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Glucose Regulation in Acute Coronary Syndromes Glucose Regulation in Acute Coronary Syndromes Implications for outcome and outcome prediction Titelpagina Inhoudsopgave Inleiding Beschouwing Conclusie Stellingen Curriculum Vitae Supplement Maarten de Mulder Stellingen bij het proefschrift Glucose Regulation in Acute Coronary Syndromes Implications for outcome and outcome prediction 1. Bij patiënten met een hartinfarct vraagt een goed risicomodel voor het voorspellen van uitkomsten om een beter risicomodel. (dit proefschrift) 2. Glucose is een onafhankelijke voorspeller van sterfte bij patiënten met een hartinfarct, ook in het huidige tijdperk van snelle reperfusie middels een percu- tane coronaire interventie. Derhalve kan zoet toch zuur zijn. (dit proefschrift) 3. Gezien het frequente vóórkomen, mag het belang van het tijdig opsporen van onontdekte diabetes bij patiënten met een hartinfarct niet worden vergeten. De praktijk is echter weerbarstig. (dit proefschrift) 4. Strikte glucose regulatie kan worden verkregen met weinig hypoglycemiëen, een dergelijk protocol is echter wel arbeidsintensief. (dit proefschrift) 5. Strikte glucose regulatie bij hyperglycemische hartinfarct patiënten die behandeld worden met een percutane coronair interventie leidt niet tot kleinere hartinfarcten. (dit proefschrift) 6. The good physician treats the disease; the great physician treats the patient who has the disease. (William Osler) 7. He who studies medicine without books sails an uncharted sea, but he who studies medicine without patients does not go to sea at all. (William Osler) 8. Don’t dream your life, live your dream. (Mark Twain) 9. Logic will take you from A to B, imagination will take you everywhere. (Albert Einstein) 10. Promoveren is een ander woord voor “stug volhouden” en “teamsport”. 11. Je hoeft niet ziek te zijn om beter te worden. Maarten de Mulder – 15 oktober 2013 Colofoon ISBN nummer: 978 90 701 1640 8 © Maarten de Mulder, The Netherlands, 2013 All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means without prior permission from the author. Or, when appropriate, of the scientific journal where the article was published. Lay out: beeldgroep MCA Printed by: Ridderprint bv, Ridderkerk, The Netherlands Glucose Regulation in Acute Coronary Syndromes Implications for outcome and outcome prediction Maarten de Mulder Glucose Regulation in Acute Coronary Syndromes Implications for outcome and outcome prediction Glucose regulatie bij het acuut coronair syndroom Betekenis voor de uitkomsten en uitkomst voorspelling Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. H.G. Schmidt en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op 15 oktober 2013 om 13:30 uur Maarten de Mulder geboren te Amsterdam Promotiecommissie Promotor: Prof.dr.ir. H. Boersma Overige leden: Prof.dr. F. Zijlstra Prof.dr. J.G.P. Tijssen Prof.dr. E.J.G. Sijbrands Copromotor: Dr. V.A.W.M. Umans Het verschijnen van dit proefschrift werd mede mogelijk gemaakt door de steun van de Nederlandse Hartstichting. Inhoudsopgave Chapter 1 Introduction 8 Introduction & Thesis Outline Part 1 Chapter 2 EuroHeart score for in-hospital mortality after PCI 20 EuroHeart score for the evaluation of in-hospital mortality in patients undergoing percutaneous coronary intervention Chapter 3 SPECT infarct size in on- and off-site PCI 42 Infarct Size in Primary Angioplasty without On-Site Cardiac Surgical Backup versus Transferal to a Tertiary Center: a single photon emission computed tomography study Chapter 4 Long term outcomes after off-site PCI 58 Long term clinical outcome and MIBI SPECT parameters in off-site percutaneous coronary interventions Part 2 Chapter 5 Admission glucose and the GRACE score 72 Admission glucose does not improve GRACE score at 6 months and 5 years after myocardial infarction Chapter 6 Admission glucose and mortality in two different 88 reperfusion era’s Elevated admission glucose is associated with increased long term mortality in myocardial infarction patients, irrespective of the initially applied reperfusion strategy Chapter 7 Comparison of diagnostic criteria to detect diabetes 106 Comparison of Diagnostic Criteria to Detect Undiagnosed Diabetes in Hyperglycemic Acute Coronary Syndrome Patients Chapter 8 Editorial with chapter 7 122 Diagnosing diabetes on admission hyperglycemia Chapter 9 Hyperglycemia management in clinical cardiology practice 130 Current management of hyperglycemia in acute coronary syndromes, a national Dutch survey Chapter 10 Tools for implementation of an intensive glucose 146 regulation protocol How to implement a clinical pathway for intensive glucose regulation in acute coronary syndromes Chapter 11 BIOMArCS 2 glucose; study design 162 Intensive Management of Hyperglycemia in Acute Coronary Syndromes Study design and rationale of the BIOMArCS 2 glucose trial Chapter 12 Glucose regulation in ACS, 178 results of the BIOMArCS 2 glucose trial Intensive Glucose Regulation in Hyperglycemic Acute Coronary Syndromes: Results of the Randomized BIOMArCS-2 Glucose Trial Chapter 13 Summary & discussion 202 Nederlandse samenvatting 209 Chapter 14 Dankwoord & CV 214 Supplement Publications 220 Portfolio 225 Co-authors 229 Databases 231 Chapter 1 1 Introduction Introduction & Thesis Outline 9 InTRoduCTIon Cardiovascular disease: trends and current status In the past decades the management of acute coronary syndromes (ACS), including myocardial infarction (MI) and unstable angina, has evolved from a strategy of watchful waiting to a highly technical intervention with anti-blood clotting drugs and percutaneous coronary intervention (PCI) with stent placement. As a result, the prognosis of patients has improved radically. In the 1960s in-hospital mortality in MI patients was as high as 30%. After the widespread introduction of coronary care units (CCU) in the 1970s this figure was reduced to approximately 15%, figure 1. Further improvements were made with the introduction of fibrinolytic drugs (1980s) and PCIs (1990s). Currently, 30 day mortality after MI admission has been reduced to 4 - 6 %. 1 Figure 1 Survival after myocardial infarction; 1960’s – 1990’s Up to 5-year case fatality after overall AMI by decade From: Parikh et al 2009 25 10 1 Introduction Despite these developments, cardiovascular disease (CVD) still is a major cause of the loss of healthy life years in developed countries. For example, in The Netherlands, ± 90,000 patients are admitted each year for an ACS whereas the annual number of fatal ischemic coronary events is as high as ±10,600. 2 In fact, for three main reasons, the burden of CVD is expected to increase in the decades ahead. First, improved survival results in an increasing prevalence of patients with chronic disease, who continue to be at risk of recurrent events. Second, this process is amplified by the aging of the general population.3 Third, a growing group of asymptomatic individuals are at risk of developing CVD due to mediating conditions such as tobacco consumption, abdominal obesity, dyslipidemia, insulin resistance and elevated blood pressure. Particularly the ‘pandemic’ of diabetes mellitus (DM) is worrisome in this respect. Burden of diabetes mellitus In the past decades the burden of DM has increased. According to the Dutch National Public Health Compass the prevalence of DM doubled in men between 1991 and 2011 and increased by 50% in women, figure 2. 4 It is estimated that the number of patients with known diabetes in The Netherlands will keep growing: from 800,000 (~5%) in 2011 to 1,3 million (~8%) inhabitants in 2025. 5 These increasing numbers are associated with increased obesity, decreased physical activity, and aging of the population. The (trends in the) prevalence of DM in The Netherlands are representative of prevalence figures in the Western World and around the globe. It is estimated that in 2012 approximately 371 million people were living with diabetes worldwide, figure 3, and this number is expected to rise to 552 million in 2030. 6 diabetes and hyperglycemia in acute coronary syndromes Through several pathophysiological mechanisms, including chronic hyperglycemia and chronic vascular inflammation, patients with diabetes have accelerated atheroscle- rosis. 7 Indeed, DM is one of the main risk factors for CVD and ACS.8 Furthermore, once CVD has been diagnosed, patients with DM have a 2 – 4 fold higher mortality as compared to their non-DM counterparts.9 Glucose metabolism is a continuum that varies gradually from normal glucose metabolism to impaired glucose tolerance to clinically manifest diabetes. The first changes in glucose concentrations can be detected as much as 3–6 years before the diagnosis of DM is established.10 Fortunately, timely lifestyle and pharmacologi- cal interventions can prevent or delay this process.11 12 Obviously, this requires that disturbed glucose metabolism is timely recognized and that patients are motivated to actually change their lifestyle. Scoring models can aid to recognize those at high risk for DM.13 11 Figure 2 Prevalence of diabetes in The netherlands; 1991 – 2011 CMR-Nijmegen, male CMR-Nijmegen, female RNH-Limburg, male RNH-Limburg, female Point prevalence of diabetes mellitus from 1991 – 2011 (3 year average), standardized and indexed to Dutch population in 2010 (1992 is 100) CMR = Continuous Morbidity Registration; RNH = RegistratieNet Huisartsenpraktijken (General Practitioners’ Registry) From: www.nationaalkompas.nl Figure
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