Advance Publication

Circulation Journal ORIGINAL ARTICLE doi: 10.1253/circj.CJ-20-1115

Impact of Chronic Kidney Disease on In-Hospital and 3-Year Clinical Outcomes in Patients With Acute Myocardial Infarction Treated by Contemporary Percutaneous Coronary Intervention and Optimal Medical Therapy ― Insights From the J-MINUET Study ―

Yousuke Hashimoto, MD; Yukio Ozaki, MD, PhD; Shino Kan, MD; Koichi Nakao, MD, PhD; Kazuo Kimura, MD, PhD; Junya Ako, MD, PhD; Teruo Noguchi, MD, PhD; Satoru Suwa, MD, PhD; Kazuteru Fujimoto, MD, PhD; Kazuoki Dai, MD; Takashi Morita, MD, PhD; Wataru Shimizu, MD, PhD; Yoshihiko Saito, MD, PhD; Atsushi Hirohata, MD, PhD; Yasuhiro Morita, MD, PhD; Teruo Inoue, MD, PhD; Atsunori Okamura, MD, PhD; Toshiaki Mano, MD; Minoru Wake, MD; Kengo Tanabe, MD, PhD; Yoshisato Shibata, MD, PhD; Mafumi Owa, MD, PhD; Kenichi Tsujita, MD, PhD; Hiroshi Funayama, MD, PhD; Nobuaki Kokubu, MD, PhD; Ken Kozuma, MD, PhD; Shiro Uemura, MD, PhD; Tetsuya Tobaru, MD, PhD; Keijiro Saku, MD, PhD; Shigeru Oshima, MD, PhD; Satoshi Yasuda, MD, PhD; Tevfik F Ismail, MD, PhD; Takashi Muramatsu, MD, PhD; Hideo Izawa, MD, PhD; Hiroshi Takahashi, PhD; Kunihiro Nishimura, MD, PhD; Yoshihiko Miyamoto, MD, PhD; Hisao Ogawa, MD, PhD; Masaharu Ishihara, MD, PhD on behalf of J-MINUET Investigators

Background: The impact of chronic kidney disease (CKD) on long-term outcomes following acute myocardial infarction (AMI) in the era of modern primary PCI with optimal medical therapy is still in debate. Methods and Results: A total of 3,281 patients with AMI were enrolled in the J-MINUET registry, with primary PCI of 93.1% in STEMI. CKD stage on admission was classified into: no CKD (eGFR ≥60 mL/min/1.73 m2); moderate CKD (60>eGFR≥30 mL/ min/1.73 m2); and severe CKD (eGFR <30 mL/min/1.73 m2). While the primary endpoint was all-cause mortality, the secondary endpoint was major adverse cardiac events (MACE), defined as a composite of all-cause death, cardiac failure, myocardial infarction (MI) and stroke. Of the 3,281 patients, 1,878 had no CKD, 1,073 had moderate CKD and 330 had severe CKD. Pre-person-days age- and sex-adjusted in-hospital mortality significantly increased from 0.014% in no CKD through 0.042% in moderate CKD to 0.084% in severe CKD (P<0.0001). Three-year mortality and MACE significantly deteriorated from 5.09% and 15.8% in no CKD through 16.3% and 38.2% in moderate CKD to 36.7% and 57.9% in severe CKD, respectively (P<0.0001). C-index significantly increased from the basic model of 0.815 (0.788–0.841) to 0.831 (0.806–0.857), as well as 0.731 (0.708–0.755) to 0.740 (0.717– 0.764) when adding CKD stage to the basic model in predicting 3-year mortality (P=0.013; net reclassification improvement [NRI] 0.486, P<0.0001) and MACE (P=0.046; NRI 0.331, P<0.0001) respectively. Conclusions: CKD remains a useful predictor of in-hospital and 3-year mortality as well as MACE after AMI in the modern PCI and optimal medical therapy era.

Key Words: Acute myocardial infarction; Chronic kidney disease; Major adverse cardiac events; Percutaneous coronary intervention

Received October 28, 2020; revised manuscript received March 4, 2021; accepted March 17, 2021; J-STAGE Advance Publication released online June 3, 2021 Time for primary review: 34 days Department of Cardiology, Fujita Health University Hospital and FHU Okazaki Medical Center, Aichi (Y.H., Y.O., S.K., T.F.I., T. Muramatsu, H.I.); Saiseikai Kumamoto Hospital Cardiovascular Center, Kumamoto (K. Nakao); Cardiovascular Center, Yokohama City University Medical Center, Yokohama (K. Kimura); Department of Integrated Medicine, Kitasato University, Sagamihara (J.A.); Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita (T.N., S.Y., H.O.); Department of Cardiology, Juntendo University Shizuoka Hospital, Shizuoka (S.S.); Department of Cardiology, National Hospital Organization Kumamoto Medical Center, Kumamoto (K.F.); Department of Cardiology, Hiroshima City Hospital, Hiroshima (K.D.); Department of Cardiology, Osaka General Medical Center, Osaka (T. Morita); Department of Cardiovascular Medicine, Nippon Medical School, Tokyo (W.S.); Department of Cardiovascular Medicine, Nara Medical University, Kashihara (Y. Saito); Department of Cardiovascular Medicine, The Sakakibara Heart Institute of Okayama, Okayama (A.H.); Department (Footnote continued the next page.) Advance Publication 2 Hashimoto Y et al.

hronic kidney disease (CKD) is known to be asso- ciated with adverse outcomes in patients presenting Editorial p ???? C with acute myocardial infarction (AMI).1–5 Serum creatinine is an important component of the GRACE one of the following: symptoms of ischemia: ECG changes score and similar scoring systems for the risk stratification indicative of new ischemia, development of pathological Q of patients presenting with acute coronary syndromes.6 waves in the ECG and imaging evidence of new loss of However, although these scoring systems have been derived viable myocardium or new regional wall motion abnor- from large robust multicenter international registry stud- malities. The type of cTn (cTnT or cTnI) measured ies, these were conducted over a decade ago.6 It is unclear depended on the attending physician, and the cut-off value whether advances in both the availability and deployment used at each institution was applied. Patients were evalu- of modern guideline-directed medical therapy, and espe- ated at baseline for demographic and clinical characteris- cially greater access to mechanical reperfusion therapy tics. STEMI was diagnosed in the presence of new ST using recent percutaneous coronary intervention (PCI) elevation at the J point in at least 2 contiguous leads ≥2 mm technology have altered outcomes in patients with CKD.7–9 (0.2 mV) in men or ≥1.5 mm (0.15 mV) in women in leads The status and importance of CKD as an independent risk V2–3 and/or ≥1 mm (0.1 mV) in other contiguous chest factor for short- and long-term mortality and major adverse leads or the limb leads.13,14 New or presumably new left cardiac events after AMI in the modern era of primary PCI bundle branch block was considered a STEMI equivalent. and recent advances in medical therapy therefore remains Urgent coronary angiography (CAG) was defined as angi- unresolved. ography performed within 48 h of hospital admission. We evaluated the prognostic significance of CKD on Optimal medical therapy (OMT) was defined as the use of in-hospital and 3-year cardiovascular outcomes in a large necessary medications for the control of cardiovascular contemporary registry cohort; the Japanese MINUET risk factors such as hypertension, diabetes, dyslipidemia study.10,11 In particular, we sought to determine the inde- and for the prevention of stent thrombosis (i.e., antiplatelet pendent impact of renal dysfunction on short- and long- therapy) based on guidelines.7–9,15 term adverse outcomes after AMI relative to potential Data on the treatment and in-hospital clinical events confounding-associated cardiovascular risk factors. were collected at the time of hospital discharge. Clinical 3-year follow up after the index MI was performed through Methods a review of medical records, telephone contact, and a mailed questionnaire.11 Study Design and Subjects This study was conducted in accordance with the Decla- The J-MINUET is a prospective observational multicenter ration of Helsinki. The protocol was approved by the eth- study (UMIN000010037). Consecutive patients hospital- ics committees of every participating institution. ized within 48 h of onset of AMI at 28 Japanese medical institutions were enrolled between July 2013 and May Study Endpoints 2014.10,11 Diagnosis of AMI was based on the ESC/ACC The primary endpoint was all-cause mortality for both in- Foundation (ACCF)/American Heart Association (AHA)/ hospital and at 3 years. The principal secondary endpoint World Heart Federation Task Force for the Universal was major adverse cardiac events (MACE), defined as a Definition of Myocardial Infarction.12 composite of all-cause death, myocardial infarction, cardiac Only type 1 AMI (spontaneous MI related to ischemia failure and stroke for both in-hospital and 3 years. Cardiac from a primary coronary event) and type 2 (MI secondary failure was defined as congestive heart failure and/or car- to ischemia because of either increased oxygen demand or diogenic shock that required treatment during the index decreased supply) were included in this registry. In brief, episode of hospitalization, or heart failure requiring re- AMI was diagnosed by the rise and/or fall of cardiac bio- hospitalization during follow up.11 Stroke was defined as markers (preferred: troponin) with at least 1 value above an acute episode of neurological dysfunction caused by the 99th percentile of the upper reference limit observed focal or global brain injury, regardless of whether the cause together with evidence of myocardial ischemia with at least was due to hemorrhage or infarction.11 Such definitions of

of Cardiology, Ogaki Municipal Hospital, Ogaki (Y. Morita); Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu (T.I.); Department of Cardiology, Sakurabashi Watanabe Hospital, Osaka (A.O.); Cardiovascular Center, Kansai Rosai Hospital, Amagasaki (T. Mano); Department of Cardiology, Okinawa Chubu Hospital, Uruma (M.W.); Division of Cardiology, Mitsui Memorial Hospital, Tokyo (K. Tanabe); Department of Cardiology, Miyazaki Medical Association Hospital, Miyazaki (Y. Shibata); Department of Cardiovascular Medicine, Suwa Red Cross Hospital, Suwa (M.O.); Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto (K. Tsujita); Division of Cardiovascular Medicine, Saitama Medical Center Jichi Medical University, Saitama (H.F.); Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, Sapporo (N.K.); Department of Cardiology, Teikyo University, Tokyo (K. Kozuma); Department of Cardiology, Kawasaki Medical School, Kurashiki (S.U.); Department of Cardiology, Sakakibara Heart Institute, Tokyo (T.T.); Department of Cardiology, Fukuoka University School of Medicine, Fukuoka (K.S.); Department of Cardiology, Gunma Prefectural Cardiovascular Center, Maebashi (S.O.), Japan; King’s College London, London, UK & Guy’s and St Thomas’ Hospital NHS Foundation Trust, London (T.F.I.), UK; Division of Medical Statistics, Fujita Health University Hospital, Toyoake (H.T.); Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Suita (K. Nishimura, Y. Miyamoto); and Department of Cardiovascular and Renal Medicine, Hyogo College of Medicine, Nishinomiya (M.I.), Japan Mailing address: Yukio Ozaki, MD, PhD, FACC, FESC, FSCAI, Department of Cardiology, Fujita Heath University Hospital and FHU Okazaki Medical Center, 1 Gotanda, Harisaki, Aichi 444-0827, Japan. E-mail: [email protected] All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] ISSN-1346-9843 Advance Publication Chronic Kidney Disease and Outcome After Acute MI 3

Table 1. Baseline Patient Characteristics No CKD eGFR Moderate CKD eGFR Severe CKD eGFR All patients >60 mL/min/1.73 m2 30–60 mL/min/1.73 m2 <30 mL/min/1.73 m2 P value (n=3,281) (n=1,878) (n=1,073) (n=330) Male (%) 75.3 78.7 72.3 65.5 <0.0001 Age (years) 69±13 65±12 73±11 73±12 <0.0001 Diabetes (%) 36.4 33.8 36.9 49.5 <0.0001 Hypertension (%) 66.5 61.1 70.7 83.5 <0.0001 Dyslipidemia (%) 52.0 53.1 51.4 47.2 0.14 Smoking (%) 65.8 70.6 60.3 56.4 <0.0001 Body mass index 23.6±3.7 23.8±3.7 23.5±3.7 22.9±3.7 <0.0001 eGFR (mL/min/1.73 m2) 64.0±26.9 82.0±18.0 47.8±8.1 15.0±8.7 <0.0001 Previous history (%) MI 12.1 9.0 15.4 18.9 <0.0001 PCI 15.3 11.8 17.9 26.3 <0.0001 CABG 2.9 1.4 3.4 10.0 <0.0001 AF 6.0 3.5 8.8 11.3 <0.0001 Stroke 11.3 8.2 13.7 20.7 <0.0001 PAD 4.6 2.1 5.5 16.8 <0.0001 Killip classification (%) <0.0001 Class 1 75.6 85.9 63.9 55.6 Class 2 9.3 7.9 10.4 13.7 Class 3 5.4 2.9 7.6 12.5 Class 4 9.7 3.4 18.1 18.2 Door-to-admission (min) 154 (70–390) 165 (79–410) 140 (60–327) 154 (60–518) 0.0003 STEMI (%) 68.9 72.2 67.2 55.8 <0.0001 Max CK (IU/L) 1,447 (518–3,178) 1,541 (557–3,225) 1,450 (544–3,243) 908 (345–2,413) <0.0001 Twice elevated CK (%) 78.7 79.5 79.5 71.5 0.0050 Urgent angiography (%) 93.1 95.5 91.6 84.5 <0.0001 Multi-vessel disease (%) 43.7 38.0 50.1 57.2 <0.0001 Initial TIMI 0/1 flow (%) 60.5 62.8 59.1 49.5 0.0022 Revascularization (%) <0.0001 None 12.9 9.9 14.6 24.3 PCI 85.1 88.7 82.8 71.7 CABG 2.1 1.4 2.6 4.0 Door-to-balloon (min) 75 (52–121) 70 (50–112) 77 (53–127) 102 (67–160) <0.0001 Final TIMI 3 flow (%) 91.8 93.3 89.3 90.6 0.0016 Length of stay (days) 14 (9–21) 13 (9–18) 16 (10–24) 15 (7–27) <0.0001 Medication (%) At admission Anti-platelet agents 26.7 18.8 32.2 53.9 <0.0001 ARB 26.2 19.6 30.3 50.9 <0.0001 ACE-I 6.6 5.6 7.6 8.8 0.025 β-blockers 14.0 9.6 16.3 31.8 <0.0001 CCB 34.4 28.1 40.3 51.8 <0.0001 Nicorandil 4.5 2.5 6.3 9.7 <0.0001 Statins 23.4 19.2 27.6 33.6 <0.0001 At discharge Anti-platelet agents 96.6 97.2 95.8 95.6 0.12 ARB 28.5 26.7 28.7 40.2 <0.0001 ACEI 52.3 56.5 51.4 26.1 <0.0001 β-blockers 68.4 67.2 70.0 70.4 0.26 CCB 22.9 19.4 25.4 37.5 <0.0001 Nicorandil 21.1 18.8 23.3 29.4 0.0001 Statins 86.9 89.8 85.3 72.9 <0.0001 ACE-I, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; PAD, peripheral artery disease; PCI, percutane- ous coronary intervention; STEMI, ST-elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction. Advance Publication 4 Hashimoto Y et al.

Figure 1. Flow-chart of the study patients. Of the 3,283 patients with AMI, 2 patients were excluded due to missing eGFR read- ings. The remaining 3,281 patients were enrolled. Patients were divided into 3 groups according to eGFR levels. Of the 3,281 patients, 1,878 patients were without CKD (eGFR ≥60 mL/min/1.73 m2), 1,073 patients had moderate CKD (60>eGFR≥30 mL/min/ 1.73 m2) and 330 patients had severe CKD (eGFR <30 mL/min/1.73 m2), including 195 hemodialysis patients. AMI, acute myocardial infarction; eGFR, estimated glomerular filtra- tion rate.

cardiac failure and stroke were consistent with those pro- (defined as eGFR <60 mL/min/1.73 m2). Over two-thirds of posed by the ACCF/AHA task force.16,17 patients presented with ST-elevation. Among the whole cohort, 93.1% underwent urgent angiography, with 85.1% Statistical Analysis receiving revascularization by PCI. The median door-to- Statistical analyses were performed using SPSS V21.0 soft- balloon time was 75 min, with over 90% of patients achiev- ware (SPSS Inc., Chicago, IL, USA). Variables with a ing TIMI 3 flow at the end of the procedure. normal distribution are expressed as mean values ± SD, Patients were divided into 3 groups according to eGFR and asymmetrically distributed data are given as median levels; 1,878 patients without CKD (eGFR ≥60 mL/ and interquartile range (IQR). Differences between the min/1.73 m2), 1,073 patients with moderate CKD groups were evaluated by one-way analysis of variance (60>eGFR≥30 mL/min/1.73 m2) and 330 patients with (ANOVA) or the Kruskal-Wallis test for continuous vari- severe CKD (eGFR <30 mL/min/1.73 m2), including 195 ables and by a chi-squared test for categorical variables. hemodialysis patients. Patients with renal dysfunction In-hospital incidence rates of mortality and MACE were tended to be significantly older and to have a higher estimated by Poisson regression analysis with adjustments preponderance of cardiovascular risk factors such as for age and sex. Odds ratios (OR) and 95% confidence diabetes and hypertension (Table 1). There was also a intervals (CI) for in-hospital outcome were calculated for significantly higher prevalence of pre-existing coronary each factor by a logistic regression analysis. Hazard ratio artery disease among those with CKD (Table 1). However, (HR) and 95% CI for 3-year outcomes were estimated by patients with CKD were more likely to present with non- a Cox proportional hazard analysis. Kaplan-Meier curves ST-elevation myocardial infarction and as a result, were illustrated cumulative survival or event-free survival for significantly less likely to receive immediate revasculariza- MACE >3 years stratified by CKD stage. Numbers of tion. At discharge, 96.6% of the patients received anti- patients at risk are indicated at the bottom of the Kaplan- platelet agents; 80.8% had either ARB or ACEI; 68.4% Meier curves. All baseline variables with P<0.05 by univari- took β-blockers; and statins were prescribed for 86.9% of able analysis were entered into a multivariable model to the patients. determine independent predictors for the endpoints. At initial discharge from hospital, a total of 212 patients To assess whether the predicted ability for each endpoint reached the in-hospital primary endpoint of all-cause mor- would improve after the addition of CKD group into a tality (Table 2). However, of these, 174 (82%) had underly- baseline model consisted of baseline variables with P<0.05 ing CKD, despite the fact that this group comprised only by univariate logistic analysis, we calculated C-index and two-fifths of the study cohort (Table 2). Age- and sex- net reclassification improvement (NRI). The C-index is adjusted in-hospital mortality rate significantly increased defined as the area under receiver-operating characteristic from 0.014% in the no CKD group through 0.042% in the (ROC) curves between individual predictive probabilities moderate CKD group to 0.084% in the severe CKD group for the events and incidence of the events, and were com- per person-days (P<0.0001). Similar results were obtained pared for the baseline model and enriched models contain- for MACE (0.11%, 0.25% and 0.33% per person-days, ing the significant risk factors plus CKD group.18 The NRI respectively, P<0.0001) (Figure 2). Accordingly, at the end indicates relatively how many patients improve their pre- of 3-year follow up, a total of 389 patients met the 3-year dicted probabilities for the endpoints.19 Differences were primary endpoint of all-cause mortality (Table 2). Of these, considered statistically significant at P<0.05. 296 (76%) had underlying CKD, although this group consisted of only 42% of the study population (Table 2). Results Similarly, for the principal secondary composite endpoint of MACE, patients with CKD were significantly over- The baseline clinical and demographic characteristics of represented (Table 2). the study cohort are summarized in Table 1. Of the 3,283 While cumulative survival over 3 years was significantly patients with AMI, 2 patients were excluded due to a miss- worse according to the degree of deterioration of CKD ing eGFR value; the remaining 3,281 patients were enrolled stages from 93.3% in the no CKD group through 79.8% in (Figure 1). Of the 3,281 patients enrolled, 1,403 had CKD the moderate CKD group to 57.2% in the severe CKD Advance Publication Chronic Kidney Disease and Outcome After Acute MI 5

Table 2. Incidence of In-Hospital and 3-Year Clinical Outcome in Each CKD Group All patients No CKD Moderate CKD Severe CKD N (%) P value (n=3,281) (n=1,878) (n=1,073) (n=330) In-hospital MACE 568 (17.3) 149 (7.9) 293 (27.3) 126 (38.2) <0.0001 Mortality 212 (6.5) 38 (2.0) 103 (9.6) 71 (21.5) <0.0001 Cardiovascular 169 (79.7) 26 (68.4) 89 (86.4) 54 (76.1) 0.035 Non-cardiovascular 43 (20.3) 12 (31.6) 14 (13.6) 17 (23.9) Cardiac failure 493 (15.2) 127 (6.8) 263 (24.8) 103 (31.7) <0.0001 Stroke 45 (1.4) 14 (0.7) 22 (2.1) 9 (2.7) 0.0011 3-year MACE 897 (27.3) 296 (15.8) 410 (38.2) 191 (57.9) <0.0001 Mortality 389 (11.9) 93 (5.09) 175 (16.3) 121 (36.7) <0.0001 Cardiovascular 216 (55.5) 34 (33.6) 107 (61.1) 75 (62.0) 0.0009 Non-cardiovascular 159 (40.9) 54 (58.1) 64 (36.6) 41 (33.9) Unknown 14 (3.6) 5 (5.3) 4 (2.3) 5 (4.1) MI 100 (3.0) 26 (2.6) 28 (2.6) 24 (7.3) <0.0001 Cardiac failure 560 (17.1) 149 (7.9) 297 (27.7) 114 (34.5) <0.0001 Stroke 124 (3.8) 57 (3.0) 43 (4.0) 24 (7.3) 0.00087 Data are presented as n (%). CKD, chronic kidney disease; MACE, major adverse cardiac events.

group (Figure 3), event-free survival for MACE over 3 years has significantly deteriorated in proportion to the degree of advance of CKD stages from 80.8% in the no CKD group through 55.7% in the moderate CKD group to 35.6% in the severe CKD group (Figure 4). The differences in mortality and MACE remained highly significant after adjusting for potential confounding factors (Table 3). On multivariable logistic and Cox regression modelling, the presence of CKD was of independent prognostic sig- nificance and improved the discriminative performance of the baseline model, incorporating other risk markers for both the primary endpoint of all-cause mortality and the principal secondary endpoints of MACE in both in-hospital and 3-year follow up. In addition, patients with severe CKD had higher risk of mortality and MACE even compared to patients with moderate CKD (Table 3). The significantly improved C-statistic also translated into a highly signifi- cant incremental NRI (Table 4).

Discussion We found that despite advances in medical therapy, and improvements in the availability and delivery of mechanical reperfusion therapy in the contemporary PCI era, the pres- Figure 2. Age- and sex-adjusted incidence rate of in-hospital ence of CKD continues to portend a significantly increased events stratified by CKD stage. A total of 212 patients reached risk of adverse outcomes for all the endpoints examined. the in-hospital primary endpoint of all-cause mortality (Left graph) and a total of 568 patients reached the in-hospital This prognostic significance was retained even after adjust- secondary composite endpoint of MACE (Right graph). The ing for known confounders. CKD also improved risk incidence of either in-hospital mortality or MACE significantly stratification when used to enrich a model with other increased in proportion to the CKD stage. CKD, chronic kidney established risk markers and, importantly, significantly disease; MACE, major adverse cardiac events. improved reclassification metrics. The association between CKD and adverse outcomes exhibited a dose-response relationship, with progressively worsening renal dysfunction being associated with a com- mortality and MACE significantly deteriorated from 7.9% mensurately worse rate of adverse events. The underlying and 2.0% in the no CKD group through to 27.3% and pathophysiologic basis for this association remains incom- 9.6% in the moderate CKD group to 38.2% and 21.5% in pletely understood, but this dose-response behavior pro- the severe CKD group (Table 2). Although the precise vides persuasive support for a causal link. mechanisms responsible for the association between in- Interestingly, the immediate drop of Kaplan-Meier hospital cardiac events and the degree of CKD are curves in severe CKD was driven by the fact that in-hospital unknown, several mechanisms have been implicated. Advance Publication 6 Hashimoto Y et al.

Figure 3. Kaplan-Meier curves showing cumulative survival over 3 years stratified by CKD stage. Cumulative survival over 3 years was significantly worse according to the degree of deterioration of CKD stages from 93.3% in the no CKD group through to 79.8% in the moderate CKD group to 57.2% in the severe CKD group. Numbers of patients at risk are indicated at the bottom of the figure. CKD, chronic kidney disease.

Figure 4. Kaplan-Meier curves showing event-free survival for MACE over 3 years stratified by CKD stage. Event-free survival for MACE over 3 years significantly deterio- rated in proportion to the degree of renal impairment from 80.8% in the no CKD group through to 55.7% in the moderate CKD group to 35.6% in the severe CKD group. Numbers of patients at risk are indicated at the bottom of the figure. CKD, chronic kidney disease; MACE, major adverse cardiac events.

Firstly, a higher incidence of acute kidney injury could strategies that impact survival with AMI.24 The resulting confer increased in-hospital mortality.20,21 While acute kidney dearth of evidence on optimal treatment strategies for such injury is associated with worse long-term outcomes after patients may thereby result in worse outcomes. MI, this effect is modified by baseline CKD status.20 CKD is strongly associated with other cardiovascular Secondly, it is also recognized that patients with CKD and risk factors such as diabetes and hypertension.1,2,23,26 The AMI experience a higher incidence of complications such latter both causes and/or contributes to CKD, but can also as bleeding and contrast nephropathy, which may have a result from it. In keeping with this, CKD was strongly deleterious impact on clinical outcome.22–24 Thirdly, the associated with a greater preponderance of cardiovascular location of the coronary culprit lesion in AMI is more risk factors.2 Furthermore, CKD patients were also sig- proximal in patients with CKD, possibly leading to higher nificantly more likely to have pre-existing coronary artery event rates or threatening a larger myocardial volume.25 disease prior to their index presentation with AMI. Hinting Finally, despite being among the highest-risk subset of at the presence of more advanced underlying atherosclerosis, patients with AMI, patients with advanced CKD have significantly fewer patients with CKD achieved TIMI 3 been generally excluded from randomized trials evaluating flow. However, despite adjusting for these pleiotropic con- Advance Publication Chronic Kidney Disease and Outcome After Acute MI 7

Table 3. Predictive Value of CKD for In-Hospital and 3-Year Clinical Outcomes After AMI Non-adjusted Adjusted† In-hospital OR (95% CI) P value OR (95% CI) P value Mortality No Ref. Ref. Moderate 5.14 (3.54–7.60) <0.0001 2.00 (1.23–3.28) 0.0050 Severe 13.3 (8.82–20.3) <0.0001 6.71 (3.91–11.7) <0.0001 Severe vs. Moderate 2.51 (1.79–3.49) <0.0001 3.17 (2.04–4.95) <0.0001 MACE No Ref. Ref. Moderate 4.34 (3.52–5.40) <0.0001 1.89 (1.43–2.49) <0.0001 Severe 7.17 (5.43–9.46) <0.0001 3.31 (2.28–4.82) <0.0001 Severe vs. Moderate 1.64 (1.26–2.13) 0.0002 1.77 (1.24–2.53) 0.0016

Non-adjusted Adjusted‡ 3-year HR (95% CI) P value HR (95% CI) P value Mortality No Ref. Ref. Moderate 3.56 (2.77–4.59) <0.0001 1.40 (0.98–2.01) 0.062 Severe 9.06 (6.92–11.9) <0.0001 3.49 (2.19–5.37) <0.0001 Severe vs. Moderate 2.54 (2.02–3.21) <0.0001 2.65 (2.05–3.42) <0.0001 MACE No Ref. Ref. Moderate 2.75 (2.37–3.19) <0.0001 1.33 (1.09–1.63) 0.0052 Severe 5.10 (4.25–6.11) <0.0001 2.45 (1.89–3.17) <0.0001 Severe vs. Moderate 1.77 (1.48–2.09) <0.0001 1.72 (1.42–2.07) <0.0001 †Adjusted for male, age, hypertension, dyslipidemia, previous AF, previous stroke, STEMI, Killip classification, twice CK↑, anti-platelet agents and β-blockers as variables with P<0.05 by univariate analysis for in-hospital endpoints. ‡Adjusted for male, age, diabetes, hypertension, dyslipidemia, current smoker, previous MI, previous PCI, previous CABG, previous PAD, previous AF, previous stroke, multi-vessel disease, STEMI, Killip classification, twice CK↑, Final TIMI 3 flow, revascularization, AKI, anti-platelet agents, nicorandil and β-blockers as variables with P<0.05 by univariate analysis for 3-year endpoints. AKI, acute kidney injury; CABG, coronary artery bypass graft; CI, confidence interval; CK, creatine kinase; MACE, major adverse cardiac events; OR, odds ratio. Other abbreviations as in Table 1.

Table 4. Discrimination of Each Predicting Model for In-Hospital and 3-Year Clinical Outcomes After AMI Using C-Index and Net Reclassification Improvement (NRI) C-index (95% CI) P value NRI P value In-hospital Mortality Basic model† 0.877 (0.849–0.904) Ref. +CKD group 0.890 (0.862–0.919) 0.040 0.627 <0.0001 MACE Basic model† 0.820 (0.798–0.842) Ref. +CKD group 0.830 (0.808–0.851) 0.011 0.306 <0.0001 3-year Mortality Basic model‡ 0.815 (0.788–0.841) Ref. +CKD group 0.831 (0.806–0.857) 0.013 0.486 <0.0001 MACE Basic model‡ 0.731 (0.708–0.755) Ref. +CKD group 0.740 (0.717–0.764) 0.046 0.331 <0.0001 †Model includes male, age, hypertension, dyslipidemia, previous AF, previous stroke, STEMI, Killip classification, twice CK↑, anti-platelet agents and β-blockers. ‡Model includes male, age, diabetes, hypertension, dyslipidemia, current smoker, previous MI, previous PCI, previous CABG, previous PAD, previous AF, previous stroke, multi- vessel disease, STEMI, Killip classification, twice CK↑, Final TIMI 3 flow, revascularization, AKI, anti-platelet agents, nicorandil and β-blockers. Abbreviations as in Tables 1,3. Advance Publication 8 Hashimoto Y et al. founding factors, the association between CKD and adverse increases in the risk of clinical outcomes for both lower events retained independent prognostic significance. and higher eGFR, while Ota et al reported that proteinuria Interestingly, patients with CKD were less likely to pres- may be a prognostic marker for long-term mortality.30,31 The ent with STEMI. The higher incidence of NSTEMI and presence of proteinuria could be some marker for the concerns about risks of inducing contrast nephropathy prediction of cardiac events. However, unfortunately, we may explain why rates of urgent angiography were lower did not collect data on proteinuria in the current study. in our cohort among this ostensibly higher risk subgroup.9 It may also suggest that the mechanisms underlying ACS Conclusions in this cohort may be pathologically distinct. We speculate that plaque erosion may be a more predominant mecha- CKD remains associated with adverse outcomes in patients nism in the CKD group, in which patients tended to be presenting with AMI, despite advances in the care of these older and have more established atherosclerosis, whereas patients prior to and after presentation. The presence of plaque rupture may be more common in younger non- CKD retained independent prognostic significance even CKD patients where less mature plaques that are more after adjusting for confounders and significantly improved vulnerable to rupture may be responsible.27,28 The higher model performance. CKD should therefore remain a key prevalence of STEMI in the non-CKD group may provide component of any model used to risk stratify patients pre- some circumstantial support for this, but the underlying senting with AMI. mechanisms require further study. Patients with CKD were more likely to experience acute Disclosures heart failure as part of their presentation with AMI (Table 2). Y.O., K. Kimura, J.A., T.N., W.S. Y. Saito, T.I., K. Tsujita, S.Y., This is despite experiencing lower peak enzyme rises (Table 1) H.I., H.O. and M.I. are members of Circulation Journal’s Editorial compared to patients without CKD. This may reflect both Team. pre-existing LV systolic dysfunction, the greater severity of the underlying coronary disease, and the more precarious IRB Information fluid balance and handling seen with progressively lower The present study was approved by the National Cerebral and renal clearance. Cardiovascular Center Institutional Review Board for Clinical The risk stratification of patients presenting with AMI Research (Reference number: M23-084). and other acute coronary syndromes remains an important challenge.6 In an era where the costs of medical care are References escalating in all healthcare settings and models of care 1. Herzog CA, Asinger RW, Berger AK, Charytan DM, Diez J, delivery are evolving, the appropriate identification and Hart RG, et al. Cardiovascular disease in chronic kidney disease. triage of patients to early intervention and revasculariza- A clinical update from Kidney Disease: Improving Global Outcomes tion is an important goal both for improving patient out- (KDIGO). Kidney Int 2011; 80: 572 – 586. 8,9,29 2. Sarnak MJ, Amann K, Bangalore S, Cavalcante JL, Charytan comes and reducing healthcare costs. Similarly, DM, Craig JC, et al. 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Impact of chronic kidney disease on utilization of coronary angiography should continue to remain an important component of any and percutaneous coronary intervention, and their outcomes in risk stratification tools, despite advances in clinical care. patients with non-ST elevation myocardial infarction. Am J Car- Our work also highlights the need for further research to diol 2018; 122: 1830 – 1836. elucidate the mechanisms by which CKD worsens out- 5. Saltzman AJ, Stone GW, Claessen BE, Narula A, Leon-Reyes S, Weisz G, et al. Long-term impact of chronic kidney disease in comes in patients with AMI. While recent data suggest patients with ST-segment elevation myocardial infarction treated that the incidence of cardiac events in this high-risk cohort with primary percutaneous coronary intervention: The has been falling in recent years, probably as a result of bet- HORIZONS-AMI (Harmonizing Outcomes With Revascular- ter risk factor control including OMT and modern primary ization and Stents in Acute Myocardial Infarction) trial. JACC Cardiovasc Interv 2011; 4: 1011 – 1019. PCI, the development of CKD nevertheless retains omi- 6. Yan AT, Yan RT, Tan M, Eagle KA, Granger CB, Dabbous nous prognostic significance that has not yet been suffi- OH, et al. In-hospital revascularization and one-year outcome of ciently ameliorated by improvements in cardiovascular acute coronary syndrome patients stratified by the GRACE risk knowledge and care. score. Am J Cardiol 2005; 96: 913 – 916. 7. 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