. The first part (Chapters 2 and 3) mainly explores the early life determinants that potentially increase the risk of premature CVD later in life. In the second part (Chapters 4, 5, and 6), we describe patient characteristics, clinical profiles, admission and management, as well as clinical outcomes in the setting of limited resources. The third part (Chapter 7) provides recent evidence on the implementation of a pilot telemedicine project in a less-developed country such as Indonesia. Lastly, in Chapter 8, we discuss all of our findings and how these relate to the current clinical practice of cardiology in a poor South-East Asian setting.

Part 1 provides an assessment on the association between infections in early life (childhood and adolescence) with the development of premature acute coronary syndrome (ACS) in adulthood (Chapter 2). Consistent evidence from high-income countries shows that severe childhood infections are independently associated with hospitalization for CVD, adverse metabolic profiles, and subclinical atherosclerosis in adulthood; but if early life infections, i.e. diseases highly prevalent in children in Indonesia, are also associated with the high incidence of adult CVD in this low-to-middle income country remains unclear. In our population-based, case-control study (153 cases and 153 controls), in both univariable and multivariable analyses we found that early life infection is associated with approximately three-fold higher odds of acquiring premature ACS. The overall association was modified by the predefined classes of the Framingham Risk Score, and this implies that infections in early life may potentiate the effects of traditional cardiovascular risk factors.

In Chapter 3, we elaborate further on the early life determinants of later life cardiovascular disease. As both maternal pregnancy complications and premature CVD are currently major health issues in South-East Asian populations, it is important to assess if pregnancy complications are associated with the occurrence of clinically manifest ACS in young adult offspring. Our findings suggest that offspring of mothers with complications during pregnancy are at increased risk of premature ACS in adulthood, particularly those whose mothers had high blood pressure and infections.

160 In part 2, we describe in detail the characteristics, management, and outcomes of patients with ACS (n = 364) and stable CAD (n = 113) in a low-to-middle income population, based on our prospective cohort study in Indonesia. We begin by presenting patient characteristics and the average short-term 9 outcomes at 30 days and 6 months after hospital admission (Chapter 4). This study showed that patients with CAD in Indonesia are predominantly young males and that they present with high-risk profiles. More than half of our cohort had metabolic syndrome and hypertension, and approximately one-third had diabetes mellitus and a history of myocardial infarction. The majority of patients came from rural areas, had a low or middle socio-economic status, and had a history of past or current smoking. From our observations, patients with CAD in Indonesia seem to present late to hospital with relatively severe illness, and rarely receive the treatment recommended by guidelines. Patients with ACS had poorer clinical outcomes compared with those with stable CAD, mainly in the first 30 days; while those with stable CAD experienced more adverse events at 6-month follow-up. In our ACS group, the rates of total mortality both at 30 days and 6 months were higher when compared with earlier reports from other studies in high-income countries. Our findings suggest that awareness of symptoms, initial management of acute CVD, as well as healthcare resources and infrastructure, should be improved in order to reduce the high rate of short-term mortality and adverse events in this population.

Chapter 5 reports on the medium-term outcomes and the predictors of mortality in patients with acute and chronic CAD, both during and after hospitalization. Subsequent to our active follow-up (median 18 (IQR 6-36) months), a total of 154 (32.3%) patients died. Our study suggests that in- hospital and medium-term mortality is high in patients with CAD in a poor South-East Asian setting. On comparison with other diagnosis groups (STEMI, unstable angina, and stable CAD), patients with non-ST-segment elevation myocardial infarction (NSTEMI) had the worst outcomes. We found that hyperglycemia on admission, heart failure or Killip Class ≥2, estimated glomerular filtration rate <60 ml/min, no revascularization (PCI or CABG), and poor adherence to after-discharge medications significantly predicted the mid-term all-cause mortality in patients with CAD in Indonesia. Our study suggests that for better survival, access to early and late hospital care and patient education should be prioritized.

In Chapter 6, we measure the adherence to guideline recommendations on performing coronary angiography (CAG) in a resource-poor Indonesian setting. The study also intended to demonstrate the short- and medium-term prognostic consequences of adherence to these guidelines. Based on our data, adherence to recommendations on CAG in this population is low. Older women with low educational and socio-economic levels tend not to undergo the procedure. The motivation of patients to refuse CAG and subsequent procedures are fear, symptom reduction, and lack of trust in the benefit of CAG. During the follow-up period (median 19 (IQR 5.5–39) months), 33% of our cohort died and 55% experienced at least one adverse event. Overall, undergoing CAG was associated with

161 Chapter 9 a significantly lower risk of short- and medium-term mortality, while in sub-group analysis, higher SYNTAX scores independently predicted a higher risk of all-cause mortality and MACE.

Part 3 (Chapter 7) addresses the implementation of the first telemedicine (i.e. Tele-ECG) program at primary care centers in a less-developed region of East Indonesia. We also assessed the impact of this program on patients’ outcomes (n = 505). From this study, we found that Tele-ECG seemed to be helpful in supporting decision-making for general practitioners (GPs) in primary care. Recurrent and moderate symptoms together with the concomitant risk factors increased the likelihood of having an abnormal ECG. Most GPs (95%) were satisfied with the performance of the Tele-ECG consultations. Our study shows that patients with a normal ECG were predominantly young females who presented with better clinical profiles and had fewer CVD risk factors than those with an abnormal ECG. Of the 88 patients in whom admission to hospital was advised, 72 (81.8%) were referred to hospital within 48 hours after the consultation. Over the total follow-up (14 ± 6.6 months), seven (1.4%) patients died and 96 (19.0%) were hospitalized for CVD.

The majority (~80%) of referred patients presented with moderate chest pain and suspected ischemic heart disease. This study suggests that the Tele-ECG program indeed supports the GPs in primary care in making a quick decision in terms of patient management. In the future, this telemedicine program is intended to accelerate the selection of high-risk patients or patients with suspected disease from rural and remote areas where there are few cardiologists, and facilities are insufficient or unavailable.

Finally in Chapter 8 (General discussion), we discuss our findings in the context of the current practice of cardiovascular care in a poor South-East Asian setting. We also share our experiences in conducting clinical research in a low-to-middle income population. Subsequently, we highlight the key problems in cardiology practice and challenges in clinical research in this population, and finally we propose a conceptual framework to improve the quality of care based on our local-evidence investigation.

162 SUMMARY OF WHAT IS ALREADY KNOWN • The burden of cardiovascular risk factors is rising rapidly in the South-East Asia region, and CVD manifests itself at a younger age in these populations. 9 • Atherosclerosis, the underlying pathology of cardiovascular disease (CVD), begins in early life. • Traditional CVD risk factors may already affect the vasculature in childhood. • Maternal complications during pregnancy (e.g. gestational hypertension, preeclampsia, preterm birth) have long been associated with increased CVD risk factors (e.g. obesity, glucose intolerance, hypertension, and metabolic syndrome) in the offspring. • Both maternal pregnancy complications and premature CVD are currently major health issues in South-East Asia. • Indonesia is the most populated nation in South-East Asia with >260 million residents, the majority are young, and ~11% live in poverty. • Between 1990 and 2016, the life expectancy of Indonesian people increased by 8 years to 71.7 years, which will add to the burden of ageing and chronic disease. • The three major health problems in Indonesia are non-communicable disease, infectious disease, and maternal/child health problems. • The top three causes of death and disability-adjusted life-years (DALYs) in Indonesia are coronary artery disease (CAD), stroke, and diabetes. CVD is the leading cause of death, responsible for ~37% of total deaths. • The risk factors for the CVD burden in Indonesia are hypertension, high cholesterol, diabetes, obesity, and cigarette smoking. High systolic blood pressure, a poor diet, and high fasting plasma glucose are factors that contribute to premature death. • Health surveys in Indonesia have shown that in the general population, ~65% of men smoke, >25% have hypertension, ~30% have high cholesterol and are overweight, ~7% have diabetes, and ~23% take little physical activity. • In Indonesia, ~80% of the whole population had no health insurance until 2013. This started in 2014 and now 180.7 million people (~70%) are insured through JKN (Jaminan Kesehatan Nasional or National Social Health Insurance Scheme). • The national healthcare budget is low. In 2013, there were too few healthcare workers to serve the estimated >2.6 million patients with CAD. In 2016, it was estimated that there were 1.5 cardiologists per 1,000,000 population. • Registry data on cardiovascular diseases and deaths in this low- and middle-income country are lacking. • Awareness, treatment, and control of CVD risk factors are poor in Indonesia.

163 Chapter 9

SUMMARY OF FINDINGS • Infections in early life increase the risk of acquiring acute coronary syndrome (ACS) in young adulthood, and may potentiate the effect of traditional cardiovascular risk factors. (Chapter 2) • Pregnancy complications are significantly associated with premature ACS in adult offspring; the associations are most marked in mothers with high blood pressure and infections during pregnancy. (Chapter 3) • Patients with CAD in Indonesia are predominantly young males and present with relatively severe illness. These patients present late at the hospital and most do not receive the guideline-recommended treatment. (Chapter 4) • At admission, 44% of our cohort were diagnosed with ST-segment elevation myocardial infarction (STEMI), 39% had been diagnosed with or had signs of heart failure, and 75% had prior hypertension. Of 211 STEMI patients, only ~11% underwent reperfusion therapy. (Chapter 4) • The rates of all-cause mortality were high in hospital (11%), at 30 days (3%), and at 6 months (7%) amongst CAD patients in Indonesia, higher than the rates reported from the high- income countries. Meanwhile, the rates of composite MACE were 26% at 30 days and 18% at 6 months. (Chapter 4) • In our cohort, patients with ACS had poorer clinical outcomes than those with stable CAD, mainly in the first 30 days of admission; while patients with stable CAD had experienced more adverse events by 6-month follow-up. (Chapter 4) • Our finding suggests that 6-month survival is significantly better in patients treated with statins, clopidogrel, and revascularization (PCI/CABG) compared with the non-guideline- treated groups. (Chapter 4) • Mortality both during and after hospitalization is incredibly high in patients with CAD in Indonesia. (Chapter 5) • In-hospital and total medium-term mortality significantly differed depending on the underlying disease (higher in non-ST-segment elevation myocardial infarction (NSTEMI) than other diagnosis groups). (Chapter 5) • The independent predictors of medium-term, all-cause mortality in CAD patients in Indonesia are hyperglycemia on admission, heart failure/Killip class ≥2, eGFR <60 ml/min, no revascularization (PCI or CABG), and poor adherence to after-discharge medications. (Chapter 5) • Poor adherence to medications predicted after-discharge mortality, and did so irrespective of the underlying CAD diagnosis (p-interaction=0.88). (Chapter 5) • Adherence to recommendations for coronary angiography (CAG) in a poor South-East Asian setting is low. Factors for not undergoing CAG were older age, female gender, low educational and socio-economic status, and the type of health insurance. (Chapter 6) • Reasons for patients refusing CAG and subsequent intervention included fear, a reduction of symptoms, and lack of trust concerning the benefit of procedure. (Chapter 6)

164 • Among CAD patients in Indonesia during the entire follow-up period (median 19 (IQR 5.5- 39) months), ~33% died and ~55% experienced at least one adverse outcome. (Chapter 6) • Undergoing CAG is significantly associated with lower short- and medium-term all-cause 9 mortality. (Chapter 6) • In patients with CAG, higher SYNTAX scores independently predicted a higher risk of all- cause mortality and MACE. (Chapter 6) • Tele-ECG is an effective tool to support GPs in primary care despite a shortage of cardiologists in this country. The majority (95%) of GPs were satisfied with each Tele-ECG consultation. (Chapter 7) • Of the total ECG recordings (n=10,001), ~73% showed normal findings. Ischemia was seen in 13%, arrhythmia in 18%, and abnormalities related to structural changes in 5%. (Chapter 7) • From our analyses, we found that patients with a normal ECG were predominantly young women, showed better clinical profiles, and had fewer CVD risk factors compared with those with an abnormal ECG. (Chapter 7) • Half of our cohort from primary care had hypertension, 22% were unaware and 33% untreated; while, ~9% of participants had known diabetes. Currently, the standard screening and detection tests for diabetes mellitus and dyslipidemia are generally unavailable in primary care services in Indonesia. (Chapter 7) • Our study shows that more female patients with angina have a normal ECG (p=0.01), while men are prone to have an ischemic ECG (p<0.01). (Chapter 7) • During the entire follow-up (14 ± 6.6 months), 7 (1.4%) patients died and 96 (19.0%) were admitted to hospital due to CVD. (Chapter 7)

165 Chapter 9

IMPLICATION TO RESEARCH FIELD AND CLINICAL PRACTICE • The observed association between early-life infections and premature coronary artery disease could be an etiologically of importance for future prevention strategies to reduce CVD burden in South-East Asia, particularly in Indonesia, where infectious diseases continue to be highly prevalent among the young populations. (Chapter 2) • From our findings, we suggest that optimizing maternal health and nutrition during pregnancy may reduce or delay the development of CVD in the offspring. (Chapter 3) • Vaccination and adequate treatment of pregnant women with infectious disease is practically of importance, especially in populations where the burden of infectious diseases is high. (Chapter 3) • The necessity of standardized data and management of pregnancy complications is essential, particularly in the low-to-middle income South-East Asia populations where the infrastructure, financial, and human resources are limited. (Chapter 3) • The stakeholders in Indonesia should focus on the improvement of primary and secondary prevention for CVD. Awareness of symptoms, standardized initial management for acute CVD, well-established infrastructures and human resources both in primary and secondary care should be improve to reduce the high rates of 30-day and 6-month mortality and morbidity in this population. (Chapter 4) • The initial severity of disease, lack of access to the guideline-recommended treatments and poor adherence to after-discharge medications are the main drivers for excess medium-term mortality. Therefore, hospitalization is an important window of opportunity to address both in-hospital and longer-term survival in patients with CAD. (Chapter 5) • Optimizing medication adherence and lifestyle correction, irrespective of the underlying CAD diagnosis, will likely help to reduce excess CAD mortality. (Chapter 5) • Education for patients and their families, awareness of CVD symptoms, good teamwork amongst clinicians, and infrastructure for invasive intervention should be improved to enhance the adherence to the guideline standard. (Chapter 6) • Standard screening for CVD risk factors should be available and affordable at primary care level in Indonesia. (Chapter 7) • Tele-ECG consulting should be continuously implemented in Indonesia, where cardiologists and distance are the main barriers in delivering cardiovascular care in this low-to-middle income country. (Chapter 7)

166 SAMENVATTING Hartvaatziekten (HVZ) zijn met 37 % de leidende doodsoorzaak in Indonesië. Indonesië is een van 9 de lage midden-inkomenslanden, waarbij de coronaire hartziekten, beroerte en diabetes de top-drie oorzaken zijn van vroege sterfte en invaliditeit.

Risicofactoren voor HVZ manifesteren zich vaak ook op jongere leeftijd. In 2013 was de prevalentie van HVZ in Indonesië >2,6 miljoen gevallen per jaar, waarbij 67% van de patiënten jonger was dan 55 jaar. Ondanks de grote last van HVZ en de risicofactoren, is er nauwelijks onderzoek gedaan naar oorzaken, symptomen, ziektemanagement en resultaten van diagnostiek en behandeling. Zeker in Oost-Indonesië en Sulawesi, een regio met allerlei beperkingen op het gebied van infrastructuur, human resources en financiën. Het proefschrift beschrijft de huidige situatie van diagnostiek en behandelingen van coronaire hartziekten waarbij gebruikt wordt van lokale ‘evidence’. Het werkstuk bestaat uit drie delen. Het eerste gedeelte beschrijven determinanten, aanwezig tijdens de eerste levensjaren, die het risico van HVZ op latere leeftijd vergroten. In het tweede gedeelte worden de specifieke patiënteigenschappen, risicoprofielen, de invloed van de praktijkvoering en de klinische uitkomsten besproken van patiënten met coronaire hartziekten. Dit alles binnen de context van de beperkte beschikbaarheid van middelen. Het derde deel bevat de ervaringen met het eerste e-health / Tele-ECG project in Oost-Indonesië. Tenslotte is Hoofdstuk 8 naast een discussiehoofdstuk opgezet als een ‘position paper’, waarin de bevindingen in de lokale context worden geplaatst en de richting wordt aangegeven hoe de praktijk van de Cardiologie in een arme socio-economische setting zich zou kunnen ontwikkelen.

Deel 1 beschrijft de samenhang tussen infecties in de jeugdjaren en de ontwikkeling van het vroegtijdige acute coronaire syndroom op de volwassen leeftijd (Hoofdstuk 2). Er is sterk bewijs uit studies in zogenaamde hoge-inkomenslanden dat infecties op de kinderleeftijd een onafhankelijke voorspeller zijn voor ziekenhuisopnames ten gevolge van HVZ, ongunstige metabole profielen zoals Diabetes Mellitus en hoog- cholesterolgehalte en subklinische teken van arteriosclerose.

Het bleef onduidelijk of de grote mate van infecties waaraan kinderen in Indonesië lijden ook een invloed hebben, naast andere factoren, voor een grotere kans van HVZ op latere leeftijd. Onze populatie -gebaseerde case-control studie laat zien dat er toch een driemaal hogere kans op HVZ wanneer men op de baby-en kinderleeftijd veel infecties had doorgemaakt. De effecten van de traditionele risicofactoren op latere leeftijd worden er kennelijk door versterkt.

In Hoofdstuk 3 werd nader gekeken of en op welke wijze zwangerschapscomplicaties bij de moeder, die veel voorkomen in Indonesië, een effect hebben op het voorkomen van klinisch manifest kransvatlijden. De bevindingen van onze studie suggereren dat nakomelingen van moeders met zwangerschapscomplicaties in hun latere leven een verhoogd risico op een acuut coronair syndroom

167 Chapter 9 hebben. In het bijzonder als de moeders hoge bloeddruk hadden en zelf ook een geschiedenis van veelvuldige infectieziekten hadden. Ook ontwikkelden zij eerder op volwassen leeftijd HVZ.

In deel twee worden de bijzondere kenmerken en behandeluitkomsten van patiënten met een acuut coronair syndroom en stabiel kransvatlijden besproken. Het betreft een prospectieve cohort studie waarbij patiënten werden gevolgd die zich in het Makassar Hartcentrum op de Eerste Harthulp melden met acute ‘pijn -op -de -borstklachten’. In Hoofdstuk 4 worden de diagnostiek, behandelmodaliteiten en de uitkomsten na 30 dagen en 6 maanden na opname gepresenteerd. Deze studie laat zien dat patiënten met kransvatziekte in Indonesië vooral jonge mannen zijn die zich presenteren met een hoog-risicoprofiel. Meer dan de helft van de patiënten leed aan het metabool syndroom, hoge bloeddruk, terwijl een derde leed aan Diabetes Mellitus of eerder al een hartinfarct had gehad. De meerderheid van de patiënten woonde op het platteland en hadden een laag tot middel-laag inkomen, voor Indonesische begrippen. Het merendeel van de patiënten rookte. We stelden vast dat de patiënten zich relatief laat meldden en met ernstige symptomen. De daaropvolgende behandeling en nabehandeling was zelden conform de geldende richtlijnen. In de eerste 30 dagen na opname waren de uitkomsten in de patiënten met acuut coronair syndroom slechter, wat men ook zou verwachten. Echter, na 6 maanden ondervonden de stabiele patiënten meer incidenten en was ook de sterfte hoger. Wij verklaren dit uit onderschatting van ernst van ziekte en ontbreken van secundaire preventie. Zeker hoger in vergelijking met de uitkomsten gerealiseerd voor een dergelijke groep in hoge-inkomenslanden. Onze bevindingen suggereren dat bewustwording van risicofactoren en symptomen bij de patiënt, maar ook diagnostische work-up en behandeling conform de richtlijnen tot sterke verbetering kan leiden.

In Hoofdstuk 5 worden middellange-termijn uitkomsten en de voorspellers voor acute en chronische kransvatziekte besproken. Tijdens de gemiddelde follow-upduur van 18 maanden (6- 36 maanden) overleden 32,3% van de patiënten, wat ook hoog is in een arme socio-economische setting. Patiënten met een non-ST-segment elevation myocardial infartion (NSTEMI) hadden de slechtste overlevingsuitkomsten. Hyperglycemie bij opname, hartfalen Killip Class>2, gestoorde nierfunctie, ontbreken van revascularisatie (PCI of CABG) en slechte inname van medicatie waren belangrijke voorspellers van sterfte. Zoals in hoofdstuk 4 ook al aangegeven, kunnen verbeterde toegang tot zorg in geval van klachten en patiënten educatie de late sterfte terugdringen, na een eerdere opname.

In Hoofdstuk 6 werd onderzocht in hoeverre de richtlijnen voor coronair angiografie werden gevolgd bij opname op de Eerste Harthulp van het Makassar Hartcentrum en wat de gevolgen hiervan zijn. De richtlijnen voor coronair angiografie worden slecht gevolgd. Oudere vrouwen uit de lagere sociaaleconomische klasse ondergaan nauwelijks de procedure. Naast financiële redenen weigeren patiënten de procedure vanwege angst, het feit dat de klachten afnemen tijdens opname en gebrek aan vertrouwen in het effect en gevolgen van de interventie. Zoals eerder gezegd

168 overleed 33 % en ondervond 55% van de patiënten een cardiovasculair adverse event. Patiënten die een coronair angiogram ondergingen hadden een significant lagere sterftekans op de korte en middellange termijn. Overigens, voorspelde een hogere SYNTAX score een hogere kans op sterfte en 9 cardiovasculaire events.

In Hoofdstuk 7 wordt de implementatie van het eerste Tele-ECG programma in Oost-Indonesië beschreven. Wij beoordeelden de impact van het programma op de zorg en de klinische uitkomsten bij een steekproef van 505 uit 10.001 patiënten. In deze regio is er een ernstig tekort aan cardiologen en wordt de primaire opvang gedaan door Eerstelijnsartsen. Het Tele-ECG is een vorm van decision- support voor deze artsen. Deze kunnen een Tele-ECG maken en met een aantal kerngegevens opsturen naar de cardioloog van dienst, die binnen 12 uur reageert. Acute patiënten dienen onverwijld naar de Eerste Harthulp te worden verwezen. Ongeveer 95% van de verwijzend artsen was tevreden.

Patiënten met een normaal ECG waren vooral vrouwen, met minder symptomen en minder risicofactoren voor HVZ. Van de 88 (17,4%) patiënten bij wie opname werd geadviseerd werden inderdaad 72 patiënten binnen 48 uur opgenomen. Gedurende de follow-up periode van 14 maanden overleed 1,4% en werd 19% van de 505 patiënten opgenomen.

In deze grote groep van patiënten met klachten, die in de ogen van de verwijzend arts een vorm van cardiologische zorg verdienden blijkt het Tele-ECG beslis ondersteunend en geruststellend te werken. Echter, gezien ook de goede uitkomsten op langere termijn vindt kennelijk selectie plaats en wordt bevestigd dat het Tele-ECG bij patiënten met beperkte symptomen en risicofactoren een beperkt of geen op sterfte ten gevolge van HVZ heeft.

Tenslotte bespreken we in Hoofdstuk 8 (General Discussion) onze bevindingen in de context van de huidige zorgpraktijk voor HVZ in een ‘poor South-East Asian setting’. Naast het delen van de onderzoekservaringen, ontkomen we er niet aan vast te stellen dat er infra structurele tekorten zijn en er vooral uitdagingen liggen op het gebied van educatie inzake de richtlijnen en bewustwording bij de patiënt. Zeker waar het secundaire preventie betreft.

Gezien de specifieke uitdagingen stellen wij een gerichte aanpak voor (zie tabellen) om de kwaliteit van zorg te verbeteren op basis van local-evidence en eigen onderzoek.

169 Chapter 9

RANGKUMAN

Penyakit kardiovaskular merupakan penyebab utama kematian di Indonesia, bertanggung jawab atas ~37% dari total kematian nasional. Indonesia termasuk salah satu negara berpendapatan menengah bawah, dimana tiga penyebab kematian dan kecacatan dini di negara ini adalah penyakit jantung koroner (PJK), stroke, dan diabetes. Faktor risiko kardiovaskular kebanyakan dimiliki dan bermanifestasi pada populasi muda. Pada tahun 2013, terdapat >2,6 juta kasus PJK, dimana 67% pasien berumur kurang dari 55 tahun. Meski angka kesakitan dan faktor risiko penyakit kardiovaskular di negara ini cukup tinggi, baik penyebab, karakteristik, manajemen, dan outcome pasien belum pernah diteliti lebih mendalam, terutama di wilayah Indonesia Timur, dimana infrakstruktur, sumber daya manusia dan pendanaan sangat terbatas. Tesis ini menjabarkan penyakit jantung koroner di Indonesia saat ini, berdasarkan investigasi dan hasil temuan setempat. Secara garis besar, kami mendeskripsikan tesis ini menjadi 3 bagian. Bagian pertama terutama mengeksplorasi faktor-faktor di awal kehidupan yang berpotensi meningkatkan risiko penyakit kardiovaskular dini di kemudian hari. Pada bagian kedua, kami menguraikan karakteristik pasien, profil klinis, kondisi saat masuk rumah sakit, manajemen, serta outcome pasien di populasi dengan keterbatasan sumber daya. Bagian ketiga menjelaskan bukti terbaru mengenai pelaksaan pilot proyek telemedicine di negara berkembang seperti Indonesia. Terakhir, di Bab 8, kami membahas semua temuan kami dan bagaimana hal tersebut berhubungan dengan kondisi pelayanan klinis penyakit jantung di populasi Asia Tenggara dengan sumber daya yang sangat terbatas.

Bagian 1 meneliti hubungan antara infeksi pada kehidupan lampau (masa kanak-kanak dan remaja) dengan terjadinya sindrom koroner akut (SKA) dini pada saat dewasa (Bab 2). Bukti konsisten sebelumnya dari negara-negara maju menunjukkan bahwa infeksi berat pada masa kanak-kanak secara bermakna berhubungan dengan rawat inap untuk penyakit kardiovaskular, profil metabolik yang buruk, dan aterosklerosis subklinik saat dewasa; namun, apakah infeksi, penyakit yang sangat lazim dijumpai pada anak-anak di Indonesia, juga berhubungan dengan tingginya insiden penyakit kardiovaskular saat ini masih belum jelas. Berdasarkan studi case-control yang kami ambil dari populasi setempat (153 kasus dan 153 kontrol), baik hasil analisis univariabel maupun multivariable, terbukti bahwa infeksi berulang yang dialami pada masa kanak-kanak berhubungan dengan meningkatnya risiko untuk menderita SKA dini sebesar tiga-kali lipat. Secara keseluruhan, hubungan tersebut dipengaruhi oleh skor risiko Framingham, dan hal ini mengidikasikan bahwa infkesi pada masa kanak-kanak dapat mempotensiasi efek dari faktor risiko tradisional penyakit kardiovaskular.

Pada Bab 3, kami menguraikan lebih lanjut faktor risiko di awal kehidupan yang dapat mengakibatkan penyakit kardiovaskular. Oleh karena komplikasi kehamilan dan penyakit kardiovaskular saat ini merupakan masalah kesehatan utama pada populasi Asia Tenggara, maka sangat penting untuk meneliti apakah komplikasi kehamilan tersebut dapat dikaitkan dengan kejadian SKA pada anak

170 dari wanita yang mengalami komplikasi. Temuan kami menunjukkan bahwa anak yang lahir dari ibu dengan komplikasi selama kehamilan memiliki risiko tinggi untuk menderita SKA dini pada saat dewasa, terutama mereka yang lahir dari ibu dengan tekanan darah tinggi dan infeksi. 9 Pada bagian 2, kami menjelaskan secara rinci karakteristik, manajemen, dan outcomes dari pasien dengan SKA (n=364) dan PJK stabil (n=113) berdasarkan studi kohort prospektif yang kami lakukan di Indonesia. Kami memulai dengan menyajikan karakteristik pasien dan rerata outcomes jangka pendek, saat 30 hari dan 6 bulan setelah masuk rumah sakit (Bab 4). Studi ini menunjukkan bahwa di Indonesia, pasien dengan penyakit kardiovaskular didominasi oleh laki-laki muda dan memiliki profil klinis yang berisiko tinggi. Lebih dari setengah dari kohort yang kami teliti menderita sindrom metabolik dan hipertensi, dan sekitar sepertiga memiliki riwayat diabetes mellitus dan infark miokard sebelumnya. Sebagian besar pasien berasal dari daerah pedesaan, dengan status sosial- ekonomi rendah atau menegah, dan memiliki riwayat merokok. Dari pengamatan kami, pasien PJK di Indonesia pada umumnya datang terlambat dalam mendapatkan penanganan awal di rumah sakit, menunjukkan penyakit yang relatif berat, dan jarang menerima perawatan yang sesuai rekomendasi. Pasien SKA memiliki outcome klinis yang lebih buruk dibandingkan dengan mereka yang menderita PJK stabil, terutama dalam 30 hari pertama; sementara mereka dengan PJK stabil mengalami lebih banyak kejadian yang tidak diinginkan (adverse events) pada follow-up bulan ke-6. Dalam grup SKA, total kematian baik saat 30 hari maupun 6 bulan, persentasinya lebih tinggi bila dibandingkan dengan temuan dari negara-negara maju lain yang dilaporkan sebelumnya. Temuan kami menunjukkan bahwa kesadaran akan gejala, manajemen awal penyakit kardiovaskular akut, serta sumber daya kesehatan dan infrastruktur, harus diperbaiki dan ditingkatkan untuk mengurangi tingkat mortalitas dan adverse events jangka pendek pada populasi ini.

Bab 5 melaporkan hasil penelitian jangka menengah dan faktor prediktor kematian pada pasien PJK akut dan kronis, baik selama dan setelah rawat inap. Setelah kami follow-up (median 18 (IQR 6-36) bulan), sebanyak 154 ( 32.3% ) pasien meninggal. Penelitian kami menunjukkan bahwa mortalitas pada pasien PJK – baik saat perawatan di rumah sakit maupun setelahnya (jangka menengah) – menunjukkan angka yang tinggi di populasi sosio-ekonomi rendah di Asia Tenggara. Dibandingkan dengan grup diagnosis lain (STEMI, unstable angina, dan PJK stabil), pasien dengan non-ST-segmen elevasi infark miokard (NSTEMI) menunjukkan outcome yang paling buruk. Studi kami membuktikan bahwa hiperglikemia saat masuk rumah sakit, gagal jantung atau kelas killip >2, tingkat filtrasi glomerulus <60 ml/menit, tidak menerima revaskuralisasi (PCI atau CABG), dan ketidak-patuhan mengkonsumsi obat setelah rawat inap, merupakan prediktor signifikan yang berhubungan dengan mortalitas jangka menengah pada pasien PJK di Indonesia. Studi kami menunjukkan bahwa untuk survival yang lebih baik, akses cepat dan berkelanjutan terhadap pelayanan rumah sakit, dan pendidikan kepada pasien harus diprioritaskan.

171 Chapter 9

Di Bab 6, kami mengukur kepatuhan terhadap pedoman yang direkomendasikan untuk melakukan angiografi/kateterisasi koroner di Indonesia dengan keterbatasan sumber daya yang ada. Penelitian ini juga dimaksudkan untuk mengukur efek jangka pendek dan menengah dari kepatuhan terhadap pedoman ini. Berdasarkan data kami, kepatuhan terhadap rekomedasi kateterisasi koroner dalam populasi Indonesia masih rendah. Wanita yang lebih tua dengan tingkat pendidikan dan sosial- ekonomi rendah cenderung tidak menjalani prosedur ini. Motivasi pasien untuk menolak kateterisasi koroner dan prosedur lanjutan, terutama disebabkan oleh ketakutan, berkurangnya gejala, dan kurangnya kepercayaan akan manfaat prosedur tersebut. Selama follow-up (median 19 (IQR 5,5- 39) bulan), 33% dari peserta kohort kami meninggal dan 55% mengalami setidaknya satu adverse event. Menjalani kateterisasi koroner berhubungan signifikan dengan risiko yang lebih rendah akan terjadinya kematian jangka pendek dan menengah; sementara dalam analisis sub-grup, memiliki skor SYNTAX yang lebih tinggi secara bermakna berhubungan dengan risiko yang lebih besar untuk terjadinya kematian dan kesakitan.

Bagian 3 (Bab 7) membahas implementasi dari program telemedicine (Tele-EKG) yang pertama kali dilaksanakan di tingkat pelayanan primer di wilayah yang kurang berkembang di kawasan Indonesia Timur. Kami juga menilai dampak program ini terhadap outcome pasien (n=505). Dari penelitian ini, kami menemukan bahwa Tele-EKG membantu dokter umum dan mendukung pengambilan keputusan di tingkat pelayanan primer terkait manajemen pasien. Gejala sedang dan berulang bersamaan dengan adanya faktor risiko, memperbesar kemungkinan untuk memiliki hasil EKG yang abnormal. Kebanyakan dokter (95%) merasa puas dengan kinerja konsultasi Tele-ECG ini. Penelitian kami menunjukkan bahwa pasien dengan EKG normal kebanyakan adalah wanita muda yang memiliki profil klinis yang baik dan memiliki lebih sedikit faktor risiko, dibandingkan dengan mereka yang memiliki EKG abnormal. Dari 88 pasien yang direkomendasikan untuk perawatan lebih lanjut di rumah sakit, 72 (81.8%) dirujuk ke rumah sakit dalam 48 jam setelah konsultasi. Setelah follow-up selama 14 ± 6.6 bulan, tujuh (1.4%) pasien meninggal dan 96 (19.0%) dirawat di rumah sakit karena penyakit kardiovaskular.

Mayoritas (~80%) pasien yang dirujuk menunjukkan nyeri dada sedang dan dicurigai menderita penyakit jantung iskemik. Di masa yang akan datang, program telemedicine ini diharapkan mampu menyeleksi pasien dengan risiko tinggi atau pasien yang dicurigai menderita penyakit kardiovaskular di pedesaan dan daerah terpencil, dimana dokter ahli jantung sangat kurang, dan fasilitas perawatan penyakit jantung masih sangat terbatas atau tidak tersedia sama sekali.

Akhirnya, di Bab 8 (General Discussion), kami mendiskusikan hasil temuan yang berhubungan dengan kondisi pelayanan kardiovaskular di Asia Tenggara yang memiliki keterbatasan sumber daya. Penulis merangkum masalah utama dalam praktek klinis kardiovaskular; serta berbagi pengalaman dan tantangan yang dihadapi dalam melaksanakan penelitian klinis di Indonesia dengan populasi masyarakat yang berasal dari tingkat sosio-ekonomi rendah dan menengah.

172 Pada akhirnya, penulis menawarkan solusi untuk meningkatkan kualitas pelayanan kardiovaskular di Indonesia. 9

173 174 175 Chapter 10

PRESS RELEASES

Press releases of manuscript presented on Chapter 2 Date : October 17, 2015 Source : European Society of Cardiology (ESC) Press Office

CHILDHOOD INFECTIONS ASSOCIATED WITH INCREASED RISK OF EARLY HEART ATTACK

Unhealthy lifestyles in adulthood appear to compound the risk

Vienna, Austria – 17 October 2015: Infections in childhood are associated with an increased risk of early heart attacks, according to research presented today at Acute Cardiovascular Care 2015 by Dr Andriany Qanitha, a PhD candidate at the Academic Medical Centre in Amsterdam, the Netherlands.1 Unhealthy lifestyles in adulthood appear to compound the risk of early heart attack.

“Cardiovascular disease (CVD) is the number one killer worldwide, including in Indonesia where it accounts for ~32% of all deaths,” said Dr Qanitha. “CVD risk factors are rising rapidly in South-East Asia, particularly in young people. Many CVD patients in Indonesia are 55 years or below, and still economically productive. This young CVD onset raises the question of whether local circumstances may play a role.”

She continued: “Infectious diseases such as typhoid fever, measles, chicken pox, bronchitis, tuberculosis and dengue fever are common in Indonesian children. We hypothesised that infections experienced in childhood and adolescence might adversely affect the vasculature and initiate atherosclerosis, leading to premature acute coronary syndromes (ACS) or heart attacks.”

This was a population-based case-control study of 153 patients with a first ACS before the age of 56 years and 153 age- and sex-matched controls with no history of ACS in Makassar, Indonesia. Severe infection was defined as fever for three days or more, or hospitalisation due to infectious disease. In Indonesia there is no reliable registry data on infection related hospitalisation and prescription of antibiotics. The researchers used a detailed questionnaire and interviews with patients and controls, plus family members (parents, aunts, uncles, siblings), to obtain information on history of infection during four periods of early life: infancy and pre-school (0–5 years), elementary school (6–13 years), junior high school (14–17 years), and senior high school (18–21 years). Interviewees were asked to verify the information with other family members if they were in doubt. The researchers used the information to calculate an infection score ranging from 0 to 4. Positive early-life infection was defined as a score of 2 or more.

Information about traditional CVD risk factors was obtained using an interviewed-questionnaire and diagnostic test results in cases and contemporary tests in controls. Data was recorded on age, sex, occupation, monthly income, educational level, dietary pattern, physical activity, smoking status, family history of heart disease, diabetes, sudden cardiac death, and known history of hypertension and diabetes. Study participants were 47 years old on average (range 28–55 years) and 81.7% were

176 male. In crude analysis, infection experienced in childhood and adolescence was associated with a three-fold higher occurrence of premature ACS later in life.

The investigators used four models which taken together adjusted for smoking status, physical activity, diet pattern, socioeconomic status, parental CVD history, and traditional risk factors. Due to 10 sample size, the analyses were restricted to less than 15 variables in one model. Adjusted odds ratios for the association between childhood infection and risk of premature ACS ranged from 2.5 to 4.2 and all were significant.

The researchers investigated whether early-life infection modifies the effect of traditional risk factors on developing early CVD. The Framingham risk score (FRS) was used to rank all participants as low, intermediate, or high risk based on age, gender, total and HDL cholesterol, smoking status, diabetes, blood pressure, and use of blood pressure medications. There was an indication for interaction between childhood infection and CVD risk factors (p=0.052). “This suggests that infection in childhood may potentiate the impact of traditional risk factors on premature ACS,” said Dr Qanitha.

The risk of premature ACS in patients with childhood infections increased with more CVD risk factors, with odds ratios of 1.5, 4.4 and 10.0 for low, intermediate, and high Framingham risk scores, respectively (all significant). “One explanation is that high exposures to infection may initiate chronic inflammation and induce atherosclerosis in the arteries,” said Dr Qanitha. “It could be that infection modifies traditional CVD risk factors and leads to the development of ACS in adult life.

She concluded: “Our findings may apply to other countries in South-East Asia where infectious disease is still prevalent. Here governments and policymakers should have a combined strategy for tackling infectious disease and cardiovascular disease. Early-life infection may be a relatively unknown contributing factor in ACS occurrence.”

References 1Dr Andriany Qanitha will present the abstract ‘Early-life infection and premature acute coronary syndrome: a case-control study’ during: Poster Session 1: Databases, Registries and Surveys on 17 October at 08:30 to 12:30 CEST

Sources of Funding The study was sponsored by the Directorate General of Higher Education (DGHE) Ministry of National Education Republic of Indonesia, based on letter No. 600/E4.4/K/2011, dated July 12, 2011.

Disclosures None. This press release is based on an abstract presented at Acute Cardiovascular Care 2015 and this does not necessarily reflect the opinion of the European Society of Cardiology.

ESC Press Office Tel: +33 (0) 4 92 94 86 27 Email: [email protected]

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Press release of manuscript presented on Chapter 2

Date : November 14, 2015 Source : Warta Kota, Tribun News (2015). (http://wartakota.tribunnews.com/2015/11/14/infeksi-pada-anak-anak-tingkat- kan-risiko-penyakit-jantung)

INFEKSI PADA ANAK TINGKATKAN RISIKO PENYAKIT JANTUNG

Siapa pun yang pernah terkena penyakit menular yang serius di masa kanak-kanak berisiko signifikan lebih tinggi untuk memiliki penyakit kardiovaskular di usia yang relatif muda.

Hal ini juga berlaku untuk penyakit anak-anak yang dianggap biasa seperti campak atau cacar air.

Mekanisme di balik fenomena ini telah diketahui sejak lama: sel-sel kekebalan yang beredar di dalam darah untuk melawan infeksi berperan dalam penciptaan plak di pembuluh darah. Hasilnya adalah aterosklerosis yang meningkatkan risiko serangan jantung dan stroke. Misalnya, penderita radang gusi kronis memiliki risiko lebih tinggi terkena serangan jantung atau stroke.

Para peneliti yang dipimpin oleh dr. Adriany Qanitha dari Academic Medical Center di Amsterdam menemukan dampak infeksi serius di masa kanak-kanak terhadap kondisi pembuluh darah. “Penyakit kardiovaskular (PKV) adalah pembunuh nomor satu di seluruh dunia, termasuk di Indonesia yang menyumbang ~32% dari semua kematian,” kata Dr Andriany Qanitha.

“Faktor risiko PKV meningkat pesat di Asia Tenggara, terutama pada orang muda. Kebanyakan pasien PKV di Indonesia berusia di bawah 56 tahun dan masih produktif secara ekonomi. PKV yang dimulai pada usia sangat muda ini menimbulkan pertanyaan apakah situasi lokal turut berperan. Penyakit menular seperti demam tifoid, campak, cacar air, bronchitis, TBC dan demam berdarah adalah umum pada anak-anak Indonesia. Kami berhipotesis bahwa infeksi yang dialami di masa kecil dan remaja mungkin memengaruhi pembuluh darah dan memicu aterosklerosis, yang menyebabkan sindrom koroner akut (SKA) atau serangan jantung.”

Studi kasus terkontrol berbasis populasi tersebut melibatkan 153 penderita sindrom koroner akut (SKA) sebelum usia 56 tahun dan 153 relawan kontrol dengan usia dan jenis kelamin sesuai yang tidak memiliki riwayat SKA di Makassar, Indonesia.

SKA termasuk berbagai bentuk penyakit kardiovaskular yang disebabkan oleh penutupan atau penyempitan parah arteri koroner seperti angina atau serangan jantung.

Di Indonesia belum ada register yang dapat diandalkan mengenai rawat inap terkait infeksi dan resep antibiotik. Para peneliti menggunakan kuesioner rinci dan wawancara dengan pasien dan relawan kontrol beserta anggota keluarga mereka (orang tua, bibi, paman, saudara), untuk mendapatkan informasi mengenai riwayat infeksi selama empat periode di awal kehidupan: bayi dan pra-sekolah (0-5 tahun), sekolah dasar (6-13 tahun), SMP (14-17 tahun), dan SMA (18-21 tahun).

178 Infeksi berat didefinisikan sebagai demam selama tiga hari atau lebih atau rawat inap karena penyakit infeksi. Terwawancara diminta untuk memastikan informasi dengan anggota keluarga lain bila mereka ragu. Para peneliti menggunakan informasi tersebut untuk menghitung skor infeksi mulai dari 0 sampai 4. Infeksi positif di awal kehidupan didefinisikan dengan skor 2 atau lebih. 10

Para peneliti juga mempertimbangkan faktor risiko lain untuk penyakit kardiovaskular seperti merokok, obesitas, hipertensi, diabetes, aktivitas fisik, pola diet dan riwayat penyakit kardiovaskular dalam keluarga.

Hasil analisis menunjukkan bahwa orang-orang yang setidaknya pernah terkena dua infeksi serius di masa kanak-kanak dan remaja berisiko hampir tiga kali lebih tinggi untuk memiliki SKA di kemudian hari. Salah satu penjelasannya adalah bahwa infeksi di masa kanak-kanak menyebabkan proses inflamasi kronis yang memicu aterosklerosis di arteri.

Dr. Qanitha menyimpulkan: “Temuan kami mungkin berlaku untuk negara-negara lain di Asia Tenggara di mana penyakit menular masih umum. Pemerintah dan para pembuat kebijakan harus memiliki strategi terpadu untuk menanggulangi penyakit menular dan penyakit kardiovaskular. Infeksi di awal kehidupan mungkin menjadi faktor yang relatif belum diketahui untuk SKA.”

Sumber Qanitha et al.: Adverse early-life environment and premature acute coronary syndrome: a case-control study, European Heart Journal: Acute Cardiovascular Care (2015) 4 (Supplement 5), S39.

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Press release of manuscript presented on Chapter 3 Date : May 24, 2017 Source : Heart Asia, British Medical Journal (BMJ)

PREGNANCY COMPLICATIONS LINKED TO HEIGHTENED HEART DISEASE RISK IN YOUNG ADULT OFFSPRING

Risks strongest for high blood pressure and infections in moms-to-be, findings suggest

Complications of pregnancy, such as high blood pressure and infections, are linked to a heightened risk of early coronary heart disease in the young adult offspring, finds research published in the online journal Heart Asia.

The findings may be particularly relevant for developing nations, where the population is in transition and new cases of both pregnancy complications and heart disease are high, suggest the researchers.

More than 600 million people live in South East Asia, most of whom are under the age of 65. But rates of premature deaths attributable to non-communicable diseases are high, with one in three occurring before the age of 60.

To find out if complications of pregnancy might be associated with the risk of early coronary heart disease, the researchers compared 153 patients with acute coronary syndrome, which includes heart attack and angina, with the same number of healthy people matched for age and sex.

The heart patients had been diagnosed before the age of 55 (average age 47), and admitted to one cardiac centre in eastern Indonesia.

Detailed information was collected from both groups on background social and economic factors, current lifestyle, cardiovascular risk factors, and parents’ history of heart disease, and this was combined with the results of a physical examination and relevant lab tests.

Maternal medical history included complications of pregnancy - specifically, high blood pressure; premature birth; and any respiratory, gut, genitourinary, malarial/dengue fever, measles, chickenpox and unspecified infections which had lasted for at least three days and/or had required admission to hospital.

Patients with premature heart disease were more likely to have relevant risk factors than their healthy counterparts. These included high blood pressure and/or diabetes, eating an unhealthy diet, and smoking.

But their mothers were more likely to have experienced pregnancy complications: 30 of their mothers (just under one in five of the whole group) had done so compared with 11 (just over 7%) in the healthy group.

180 When all the data were analysed, those whose mothers had experienced a complication of pregnancy were almost three times as likely to develop early coronary artery heart disease as those whose mothers had had a problem-free pregnancy. 10 The findings held true, irrespective of potentially influential risk factors, such as lifestyle and unfavourable lab test results.

This is an observational study so no firm conclusions can be drawn about cause and effect. Nevertheless, the researchers suggest that maternal ill health during pregnancy might compromise fetal health by disrupting normal physiological processes, potentially leaving the developing baby vulnerable to subsequent heart disease.

And they say their findings point to the need to ensure optimal health and nutrition of a mum-to-be throughout her pregnancy as this might help stave off or curb the risk of early heart disease in her children. This includes prompt and appropriate treatment of any illness and preventive healthcare, such as vaccination, they say.

Journal Reference Andriany Qanitha, Bastianus A J M de Mol, David P Burgner, Peter Kabo, Dara R Pabittei, Irawan Yusuf, Cuno S P M Uiterwaal. Pregnancy-related conditions and premature coro‐nary heart disease in adult offspring. Heart Asia, 2017; 9 (1): 90 DOI: 10.1136/heartasia-2017-010896

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Press release of manuscript presented on Chapter 4 Source : UMCU Featured Article

RECENT PUBLICATION ON CASES OF CORONARY ARTERY DISEASE IN SOUTH-EAST ASIA

The article “Characteristics and the average 30-day and 6-month clinical outcomes of patients hospitalised with coronary artery disease in a poor South-East Asian setting: the first cohort from Makassar Cardiac Center, Indonesia” published on 27 June 2018 concerns cases of patients with coronary artery disease primarily in poor areas of Indonesia.

The challenges that arise from non-communicable diseases (NCDs) are becoming increasingly relevant in the field of public health. It is especially important to analyze such diseases with a global perspective and to conduct research in areas where people are more likely at risk than others. This article concerns patients hospitalized with coronary artery disease (CAD), a type of cardiovascular disease (CVD), in the context of a poor South-East Asian setting. South-East Asia accounts for about 25% of the world’s population but about 40% of the world’s poor. Rising population in conjunction with high poverty levels has created an epidemiological transition that leads to high rates of premature death by NCDs, especially due to CVD. So far there is limited data on characteristics at admission and clinical outcomes in patients with CAD, so this article aims to fill in these knowledge gaps.

This study examined 477 consecutive patients with CAD that were admitted to the Makassar Cardiac Center, DR. Wahidin Sudirohusodo Hospital, in Makassar, Indonesia. Data was collected between February 2013 and December 2014 and the results examined characteristics of admission and clinical outcomes at 30-day and 6-month follow-up periods. Out of 477 patients, 53.9% were under the age of 60 and 72.7% were male. Mortality rates were 13.4% at the 30-day and 7.3% at the 6-month check-up, higher than previous reports in other countries. In general, patients with CAD in Indonesia had high blood pressure, and most came from rural areas and from low and middle socioeconomic status. In addition, many patients were current or former smokers, had poor dietary habits with high consumption of sugar and deep-fried food, and had low physical activity. These findings are especially interesting when compared to that of other countries. For example, South-East Asia has far less overweight or obese inhabitants than Western countries (22% in South-East Asia versus 67% in the United Kingdom and 70% in the United States), but diabetes is among the top three risk factors in Indonesia. In addition, physical inactivity levels in Indonesia (58.1%) are higher than that of Malaysia (51.6%), the United Kingdom (40.0%) and the United States (35.0%). The instances of disease in Indonesia are certainly aided by widespread areas of low income. People in poorer areas are not only more likely to contract diseases such as CAD, but they are also more likely to be unaware of their symptoms and more likely to lack proper hospital infrastructure and resources. Further, CAD patients in this poor setting more often present in the hospital with severe illness and prolonged delay from the first symptom, and most do not receive the guidelines-recommended treatment during hospitalization. This study took this presumption that poorer areas are more likely to be struck by diseases and investigated the characteristics of patients that get admitted with the prevalent CAD.

You can read the full article here: https://www.ncbi.nlm.nih.gov/pubmed/29950477

182 MANUSCRIPTS PRESENTED IN THIS THESIS

Qanitha A, de Mol BA, Pabittei DR, Mappangara I, van der Graaf Y, Dalmeijer GW, Burgner DP, Uiterwaal CS. Infections in early life and premature acute coronary syndrome: A case-control 10 study. Eur J Prev Cardiol. 2016;23:1640-1648. doi: 10.1177/2047487316640656.

Qanitha A, de Mol BAJM, Burgner DP, Kabo P, Pabittei DR, Yusuf I, Uiterwaal CSPM. Pregnancy- related conditions and premature coronary heart disease in adult offspring. Heart Asia. 2017;9:90-95. doi: 10.1136/heartasia-2017-010896.

Qanitha A, Uiterwaal CSPM, Henriques JPS, Alkatiri AH, Mappangara I, Mappahya AA, Patellongi I, de Mol BAJM. Characteristics and the average 30-day and 6-month clinical outcomes of patients hospitalised with coronary artery disease in a poor South-East Asian setting: The first cohort from Makassar Cardiac Center, Indonesia. BMJ Open. 2018;8:e021996. doi: 10.1136/ bmjopen-2018-021996.

Qanitha A, Uiterwaal CSPM, Henriques JPS, Mappangara I, Idris I, Amir M, de Mol BAJM. Predictors of medium-term mortality in patients hospitalised with coronary artery disease in a resource-limited South-East Asian setting. Open Heart. 2018;5:e000801. doi: 10.1136/ openhrt-2018-000801

Qanitha A, Uiterwaal CSPM, Henriques JPS, Mappangara I, Amir M, Saing SG, de Mol BAJM. Adherence to guideline recommendations for coronary angiography in a poor South-East Asian setting: Impact on short- and medium-term clinical outcomes. Under review

Qanitha A, Mappangara I, Uiterwaal CSPM, Henriques JPS, de Mol BAJM. Tele-ECG consulting and outcomes on primary care patients in a low-to-middle income country: The first experience from Makassar Telemedicine Program. Submitted

Qanitha A, Uiterwaal CSPM, Henriques JPS, Qalby N, de Mol BAJM. Clinical cardiology in a South- East Asian setting: lessons from the present towards improvement. Submitted

183 Chapter 10

CONTRIBUTING AUTHORS

Abdul H Alkatiri, MD Department of Cardiology and Vascular Medicine, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia

Ali A Mappahya, MD, DR Department of Cardiology and Vascular Medicine, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia

Bastianus A.J.M de Mol, MD, PhD Department of Cardio-thoracic Surgery, AMC Heart Center, Amsterdam University Medical Center, The Netherlands

Cuno S.P.M Uiterwaal, MD, PhD Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands

Dara R Pabittei, MD, PhD Department of Physiology, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia

David P Burgner, MD, PhD Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia Murdoch Children’s Research Institute, Parkville, Victoria, Australia Department of Paediatrics, Monash University, Clayton, Victoria, Australia

Gerdien W Dalmeijer, PhD Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands

Idar Mappangara, MD, DR Department of Cardiology and Vascular Medicine, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia

Ilhamjaya Patellongi, MD, DR Department of Physiology, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia

Irawan Yusuf, MD, PhD Department of Physiology, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia

Irfan Idris, MD, DR Department of Physiology, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia

Jose P.S Henriques, MD, PhD Department of Cardiology, AMC Heart Center, Amsterdam University Medical Center, The Netherlands

184 Muzakkir Amir, MD, DR Department of Cardiology and Vascular Medicine, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia 10 Nurul Qalby, MD Department of Cardio-thoracic Surgery, AMC Heart Center, Amsterdam University Medical Center, The Netherlands

Peter Kabo, MD, PhD Department of Cardiology and Vascular Medicine, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia

Sumarsono G Saing, S.Si, M.Adm.Kes Catheterization Laboratory Unit, DR. Wahidin Sudirohusodo General Hospital, Makassar, Indonesia

Yolanda van der Graaf, MD, PhD Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands

185 Chapter 10

PHD PORTFOLIO

Name PhD student : Andriany Qanitha, MD, MSc PhD period : 2012 – 2018 Name PhD supervisors : Prof. B. A. J. M de Mol, MD, PhD, JD (AMC–UvA) Prof. J. P. S. Henriques, MD, PhD (AMC–UvA) C. S. P. M. Uiterwaal, MD, PhD (UMC Utrecht)

1. PHD TRAINING Workload Year (ECTS) General courses (AMC Graduate School)

− The AMC World of Science 2012 0.7 − Pubmed 2012 0.6 − EndNote/citation manager 2014 0.1 − Embase/Medline via Ovid 2014 0.1 − Scientific Writing in English 2014 1.5 − Oral Presentation in English 2015 0.8 − EndNote 2015 0.1 − Clinical Data Management 2015 0.2 − Computing in R 2016 0.4

General courses (Post-graduate MSc, UMC Utrecht)

− Introduction to Epidemiology 2012 3.0 − Study Design in Etiologic Research 2012 4.5 − Classical Methods in Data Analysis 2012 6.0 − Introduction to Statistics 2014 1.5 − Presentation and Writing of Research Proposal 2014 1.0 − English for Academic Purposes 2014 3.0 − Research Ethics and Society 2014 1.0 − Modern Methods in Data Analysis 2015 4.5 − Academic Writing 2015 1.0

Specific courses (AMC Graduate School)

− Clinical Epidemiology: Observational Epidemiology 2012 0.6 − Clinical Epidemiology (on-line by elevate UMC Utrecht) 2012 1.5 − Practical Biostatistics (individual) 2014 1.1 − Clinical Epidemiology: Systematic Reviews 2014 0.3 − PhD training in Cardiovascular Disease: Vascular Biology 2014 1.5 − Genetic Epidemiology 2015 1.1

186 Laboratory work (AMC Vasculaire Geneeskunde)

− Practical: How to measure carotid intima-media thickness 2012 60 hours (cIMT) and flow-mediated dilaton (FMD) by ultrasound 10 − Practical: How to read and analyse data on carotid intima-me- 2012 30 hours dia thickness (cIMT)

Specialization program: Clinical Epidemiology (UMC Utrecht)

− Clinical Epidemiology 2012 1.5 − Clinical Trials and Drug Risk Assessment 2012 1.5 − Therapeutic Meta-Analysis 2014 1.5 − Advanced Diagnostic Research 2014 1.5 − Prognostic Research 2014 1.5 − Advanced Topics in Etiologic Research: Confounding and 2014 1.5 Effect Modification − Systematic Reviews in Diagnostic and Prognostic Research 2014 1.2 − Molecular Epidemiology of Chronic Disease 2015 1.5 − Inference and Models 2015 1.5

Training, workshop, and summer school

− Advanced Cardiac Life Support (ACLS), organized by The 2014 3 days Indonesian Heart Association (PERKI), Makassar, Indonesia − Utrecht University Summer School: Why translational 2016 1.5 ECTS medicine fails – and what to do about it, Utrecht, Netherlands − Acting at the core of cardiovascular disease: new perspectives, 2016 1.0 CME Rome, Italy − European Resuscitation Council – CPR and AED Refresher 2016 1.5 CME Workshop, Rome, Italy − Intellectual property and patent workshop, by Innovation 2017 2 hours Exchange Amsterdam (IXA, UvA), Amsterdam, Netherlands − Training on Good Clinical Practice (GCP), Malang, Indonesia 2018 26 hours

Webinars

− ESC Webinar on Ventricular arrhythmias and sudden cardiac 2015 1.0 CME death: What’s new in the 2015 ESC guidelines? − How to ensure protection of patients at risk for SCD? An ap- 2015 1.0 CME proach to screening − Non-ST Elevation Acute Coronary Syndrome: what is new in 2015 1.0 CME the 2015 guidelines? − ACCA Webinar on Treatment of severe bleeding under oral 2016 1.0 CME anticoagulants – old and new strategies

187 Chapter 10

− EACPR webinar on Hypertension: Old problem, new ap- 2016 1.0 CME proaches − ESC Webinar: ESC-STEMI New Guidelines into Practice. Reper- 2017 1.0 CME fusion and long-term heart failure − ESC Webinar: What’s new in the ESC Heart Failure Guidelines? 2017 1.0 CME Clinical implementation strategy − ESC Webinar: “The year 2017 in cardiology. A resume of the 2017 1.0 CME most impactful innovations in prevention, heart failure, ar- rhythmias and valvular heart disease” − EHRA Webinar on Use of oral anticoagulants in AF patients 2017 1.0 CME undergoing cardioversion − Council on Stroke Webinar: Routine search for underlying 2018 1.0 CME cause of ischemic stroke − New 2018 Arterial Hypertension guidelines: which cut-off for 2018 1.0 CME which patients?

2. INTERNATIONAL AND NATIONAL CONGRESSES AND PRESENTATIONS

− Makassar Cardiovascular Updates 2014, Makassar, Indonesia 1 hour (oral/participant) − Acute Cardiovascular Care (ACC–ESC) Congress 2015, Vienna, Austria 16 CME (poster/participant) − European Society of Cardiology (ESC) Congress 2016, Rome, Italy 27 CME (poster/participant) − 16th World Cardiology Conference 2016, Dubai, UAE (oral/speaker) 18 CPD − The 21st Asian-Pacific Society of Cardiology Congress 2017, 3 days Singapore (poster/participant) − American Heart Association (AHA) Scientific Event 2017, Anaheim, 43,75 CME California, USA (poster/participant) − Makassar Cardiovascular Updates 2018, Makassar, Indonesia (oral/ 1 hour speaker)

3. TEACHING Workload Year (ECTS) Lecturing − Physiology of Respiratory System, Faculty of Medicine, 2014 2 hours University of Hasanuddin, Indonesia − Physiology of Heart, Faculty of Medicine, University of 2014 2 hours Hasanuddin, Indonesia

188 − Physiology of Circulation, Faculty of Medicine, University of 2014 2 hours Hasanuddin, Indonesia − Physiology of Body Fluid, Faculty of Medicine, University of 2014 2 hours Muhammadiyah Makassar, Indonesia 10

Supervising

− Data collection of Master thesis in Facult 2014 20 hours (Determinants of early coronary atherosclerosis at Dr. Wahidin Sudirohusodo Hospital Makassar in 2014) − Data collection of Master thesis in Department of Cardiology 2015 20 hours and Vascular Medicine, Faculty of Medicine, University of Hasanuddin, Indonesia (Correlation between uric acid and the severity of stenosis in patients with coronary artery disease) − Data analysis of Master thesis Department of Paediatric, 2016 2 hours Faculty of Medicine, University of Hasanuddin, Indonesia (Impact of obesity on pubertal staging)

4. PARAMETERS OF ESTEEM Grants − Direktorat Jenderal Pendidikan Tinggi (DIKTI) Kementerian Pendidikan 2011 Nasional, Republic of Indonesia, based on letter No. 600/E4.4/K/2011, dated July 12, 2011. − Educational Grant from European Society of Cardiology (ESC) 2016 congress. Memberships − Indonesian Medical Doctor Association/Ikatan Dokter Indonesia (IDI) 2009 – present − Acute Cardiovascular Care Association (ACCA) of ESC (ESC ID: 554862) 2015 - 2016 − Young Thrombosis Research Group, organized by European Society of 2016 Cardiology (ID: YTRG/554862/20160126) − European Society of Cardiology (ESC) Professional Member (ESC ID: 2017 554862) − American Heart Association (AHA ID: 221253154) 2016 - present − Heart Failure Association of ESC (HFA) (ESC ID: 554862) 2017 − ESC Council for Cardiology Practice (ESC ID: 554862) 2018 - present

189 Chapter 10

5. PRESS-RELEASE OF PUBLICATIONS

− Childhood infections associated with increased risk of early heart 2015 attack – Unhealthy lifestyles in adulthood appear to compound the risk. European Society of Cardiology (ESC) on Acute Cardiovascular Care Congress

− Pregnancy complications linked to heightened heart disease risk in 2017 young adult offspring – Risks strongest for high blood pressure and infections in moms-to-be. Heart Asia, British Medical Journal (BMJ) − Recent Publication on Cases of Coronary Artery Disease in South-East 2018 Asia. The article “Characteristics and the average 30-day and 6-month clinical outcomes of patients hospitalised with coronary artery disease in a poor South-East Asian setting: the first cohort from Makassar Cardiac Center, Indonesia” published on 27 June 2018 concerns cases of patients with coronary artery disease primarily in poor areas of Indonesia University Medical Center Utrecht

6. PEER-REVIEW Childhood infections and common carotid intima media thickness in 2018 adolescence (Epidemiology and Infections Journal, Cambridge University Press)

7. OTHER

Erasmus + HEALTH-I: Indonesian blended learning and capacity building 2017 - 2020 project A collaboration project of UMC Utrecht, UCL London, UAB Barcelona, FK UI, FK UGM, FK UNPAD, and FK UNHAS

190 ACKNOWLEDGEMENT

“Then when you have taken a decision, put your trust in Allah” (Qur’an 3;159)

Personally, that’s an important life grip for me. As a young medical student, I’ve never imagined that 10 myself will arrive at this current point: doing research, having some international publications, and finally, finishing a PhD degree abroad!

What a great and life changing 6-year I’ve been through! And for that, I would say alhamdulillahi rabbil ‘alamiin, all praises to Allah, the Entirely Merciful, the Especially Merciful.

I am so grateful to have these following people who made this PhD journey possible and enjoyable.

First and foremost, I would like to convey my truly gratitude to Professor dr.mr. Bastianus A.J.M de Mol, a very kind-hearted and wise man I’ve known. Dear Prof. Bas, I cannot thank you enough for everything you’ve done for me during my PhD life. You were always very supportive and encouraging me academically and emotionally. Every time I felt down and I got stuck with my research, you would always ‘re-charge’ my enthusiasm to continue the journey! I’ve never left your room, but got a fresh ‘energy’ to continue the works! I don’t know, but until now I think I’ve never heard something negative from you. Thank you for always believing me, even sometimes I didn’t believe myself, though. I am so thankful for all the ‘positive’ words you said, that matter for me! I was so fortunate to have you as my first supervisor!

Secondly, I would like to express my huge appreciation to Associate Professor dr. Cuno S.P.M Uiterwaal. Dear Prof. Cuno, finally! :D I will be forever thankful for all your immense guidance, since the very beginning, until the very last steps of my PhD life. Apparently, you are the reason why I am currently in love in ‘doing research’! Thank you for all the discussions, skype meetings, and very detailed corrections to my manuscripts! I am so grateful that you always got me back into the track, when I got lost somewhere during my research! You always challenged me to think critically, made relevance research questions, and speak up of what I am thinking. I am so inspired by your dedication and work to the science and education. Thank you for making my PhD life so much easier and fun! (:

Further, my sincere thanks extend to Professor dr. Jose P.S. Henriques. Dear Prof. Jose, I am so honor to have you as my supervisor during the last three years of my PhD program. Thank you for all the insightful and critical comments you gave! Even sometimes the manuscripts were ready to be submitted, you came with a new idea and revisions should be addressed. However, that’s what made my manuscripts beautiful and publishable! Thank you for all the discussions (mostly we did it through emails). Thank you for your supports and cares!

I cannot be here, at the last stage of this PhD journey, without any assistance from Professor dr. Yolanda van der Graaf. Dear Prof. Yolanda, I am so thankful for all your tremendous guidance in the beginning of my research project. Thank you for helping me to conceive my research platform. I admire your criticism and pragmatism in doing research. Thank you for everything!

191 Chapter 10

To the one that I’ve never met directly before, but I admire him through all his critical thinking, expertise, and constructive advice: Professor dr. David P Burgner. Dear Dave, I am so happy to have a collaboration with you in writing my first two articles. Thank you for all the skype meetings and your quick feedbacks! Hopefully, someday I have an opportunity to collaborate with you again. :)

My deepest gratitude extends to the committee members: Professor dr. A.C. van der Wal, Professor dr. B.J.M. Mulder, Professor dr. R.J.G. Peters, Professor dr. J.J. Piek, Professor dr. H.M. Verkooijen, and Dr. M.J.M. Cramer. Thank you very much for your willingness to chair my defense, I do appreciate it!

Untuk Ayahanda dan guruku: Professor dr. Irawan Yusuf, PhD, I am so much grateful to have you as a teacher and role model. You always got me mesmerized with all your ‘open-minded’ and ‘out of the box’ thought. Thank you for teaching me on how to be and how to act as a medical doctor and medical educator. Afterwards, you guide me to be a medical researcher. I still remember at the time I was asking your permission (as the Dean), that I was eager to continue my education as a specialist. At that time, you just answered, “No, you have to go abroad!” I closed your door with a bit disappointment, and I just said to myself “O God! What I supposed to do? My English is not really good, I’ve never go abroad, and I have done nothing with research before.” But, now, I just want to convey my great great gratitude for the path you had chosen for me. I’m so grateful for that!

Professor dr. Budu, Sp.M(K), M.Med.Ed, PhD, our beloved Dean, a very kind man. Dear Prof. Budu, I am so thankful for all your supports and cares. Through your leadership, I learnt on how to stay humble and keep our feet still on earth, no matter how high the achievements we got! Thank you for showing us the priceless values in life!

Dear Professor DR.dr. A. Asadul Islam, Sp.BS(K), I thank you very much for all the supports and agreements through your leadership on previous period. I got a lot of financial supports for all the international and national congresses under your tenure. Thank you for giving opportunities for the young staff to share our works.

Dear Prof. DR. dr. Haerany Rasyid, Sp.PD-KGH, Sp.GK; DR. dr. Rina Masadah, Sp.PA(K), M.Phil; dr. Irwin Aras, M.Epid;; and dr. Firdaus Hamid, PhD. I am happy to have the so-friendly leaders like you. Thank you for involving me in your academic and non-academic activities. Can’t wait to have the other great travels with you! ;’)

This acknowledgment extended to all my teachers and family in Department of Physiology, Faculty of Medicine, Hasanuddin University: Professor DR. dr. A. Wardihan Sinrang, M.SAnd; DR. dr. Ilhamjaya Patellongi, M.Kes; DR. dr. Irfan Idris, M.Kes; dr. Aryadi Arsyad, M.MbiomedSC, PhD; dr. Rini Rachmawaty Bachtiar, Sp.PD-KG,MARS; dr. Citra Rosyidah, Sp.S, M.Kes; dr. Andi Aryandy, PhD; dr. Qushay Umar Malinta, MS; and Pak Marthen. I am so grateful for all the supports and positive environment we built in our Department. Thank you!

To all my teachers, supervisors, and colleagues in Department of Cardiology and Vascular Medicine,

192 Makassar Cardiac Center, Hasanuddin University: Prof. DR. dr. Ali Aspar Mappahya, Sp.PD, Sp.JP(K); Prof. DR. dr. Peter Kabo, PhD, Sp.FK, Sp.JP(K); DR. dr. Idar Mappangara, Sp.PD, Sp.Jp(K); DR. dr. Muzakkir Amir, Sp.JP(K); DR. dr. Abdul Hakim Alkatiri, Sp.JP(K); dr. Pendrik Tandean, Sp.PD-KKV; dr. Zaenab Djafar, Sp.PD, Sp.JP; dr. Almudai, Sp.PD, Sp.JP; dr. Akhtar Fajar Muzakkir, Sp.JP(K); dr. A. Alief Utama Armyn, 10 Sp.Jp; and dr. Aussie F Ghaznawie, Sp.Jp. I thank you for all the supports, assistance, and guidance during my research project. Thank you for allowing me to collect the data from your patients and access the hospital medical records. Without your collaboration, this journey could never come to an end.

For all good friends and seniors at Faculty of Medicine, Hasanuddin University: Ka Asty, Ka Fika, Ka Shelly, Om Daus Kasim, Ka Alfian, Ka Oce, Gita, and Ka Aco. Many thanks for having me as a partner in your working life! ;D

Yang saya cintai dan hormati keluarga besar drs. H.A.M. Nurdin Halid dan Hj. A. Nurbani Halim, dan puang-puang semua yang tidak dapat saya sebutkan satu-persatu. Yang saya cintai dan sayangi keluarga besar M.Jusuf Arief dan H.M. Abu bakar, opu-opu semua. Terima kasih atas segala dukungan dan do’anya selama ananda menyelesaikan studi di Belanda.

Untuk orang tuaku di Belanda: Tante ida dan Om Bambang. Terima kasih tidak sebanding dengan kebaikan yang om dan tante lakukan kepada saya dan keluarga. Om dan tante dengan ikhlas selalu membantu saya, menyediakan tempat tinggal dan makanan untuk saya, dari gadis, menikah, sampai hamil dua kali di Belanda. Om dan tante yang memelihara saya di sana. Hanya Allah yang dapat membalas kebaikan tersebut. Inshaa Allah menjadi amal jariyah untuk om dan tante. Aaamiin..

Homesick is not a word for me during my study in The Netherlands, since I have all these lovable and very kind people. Untuk Ka Abbas dan Mba Dwi; Tante Atik dan Om Agrar; Tante Titin dan Om Marconi; Tante Su, dan Tante Sri. Saya seperti mendapatkan keluarga di Belanda. Thank you for all your priceless help and kindness. Terima kasih banyak atas segalanya.

Untuk teman-teman seperjuangan di Belanda, teman rasa saudara: Kak Daus; Kak Sultan; Kak Ruslin dan Kak Nila; Kak Yani dan Kak Yanti; Kak Syafri dan Mba Nossya, terima kasih banyak untuk semuanya! Thank you for all the foods, laughs, and stories we shared together. Will be missing those moments!

Untuk “grup yang membangun”: Kak Nana (dr. Dara Rosmailina Pabittei, PhD) dan Dodo (dr. Aldian Irma, PhD soon to be) thank you for everything!! Thank you for all the weekends we spent together, for all the crazy chit-chat and talks we had, and all the ‘dreams’ we shared. Thank you for kept me sane throughout this long journey! You’re not friends, you’re sisters for me!! Will be missing our travel to Roermond!;p

To all best friends and MSc colleagues in Utrecht: Mba Nikmah, Ary, Mba Alfi, Putri, Cindy (China), Amy (Malaysia), Jam and Tom (Thailand). Thank you for all the time, discussions, and lunch we had

193 Chapter 10 together! I am bit introvert, so having you all at that time was great for me!

Dear best friends: Nyngsi, Nisrina, Zulfa, Asdah, Isma, Dian, Liza, Tumas, Windy, Linda, Eni, Amel, Nanda, Hilmiah, Santi, Titi, Rizma, Aji Ana, Bulqis, Om Taz, Om Umar, Ika Kartika Sari, and Nani Panrelli. Thank you for our friendship since we were in undergraduate or high schools. A bunch of loves and thanks to my big family of Avicenna (FKUH 2003).

Dear friends and colleagues in The Netherlands: Qalby, Karis, Mbak Hana, Ocank, Kak Isdah, Amy, Beby, Faqih, Mba Tiwi. Thank you for all the moments we had! Dear Luisa and Marjenne, thank you for all your assistance and kind help during my study in Amsterdam. Dear mba Dita, thank you for the beautiful layout of this thesis.

Last but never the least, my beloved family!

Untuk kedua orang tuaku yang sangat saya cintai dan muliakan, H.M. Harry Yusuf dan Hj. Jumiati, S.Sos. Terima kasih banyak atas segala didikan dan do’a ibu dan tetta.. Segala kebaikan yang saya dapatkan sampai hari ini adalah berkat do’a ibu dan tetta. Terima kasih tetta telah mengajarkan saya kerja keras dan kejujuran. Terima kasih ibu yang selalu mengingatkan saya untuk sabar dan tidak pernah meninggalkan shalat. Semoga ananda bisa menjadi jalan kebaikan dan ladang pahala untuk ibu dan tetta kelak. Aamiin Allahumma Aaamiin.

Untuk mertuaku yang sangat baik hati dan sangat saya cintai: Drs. H.M.Rosalim H.A.B, MSi dan Hj. A. Syamsiar Halid, S.Sos, MSi. Terima kasih banyak appi dan attasiakuu atas segala kebaikan, dukungan moril, dan do’anya selama ananda menyelesaikan studi di Belanda. Terima kasih sudah mau menjaga cucu ta, terima kasih sudah mengurus kami semua, appi, attasiaa..

Untuk Saudaraku yang sangat saya cintai dan banggakan: Ka Inal dan Irma; Ka Fauzan dan Ka Fitri; Ka Fariq dan Ka Resti; Alief dan Ulan; Wiwi.. Alhamdulillah saya memiliki saudara-saudara yang selalu peduli dan sangat baik. Terima kasih banyak atas segalanya, terutama mau direpotkan menjaga bocah! :’D

My dearest Mono!! Thank you for always supporting me! Thank you for taking care our children when I was millions miles away. I am happy to have you by my side!

My entire world: Rafan and Miqaila. Thank you for your companion, darling! You both grew inside my body during this journey: studied with me in the class, not rarely we continue till the late night for the exams. You stayed calm when I was trying to understand the statistics, and until the last minutes before your birth, I was trying to submit my first manuscript! Semoga kalian tumbuh menjadi anak yang shaleh dan bermanfaat untuk orang lain..Aamiin ya Allah..

Lastly, I would express my gratitude to The Netherlands. There’s a time when sometimes I miss to be back there. It’s like a second home. Thank you!

194 CURRICULUM VITAE

Andriany Qanitha was born on January 25, 1986 in Ujung Pandang, Indonesia. In August 2003, she started her study in the Faculty of Medicine University of Hasanuddin (FMUH), and graduated her 10 Medical Bachelor (S.Ked.) with cum laude (GPA 3.65/4.00). Later on, in 2008, she completed her Medical Doctor (dr.) and has been awarded as the best University graduate with a perfect GPA (4.00/4.00), the first ever since the FMUH has been established in 1956. For that achievement, she had been promoted as a junior lecturer at Department of Physiology and Medical Education Unit, FMUH. Along with her tasks as a lecturer, she also practiced as a GP in Emergency Department in a Mother and Child Hospital and two primary care clinics in Makassar (2009–2011). From elementary to junior high school, she always gained herself at the first rank. In Junior high school she got a perfect score on mathematics, and thereafter she represented the SMU Negeri 17 Makassar in mathematics and accountancy competitions (senior high school). Just then, she passed the National Selection Exam to enter the Faculty of Medicine. As an undergraduate student, she actively involved in the learning environment as a lecturer assistant at Department of Physiology.

In February 2013, she started to work on the research project described in this thesis under supervision of Professor dr. Bastianus A.J.M de Mol, PhD (AMC-Amsterdam UMC) and Associate Professor dr. Cuno S.P.M Uiterwaal, PhD (UMC Utrecht) with a full scholarship from the Directorate General of Higher Education of the Ministry of National Education (DIKTI), Republic of Indonesia. Combined with her PhD in Department of Cardio-thoracic Surgery at AMC Heart Center, she also enrolled in MSc Post-graduate Program at the University Medical Center Utrecht, with specialization on Clinical Epidemiology (2012–2015). Currently, she is involved as one of the PICs for Hasanuddin University in the Erasmus+ HEALTH-I: Indonesian Blended Learning and Capacity Building Project, a collaboration project between UMC Utrecht, University College London, The Autonomous University of Barcelona, and four institutions in Indonesia (Faculty of Medicine of University of Indonesia, University of Gajah Mada, University of Padjajaran, and University of Hasanuddin). After completing her PhD, she is planning to pursue her passion as a cardiologist, where she can combine clinical cardiology and research in the future.

195 196 Andriany Qanitha Andriany Learning f�om the local evidence local the Learning f�om in a resource-poor Indonesian setting Etiology, management, and outcomes outcomes and management, Etiology, of patients with coronary artery with coronary of patients disease

Etiology, management, and outcomes of patients with coronary artery disease in a resource-poor Indonesian setting Andriany Qanitha