ORIGINAL ARTICLE. Ischemic Heart Disease

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1 Circulation Journal Official Journal of the Japanese Circulation Society ORIGINAL ARTICLE Ischemic Heart Disease Distinct Survival Benefits of Angiotensin-Converting Enzyme Inhibitors/Angiotensin II Receptor Blockers in Revascularized Coronary Artery Disease Patients According to History of Myocardial Infarction Tomohiro Nishino, MD; Yutaka Furukawa, MD; Shuichiro Kaji, MD; Natsuhiko Ehara, MD; Hiroki Shiomi, MD; Kitae Kim, MD; Takeshi Kitai, MD; Makoto Kinoshita, MD; Takeshi Morimoto, MD; Ryuzo Sakata, MD; Takeshi Kimura, MD on behalf of the CREDO-Kyoto PCI/CABG registry cohort-2 investigators Background: It is controversial whether angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) provide significant survival benefits in patients with coronary artery disease (CAD) but without myocardial infarction (MI). This study investigated whether the association of ACEI/ARB therapy with clinical outcome in patients undergoing percutaneous coronary intervention (PCI) was affected by history of MI. Methods and Results: A total of 11,590 patients undergoing first PCI were divided into 2 groups: those with MI and those without MI. All-cause and cardiovascular mortality were compared between the patients with and without ACEI/ ARB at discharge in each group. In patients with MI, significantly lower 3-year all-cause/cardiovascular mortality for patients with ACEI/ARB relative to those without ACEI/ARB was noted in the total patients (all-cause: 6.6% vs. 11.7%, P<0.0001; cardiovascular: 3.8% vs. 6.9%, P<0.0001) and in the 1,007 propensity score-matched pairs (allcause: 8.2% vs. 11.3%, P=0.018; cardiovascular: 3.7% vs. 5.7%, P=0.014). In patients without MI, however, allcause (5.2% vs. 5.6%, P=0.56) and cardiovascular (3.2% vs. 3.0%, P=0.23) mortality were similar regardless of whether ACEI/ARB were used or not; and similarly in the 2,061 propensity score-matched pairs (all-cause: 4.1% vs. 5.4%, P=0.33; cardiovascular: 1.4% vs. 2.1%, P=0.30). Conclusions: Use of ACEI/ARB at hospital discharge was associated with lower all-cause/cardiovascular mortality in revascularized CAD patients with MI, but not in those without MI. (Circ J 2013; 77: ) Key Words: Angiotensin; Coronary artery disease; Myocardial infarction; Outcomes; Revascularization Preventive effects of renin-angiotensin system (RAS) inhibition on cardiovascular morbidity and mortality have been shown in patients with heart failure 1 4 or a history of myocardial infarction (MI). 5 8 Controversy remains, however, as to whether RAS inhibition with angiotensinconverting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) can provide a cardiovascular protective effect in patients with coronary artery disease (CAD) but without left ventricular systolic dysfunction due to MI. In the Heart Outcomes Prevention Evaluation (HOPE) and the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA), patients with coronary or other vascular disease, or with cardiovascular risk factors had reduced incidence of death from cardiovascular causes or acute MI when assigned to ACEI as compared with placebo. 9,10 In the Prevention of Events with Angiotensinconverting Enzyme Inhibition (PEACE) trial, however, the addition of an ACEI provided no further benefit in patients with stable CAD and preserved left ventricular function when they were receiving standard medical therapy. 11 In addition, data are limited that assessed whether ACEI/ ARB are beneficial for patients with CAD after coronary revascularization by percutaneous coronary intervention (PCI). In principle, patients undergoing PCI have at least 1 severe Received July 24, 2012; revised manuscript received October 24, 2012; accepted December 5, 2012; released online December 29, 2012 Time for primary review: 15 days Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe (T.N., Y.F., S.K., N.E., K.K., T. Kitai, M.K.); Department of Cardiovascular Medicine (T.N., H.S., T. Kimura), Department of Cardiovascular Surgery (R.S.), Kyoto University Graduate School of Medicine, Kyoto; and Center for General Internal Medicine and Emergency Care, Kinki University School of Medicine, Osaka-Sayama (T.M.), Japan Mailing address: Yutaka Furukawa, MD, Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Minatojima-minamimachi, Chuo-ku, Kobe , Japan. furukawa@kcho.jp ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 ACEI/ARB in Patients With or Without MI 1243 Figure 1. Study flow chart. ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; CABG, coronary artery bypass grafting; MI, myocardial infarction; PCI, percutaneous coronary intervention. coronary stenosis, and tend to have more risk factors for future cardiovascular events. For those reasons, we chose the Coronary Revascularization Demonstrating Outcome study in Kyoto (CREDO-Kyoto) PCI/CABG registry cohort 2 as the present study cohort. The aim of this study was to determine whether use of ACEI/ARB reduces morbidity and mortality in patients with CAD undergoing their first PCI who do not have a history of MI. Methods The study protocol conformed to the ethics guidelines of the 1975 Declaration of Helsinki as reflected in the priori approval by the Human Research Committees of all participating institutions. Because the subjects were retrospectively enrolled, written informed consent from the patients was waived, but we excluded those patients who refused participation in the study when contacted for follow-up. This strategy is concordant with the guidelines for epidemiological studies issued by the Ministry of Health, Labor and Welfare of Japan. Subjects Participants of the CREDO-Kyoto registry cohort 2 have been previously described. 12,13 In brief, a total of 15,939 patients underwent PCI or coronary artery bypass graft (CABG) as their first coronary revascularization procedure among 26 centers in Japan during the 3 years ( ) of enrollment (Appendix S1). Excluding 67 patients who refused study participation, 2,785 patients who underwent CABG, 342 patients who died during the index hospitalization, and 1,155 patients with malignant disease, 11,590 patients (with history of MI, n=5,211; without history of MI, n=6,379) constituted the study group for the current analyses. Patients in each group were further divided into 2 groups according to ACEI/ARB therapy at discharge: 3,812 patients with ACEI/ARB, and 1,399 patients without ACEI/ARB in the MI group; and 3,152 patients with ACEI/ARB, 3,227 patients without ACEI/ARB in the non-mi group (Figure 1). Data Collection, Definitions and Follow-up Demographic, angiographic, and procedural data were collected from hospital charts or databases according to pre-specified definitions by experienced clinical research coordinators in the independent research organization (Research Institute for Production Development, Kyoto, Japan; Appendix S2). Uncontrolled hypertension was defined as systolic blood pressure 140 mmhg and/or diastolic blood pressure 90 mmhg. Renal dysfunction was defined as egfr <30 ml min m 2 according to the Modification of Diet in Renal Disease formula modified for Japanese patients, or need for dialysis; 14 and anemia was defined as blood hemoglobin (Hb) <11.0 g/dl. Other definitions of baseline clinical characteristics have been described previously. 12 The patients were followed up with respect to mortality for a median of 2.6 years (958 days). The main outcome measures in the current analysis were all-cause death and cardiovascular death. All deaths were confirmed by medical records or telephone interviews with the patients families. Death was regarded as cardiac in origin unless obvious non-cardiac causes could be identified. Vascular death was defined as death related to aortic, cerebral, renal and peripheral vascular disease. Cardiovascular death was defined as a composite of cardiac death and vascular death. Cardiovascular death MI, stroke, and hospitalization due to heart failure were

3 1244 NISHINO T et al. Table 1. Baseline Patient Characteristics vs. History of MI MI (+) (n=5,211) MI ( ) (n=6,379) P-value Clinical characteristics Age (years) 67.1± ± Age 75 years Male BMI (kg/m 2 ) 23.7± ± BMI 25.0 kg/m < Uncontrolled hypertension Diabetes mellitus < On insulin therapy < Current smoking < Heart failure < Mitral regurgitation grade 3/ < LVEF (%) 53.2± ±11.4 < LVEF <40% < Prior stroke Peripheral vascular disease < Multivessel disease Unprotected LMCA Target of CTO egfr <30 ml min m 2, not on dialysis Dialysis < Atrial fibrillation Anemia (Hb <11 g/dl) COPD Liver cirrhosis Baseline medication Medication at hospital discharge Antiplatelet therapy Thienopyridine < Aspirin Other medications Statins < β-blockers < ACEI/ARB < Spironolactone Nitrates < Calcium channel blockers < Nicorandil < Warfarin < Data given as %, mean ± SD or median (interquartile range). ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; BMI, body mass index; CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; CTO, chronic total occlusion; egfr, estimated glomerular filtration rate; Hb, hemoglobin; LMCA, left main coronary artery disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction. adjudicated using original source documents by a clinical event committee (Appendix S3). Statistical Analysis All continuous variables are expressed as mean ± SD. Differences in the baseline characteristics and treatments between the patients with MI and those without MI were assessed using Pearson s chi-square test for categorical data and Student s t- test for continuous data. Cumulative incidence was estimated with the Kaplan-Meier method and differences were assessed with the log-rank test. The Cox proportional hazards model was used to adjust the results for baseline differences between the groups. To identify significant and independent predictors of clinical outcomes, we listed the following clinically relevant baseline demographic and clinical factors as potential riskadjusting variables: age 75 years; gender; BMI 25 kg/m 2 ; diabetes mellitus (DM); multivessel disease; unprotected left main CAD; chronic total occlusion; severe mitral regurgitation (grade 3/4); prior stroke; atrial fibrillation; peripheral vascular disease; renal dysfunction; hemodialysis; current smoking; uncontrolled hypertension; anemia (Hb >11 g/dl); chronic obstructive pulmonary disease; liver cirrhosis. The following cardiovascular pharmacotherapies at hospital discharge were also listed: statins; β-blockers; spironolactone; nitrates; calcium channel blockers; nicorandil; warfarin. To reduce selection bias, we also performed rigorous adjustment for differences in the

4 ACEI/ARB in Patients With or Without MI 1245 Table 2. Baseline MI Patient Characteristics vs. Use of ACEI/ARB: Before Propensity Score Matching ACEI/ARB (+) (n=3,812) ACEI/ARB ( ) (n=1,399) P-value Clinical characteristics Age (years) 66.7± ± Age 75 years < Male BMI (kg/m 2 ) 23.9± ±3.5 < BMI 25.0 kg/m < Uncontrolled hypertension < Diabetes mellitus On insulin therapy Current smoking Heart failure Mitral regurgitation grade 3/ LVEF (%) 53.1± ± LVEF <40% Prior stroke Peripheral vascular disease Multivessel disease Unprotected LMCA Target of CTO < egfr <30 ml min m 2, not on dialysis < Dialysis < Atrial fibrillation Anemia (Hb <11 g/dl) < COPD Liver cirrhosis Baseline medication Medication at hospital discharge Antiplatelet therapy Thienopyridine Aspirin Other medications Statins < β-blockers < Spironolactone Nitrates Calcium channel blockers Nicorandil Warfarin Data given as %, mean ± SD or median (interquartile range). Potential independent variable selected for multivariate analysis. Abbreviations as in Table 1. baseline characteristics using propensity score matching. Using multivariate logistic regression, a propensity score model was created to estimate the likelihood of ACEI/ARB use. The propensity model included age, sex, BMI, uncontrolled hypertension, DM, renal dysfunction, current smoking, heart failure, multivessel disease, unprotected left main CAD, chronic total occlusion, mitral regurgitation, left ventricular ejection fraction (LVEF), prior stroke, peripheral vascular disease, atrial fibrillation, anemia, and medication (statins, β-blockers, nitrates, calcium channel blockers, and warfarin). A nearest-neighbor matching algorithm was used to match patients within a caliper width of 0.2 SD of the logit of the propensity score. After propensity score matching, the baseline covariates were compared between the 2 groups with the paired t-test or Wilcoxon signed-rank test for continuous variables and the McNemar test for categorical variables. Survival curves were constructed with Kaplan-Meier estimates and compared with the log-rank test. For Kaplan-Meier analysis, we analyzed all clinical events by time to first event. Statistical analysis was conducted by 2 physicians (T. Nishino and S. Kaji) using JMP 9.0 (SAS Institute, Cary, NC, USA), SPSS version 17.0 (SPSS, Chicago, IL, USA), and R (R Foundation for Statistical Computing, Vienna, Austria). All statistical analysis was 2-tailed, and P<0.05 was considered statistically significant. Results Differences in Baseline Characteristics vs. Presence of History of MI Among the 11,590 patients, 45.0% (n=5,211) had a history of

5 1246 NISHINO T et al. Table 3. Baseline Non-MI Patient Characteristics vs. Use of ACEI/ARB: Before Propensity Score Matching ACEI/ARB (+) (n=3,152) ACEI/ARB ( ) (n=3,227) P-value Clinical characteristics Age (years) 68.3± ± Age 75 years Male BMI (kg/m 2 ) 24.2± ±3.2 < BMI 25.0 kg/m < Uncontrolled hypertension < Diabetes mellitus < On insulin therapy < Current smoking Heart failure < Mitral regurgitation grade 3/ LVEF (%) 61.8± ±10.3 < LVEF <40% < Prior stroke < Peripheral vascular disease Multivessel disease < Unprotected LMCA Target of CTO egfr <30 ml min m 2, not on dialysis < Dialysis Atrial fibrillation Anemia (Hb <11 g/dl) COPD Liver cirrhosis Baseline medication Medication at hospital discharge Antiplatelet therapy Thienopyridine Aspirin Other medications Statins < β-blockers < Spironolactone Nitrates Calcium channel blockers < Nicorandil Warfarin < Data given as mean ± SD or median (interquartile range). Potential independent variable selected for multivariate analysis. Abbreviations as in Table 1. MI and 55.0% (n=6,379) did not. Compared with patients without MI, patients with MI had significantly lower LVEF (53.2±12.7% vs. 63.0±11.4%, P<0.0001), higher incidences of concomitant heart failure (27.4% vs. 10.6%, P<0.0001) and current smoking (40.6% vs. 27.2%, P<0.0001), and lower incidence of DM (35.0% vs. 39.3%, P<0.0001). The following medications commonly used for cardiovascular prevention were more frequently prescribed in patients with MI than those without MI at hospital discharge: ACEI (31.6% vs. 13.8%, P<0.0001), ARB (43.6% vs. 37.8%, P<0.0001), ACEI/ ARB (73.2% vs. 49.4%, P<0.0001), statins (55.7% vs. 51.0%, P<0.0001), and β-blocker (41.5% vs. 23.2%, P<0.0001; Table 1). Baseline Characteristics in MI Patients vs. ACEI/ARB Therapy (Before Propensity Score Matching) Among the patients with MI, patients with ACEI/ARB were younger (66.7±11.8 years vs. 68.1±12.2 years, P=0.0003), and had a higher incidence of uncontrolled hypertension (46.8% vs. 35.3%, P<0.0001) relative to those without ACEI/ARB, but a lower incidence of renal dysfunction (2.6% vs. 6.8%, P<0.0001) and of anemia (8.7% vs. 13.2%, P<0.0001). LVEF was comparable between patients with and without ACEI/ ARB (53.1±12.5% vs. 53.4±13.3%, P=0.45). Statins and β-blockers were more frequently, but spironolactone was less frequently, prescribed in patients with ACEI/ARB than in patients without ACEI/ARB (statins: 59.2% vs. 46.1%, P<0.0001; β-blockers: 46.2% vs. 28.8%, P<0.0001; spironolactone: 8.5% vs. 10.4%, P=0.031; Table 2).

6 ACEI/ARB in Patients With or Without MI 1247 Figure 2. Cumulative unadjusted incidences of (A,B) all-cause and (C,D) cardiovascular death according to the use of angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB). In (A,C) patients with a history of myocardial infarction (MI), the incidences of (A) all-cause and (C) cardiovascular death were significantly lower in patients with ACEI/ARB therapy. But in (B,D) patients without a history of MI, the incidences of (B) all-cause and (D) cardiovascular death were similar between patients with and without ACEI/ARB therapy.

7 1248 NISHINO T et al. Table 4. Baseline MI Patient Characteristics vs. Use of ACEI/ARB: After Propensity Score Matching ACEI/ARB (+) (n=1,007) ACEI/ARB ( ) (n=1,007) P-value Clinical characteristics Age (years) 68.5± ± Age 75 years Male BMI 25.0 kg/m Uncontrolled hypertension Diabetes mellitus On insulin therapy Current smoking Heart failure Mitral regurgitation grade 3/ LVEF (%) 53.4± ± LVEF <40% Prior stroke Peripheral vascular disease Multivessel disease Unprotected LMCA Target of CTO egfr <30 ml min m 2, not on dialysis Dialysis Atrial fibrillation Anemia (Hb <11 g/dl) COPD Liver cirrhosis Baseline medication Medication at hospital discharge Antiplatelet therapy Thienopyridine Aspirin Other medications Statins β-blockers Spironolactone Nitrates Calcium channel blockers Nicorandil Warfarin Data given as %, mean ± SD or median (interquartile range). Potential independent variable selected for multivariate analysis. Abbreviations as in Table 1. Baseline Characteristics in Non-MI Patients vs. ACEI/ARB Therapy (Before Propensity Score Matching) Among the patients without MI, patients with ACEI/ARB were older (68.3±10.3 years vs. 67.4±10.5 years, P=0.0006), and had lower LVEF and a higher incidence of uncontrolled hypertension, DM, heart failure, multivessel disease and renal dysfunction. Statins and β-blockers were more frequently prescribed in patients with ACEI/ARB than in patients without ACEI/ARB (statins: 54.4% vs. 47.7%, P<0.0001; β-blockers: 27.6% vs. 18.9%, P<0.0001; Table 3). ACEI/ARB and Unadjusted/Adjusted All-Cause and Cardiovascular Mortality in MI Patients Among the patients with a history of MI, unadjusted incidence rates of all-cause as well as cardiovascular mortality were significantly lower in patients with ACEI/ARB than those with- out ACEI/ARB at discharge. After adjustment by multivariate Cox regression analysis, use of ACEI/ARB remained an independent predictor of lower risk for all-cause mortality. There was a trend toward lower risk for cardiovascular mortality in patients with ACEI/ARB compared to those without ACEI/ ARB (Figure 2; Table S1). ACEI/ARB and Unadjusted/Adjusted All-Cause and Cardiovascular Mortality in Non-MI Patients In contrast to the impact of ACEI/ARB on mortality in patients with MI, in the patients without a history of MI, both unadjusted and adjusted incidence rates of all-cause as well as cardiovascular mortality were similar between patients with ACEI/ARB and those without ACEI/ARB at discharge (Figure 2; Table S1).

8 ACEI/ARB in Patients With or Without MI 1249 Table 5. Baseline Non-MI Patient Characteristics vs. Use of ACEI/ARB: After Propensity Score Matching ACEI/ARB (+) (n=2,061) ACEI/ARB ( ) (n=2,061) P-value Clinical characteristics Age (years) 67.9± ± Age 75 years Male BMI 25.0 kg/m Uncontrolled hypertension Diabetes mellitus On insulin therapy Current smoking Heart failure Mitral regurgitation grade 3/ LVEF (%) 63.7± ± LVEF <40% Prior stroke Peripheral vascular disease Multivessel disease Unprotected LMCA Target of CTO egfr <30 ml min m 2, not on dialysis Dialysis Atrial fibrillation Anemia (Hb <11 g/dl) COPD Liver cirrhosis Baseline medication Medication at hospital discharge Antiplatelet therapy Thienopyridine Aspirin Other medications Statins β-blockers Spironolactone Nitrates Calcium channel blockers Nicorandil Warfarin Data given as %, mean ± SD or median (interquartile range). Potential independent variable selected for multivariate analysis. Abbreviations as in Table 1. ACEI/ARB and Unadjusted 3-Year Incidence of Cardiovascular Events Unadjusted 3-year event rates of all-cause death, cardiovascular death, MI, hospitalization due to heart failure, and stroke are listed in Table S2. In addition to the reduced all-cause and cardiovascular mortality, the incidence of hospitalization due to heart failure was significantly lower in MI patients with ACEI/ARB. The incidence of each component of cardiovascular events was similar between the patients with ACEI/ARB and those without ACEI/ARB therapy among the non-mi patients, except for the significantly higher incidence of hospitalization due to heart failure in patients with ACEI/ARB. Characteristics of Propensity Score-Matched Pairs vs. ACEI/ARB and Presence of History of MI One-to-one matching was performed, and 1,007 patients with MI and 2,061 patients without MI were enrolled in the propensity score-matched group, respectively. As shown in Tables 4,5, there were no significant differences with respect to the baseline variables between the propensity score-matched groups both in the MI(+) cohort and in the MI( ) cohort. All-Cause and Cardiovascular Mortality in Propensity Score-Matched Patients Figure 3 shows the cumulative incidences of all-cause and cardiovascular death during follow-up in the propensity scorematched groups with or without ACEI/ARB therapy. In the patients with a history of MI, the incidences of all-cause and cardiovascular death were significantly lower in patients with ACEI/ARB than those without ACEI/ARB. In the patients without a history of MI, however, the incidences of all-cause and cardiovascular death were similar between patients with

9 1250 NISHINO T et al. Figure 3. Cumulative incidences of (A,B) all-cause and (C,D) cardiovascular death according to the use of angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) in the propensity score-adjusted patient groups. In (A,C) patients with a history of myocardial infarction (MI), the adjusted incidences of (A) all-cause and (C) cardiovascular death were significantly lower in patients with ACEI/ARB therapy. But in (B,D) patients without a history of MI, the adjusted incidences of (B) all-cause and (D) cardiovascular death were similar between patients with and without ACEI/ARB therapy.

10 ACEI/ARB in Patients With or Without MI 1251 and those without ACEI/ARB. Further adjustment by multivariate analysis verified the association between the use of ACEI/ARB and the significantly reduced mortality risk among the patients with MI. The adjusted mortality risks were similar between the patients with ACEI/ARB and those without ACEI/ ARB among the patients without MI (Table S3). Cumulative incidences of MI and hospitalization due to heart failure during follow-up in propensity score-matched pairs were similar between patients with and without ACEI/ARB both in patients with a history of MI and in patients without MI (Figure S2). Discussion In the current study, RAS inhibition by ACEI/ARB was associated with lower all-cause and cardiovascular mortality in the patients with a history of MI who underwent PCI for the first time. In the patients without a history of MI, however, survival benefits of ACEI/ARB at discharge were not seen. The findings were confirmed on propensity score analysis, although the adjusted risk for cardiovascular death was not significantly lower in the ACEI/ARB-treated patients among the patients with a history of MI. In addition to their use as anti-hypertensives in cardiovascular primary prevention, ACEI/ARB have also been found to have cardiovascular protective effects in patients with heart failure due to left ventricular systolic dysfunction 2 4 and in patients with MI. 5,6,8,15 There remains controversy, however, regarding the survival benefit of ACEI/ARB in stable CAD patients without a history of MI. The current study, in concordance with the PEACE trial, 11 did not find significant survival benefits of ACEI/ARB in secondary prevention for CAD patients without a history of MI and with preserved LVEF. Contrary to the results of the PEACE trial, the HOPE trial found significantly lower incidences of all-cause and cardiovascular death in ramipril-treated patients than in placebotreated patients. 9 A possible explanation for this discrepancy may be the differences in subject characteristics with regard to CAD. For instance, all of the present patients, as compared with 40% in the HOPE trial and 72% in the PEACE trial, underwent coronary revascularization by PCI before entering the follow-up period. Patients who underwent PCI might be at lower cardiovascular risk than those with clinically significant CAD who did not undergo revascularization therapy, because hospitalization for PCI could be an opportunity for lifestyle modification and medical therapy optimization. Thus, the present patients might be managed more intensively with respect to CAD, which could be associated with the lower risk for adverse cardiovascular events. There were also notable differences in the medical therapy: 51% of the present non-mi patients and 29% of the patients in HOPE were treated with statins (or other lipid-lowering agents) at baseline. Although the survival benefit of PCI has not been fully established, more recent and intensive patient management in the current study compared with the HOPE trial may, in part, contribute to the contradictory results of these studies. The survival benefit due to RAS inhibition in patients with a history of MI seen in the current study is a consistent finding. 16,17 The RAS plays an important role in cardiovascular homeostasis and pathophysiology Systemic RAS as well as local RAS such as cardiac and vascular RAS are crucially involved in the pathogenesis and progression process of cardiovascular diseases including CAD Because ACEI/ARB can inhibit systemic RAS and both cardiac and vascular local RAS, the effect of RAS inhibition by ACEI/ARB may be dif- ferent depending on the significance of each RAS in each pathologic condition. CAD patients with a history of MI have myocardium injury and cardiac dysfunction. Because myocardial injury can be a strong stimulus to activate various neurohumoral factors including RAS, 24,25 patients with MI may be more susceptible to the activity of cardiac local RAS than stable CAD patients. Thus, the existence of local RAS may be a possible explanation for the differing effects of RAS inhibition by ACEI/ARB on outcome in CAD patients with vs. those without a history of MI. Study Limitations Several limitations of the present study should be considered. This study is an observational study and had limitations common to all observational studies caused by differences in patient background characteristics among groups. Use of multivariate and propensity score analysis to remove bias can never be completely successful. Because the information on medical therapy was obtained only at hospital discharge, adherence to medication and the cross-over of medications have not been considered. ACEI/ARB treatment included different ACEI/ ARB at different doses. We could not compare the efficacy of different ACEI/ARB at fixed doses in a head-to-head fashion. The relatively short mean follow-up period (2.6 years) might be sufficient to compare the event rates in high-risk patients with MI, but might be too short to assess outcome in patients without MI who have lower cardiovascular risk. Considering the low cardiovascular risks in the Japanese patients, the incidence of cardiovascular death might not be sufficient to identify consistently lower adjusted risk for cardiovascular death in the patients with ACEI/ARB relative to those without ACEI/ ARB among the patients with a history of MI. Finally, the cardiovascular event rates in the participants in the CREDO-Kyoto registry were lower than those in many other studies conducted outside Japan. 26 We should be careful in extrapolating the results of this study outside Japan. Conclusions Use of ACEI/ARB at hospital discharge was associated with lower mortality in patients with a history of MI who underwent PCI. No significant association between the use of ACEI/ ARB at discharge and incidence of all-cause/cardiovascular deaths, however, was seen in patients without a history of MI in the current study. Further investigation may be needed to assess the survival benefits of ACEI/ARB in addition to coronary revascularization and other medical therapies in stable CAD patients without MI. Acknowledgments We appreciate the collaboration of the co-investigators in the CREDO- Kyoto PCI/CABG Registry Cohort-2. This study was supported by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. None. Disclosures Funding This study was funded in part by PMDA (Pharmaceuticals and Medical Devices Agency) in Japan. References 1. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS): The CONSENSUS trial study group. N Engl

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Unadjusted and Adjusted Risks for All-Cause/Cardiovascular Death According to the Use of ACEI/ARB Therapy in Propensity Score-Matched Pairs Figure S1. Cumulative unadjusted incidences of myocardial infarction and hospitalization due to heart failure according to the use of ACEI/ARB. Figure S2. Cumulative incidences of myocardial infarction and hospitalization due to heart failure according to the use of ACEI/ARB in the propensity score-adjusted patient groups. Please find supplementary file(s);