Effect of eplerenone in percutaneous coronary intervention-treated post-myocardial infarction patients with left ventricular systolic dysfunction: a subanalysis of the EPHESUS trial

EPHESUS trial

EPHESUS was a large multicentre, double-blind randomized controlled clinical trial that assessed the impact of eplerenone upon clinical outcomes in patients with LVSD after AMI.1 Patients (n = 6632) were randomized to receive eplerenone (n = 3319) or placebo (n = 3313). Eplerenone was initiated at 25 mg/day at ∼7 days after AMI and titrated at 4 weeks to 50 mg/day, if serum potassium was <5 mmol/L. About 24% patients in the EPHESUS trial received PCI as a treatment of AMI while others were treated with thrombolysis (27%), CABG (1%), or conservative medical treatment (48%). Patients were followed-up for an average of 16 months.

EPHESUS PCI substudy

This substudy evaluated the effect of eplerenone administration in the PCI-treated subgroup of patients in the EPHESUS trial. We analysed the PCI-treated (n = 1580) vs. non-PCI-treated (n = 5052) patients. Furthermore, we compared the baseline characteristics and clinical outcomes in PCI-treated patients in the eplerenone- (n = 799) and placebo- (n = 781) treated groups.

Statistical analysis

Data are presented as mean ± SD or proportion and percentage, as indicated. Continuous variables were analysed using the Mann–Whitney test and categorical variables with the χ² test. Multivariate analyses were performed using the Cox regression method. Hazard ratios (HRs) along with the 95% confidence interval (CI) are presented. P-values <0.05 were considered significant. All statistical analyses were performed using SAS® 9.2 software (SAS Institute, Cary, NC, USA).

The EPHESUS PCI cohort is different from the non-PCI cohort

The baseline demographic and clinical characteristics of PCI-treated (n = 1580) and non-PCI-treated (n = 5052) patients in the EPHESUS trial are shown in Table 1. The PCI-treated patients were younger, and had better renal function, fewer co-morbidities, and higher prescription of evidence-based medication including beta-blockers, ACE inhibitors, and statins. Cardiovascular mortality was significantly lower in PCI-treated patients as compared with non-PCI-treated patients (7% vs. 16%, P < 0.0001), but the incidence of non-fatal events was similar in the two groups (Table 1).

Eplerenone improves outcomes in both the PCI-treated and the non-PCI-treated cohort

Eplerenone treatment was similarly effective in reducing mortality, cardiovascular events, and hospitalization in both PCI-treated and non-PCI-treated AMI patients with LVSD (Figure 1). On multivariate Cox regression analysis, with eplerenone and PCI as co-variables, both PCI and eplerenone administration were independently associated with better clinical outcomes (Table 2).

Baseline characteristics of the EPHESUS PCI cohort

The baseline characteristics of the EPHESUS PCI cohort treated with placebo or eplerenone were similar (Table 3). The mean age of the patients was 60 years, with 77% male patients. The two groups were similar in terms of age, gender, ethnicity, LV function, co-morbidities, and prescription of medication at discharge (Table 3). There was no significant difference in adverse events between the eplerenone- or placebo-treated EPHESUS PCI cohort: hyperkalaemia (2.4% vs. 3.3%, P = 0.33), hypokalaemia (1.7% vs. 0.8%, P = 0.10), gynaecomastia in men (0.6% vs. 0.6%, P = 1.00), and renal dysfunction (3.2% vs. 2.0%, P = 0.13).

Eplerenone does not affect PCI-related clinical outcomes

Eplerenone, compared with placebo, in the PCI cohort did not impact upon the incidence of sudden cardiac death, non-fatal MI, or stroke (Table 4). Although there was a statistically significant reduction in events related to heart failure and hospital admissions, there was no effect upon PCI-related adverse outcomes, including recurrence of angina pectoris, unstable angina, AMI, or need for further revascularization (Table 4).

Eplerenone improved outcomes in both the PCI-treated and non-PCI-treated population

Mineralocorticoid receptor antagonists are strongly recommended for patients with LVSD and symptoms of heart failure,12, 13 based on morbidity and mortality benefits seen in three landmark trials: RALES, EPHESUS, and EMPHASIS-HF.1, 14, 15 The RALES trial consisted of patients with advanced heart failure, the EPHESUS trial included patients with LVSD after AMI, and the EMPHASIS-HF trial enrolled patients with heart failure and mild (NYHA class II) symptoms.1, 14-16 In RALES, spironolactone produced 30% relative reduction in mortality during an average follow-up of 24 months.14 In EMPHASIS-HF, eplerenone was associated with a 24% reduction in cardiovascular death and a 42% reduction in hospitalization for heart failure.15 Only the EPHESUS trial specifically examined patients with LVSD after an AMI and showed that eplerenone produced 15% reduction in all-cause mortality, 17% reduction in cardiovascular mortality, and 21% reduction in sudden cardiac death.1 In contemporary practice, most patients with AMI receive PCI treatment.4 Our data show that eplerenone confers similar benefit in patients with AMI and LVSD whether or not they are treated with PCI. The outcomes observed in the PCI subgroup were similar to those reported in the full EPHESUS cohort.1 Our analysis shows that PCI itself was associated with a major reduction in adverse outcomes in AMI patients, consistent with numerous other reports.17, 18 However, eplerenone administration was also an independent factor associated with improved outcomes, emphasizing the importance of MR antagonism in LVSD after AMI, including patients treated with primary PCI. Therefore, prescribing eplerenone to patients with AMI and LVSD remains beneficial in patients treated with and without PCI.

Whilst the EPHESUS trial included patients with all forms of AMI [unstable angina, non-ST segment elevation myocardial infarcion (NSTEMI), and STEMI] and there was a delay in commencing eplerenone, a recently reported clinical trial (REMINDER: impact of eplerenone on cardiovascular outcomes in patients post myocardial infarction, NCT-01176968) has shown that early use of eplerenone can improve the outcome of patients presenting with acute STEMI without heart failure.19 Over 1000 patients were randomized (n = 506/group) to initiation of eplerenone or placebo within 12–24 h of STEMI. Eplerenone 25 or 50 mg/day (89% patients received 50 mg/day) produced a significant reduction (HR 0.58, 95% CI 0.45–0.75, P < 0.0001) in the primary endpoint (a composite of cardiovascular mortality, ventricular arrhythmia, clinical or subclinical heart failure at 1 month) at a mean follow-up of 10.5 months.19 ALBATROSS (Aldosterone blockade early after acute myocardial infarction; NCT-01059136) is an ongoing multicentre, open-labelled, randomized trial to assess the effects of MR blockade with a 200 mg i.v. bolus of potassium canrenoate followed by 25 mg/day spironolactone for 6 months in 1600 patients with STEMI or high risk NSTEMI.20

Eplerenone did not affect PCI-related outcomes

Mineralocorticoid receptors are widely distributed in the vascular system, including endothelial cells, endothelial progenitor cells (EPCs), vascular smooth muscle cells (VSMCs), and intact vessels.8, 21, 22 These receptors also influence vascular function and remodelling;6, 23 MR activation has been shown to increase proliferation of VSMCs6 and to impair differentiation and proliferation of EPCs.7 These characteristics suggest that MR activation is a potential stimulus for neointimal proliferation and restenosis. In humans, elevated baseline plasma aldosterone levels directly correlate with risk of restenosis24 and inversely correlate with circulating EPCs and endothelial colony-forming units.8 Mineralocorticoid receptor antagonists reduce atherosclerosis,23, 25 prevent adverse vascular remodelling,26 and attenuate post-angioplasty neointimal proliferation in experimental animals.9, 11, 27

Spironolactone has been shown to inhibit neointimal proliferation after balloon angioplasty of iliac arteries in rabbits.27 However, these results could not be reproduced in a porcine coronary angioplasty model,9, 28 which is the gold standard pre-clinical model for restenosis. Additionally, a single-centre clinical trial failed to show any effect of spironolactone in reducing restenosis.29 Nevertheless, promising experimental data have been obtained with eplerenone.9-11 Our data suggest that, like spironolactone, eplerenone does not appear to affect PCI-related clinical outcomes. Therefore, eplerenone cannot currently be recommended for patients undergoing PCI without co-existing AMI or LVSD.

Study limitations

This study has several limitations. It is a post-hoc analysis with inherent shortcomings of any such study. Patients in the EPHESUS PCI cohort did not have routine angiographic follow-up to document any effect of eplerenone on angiographic restenosis; however, our assessment of clinical events is perhaps more relevant than angiographic outcomes.

Funding

The EPHESUS trial was funded by Pharmacia/Pfizer.

Conflict of interest: I.S. has received grants and honoraria from Novartis, Pfizer, Vifor, and Jansen. B.P. has received honoraria from Pfizer and serves on the advisory boards for Pfizer and Novartis. F.Z. has received honoraria from Pfizer, Novartis, Roche, Servier, AstraZeneca, and Takeda. All other authors have no conflicts to declare.