What is the role of aldosterone antagonist therapy in patients with ST-segment elevation myocardial infarction without heart failure or left ventricular ejection fraction greater than 40%?
In this systematic review and meta-analysis of 10 randomized clinical trials with 4147 unique patients who presented with ST-segment elevation myocardial infarction, treatment with aldosterone antagonists was associated with significantly reduced mortality and significantly increased left ventricular ejection fraction at follow-up.
Patients who present with ST-segment elevation myocardial infarction could have survival benefit from initiation of treatment with aldosterone antagonists.
Treatment with aldosterone antagonists is recommended and has been shown to have beneficial effects in patients with ST-segment elevation myocardial infarction (STEMI) and left ventricular ejection fraction (LVEF) less than 40%. However, the role of aldosterone antagonists in patients with ejection fraction greater than 40% or without congestive heart failure is not well known.
To perform a systematic review and meta-analysis using standard techniques to determine the role of therapy with aldosterone antagonists in this patient population.
PubMed, Embase, CINAHL, and Cochrane Central databases were searched and a manual search for relevant references from the selected articles and published reviews was performed from database inception through June 2017.
Randomized clinical trials that evaluated treatment with aldosterone antagonists in patients with STEMI without clinical heart failure or LVEF greater than 40% were included.
Data Extraction and Synthesis
Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used to conduct and report the meta-analysis, which used a random-effects model. Two investigators independently performed the database search and agreed on the final study selection. A manual search was performed for relevant references from the selected articles and published reviews.
Main Outcomes and Measures
The outcomes analyzed were mortality, new congestive heart failure, recurrent myocardial infarction, ventricular arrhythmia, and changes in LVEF, serum potassium level, and creatinine level at follow-up.
In all, 10 randomized clinical trials with a total of 4147 unique patients were included in the meta-analysis. In patients who presented with STEMI without heart failure, treatment with aldosterone antagonists compared with control was associated with lower risk of mortality (2.4% vs 3.9%; odds ratio [OR], 0.62; 95% CI, 0.42-0.91; P = .01) and similar risks of myocardial infarction (1.6% vs 1.5%; OR, 1.03; 95% CI, 0.57-1.86; P = .91), new congestive heart failure (4.3% vs 5.4%; OR, 0.82; 95% CI, 0.56-1.20; P = .31), and ventricular arrhythmia (4.1% vs 5.1%; OR, 0.76; 95% CI, 0.45-1.31; P = .33). Similarly, treatment with aldosterone antagonists compared with control was associated with a small yet significant increase in LVEF (mean difference, 1.58%; 95% CI, 0.18%-2.97%; P = .03), a small increase in serum potassium level (mean difference, 0.07 mEq/L; 95% CI, 0.01-0.13 mEq/L; P = .02), and no change in serum creatinine level (standardized mean difference, 1.4; 95% CI, −0.43 to 3.24; P = .13).
Conclusions and Relevance
Treatment with aldosterone antagonists is associated with a mortality benefit in patients with STEMI with LVEF greater than 40% or without heart failure.
Primary percutaneous coronary intervention (PCI) or timely thrombolysis is recommended for patients presenting with ST-segment elevation myocardial infarction (STEMI).1,2 Despite significant improvement in guidelines-directed revascularization with PCI or thrombolysis, STEMI is associated with significant morbidity and mortality of up to 23% within 5 years after PCI, with a significant number of deaths occurring within the first 30 days.3 After STEMI, irreversible injury during the ischemia period may lead to necrosis, inflammation, and fibrosis in the reperfusion phase, leading to molecular and mechanical changes that eventually contribute to the ventricular remodeling process.4-6 Ventricular remodeling predisposes patients to higher morbidity and mortality and therefore has been the focus of therapy to improve long-term outcomes after STEMI.7
Aldosterone, which is a mineralocorticoid hormone, has been linked to the development of ventricular remodeling through the promotion of tissue fibrosis.5 Elevated aldosterone levels have been shown to correlate with worse adverse clinical outcomes, including mortality; therefore, reduction of aldosterone levels has been a target to improve long-term clinical outcomes in patients with coronary artery disease and patients who have experienced myocardial infarction (MI).8-10Quiz Ref ID On the basis of the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial, treatment with aldosterone antagonists (AAs) has been recommended for patients with acute MI with ejection fraction less than 40% and clinical heart failure or diabetes.2,11 Thus far, the usefulness of AAs in treating patients with STEMI with left ventricular ejection fraction (LVEF) greater than 40% has not been defined, although a number of randomized clinical trials (RCTs) have evaluated the role of AA therapy in patients with STEMI without clinical heart failure or LVEF greater than 40%; only 1 study12 showed a survival benefit associated with AA therapy in patients with STEMI, whereas other studies had inconclusive findings.13,14 Thus, to better define the role of AA therapy in patients with STEMI without clinical heart failure or LVEF greater than 40%, we performed this systematic review and meta-analysis of randomized clinical trials.
Data Sources and Search Strategy
We complied with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to conduct and report this meta-analysis after writing a study protocol.15 We searched the PubMed, Embase, CINAHL, and Cochrane Central Register of Clinical Trials electronic databases for English-language references from inception through June 2017 using the search terms aldosterone antagonists OR AA OR spironolactone OR eplerenone OR canrenoate AND ST elevation myocardial infarction OR acute myocardial infarction OR STEMI. Two of us (K.D. and S.S.) independently performed the database search and agreed on the final study selection. A manual search was performed for relevant references from the selected articles and published reviews.
Those RCTs evaluating the effects of treatment with AAs in patients with STEMI without heart failure or with LVEF greater than 40% in adult patients (≥18 years) were selected for the systematic review and meta-analysis. Those studies that did not report on clinical or biochemical outcomes were excluded. Also excluded were studies evaluating patients after STEMI with LVEF less than 40%, meeting abstracts, and nonrandomized studies.
Four investigators worked in 2 groups (K.D. and A.H.; S.P.S. and S.S.) to extract data from the selected studies in duplicate using a standardized data extraction form. Data were obtained on study characteristics that included study design, patient selection, inclusion and exclusion criteria, follow-up duration, number of patients, type and dosing of AAs and outcomes, patient demographic and baseline characteristics, and outcomes of interest reported at follow-up.
Mortality, MI, new congestive heart failure (CHF), ventricular arrhythmia, and change in LVEF, serum creatinine level, and potassium level were the major outcomes of interest. Analysis of an outcome was only performed if at least 2 studies reported that outcome.
We performed the statistical analyses with use of Review Manager software (RevMan, version 5.3; Cochrane Collaboration, Nordic Cochrane Center) and used a random-effects model to compute overall effects. The continuous variables were analyzed as mean difference (MD) or standardized MD with 95% CI depending on the units of reporting. For the categorical variables, we calculated the odds ratio (OR) with 95% CI using the total number of events and patients as reported in the individual studies. Study heterogeneity was evaluated with the Cochran Q and I2 index, and significant heterogeneity (I2>60%) was explored with sensitivity analyses. We planned prespecified subgroup analyses based on the duration of follow-up (≥6 months vs <6 months), type of AA used (spironolactone, eplerenone, or canrenoate potassium), and size of study (small defined as a total number of participants of <100 in each arm).
We performed additional sensitivity analyses with use of a Bayesian Markov Chain Monte Carlo model16 and reported categorical variables as OR with 95% credible interval. A random-effects model with informative priors was adopted for final interpretation of the results.2,3 To achieve convergence, a burn-in phase of 20 000 simulations was performed followed by 50 000 simulations for the final analyses.17,18 Conversion was confirmed by inspection of Gelman Rubin graphs.19 The Bayesian analysis was performed with use of WinBUGS software, version 1.4 (MRC Biostatistics Unit) and the Microsoft Excel–based tool NetMetaXL.20
Description of Included Studies
eFigure 1 in the Supplement shows the PRISMA flow diagram of study selection. A total of 319 citations were retrieved after the initial search of electronic databases and the manual search. After 29 duplicates were removed, 291 eligible citations were screened, which resulted in 25 publications for full-text review. Finally, we excluded 15 studies that did not meet the specified criteria and were left with 10 publications for qualitative and quantitative analysis (meta-analysis).
Table 1 and Table 2 show the individual study and patient characteristics of the included studies. Inclusion and exclusion criteria are presented in the eTable in the Supplement. Ten studies had enrolled 4147 patients, with 2093 patients in the AA arms and 2054 patients in the control arms. Three studies each originated from Italy13,25,26 and Turkey21-23; 1 study each originated from Japan,24 China,6 and France12; and 1 study was an international study.14 The AAs used were spironolactone, eplerenone, canrenoate, and canrenoate followed by spironolactone. Follow-up duration was variable: 6 to 12 months for 8 studies,6,12-14,21-23,25 1 month for 1 study,24 and 10 days for 1 study.26 Revascularization was performed with primary PCI, thrombolysis, or both in all studies except the 2001 study by Di Pasquale et al,26 which included patients for whom thrombolysis was contraindicated or who did not achieve reperfusion after thrombolysis.
Quiz Ref IDTherapy with AAs compared with a control group (from 9 studies) reduced the risk of mortality (2.4% vs 3.9%; OR, 0.62 [95% CI, 0.42-0.91]; P = .01; I2 = 0) (Figure 1). No difference was noted in the risk of MI (1.6% vs 1.5%; OR, 1.03 [95% CI, 0.57-1.86]; P = .91; I2 = 0) (eFigure 2 in the Supplement), CHF (4.3% vs 5.4%; OR, 0.82 [95% CI, 0.56-1.20]; P = .31; I2 = 0) (eFigure 3 in the Supplement), and ventricular arrhythmia (4.1% vs 5.1%; OR, 0.76 [95% CI, 0.45-1.31]; P = .33; I2 = 13) (eFigure 4 in the Supplement) between the AA group and the control group.
Change in LVEF and Biochemical Profile
Quiz Ref IDTreatment with AAs compared with a control group resulted in a small yet significant increase in LVEF (MD, 1.58% [95% CI, 0.18%-2.97%]; P = .03; I2 = 99) (Figure 2), a small increase in serum potassium level (MD, 0.07 mEq/L [95% CI, 0.01-0.13 mEq/L]; P = .02; I2 = 99; to convert to millimoles per liter, multiply by 1.0) (eFigure 5 in the Supplement), and no change in serum creatinine level (standardized MD, 1.4 [95% CI, −0.43 to 3.24]; P = 13; I2 = 100; to convert to micromoles per liter, multiply by 76.25) (eFigure 6 in the Supplement).
Sensitivity and Subgroup Analyses
We performed subgroup analyses on the clinical outcomes based on the individual AA agents, duration of follow-up (≥6 months vs <6 months), study size (small vs large), and combined mode of administration (intravenous vs oral) with follow-up duration. When analyses were restricted to individual agents vs control, mortality benefit was not observed for individual agents. Analysis based on the duration of follow-up (6-12 months) showed reduced mortality risk associated with therapy with AAs compared with control, consistent with the primary analysis. Similarly, we performed an analysis that included the larger studies (≥100 patients in each arm)6,12-14 that showed reduced mortality (OR, 0.57 [95% CI, 0.35-0.94]; P = .03; I2 = 18) and similar risk of MI (OR, 0.96 [95% CI, 0.52-1.77]; P = .89; I2 = 0), CHF (OR, 0.90 [95% CI, 0.60-1.37]; P = .63; I2 = 0), and ventricular arrhythmia (OR, 0.65 [95% CI, 0.16-2.68]; P = .55; I2 = 33) associated with AA therapy, consistent with the primary analyses. The comparison of intravenous administration of AAs followed by oral administration of AAs with up to 6 months of follow-up vs oral administration of AAs with up to 12 months of follow-up did not show a difference in the clinical outcomes. Because canrenoate is approximately 30% less potent than spironolactone,27 to address the effect of dosing in various outcomes, we performed additional analyses after excluding the studies that used low-dose canrenoate (Di Pasquale et al13,26), which had results that were consistent with the primary outcomes. The analysis excluding the 2001 study by Di Pasquale et al,26 which included patients who did not undergo or achieve reperfusion, showed a mortality benefit associated with receipt of AAs. Furthermore, we performed sensitivity analyses with use of a Bayesian model for mortality, MI, CHF, and ventricular arrhythmia, and the results were not significantly different from those of the primary analysis (eFigure 7 in the Supplement).
Study Quality and Publication Bias
The studies were of moderate to high quality according to the Cochrane Collaboration’s bias assessment tools.28 One study showed bias for blinding of participants or personnel.12 One study showed bias for blinding of participants and personnel and outcomes.23 Five studies showed bias for allocation concealment and blinding of participants, personnel, or outcome.6,21,22,24,25Quiz Ref ID Publication bias was tested by visual examination of the funnel plots, which were symmetrical and showed no evidence of publication bias for mortality outcome (eFigure 8 in the Supplement). Publication bias was not tested for other outcomes because of the small overall number of studies available for meaningful assessment of publication bias (<10 studies).
The major finding of our meta-analysis was the reduced risk of mortality associated with receipt of AAs compared with a control group in patients with STEMI without heart failure or reduced LVEF less than 40%. The risks of CHF, MI, and ventricular arrhythmia were, however, similar for both the AA group and the control group. Therapy with AAs was associated with small increases in LVEF and serum potassium level, and no difference was observed in serum creatinine level. Overall mortality rate after STEMI in this study was 3.14% at follow-up, which is lower than the mortality rate of 4% at 1 year of follow-up reported in a recent study.29
To our knowledge, this is the first meta-analysis to systematically review the role of therapy with AAs in patients who presented with STEMI and did not have significant LV dysfunction or CHF. The results of pooled analyses of 2 trials that were included in this meta-analysis were presented at the European Society of Cardiology meeting in 2017 and showed mortality benefit in the AA-treated group vs the standard therapy group (0.4% vs 1.6%; stratified OR, 0.22 [95% CI, 0.07-0.65]; P = .006),30 which is consistent with our results. One important observation in our meta-analysis was the reduction in mortality without a reduction in the outcomes of MI, CHF, or ventricular arrhythmia, similar to the results of the EPHESUS trial.11 The EPHESUS trial reported a significant reduction in all-cause and cardiovascular-associated mortality without a difference in the incidence of MI or CHF or a reduction in hospitalizations related to ventricular arrhythmia. A possible mechanism for mineralocorticoid receptor antagonists to reduce mortality is prevention of electrical remodeling that precedes cardiomyocyte hypertrophy following MI.31 In addition, animal studies have shown that mineralocorticoid receptor expression in the heart results in cardiac arrhythmia–related death that could be prevented by treatment with spironolactone.32 Similarly, immediate treatment with mineralocorticoid receptor blocker results in MI healing by modulation of the inflammatory response.33
Patients without clinical heart failure at presentation to the hospital constitute a large proportion of patients with STEMI. In 4 years of data (from 1994 to 1998) from the National Registry of Myocardial Infarction-2 study, 80.9% of 190 518 patients admitted to the hospital with STEMI presented without heart failure.34 Another recent report, based on a large database from the Nationwide Inpatient Sample, revealed a decreasing number of cases of heart failure at presentation, from 25.4% of cases in 2003 to 20.7% in 2010, among 1 990 002 admissions of patients with STEMI.35 This epidemiologic trend was most likely the result of improved pharmacotherapy and revascularization, which minimized the extent of injury caused by acute coronary occlusion in patients with STEMI. In addition, these data show that the incidence of patients with STEMI without heart failure may increase in the future, making such patients an important population group in which to establish interventions to improve outcomes.
The Randomized, Placebo-Controlled Trial Evaluating the Safety and Efficacy of Early Treatment with Eplerenone in Patients with Acute Myocardial Infarction (REMINDER)14 and the Aldosterone Lethal Effects Blocked in Acute Myocardial Infarction Treated with or Without Reperfusion to Improve Outcome and Survival at 6 Months’ Follow-up (ALBATROSS)12 trial were 2 of the most recent studies that investigated the role of AAs in patients with STEMI without heart failure or significant LV dysfunction. Although neither trial demonstrated a meaningful benefit of treatment with AAs in the study population, the REMINDER trial showed lower brain-type natriuretic peptide levels without other clinical benefits in participants treated with AAs, and the ALBATROSS trial, which seemingly did not establish the benefit of AAs in the overall study population, showed significant benefit of treatment with AAs in a post hoc analysis restricted to patients with STEMI. At this point, there are 2 ongoing or just completed trials in the ClinicalTrials.gov database. The Early Mineralocorticoid Receptor Antagonist Treatment to Reduce Myocardial Infarct Size (MINIMISE-STEMI) trial, which is now completed, aims to compare the effect of spironolactone vs placebo on infarct size in patients with STEMI.36 The Colchicine and Spironolactone in Patients with STEMI/SYNERGY Stent Registry (CLEAR-SYNERGY) trial plans to compare the effects of colchicine and spironolactone vs placebo in a 2 × 2 factorial design on clinical outcomes after PCI in patients with STEMI (ClinicalTrials.gov Identifier: NCT03048825). These trials may shed further light on the role of spironolactone in patients with STEMI.
There are several implications of this meta-analysis. STEMI and its adverse effects on morbidity and mortality remain major cardiovascular problems, and there is a constant search for therapies to improve survival and other clinical outcomes. The mortality benefit observed in the meta-analysis was substantial (38% reduction). One concern among physicians is the possibility of adverse effects associated with AA use, namely, hyperkalemia, acute kidney injury, and gynecomastia. Although our meta-analysis indicated that AA use was associated with elevated serum potassium levels, the clinical implications of such a small increase in serum potassium level are unclear. However, the serum potassium levels of patients who initiate treatment with AAs should be closely monitored during follow-up. No increase in serum creatinine levels was observed in the meta-analysis, which is reassuring. Our meta-analysis clearly showed a small but significant improvement in LVEF, the clinical significance of which is unclear.
Quiz Ref IDA potential limitation of our meta-analysis is the lack of patient-level data, which our study was not designed to provide. There was variation in the type of AA agents, the mode of administration (oral vs intravenous), the duration of follow-up, and the use of concomitant therapy, including β-blocker use and reperfusion and revascularization strategies; we tried to explore most of these factors with subgroup analyses. Not all studies reported on each outcome of interest, and some of the studies were not designed to measure clinical outcomes, which may be a limitation. However, our meta-analysis has been strengthened by the inclusion of all randomized trials published on this subject. In addition, the results were mainly driven by the ALBATROSS trial,12 although there was a strong trend toward improved survival when analysis was performed after exclusion of this study (OR, 0.70 [95% CI, 0.47-1.04]; P = .08; I2 = 0).
On the basis of this meta-analysis, we conclude that AAs are associated with a mortality benefit in patients with STEMI with LVEF greater than 40% or without heart failure. Future adequately powered randomized studies should confirm these findings.
Accepted for Publication: February 8, 2018.
Corresponding Author: Kalgi Modi, MD, Division of Cardiovascular Medicine, Louisiana State University Health Sciences Center, 1541 Kings Hwy, Shreveport, LA 71130 (firstname.lastname@example.org).
Published Online: May 21, 2018. doi:10.1001/jamainternmed.2018.0850
Author Contributions: Dr Dahal is guarantor of the study, had full access to all of the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Dahal, Hendrani, Dominic.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Dahal, Hendrani, Sharma, Singireddy.
Critical revision of the manuscript for important intellectual content: Hendrani, Reddy, Dominic, Mina, Modi.
Statistical analysis: Dahal, Hendrani, Mina, Sharma.
Administrative, technical, or material support: Hendrani, Mina.
Study supervision: Sharma, Singireddy, Reddy, Dominic, Modi.
Conflict of Interest Disclosures: None reported.
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