INTRODUCTION
Acute myocardial infarction (AMI) remains a major contributor to morbidity and mortality worldwide, particularly in old populations.1-3) As the global population ages and life expectancy increases, the management of AMI in patients over the age of 70 has become a critical area of clinical focus. Percutaneous coronary intervention (PCI) is a widely adopted revascularization strategy for these patients; however, the optimal pharmacological management following PCI, particularly in regard to long-term cardiovascular (CV) outcomes, continues to pose a clinical challenge.4,5)
Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are essential components of the therapeutic regimen for CV diseases, including AMI and heart failure, particularly in patients with left ventricular (LV) systolic dysfunction.4) Both drug classes are recognized for their ability to reduce afterload, prevent adverse LV remodeling, and improve survival rates.6) Numerous studies have demonstrated the efficacy of ACEI in the post-AMI setting, while ARB have been shown to offer comparable benefits.7-12) Consequently, ARB have become increasingly utilized in the treatment of heart failure, hypertension, and diabetic nephropathy, often beyond cases where ACEI-related side effects such as cough or angioedema limit their use.13) Despite the expanding role of ARB in clinical practice, concerns regarding their potential association with adverse CV outcomes have been raised. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial highlighted an unexpected increase in the risk of myocardial infarction (MI) in hypertensive patients treated with valsartan compared to amlodipine, despite similar blood pressure reductions.14) This observation, often referred to as the “ARB-MI paradox,” has raised questions about the safety of ARB in certain patient populations, particularly with regard to MI recurrence.
In older patients who have undergone PCI following AMI, the comparative efficacy of ACEI and ARB in preventing cardiac death and recurrent MI remains unclear. Given the increasing use of ARB and their proposed CV benefits, further investigation into their long-term effects compared to ACEI in this high-risk population is warranted. Therefore, the objective of this study was to evaluate the long-term clinical outcomes of ACEI versus ARB in AMI patients aged 70 and older who successfully underwent PCI, with a focus on the incidences of CV mortality and recurrent MI.
MATERIALS AND METHODS
Study Population and Data Collection
The study population was derived from the Korean Acute Myocardial Infarction–National Institutes of Health (KAMIR–NIH) registry,15) a nationwide, multicenter, prospective cohort designed to establish a prognostic and surveillance framework for AMI patients. This registry collects data via a web-based platform, allowing for standardized reporting across participating centers. Between November 2011 and October 2015, patients hospitalized for AMI who provided written informed consent were consecutively enrolled in the study. This study was approved by the Institutional Review Board of Chonnam National University Hospital (IRB No. CNUH-2011-172). Data collection was carried out by the attending physicians, supported by trained clinical research coordinators, utilizing web-based case report forms integrated into the Korea NIH clinical data management system. For this analysis, inclusion criteria encompassed consecutive patients aged 18 years or older who were diagnosed with either ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI), and who subsequently underwent PCI. The diagnosis of AMI was based on the criteria established by the universal definition of MI,16) as determined by the investigators. Exclusion criteria comprised the following: prescription of neither ACEI nor ARB (or both) at discharge, lack of echocardiographic evaluation, or incomplete clinical records. Patients who died during the index hospitalization were also excluded from the final analysis.
PCI Procedure
Coronary angiography and PCI were performed in accordance with current standard procedural guidelines,17) using either the femoral or radial approach. Unfractionated heparin (50–100 IU/kg) was administered prior to the procedure. Patients received loading doses of antiplatelet agents, including 300 mg of aspirin and either 600 mg of clopidogrel, 60 mg of prasugrel, or 180 mg of ticagrelor, unless they had already been treated with these agents prior to intervention. Throughout the hospitalization period, patients were managed with a comprehensive regimen, which included antiplatelet therapy, beta-blockers, renin-angiotensin-aldosterone system (RAAS) inhibitors, and lipid-lowering medications. Following discharge, patients were advised to maintain the same therapeutic regimen. Dual antiplatelet therapy was recommended for a duration of at least 12 months for those who had undergone PCI.
Definitions and Clinical Outcomes
The primary outcome for this study was defined as a composite of cardiac death or recurrent MI within a 3-year follow-up period. Secondary outcomes included each individual component of the primary outcome, as well as all-cause mortality, hospitalization for heart failure, any revascularization, stent thrombosis, and stroke over the same 3-year follow-up duration. All deaths were classified as cardiac in origin unless a clear non-cardiac cause could be identified. Recurrent MI was defined as the reappearance of ischemic symptoms accompanied by new ST-segment elevation on electrocardiogram or a re-elevation of cardiac biomarkers to at least twice the upper limit of normal, occurring after the index PCI. Hospitalization for heart failure was classified as a readmission due to worsening heart failure that required escalated care beyond standard outpatient management. Any revascularization encompassed repeat PCI or coronary artery bypass grafting (CABG) on either target or non-target vessels. Routine clinical follow-ups were conducted at 6, 12, 24, and 36 months through outpatient visits to the cardiology department, with additional follow-ups if clinical events occurred. For patients unable to attend in person, follow-up data were obtained through telephone interviews. Clinical events were identified by the attending physician and confirmed by the principal investigator at each participating hospital. Centralized adjudication of events was not performed.
Statistical Analysis
Continuous variables are presented as mean±standard deviation, while categorical variables are reported as frequencies and percentages. Comparisons between the two groups for continuous variables were performed using the Student t-test, and categorical variables were analyzed using Pearson chi-square test. Given the non-randomized nature of this study, propensity score matching (PSM) was employed to minimize potential confounding. A multiple logistic regression model was utilized to calculate propensity scores, adjusting for variables that could influence the outcomes: age, sex, body mass index (BMI), smoking history (current or ex-smoker), Killip class on admission, left ventricular ejection fraction (LVEF), CV risk factors (such as hypertension, diabetes mellitus, dyslipidemia, heart failure, chronic kidney disease [CKD], previous MI or angina, and history of stroke), type of MI (STEMI or NSTEMI), infarct-related artery (IRA), multivessel disease (MVD), and concomitant medications (including aspirin, P2Y12 inhibitors, beta-blockers, and statins). Patients receiving ACEI were matched 1:1 with those receiving ARB using a nearest neighbor matching algorithm, with a caliper width of 0.1 standard deviations of the propensity score. Kaplan-Meier survival analysis was used to estimate clinical outcomes over a 3-year follow-up period, and differences between the groups were assessed using the log-rank test both before and after propensity matching. Cox proportional hazards models were applied to calculate hazard ratio (HR) and 95% confidence interval (CI) for each clinical outcome comparing ACEI and ARB use. To further evaluate independent associations between medications and clinical outcomes, multivariate Cox regression analysis was conducted. The model included the following covariates: age, sex, smoking status, Killip class on admission, hypertension, diabetes mellitus, dyslipidemia, CKD, previous MI or angina, and history of stroke, LVEF, type of MI, IRA, MVD, and use of aspirin, P2Y12 inhibitors, beta-blockers, and statins. A two-sided p-value of less than 0.05 was considered statistically significant for all analyses. Data processing and statistical analyses were performed using SPSS software (version 20.0; IBM SPSS, Armonk, NY, USA) and R version 3.1.3 (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS
A total of 13,104 consecutive patients were initially included from the KAMIR–NIH registry. Of these, 10,341 patients were excluded for the following reasons: 504 patients died during the index hospitalization; 1,369 patients did not undergo PCI; 152 patients underwent unsuccessful PCI; 739 patients were treated with plain old balloon angioplasty; 290 patients received bare-metal stents; 44 patients underwent CABG; 119 patients lacked echocardiographic data; 1,737 patients were not prescribed either ACEI or ARB at discharge; 60 patients received both ACEI and ARB; and 5,327 patients were under the age of 70. As a result, 2,763 patients who were prescribed either ACEI (n=1,583) or ARB (n=1,180) at discharge were included in the final analysis. The selection between ACEI and ARB was left to the discretion of the treating physicians, with ACEI being prescribed more often at discharge. PSM was subsequently performed, yielding 1,115 patients in each group for comparison.
Baseline Clinical Characteristics
In the entire cohort, patients with ACEI at discharge had a higher prevalence of current smoking (19.6% vs. 15.9%; p=0.014), presented more frequently with STEMI (50.1% vs. 39.5%; p<0.001), were more likely to have MVD (61.6% vs. 55.3%; p=0.001), and were more often prescribed beta-blockers at discharge (90.3% vs. 82.9%; p<0.001) compared to those discharged with ARB. On the other hand, patients discharged with ARB had a higher prevalence of hypertension (62.0% vs. 70.0%; p<0.001), diabetes mellitus (28.0% vs. 36.0%; p<0.001), CKD (26.4% vs. 30.2%; p=0.029), and had slightly higher LVEF (50.1±11.0 vs. 52.1±11.4; p<0.001) at discharge. No significant differences were observed between the two groups in terms of age, sex distribution, Killip class ≥2, rates of dyslipidemia, previous MI, prior angina, heart failure, stroke history, IRA, or the use of aspirin, P2Y12 inhibitors, and statins. Following PSM, baseline characteristics between the two groups were well balanced (Table 1).
In the entire cohort, 43% of patients with ACEI at discharge continued this regimen at 1 year, while 35% had cross-over to ARB. In contrast, 70% of patients with ARB at discharge remained on ARB at 1 year, with only 1.2% had cross-over to ACEI. At 2 years, 30% of the patients originally on ACEI continued same regimen, while 61% of those discharged with ARB persisted with ARB therapy. The cross-over rates in the PSM cohort mirrored these trends observed in the entire cohort.
Clinical Outcomes
In entire cohort, the use of ACEI at discharge was associated with a lower incidence of cardiac death or recurrent MI (8.9 vs. 11.9%; HR=0.75, 95% CI 0.59–0.96; p=0.021) (Table 2, Fig. 1A) compared to those with ARB at 3 years. The incidences of cardiac death (6.1 vs. 8.6%; HR=0.72, 95% CI 0.54–0.96; p=0.024), recurrent MI (3.0 vs. 4.8%; HR=0.66, 95% CI 0.44–0.97; p=0.036), and all-cause death (10.0 vs. 14.8%; HR=0.69, 95% CI 0.55–0.85; p=0.001) at 3 years were also lower in the use of ACEI at discharge. (Table 2, Supplementary Fig. S1). However, there were no significant differences in the incidences of hospitalization due to heart failure, any revascularization, stent thrombosis, and stroke between two groups.
In PSM cohort, the ACEI at discharge was still associated with a lower incidence of cardiac death or recurrent MI (8.2 vs. 12.1%; HR=0.66, 95% CI 0.51–0.86; p=0.002) (Table 2, Fig. 1B). Additionally, the incidences of cardiac death (5.5 vs. 8.7%; HR=0.61, 95% CI 0.44–0.84; p=0.003), recurrent MI (3.0 vs. 4.9%; HR=0.60, 95% CI 0.39–0.93; p=0.021), and all-cause death (9.2 vs. 15.2%; HR=0.60, 95% CI 0.47–0.76; p=0.001) were consistently lower in ACEI at discharge compared to ARB at discharge (Table 2, Fig. 2). As with the entire cohort, no significant differences were observed between two groups regarding hospitalization due to heart failure, any revascularization, stent thrombosis, and stroke.
Subgroup analyses were performed to compare a composite of cardiac death or recurrent MI among patients discharged with either ACEI or ARB, utilizing a Cox proportional hazards model within PSM cohort (Fig. 3). Among specific subgroups—including male patients, in all stages of Killip class, non-smokers, patients with hypertension, patients without diabetes mellitus, those with reduced LVEF, those presenting with NSTEMI, patients with IRA as non-LAD, patients with MVD, and patients taking beta-blockers or statins—ACEI use at discharge was associated with a significantly lower incidence of the cardiac death or recurrent MI compared to ARB use. Notably, no significant interactions were observed between the use of ACEI or ARB at discharge and any of the subgroups analyzed.
DISCUSSION
This study evaluated the long-term clinical outcomes of ACEI versus ARB in older patients aged 70 years and older with AMI who underwent successful stent implantation. Over a 3-year follow-up, our findings revealed that the ACEI use at discharge was associated with lower incidence of cardiac death or recurrent MI compared to ARB use. Additionally, the incidence of all-cause death was lower in patients prescribed ACEI than in those prescribed ARB. However, no significant differences were observed between the two groups in hospitalization for heart failure, any revascularization, stent thrombosis, or stroke.
RAAS inhibitors play a pivotal in the post-AMI management of older patients, particularly those with LVEF ≤40%, heart failure, anterior MI, hypertension, diabetes mellitus, or CKD, following successful PCI.4,18,19) These medications have been shown to significantly reduce mortality, recurrent MI, and the incidence of heart failure in this population. RAAS inhibitor therapy should ideally be initiated promptly, ideally within 24 hours post-PCI for clinically stable patients, and continued long-term to sustain CV benefits. Despite similar mechanisms of action in blocking the RAAS, ACEI remain the preferred therapy in post-AMI management, particularly in older patients, due to their established mortality benefits. ARB serve as an alternative for patients unable to tolerate ACEI due to adverse effects such as cough or angioedema.
The clinical trials and observational studies evaluating the comparative efficacy of ACEI and ARB in patients with AMI have yielded inconsistent findings on long-term outcomes. The Valsartan in Acute Myocardial Infarction (VALIANT) trial,10) which directly compared the valsartan with captopril, found no significant differences in overall mortality. However, subgroup analyses suggested ACEI may provide better mortality benefits, particularly in older patients. This aligns with present study, where ACEI demonstrated superior outcomes in reducing cardiac death and all-cause mortality in the older population. Additionally, the SAVE20) and the TRACE trial21) reported significant reductions in cardiac death when ACEI were used in patients with LV dysfunction post-MI. In observational registry study of AMI patients with hypertension, ACEI were associated with lower incidences of mortality and recurrent MI during 2-year follow-up period,22) and other registry study23) has reported that ARB may be less effective than ACEI in reducing all-cause mortality, major adverse CV events, or the need for repeat revascularization in AMI patients, a finding consistent with the results observed in our study.
The Heart Outcomes Prevention Evaluation (HOPE) trial,24) which evaluated the use of ramipril in high-risk patients, including those with a history of MI, demonstrated a substantial reduction in recurrent MI. ARB, in contrast, while effective, have generally shown less pronounced benefits in preventing recurrent ischemic events compared to ACEI. The present study showed this trend, showing that ACEI are more effective than ARB in reducing recurrent MI in patients over 70 years old. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study,9) which directly compared ACEI and ARB, found that ARB were non-inferior to ACEI in overall CV outcomes, but this non-inferiority was achieved without a superiority in mortality reduction, as observed in our study.
Older patients with AMI represent a high-risk group with significant CV morbidity and mortality. Previous study demonstrated that the administration of ACEI or ARB is associated with a reduction in all-cause mortality and CV death when compared to those who did not receive these agents.25) The enhanced survival benefit of ACEI or ARB in older patients with AMI may be attributed to their more robust effects on remodeling and endothelial function, which are critical in the setting of post-AMI recovery. Especially, ACEI have been shown to prevent LV hypertrophy and adverse cardiac remodeling, which are common sequelae of AMI and contribute to long-term mortality and morbidity. The lower recurrent MI rate observed with ACEI use further supports their role in stabilizing atherosclerotic plaques and reducing further ischemic events. However, some studies have suggested ARBs may yield more favorable CV outcomes compared to ACEI.7,26) Moreover, another study has found no significant difference between ACEI and ARB for major adverse CV events.27) These findings suggest that the choice between ACEI and ARB should be individualized, considering patient tolerance and specific clinical circumstances. Furthermore, evidence from younger cohorts with AMI suggests that ACEI may have greater efficacy than ARB.23) This study, focusing on AMI patients aged 70 years and older who underwent successful PCI with DES, demonstrated that ACEI use at discharge were associated with improved long-term clinical outcomes, including lower rates of CV death, all-cause death, and recurrent MI, compared to ARB use.
The better clinical outcomes of ACEI compared to ARB can be explained by the following mechanisms. ACEI increase bradykinin levels by inhibiting its degradation by ACE. Elevated bradykinin levels contribute to cardioprotection through enhanced nitric oxide and prostacyclin production, improved endothelial function, and reduced myocardial remodeling. In contrast, ARB do not affect bradykinin degradation, resulting in a lack of this additional cardioprotective mechanism.28) ARB have been suggested to modulate sphingosine kinase activity, potentially disrupting the equilibrium between sphingosine and its phosphorylated derivative, sphingosine-1-phosphate (S1P). This disruption may result in elevated sphingosine levels alongside reduced S1P availability, shifting cellular signaling toward pro-apoptotic and pro-inflammatory pathways. Such alterations could compromise vascular integrity and promote inflammatory responses, thereby contributing to an increased susceptibility to MI.29-31) ARB selectively inhibits angiotensin II (Ang II) type 1 receptors, leading to a compensatory increase in Ang II levels. This upregulation results in heightened stimulation of Ang II type 2 receptors (AT2R), which has been implicated in promoting the release of leukocyte-derived matrix metalloproteinase-1, contributing to the destabilization and rupture of atherosclerotic plaques. Furthermore, excessive AT2R activation may induce apoptosis and suppress angiogenesis, potentially impairing collateral vessel formation under ischemic conditions.28)
However, the most common side effect of ACEI is cough, which is particularly prominent in East Asian populations and more frequently observed in older patients.32,33) In our study, which included older patients, approximately 35% of patients with ACEI at discharge had cross-over to ARB during the follow-up period—a rate higher than that reported in the previous study.34) This observation suggests that adverse effects such as cough may have contributed to the cross-over to ARB. Despite this high cross-over rate, patients initially ACEI use at discharge associated with better 3-year clinical outcomes, underscoring the possibility that the cardioprotective benefits of ACEI outweigh the drawbacks associated with their side effects. These findings underscore the importance of further research into the clinical implications of cross-over and the potential long-term advantages of initiating treatment with ACEI in older AMI patients.
This study has several limitations that should be considered when interpreting the results. First, the analysis of this study was based on non-randomized, observational registry data. The decision to prescribe ACEI or ARB was at the attending physician’s discretion, and the underlying rationale for these decisions was not documented. In our study, patients discharged with ARB had a significantly higher incidence of hypertension, diabetes mellitus, and CKD before PSM. Despite efforts to adjust for various confounding factors through PSM and multivariate analyses, we hypothesize that these baseline characteristics may contribute substantially to the observed differences in clinical outcomes between the two groups. The observational design still provides valuable insights, considering the challenges of conducting randomized trials for ACEI and ARB in older AMI patients. Despite its limitations, this registry provides important information about the clinical outcomes associated with different RAAS inhibitors. Second, the comparison of ACEI versus ARB was based on medications prescribed at discharge. Medication adherence was only recorded at discharge and then at 1-, 2-, and 3-year, we could not verify whether patients consistently adhered to their prescribed regimens throughout the 3-year period. In the entire cohort, 43% of patients with ACEI at discharge continued this regimen at 1 year, while 35% had cross-over to ARB. In contrast, 70% of patients with ARB at discharge remained on ARB at 1 year, with only 1.2% had cross-over to ACEI. At 2 years, 30% of the patients originally on ACEI continued same regimen, while 61% of those discharged with ARB persisted with ARB therapy. The cross-over rates in the PSM cohort mirrored these trends observed in the entire cohort. It is possible that changes in these medications during follow-up period influenced the long-term clinical outcomes. Third, the identification of clinical events was determined by the attending physicians and then confirmed by the principal investigator at each participating hospital, rather than through central adjudication. This decentralized method of event identification may have led to incomplete capture of some events in the database, potentially affecting the accuracy and comprehensiveness of the study. Fourth, this study did not include follow-up data on LV systolic function, as a result, we were unable to evaluate whether improvements or deteriorations in LV function contributed to the long-term clinical outcomes.
In conclusion, ACEI appear to offer significant benefits over ARB in reducing cardiac death, recurrent MI, and all-cause mortality in older patients with AMI after successful stent implantation. Given the superior survival benefit associated with ACEI, they should be considered the preferred choice in this patient population, with ARB reserved for those who cannot tolerate ACEIs. Further randomized controlled trials are needed to confirm these findings and explore the long-term implications of ACEI versus ARB therapy in older post-AMI patients.
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