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Abstract

Aim:

Renin–angiotensin–aldosterone system inhibitors (RASIs) are widely used in high-risk cardiovascular (CV) diseases, including acute myocardial infarction (AMI). However, it is not yet clear which class of RASIs provides specific benefits to patients with AMI. The present study aimed to evaluate whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) had any different effects on long-term CV and all-cause mortality in patients with AMI who received either agent from admission and were discharged alive from the hospital.

Methods:

We analyzed data of patients with AMI from the Korea Acute Myocardial Infarction Registry-National Institutes of Health registry. Cardiovascular and all-cause mortality at 12 months after AMI were assessed.

Results:

Among 12 481 patients with AMI who were discharged alive, RASI treatment was as follows: ACEIs (n = 5910), ARBs (n = 4009), and no RASI (n = 2562). After adjustment for multiple factors, compared with no RASI therapy, ACEI therapy was associated with lower hazard ratios (HRs) for 1-year CV and total mortality rates, whereas ARB therapy was not. In a direct comparison, compared with ARB treatment, ACEI treatment was associated with lower HRs (95% confidence interval) for CV and total mortality: 0.562 (0.420-0.753) and 0.567 (0.451-0.713), respectively. The superiority of ACEI to ARB was also observed across several subgroups. The mortality differences between the 2 treatment groups were reproduced in a propensity-score matched analysis (n = 2855 each).

Conclusions:

Our study of a recent AMI registry data revealed that ACEI therapy in patients with AMI was associated with better long-term survival benefits than ARB therapy.

Keywords

angiotensin-converting enzyme inhibitors angiotensin receptor blockers acute myocardial infarction and mortality

Introduction

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) are widely used in patients with high cardiovascular (CV) risks.^1
-3 Major guidelines have recommended the use of ACEIs in patients with acute myocardial infarction (AMI) with left ventricular ejection fraction (LVEF) ≤40% or heart failure, hypertension, diabetes, or stable chronic kidney disease, unless contraindicated.^4
-6 In addition, for lower risk patients recovering from ST-segment elevation myocardial infarction (STEMI), ACEI treatment is still a reasonable option.⁴ Angiotensin II type 1 receptor blockers are indicated in patients who are intolerant of ACEIs.^4,5

Because of the quite different modes of actions of these 2 types of agents as renin–angiotensin–aldosterone system inhibitor (RASI), the question of whether clinically meaningful differences in the cardioprotective activities exist between ACEIs and ARBs has long been raised. Few comparative randomized clinical trials (RCTs) involving ACEIs and ARBs have been performed. Some large-scale RCTs have shown comparable efficacy for CV and all-cause mortality between ACEIs and ARBs.^7
-9 However, the other large-scale RCT (Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan, OPTIMAAL) showed that losartan was associated with higher CV mortality and failed to show the noninferiority of losartan to captopril with respect to decreasing all-cause mortality in patients with AMI and evidence of heart failure or left-ventricular dysfunction.¹⁰ Another head-to-head trial on a much smaller scale (n = 722), which was performed more than 2 decades ago, reported that treatment with losartan was associated with an unexpected lower mortality than that found with captopril in patients aged older than 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE).¹¹ However, the results of the ELITE study were not reproduced in a subsequent larger RCT (ELITE II study, n = 3152).⁹ Many studies using AMI registry data have also provided conflicting results.^12
-14 In a large Swedish registry study, treatment with either ACEIs or ARBs after myocardial infarction (MI) was associated with improved survival after 1 year and 3 years with no difference in the results between ACEI and ARB use.¹⁴ In contrast, Hara et al¹² compared 5-year survival benefits of ACEIs and ARBs in patients with AMI registered in the Osaka Acute Coronary Insufficiency Study (OACIS) and showed that ACEIs were associated with better survival than ARBs from 2 to 5 years after an AMI event. Furthermore, some meta-analyses have suggested that ACEIs may be superior to ARBs in preventing MI¹⁵ or decreasing all-cause mortality by showing that ARBs do not decrease mortality rates in various patients with or without heart failure,^16,17 in hypertension trials,^18,19 and in patients with diabetes.²⁰ To make things more complex, there have been much progression in both medical and intervention therapies for AMI, including dual antiplatelet therapy (DAPT) and percutaneous coronary intervention (PCI), which many guidelines recommend.^6,21,22 Thus, it is necessary to reflect recent trends in AMI treatment to determine a difference in the clinical outcomes between ACEIs and ARBs in those high-risk patients.

We investigated whether ACEIs and ARBs had comparable long-term survival benefits (ie, all-cause and CV mortality) in a large cohort of post-AMI patients, using a recent nationwide prospective registry data in Korea, the Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH) registry.

Methods

Study Population

We obtained data of patients with AMI from the KAMIR-NIH registry, which aimed to evaluate the clinical characteristics, management, and long-term outcomes of patients with AMI in Korea, as detailed previously.²³ Briefly, patients hospitalized for AMI in 20 tertiary university hospitals capable of PCI in Korea were enrolled from November 2011 to December 2015. The KAMIR-NIH registry documented initial presentation at the emergency department, all consecutive variables and values at baseline admission, CV risk factors, and other comorbidities. Major outcomes, procedures, medications, and complications during hospitalization were also recorded, and follow-up data after discharge were recorded at 6, 12, 24, and 36 months. The follow-up data were collected from the patients by attending physicians, and web-based case report forms were completed. If the patients did not visit the hospitals, the outcome data were assessed by telephone interviews.

Regardless of previous RASI therapy before the index event, patients were included in this study if they received an ACEI, an ARB, or either drug after admission due to AMI and were discharged alive from the hospital with those agents. The patients were classified into 3 groups: ACEI, ARB, and no RASI groups, respectively. Otherwise, specified patients who received both agents were not included in the analysis. Investigators tried to maintain optimal discharge medications at their discretion based on local guidelines and checked their patients at least 1 to 3 months as usual in real-world clinical settings of tertiary medical centers in Korea. We assumed that either agent was continuously maintained after discharge during the follow-up. Angiotensin-converting enzyme inhibitors included 6.25 to 150 mg of captopril, 0.5 to 2.5 mg of cilazapril, 2.5 to 20 mg of enalapril, 10 mg of fosinopril, 2.5 to 5 mg of imidapril, 1.88 to 15 mg of moexipril, 2 to 8 mg of perindopril, and 1.25 to 10 mg of ramipril, per day, respectively, while the daily doses and the names of ARBs were 2 to 32 mg of candesartan, 600 mg of eprosartan, 15 to 120 mg of fimasartan, 75 to 300 mg of irbesartan, 12.5 to 100 mg of losartan, 5 to 80 mg of olmesartan, 20 to 160 mg of telmisartan, and 20 to 320 mg of valsartan, respectively.

The study protocol was reviewed and approved by the institutional review board at each participating center. All of the participants provided written informed consent. The registries and this study conformed to the Declarations of Helsinki.

Data Collection

Clinical data about medical illnesses and CV risks were obtained in addition to the list of medications taken before admission, during hospitalization, and after discharge, as detailed previously.²³ Blood tests at admission, echocardiography within 3 days of the PCI, and lipid profile assessment after an overnight fast were performed as per usual guidelines.^5,6,24 Estimated glomerular filtration rate (eGFR) was calculated from the serum creatinine level on admission using the Chronic Kidney Disease Epidemiology Collaboration equation. The diagnosis of diabetes was based on the known history of diabetes obtained by interviewing the hospitalized patients and reviewing the medical records. In addition, patients were considered to have diabetes if they were treated with insulin or oral hypoglycemic agents that were prescribed during hospitalization and included in the discharge medications. Finally, patients who had hemoglobin A1c level of 6.5% or more were considered diabetic, while those with hemoglobin A1c level of 5.7% to 6.4% were considered prediabetic. Otherwise, patients were considered nondiabetic controls, even though their random glucose level at admission was above the diagnostic criteria. Although no systematic testing for type of diabetes was performed, all of the patients were type 2 diabetics clinically.

Statistical Analysis

Categorical variables are expressed as numbers and percentages, and continuous variables are expressed as the mean (standard deviation [SD]). Differences in baseline characteristics between groups were tested by 1-way analysis of variance with Tukey post hoc analysis, t tests, or Mann-Whitney U tests for continuous variables appropriately and χ² tests for categorical variables. Survival plots were depicted using Kaplan-Meier curves, and the difference according to specific therapy was tested by log-rank tests. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for CV and all-cause MB mortality at 1 year, adjusting for age, sex, systolic blood pressure (SBP) and diastolic blood pressure, body mass index (BMI), Killip class, past medical illness (hypertension, MI, heart failure), current smoking, serum glucose, eGFR, serum creatine kinase creatine kinase-muscle/brain (CK-MB), plasma total cholesterol, prevalent prediabetes/diabetes, LVEF, medications from admission (DAPT, β-blockers, statins), presentation with STEMI or non-STEMI, and revascularization therapies (PCI/coronary artery bypass grafting [CABG] or others). In addition to the abovementioned main analyses, we performed propensity score (PS) matching using the logistic regression model with all variables from the fully adjusted model to reduce potential confounding effects due to heterogeneity in baseline characteristics. Angiotensin-converting enzyme inhibitor-treated patients were then 1-to-1 matched to ARB-treated patients according to PSs with the nearest available matching method. The procedure generated 2855 well-matched pairs with a caliper width of 0.05 SD of the logit of the PSs.²⁵ Then, we compared the mortality differences between the matched ACEI and ARB groups as in the main analysis. All analyses were performed using IBM SPSS Statistics 23 (IBM Corp, Armonk, New York).

Results

There were 13 707 patients with AMI who were enrolled for the registry in KAMIR-NIH. However, 603 patients were excluded due to various reasons, as described in Supplemental Figure 1. In addition, 552 (4.2%) patients were destined to in-hospital mortality or hopeless discharge, the rate of which was comparable between the ACEI and ARB treatment groups. We also excluded patients with ACEI and ARB combination therapy because most guidelines are against the combination therapy (n = 71; Supplemental Figure 1). Of the remaining 12 481 patients, 9919 patients were treated with ACEI (n = 5910) or ARB (n = 4009), while others received neither agent (n = 2562, no RASI group) at survival discharge. In the present study, the reasons for no prescription of either ACEIs or ARBs were not recorded. However, as mentioned above, it is not clear under current guidelines whether all patients with AMI, regardless of cardiorenal function and comorbidities, including low-risk patients with non-STEMI, should start and maintain either ACEIs or ARBs.

The clinical characteristics of the 3 groups are presented in the Table 1, showing a significant heterogeneity between groups. A total of 355 CV deaths (108 [4.3%] in the no-RASI group, 108 [1.9%] in the ACEI group, and 139 [3.5%] in the ARB group) and 553 all-cause deaths (157 [6.3%] in the no RASI group, 170 [2.9%] in the ACEI group, and 226 [5.7%] in the ARB group) were recorded during the median follow-up period of 369 days (interquartile range 346 to 390). Kaplan-Meier survival analysis demonstrated that the ACEI group had better 1-year CV and all-cause mortality than the other 2 groups (Figure 1). The mortality comparisons between each RASI groups and no RASI group are presented in the Supplemental Tables S1 and 2.

Table 1.

Baseline Characteristics of the Patients With AMI Based on the Treatment Groups.^a

Parameters	No RASI (n = 2562)	ACEI (n = 5910)	ARB (n = 4009)	P Values
Age (years)	64.2 (12.7)^b	62.4 (12.5)^c	64.8 (12.4)^b	<.01
Male, n (%)	1901 (74.2)^b	4561 (77.2)^c	2819 (70.6)^d	<.01
BMI (kg/m²)	23.7 (3.3)^b	24.1 (3.2)^b	24.2 (3.4)^b	.113
Past medical history, n (%)
Hypertension	1189 (46.4)^b	2781 (47.1)^b	2344 (58.5)^c	<.01
Myocardial infarction	204 (8.0)^b	373 (6.3)^c	395 (9.9)^d	<.01
Heart failure	42 (1.6)^b	68 (1.2)^b	80 (2.0)^c	.114
Current smoker, n (%)	959 (37.4)^b	2590 (43.8)^c	1396 (34.8)^d	<.01
Discharge medication, N (%)
Statins	2264 (88.4)^b	5624 (95.2)^c	3794 (94.6)^c	<.01
DAPT	2300 (89.8)^b	5767 (97.6)^c	3837 (95.7)^d	<.01
β-Blockers	1648 (64.3)^b	5420 (91.7)^c	3396 (84.7)^d	<.01
White blood cells (× 10³/μL)	10.4 (6.2)^b	10.6 (4.0)^b	10.1 (3.9)^c	<.01
Hemoglobin (g/dL)	13.6 (2.1)^b	14.1 (1.9)^c	13.6 (2.2)^b	<.01
Diabetes, n (%)	860 (33.6)^b	1839 (31.1)^c	1539 (38.4)^d	<.01
Glucose (mg/dL)	165.4 (79.9)^b	165.7 (76.2)^b	169.0 (81.5)^b	.089
Total cholesterol (mg/dL)	174.2 (47.1)^b	183.6 (45.1)^c	174.05 (45.8)^b	<.01
Serum creatinine (mg/dL)	1.2 (1.3)^b	1.0 (0.9)^c	1.2 (1.3)^b	<.01
CK-MB (IU/L)	110.2 (153.5)^b	119.0 (178.1)^b	91.1 (132.4)^c	<.01
eGFR (mL/min/1.73m²)	77.9 (28.3)^b	82.0 (23.1)^c	79.0 (27.2)^b	<.01
Systolic BP (mm Hg)	126.7 (28.1)^b	133.5 (29.3)^c	131.2 (28.5)^d	<.01
Diastolic BP (mm Hg)	76.95 (17.4)^b	80.18 (17.6)^c	79.6 (17.6)^c	<.01
Killip class ≥3, N (%)	363 (14.2)^b	586 (9.9)^c	458 (11.4)^d	<.01
STEMI, N (%)	1121 (43.8)^b	3186 (53.9)^c	1598 (39.9)^d	<.01
LVEF (%)	52.1 (11.3)^b	51.2 (10.6)^c	53.8 (11.1)^d	<.01
PCI or CABG (%)	2154 (84.1)^b	5636 (95.4)^c	3687 (92.0)^d	<.01

Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; AMI, acute myocardial infarction; ARB, angiotensin II type 1 receptor blockers; BMI, body mass index; BP, blood pressure; CABG, coronary artery bypass grafting; CK, creatine kinase; DAPT, dual antiplatelet therapy; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; RASI, renin–angiotensin–aldosterone system inhibitors; STEMI, ST-segment elevation myocardial infarction; CK-MB, creatine kinase-muscle/brain

^aN = 12 481. Data are expressed as the mean (standard deviation) or n (%), unless otherwise specified. Different superscript letters (b, c, and d) indicate statistically significant differences among experimental groups (ANOVA and Tukey tests for continuous variables and χ² test for categorical variables; P < .05, respectively).

Figure 1.

One-year Kaplan-Meier survival curves of the patients with AMI according to RASI therapy. Shown are the estimates of the probability of an occurrence of CV and all-cause mortality in patients with AMI after survival discharge according to RASI therapy: (A) CV mortality; (B) all-cause mortality. AMI indicates acute myocardial infarction; CV, cardiovascular; RASI, renin-angiotensin-aldosterone system inhibitors.

Then, we analyzed 9919 patients for direct comparisons between the ACEI and ARB groups for CV and all-cause mortality at 1 year after the AMI events to see if ACEI therapy provides better survival outcomes than ARB therapy. As presented in Table 1, patients treated with ACEIs were more likely to be male, to present with STEMI, and to have higher levels of SBP and total cholesterol, whereas the ARB group was more likely to be older, to be smokers, to present with a higher grade of Killip class (≥3), to have a history of hypertension, previous MI, or heart failure, and to have high levels of serum creatinine, suggesting heterogeneity between the 2 treatment groups.

Cox regression analyses after adjustment for multiple factors revealed that compared with ARB treatment, ACEI treatment was associated with lower 1-year CV and all-cause mortality: for CV mortality, adjusted HR (95% CI): 0.562 (0.420 to 0.753), P < .01; for all-cause mortality, adjusted HR (95% CI): 0.567 (0.451-0.713), P < .01, Table 2. These clear benefits of ACEI versus ARB with respect to the mortality were also evident at 6 months after survival discharge (data not shown). There were 100 (1.7%) follow-up losses in the ACEI group, while 47 (1.2%) occurred in the ARB group (P < .042). Thus, we reanalyzed all-cause mortality after we hypothesized that all of the lost participants in ACEI group died and all of the lost participants in the ARB group were alive at 1 year after the AMI events. Even after this hypothesis-based adjustment for the follow-up losses, the ACEI treatment was still associated with a reduced HR for all-cause mortality compared with the ARB treatment: adjusted HR (95% CI): 0.576 (0.459-0.724), P < .01.

Table 2.

One-Year CV and All-Cause Mortality and HRs (95% CIs) of Mortality for the ACEI Versus ARB Groups.^a

Outcomes	ACEI group	ARB group	P Values
Outcomes in the total cohort
CV mortality
Events, n (%)	108/5810 (1.9)	139/3962 (3.5)	<.01
Unadjusted HR (95% CI)	0.508 (0.395-0.654)		<.01
Adjusted HR (95% CI)	0.562 (0.420-0.753)		<.01
All-cause mortality
Events, n (%)	170/5810 (2.9)	226/3962 (5.7)	<.01
Unadjusted HR (95% CI)	0.492 (0.403-0.601)		<.01
Adjusted HR (95% CI)	0.567 (0.451-0.713)		<.01
Outcomes in the propensity score-matched groups
CV mortality
Events, n (%)	59/2811 (2.1)	95/2822 (3.4)	<.01
Unadjusted HR (95% CI)	0.592 (0.427-0.820)		<.01
Adjusted HR (95% CI)	0.591 (0.424-0.825)		<.01
All-cause mortality
Events, n (%)	93/2811 (3.3)	147/2822 (5.2)	<.01
Unadjusted HR (95% CI)	0.605 (0.467-0.786)		<.01
Adjusted HR (95% CI)	0.604 (0.464-0.787)		<.01

Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II type 1 receptor blockers; CI, confidence interval; CV, cardiovascular; HR, hazard ratio.

^aFollow-up loss at 1-year: 100 cases among 5910 patients in angiotensin-converting enzyme inhibitors (ACEI) group; 47 cases in 4009 patients in the angiotensin II type 1 receptor blockers (ARB) group. Data are expressed as n and/or %. Values are based on time of death. Hazard ratios (HRs [95% CIs]) were obtained by Cox regression analyses. Adjusted for age, sex, systolic and diastolic blood pressures (BPs), body mass index (BMI), Killip class, past medical history (hypertension, myocardial infarction [MI], heart failure), current smoking, serum glucose, estimated glomerular filtration rate (eGFR), total cholesterol, creatine kinase MB (CK-MB), prevalent prediabetes and diabetes, left ventricular ejection fraction (LVEF), discharge medications (dual antiplatelet therapy [DAPT], β-blockers, statins), and ST-segment elevation myocardial infarction (STEMI) or non-STEMI, and percutaneous coronary intervention (PCI)/coronary artery bypass grafting (CABG).

Nowadays, the majority of patients with AMI are receiving PCI, with some patients receiving CABG, as a revascularization therapy. In the present study, the proportion of patients treated with PCI/CABG was 95.4% and 91.9% in the ACEI group and in the ARB group, respectively (P < .05). The differences in CV and all-cause mortality between the ACEI and ARB groups did not change when we analyzed selected patients with AMI treated with PCI/CABG (data not shown).

We matched ACEI- versus ARB-treated patients in a 1:1 ratio (2855 patients in each group) according to the PS (Supplemental Table S3). Again, adjusting for multiple factors as in the main analysis, compared with ARB treatment, ACEI treatment was associated with lower 1-year CV and all-cause mortality: adjusted HRs (95% CIs): 0.591 (0.424 to 0.825), P < .01; and 0.604 (0.464 to 0.787), P < .01, respectively, (Table 2, Figure 2). There were 42 (1.5%) follow-up losses in the ACEI group and 32 (1.1%) in the ARB group in the PS-matched analysis (P = .245). Under a similar analysis and hypothesis-based adjustment for the follow-up losses as in the main analysis, compared with ARB treatment, ACEI treatment maintained a lower adjusted HR (95% CI) for all-cause mortality: 0.627 (0.482-0.817), P < .01.

Figure 2.

Adjusted HRs (95% CIs) for 1-year CV and all-cause mortality in the ACEI group versus the ARB group. Fully adjusted HRs (95% CIs) for 1-year CV (A) and all-cause (B) mortality in the total cohort and specific subgroups are presented (n = 9919) with their numbers and event rates. The fully adjusted HRs (95% CIs) for the mortality in the propensity score (PS)-matched ACEI and ARB groups (n = 2855 each) are also presented. ACEI indicates angiotensin-converting enzyme inhibitors; ARB, angiotensin II type 1 receptor blockers; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; PS, propensity score.

Finally, we also compared the mortality between the 2 treatment groups across several subgroups: patients with STEMI and with non-STEMI, with and without prediabetes/diabetes, with LVEF <40% and ≥40%, and with eGFR <60 mL/min/1.73 m² and ≥60 mL/min/1.73 m². Results were consistent throughout those subgroups, with only STEMI subgroup showing not a significant difference but a strong tendency toward favoring ACEIs compared with ARBs (P = .070; Figure 2).

Discussion

The present study provides evidence that compared with ARB treatment, ACEI treatment from admission in patients with AMI who were discharged alive is associated with more favorable effects on both CV and all-cause mortality at 1 year after an AMI event. Although it is not a head-to-head RCT of the 2 classes of agents, our registry data are among the latest real-world data which reflected the most recent secular trends of AMI treatment.

In the present study, we presented evidence of the superiority of ACEIs to ARBs with regard to 1-year CV and all-cause mortality in several ways. First, we directly compared ACEIs and ARBs for CV and all-cause mortality. Hazard ratios for 1-year CV and all-cause mortality were lower in the ACEI group than in the ARB group. Furthermore, the results did not change after exclusion of early 30-day death after hospital discharge. Second, the PS-matched analysis also showed very similar results. Third, considering the follow-up losses, even after we hypothesized that all of the lost participants in the ACEI group died and all of the lost participants in the ARB group were alive at 1 year after the AMI events, compared with ARB treatment, ACEI treatment was consistently associated with a lower HR for all-cause mortality, in both the main analysis and the PS-matched analysis. Fourth, the favorable effect of ACEIs over ARBs was consistent across several subgroups. Fifth, further analysis of selected patients treated with PCI or CABG also showed the superiority of ACEIs to ARBs in both CV and all-cause mortality.

Our results are in line with those from a large-scale AMI registry study, the OACIS, in Japan.¹² The OACIS results showed that compared with ARB treatment, ACEI treatment was associated with a better 5-year survival rate, with the effect being evident after 2 years. However, survival rates from 2 to 5 years after discharge were similar between the ARB group and the no RASI group.¹² Interestingly, our results showed that the clear benefits of ACEIs versus ARBs on the mortality were already evident at 6 months after survival discharge.

Although the comparative efficacies of ACEIs and ARBs have been much debated for a long time, head-to-head randomized trials of ACEIs versus ARBs are few.⁷ Several studies including RCTs and meta-analyses have shown that ACEIs provide a better survival benefit than what ARBs provide in patients with various CV risks.^10,19,20 Furthermore, many previous RCTs of ARBs and meta-analyses of RCTs did not exhibit a consistent mortality benefit of ARBs compared with placebo.^26

-29 Addressing these issues with the introduction of “the ARB-MI paradox,” Strauss et al^15,29,30 had reviewed in detail the evidence of less favorable effects of ARBs on fatal MI, CV death, and all-cause mortality compared with placebo or other agents including ACEIs. Furthermore, some studies observed an increased death from CV causes with ARB treatment compared with ACEI treatment or placebo.^10,27,31 Thus, we have focused on mortality difference between the 2 drug groups in the present study. However, adjusted HR for a composite outcome composed of nonfatal MI, nonfatal stroke, and CV death was also significantly lower in the ACEI group compared with the ARB group in the present study (data not shown).

The reason why ACEIs may be associated with a lower risk of death can be explained by the following mechanisms. In addition to the suppression of angiotensin II (AG II) production, ACEI prevents the breakdown of bradykinin, causes various actions via angiotensin (1-7) and/or angiotensin (1-9), augments the release of tissue plasminogen activator, and elicits outside-in signaling transduction molecules, leading to an increase in both the expression and activity of cyclooxygenase-2.^32,33 Angiotensin II type 1 (AT1) receptor blockade with ARBs increase the levels of AG II, with its attendant direct tissue toxicity. Chronic overstimulation of AT2 receptors by increased AG II may not be beneficial for the CV system, while AT4 receptors during chronic AT1 blockade may mediate the release of plasminogen activator inhibitor 1.¹⁵ Rather than the intensity of RAS blockade, the class of RASI seemed to play a causal role in the differences of the mortality outcomes in our results, because the differences were observed in the users of submaximal doses of the drugs, but not in the users of maximal or higher than maximal doses of the drugs, in which the dose level was assessed based on guidelines for hypertension therapy or drug information provided by manufacturers.³⁴

Interestingly, the clear evidence of the favorable effect of ACEIs over ARBs on mortality in patients with AMI in the 2 large-scale AMI registry datasets (ie, the present study used KAMIR-NIH from Korea and the OACIS from Japan) raised a question of whether there is any ethnic difference in ACEI effects between Caucasian and Asian patients, which has been suggested in some studies.^35
-37 Although different therapeutic responses to ACEIs between black and white population have been reported, differences between Asian and Caucasian have not been extensively studied.³⁸ Angiotensin-converting enzyme genotype according to insertion/deletion (I/D) in intron 16 of the ACE gene account for more than 40% of the variance in responses to ACEI.³⁹ It was reported that subjected with I/I genotype showed better and longer response to enalapril than patients with D/D genotype.⁴⁰ The I allele was shown to be more prevalent in Chinese people compared with Caucasians, whereas the D/D genotype was less prevalent.⁴⁰ Interestingly, the incidence of ACEI-induced cough was reported to be higher in East Asian (Chinese, Japanese, or Korean) than in Caucasian patients³⁷ and to be more prevalent in patients with I/I genotype than other genotypes.⁴¹ Bradykinin may have a role in both beneficial and adverse effects in a case-dependent manner. Further studies are needed to clarify whether East Asian people respond better to ACEIs than other people.

The strengths of our analysis include the large sample size of the prospective nationwide AMI registry cohort in Korea, which included extensive clinical characteristics recoded both at admission and at discharge, reflecting the recent real-world AMI management status under current guidelines. In addition, the present study consistently showed the superiority of ACEIs over ARBs regarding survival benefits in patients with AMI even after various adjustments and analyses. The present study also has several limitations. First, it was a prospective observational study based on AMI registry data in which many important clinical variables were not matched at enrollment, although we tried to adjust for multiple variables and also performed a PS-matched analysis. In addition, there may be still a possibility of unadjusted factors influencing clinical outcomes. Second, although we encouraged completion of the clinical parameters in a web-based format, there were still missing values that could not be ignored with significant number of follow-up losses. Third, although the investigators encouraged patients to adhere to drug therapy at the hospital and after discharge, detailed and systematic assessment on the adherence was not performed strictly but recorded in detail 12 months after discharge. Although we could not record drug adherence rate and crossover rate between the 2 classes of the drugs in the deceased patients, when we assessed adherence to drugs among survivors at 1 year after discharge, 15.9% of initial ACEI users and 5.9% of initial ARB users had not maintained the respective drug over the previous 2 visit periods. In addition, the rate of ACEI-to-ARB switch among survivors was at least 7.7% at 12 months, while the ARB-to-ACEI crossover was only about 0.5%. Among statin users, only 1.5% of the patients were not maintaining the statins over those periods. We believe that the gap between the drugs may reflect intolerance to ACEIs or other reasons, but may not be a compliance issue (considering the high adherence rate in statin users). Finally, the 1-year follow-up period may not be long enough to compare with other clinical studies, although the clinical benefits were evident at as early as 6 months in our study.

Conclusions

In the present study, by analyzing a large AMI registry data, we showed that ACEI therapy in patients with AMI provided better long-term survival benefits than ARB therapy.

Supplemental Material

Supplemental_Figure_1 - Angiotensin-Converting Enzyme Inhibitors Provide Better Long-Term Survival Benefits to Patients With AMI Than Angiotensin II Receptor Blockers After Survival Hospital Discharge

Supplemental_Figure_1 for Angiotensin-Converting Enzyme Inhibitors Provide Better Long-Term Survival Benefits to Patients With AMI Than Angiotensin II Receptor Blockers After Survival Hospital Discharge by In Suck Choi, Ie Byung Park, Kiyoung Lee, Tae Hoon Ahn, Ju Han Kim, Youngkeun Ahn, Sung-Chull Chae, Hyo-Soo Kim, Young Jo Kim, Myeong Chan Cho, Chong Jin Kim, Myung Ho Jeong, Dae Ho Lee, and on behalf of the Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH) investigators in Journal of Cardiovascular Pharmacology and Therapeutics

Supplemental Material

Supplemental_Tables_R1 - Angiotensin-Converting Enzyme Inhibitors Provide Better Long-Term Survival Benefits to Patients With AMI Than Angiotensin II Receptor Blockers After Survival Hospital Discharge

Supplemental_Tables_R1 for Angiotensin-Converting Enzyme Inhibitors Provide Better Long-Term Survival Benefits to Patients With AMI Than Angiotensin II Receptor Blockers After Survival Hospital Discharge by In Suck Choi, Ie Byung Park, Kiyoung Lee, Tae Hoon Ahn, Ju Han Kim, Youngkeun Ahn, Sung-Chull Chae, Hyo-Soo Kim, Young Jo Kim, Myeong Chan Cho, Chong Jin Kim, Myung Ho Jeong, Dae Ho Lee, and on behalf of the Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH) investigators in Journal of Cardiovascular Pharmacology and Therapeutics

Footnotes

Authors’ Note

I. S. Choi contributed to analysis and interpretation, drafted manuscript, critically revised manuscript, gave final approval, and agrees to be accountable for all aspects of work ensuring integrity and accuracy; I. B. Park: contributed to analysis and interpretation, drafted manuscript, critically revised manuscript, gave final approval, and agrees to be accountable for all aspects of work ensuring integrity and accuracy; K. Y. Lee contributed to analysis and interpretation, drafted manuscript, critically revised manuscript, gave final approval, and agrees to be accountable for all aspects of work ensuring integrity and accuracy; T. H. Ahn contributed to conception and design, contributed to acquisition, gave final approval, and agrees to be accountable for all aspects of work ensuring integrity and accuracy; J. H. Kim contributed to conception and design, contributed to acquisition, gave final approval, and agrees to be accountable for all aspects of work ensuring integrity and accuracy; Y. K. Ahn contributed to conception and design, contributed to acquisition, gave final approval, and agrees to be accountable for all aspects of work ensuring integrity and accuracy; S. C. Chae contributed to conception and design, contributed to acquisition, gave final approval, and agrees to be accountable for all aspects of work ensuring integrity and accuracy; H. S. Kim contributed to conception and design, contributed to acquisition, gave final approval, agrees to be accountable for all aspects of work ensuring integrity and accuracy; Y. J. Kim contributed to conception and design, contributed to acquisition, gave final approval, and agrees to be accountable for all aspects of work ensuring integrity and accuracy; M. C. Cho contributed to conception and design, contributed to acquisition, gave final approval, and agrees to be accountable for all aspects of work ensuring integrity and accuracy; C. J. Kim contributed to conception and design, contributed to acquisition, gave final approval, and agrees to be accountable for all aspects of work ensuring integrity and accuracy; M. H. Jeong contributed to conception and design, contributed to acquisition, analysis, and interpretation, critically revised manuscript, gave final approval, and agrees to be accountable for all aspects of work ensuring integrity and accuracy; D. H. Lee contributed to analysis and interpretation, drafted manuscript, critically revised manuscript, gave final approval, and agrees to be accountable for all aspects of work ensuring integrity and accuracy.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by a fund (2016-ER6304-01) from Research of Korea Centers for Disease Control and Prevention and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Korea (HI16C1997).

Supplemental Material

Supplemental material for this article is available online.

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