Eplerenone Is Not Superior to Older and Less Expensive Aldosterone Antagonists

CLINICAL RESEARCH STUDY

Eplerenone Is Not Superior to Older and Less Expensive Aldosterone Antagonists Saurav Chatterjee, MD,a Chaim Moeller, MD,a Nidhi Shah, MD,a Oluwaseyi Bolorunduro, MD, MPH,a Edgar Lichstein, MD,a Norbert Moskovits, MD,a Debabrata Mukherjee, MD, MSb a

Maimonides Medical Center, Brooklyn, NY; bTexas Tech University Health Sciences Center, El Paso

ABSTRACT INTRODUCTION: Eplerenone is publicized to be extremely effective in reducing mortality from heart failure, with a reasonable side-effect profile. However, it is much more expensive compared with older aldosterone antagonists. We reviewed available evidence to assess whether increased expense was justified with outcomes data. METHODS AND RESULTS: The authors searched the PubMed, CENTRAL, CINAHL, and EMBASE databases for randomized controlled trials from 1966 through July 2011. Interventions included aldosterone antagonists (Aldactone [Pfizer, NY, NY], canrenone, eplerenone) in systolic heart failure. The comparator included standard medical therapy or placebo, or both. Outcomes assessed were mortality in the intervention versus the comparator groups, and rates of adverse events at the end of at least 8 weeks of follow-up. Event rates were compared using a forest plot of relative risk (RR) (95% confidence interval [CI]) using a random-effects model (Mantel-Haenszel) between the aldosterone antagonists and controls. We included 13 studies for aldosterone antagonists other than eplerenone, and 3 studies for eplerenone. There was significant reduction of mortality with all aldosterone antagonists, but eplerenone (15% mortality relative reduction; RR 0.85; 95% CI, 0.77-0.93; P ⫽ .0007) was outperformed by other aldosterone antagonists, namely, spironolactone and canrenone (26% mortality relative reduction; RR 0.74; 95% CI, 0.66-0.83; P ⬍.0001). Reduction in cardiovascular mortality with eplerenone was 17% (RR 0.83; 95% CI, 0.75-0.92; P ⫽ .0005), while that with other aldosterone antagonists was 25% (RR 0.75; 95% CI, 0.67-0.84, P ⬍.0001), without contributing significantly to an improved side-effect profile. CONCLUSION: Eplerenone does not appear to be more effective in reducing clinical events compared with older, less expensive aldosterone antagonists. © 2012 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2012) 125, 817-825 KEYWORDS: Cost-benefit analysis; Heart failure; Meta-analysis

The selective mineralocorticoid receptor antagonist, eplerenone, has been in the news recently for decreasing mortality and hospitalizations in patients with mildly symptomatic heart failure.1 Previously, it had been shown to decrease Funding: None. Conflict of Interest: Dr Lichstein reports receiving honoraria from Boston Scientific. The other authors have no conflicts to disclose pertaining to this manuscript. Authorship: Saurav Chatterjee 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. All authors had access to the data and a role in writing the manuscript. Requests for reprints should be addressed to Saurav Chatterjee, MD, Department of Internal Medicine, Maimonides Medical Center, 864 49th Street, Apt. C11, Brooklyn, NY 11220. E-mail address: [email protected]

0002-9343/$ -see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2011.12.018

mortality and rehospitalizations from cardiovascular reasons in patients with post-myocardial infarction ventricular dysfunction.2 Aldosterone, via the renin-angiotensin-aldosterone system, causes deleterious effects on the cardiovascular and renal physiology by causing endothelial dysfunction and cardiac myocyte remodeling.3,4 Eplerenone, like spironolactone, is a competitive antagonist of the aldosterone receptor.5 Eplerenone reportedly exhibits 10- to 20fold lower affinity6 for the aldosterone receptor in vitro compared with spironolactone, while having 50%-75% potency.7 Often eplerenone is touted as being cost-effective,8 despite being much more expensive than its predecessors, spironolactone and its active metabolite, canrenone. Each eplerenone tablet costs approximately 10 times that of spironolactone for a comparable dose.9 In view of this cost

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discrepancy, we decided to indirectly compare eplerenone with spironolactone and canrenone by doing a systematic review, in the absence of a head-to-head comparison study/ randomized trial comparing the 2 in a population with left ventricular dysfunction.

METHODS Search Strategy

statistics 0.84). We performed objective assessment of the trials using the method specified in the Cochrane Handbook of Systematic Reviews10—assessing for and assigning a quality score based on randomization, concealment, blinding, intention to treat, baseline comparisons, concomitant interventions, and completeness of follow-up.

CLINICAL SIGNIFICANCE

Outcomes Assessment

Our primary outcome was all● Eplerenone is not as efficacious as older We systematically searched cause mortality at the end of the PubMed, Embase, Cumulative Inaldosterone antagonists in preventing duration of follow-up. Secondary dex to Nursing and Allied Health clinical outcomes. outcome of interest was cardioLiterature (CINAHL) and Co● Eplerenone poorly justifies its increased vascular mortality, and for safety chrane Central Register of Conexpense with available outcomes data. outcomes, we used definitions of trolled Trials (CENTRAL) for trihyperkalemia and gynecomastia als that randomized study ● Rate of all-cause mortality reduction as per the primary trial publicaparticipants to an aldosterone anwas less with eplerenone compared with tion, where available. tagonist versus placebo/comparaolder aldosterone antagonists. tor without an aldosterone antag● Rates of hyperkalemia were worse with onist from 1966 through July Statistical Analysis eplerenone. 2011. The following medical subMeta-analysis was performed as ject heading terms were included per the recommendation of the ● Only gynecomastia appeared to be less for MEDLINE search and adapted Cochrane Collaboration and in with eplerenone usage over older aldofor other databases as needed: “alline with the Preferred Reporting sterone antagonists. dosterone antagonist,” “spironoItems for Systematic Reviews and lactone,” “canrenone,” “AldacMeta-Analyses (PRISMA) statetone [Pfizer, NY, NY],” and ment.11 Owing to the differences “eplerenone.” In addition to searching the databases, the expected among studies (particularly in control group therreference lists of all included studies, meta-analyses, and apies), pooled treatment effects were estimated as per a reviews were manually searched. There was no language priori agreement using risk ratio with Mantel-Haenszel restriction for the search. method, using a random-effects model. Heterogeneity was assessed by chi-squared tests and the I2 statistic—we defined I2 ⬍50% to be low-intermediate (not high) heterogeInclusion and Exclusion Criteria neity, as per the Cochrane Handbook of Systematic ReWe included trials that studied adults (18⫹ years) and views.10 Publication bias was estimated using funnel plots randomized them to a therapy of aldosterone antagonists and the regression test of Egger. and comparators. Eligible trials had to be randomized conWe assessed a quality score for each included trial and trolled clinical trials comparing aldosterone antagonists verassigned a score of 1 for low quality, 2 for intermediate, and sus comparators (could be placebo, angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, or beta3 for high quality trials. For statistical analysis, we used blockers, but not another aldosterone antagonist); enrolled Review Manager Version 5.1 (Copenhagen: The Nordic symptomatic or asymptomatic patients with left ventricular Cochrane Centre, The Cochrane Collaboration, 2008). A dysfunction; were ⱖ8 weeks in duration; and were able to 2-sided P-value of ⬍.05 was considered significant for all report at least one of the clinical outcomes of interest. We analyses. included trials in which the subjects were given the interAdjusted indirect comparison of pooled estimates also vention or comparator without regard to time duration. We were performed for only the mortality outcome (with low excluded trials of patients that did not report outcomes of heterogeneity for both eplerenone and other aldosterone interest or that did not include human participants. In cases antagonists [AAs]) according to Song et al.12 Specifically, of multiple publications involving the same or a portion of we generated from fixed-effect odds ratio (OR) comparing the same patients, the article with the most complete data eplerenone or older aldosterone antagonists vs comparator, was selected. an interaction OR for eplerenone or other aldosterone antagonists, with pertinent 95% confidence interval (CI) and z-scores for 2-tailed hypothesis testing (P significant if Data Collection and Processing ⬍.05). Specifically, these interaction ORs are calculated Two authors (SC, NM) reviewed the trials to ensure that according to the following: ln (OR eplerenone vs other they met inclusion criteria, and abstracted the data, and this AAs) ⫽ ln (OR eplerenone vs comparator) ⫺ ln (OR other was checked for accuracy by the other authors. DisagreeAAs vs comparator), and var (ln [OR eplerenone vs other ments were resolved by consensus (15% of the time; kappa

Eplerenone versus Older Aldosterone Antagonists

Iden
fica
on

Chatterjee et al

Records iden
fied through database searching (n = 2212 )

819

Addi
onal records iden
fied through other sources (n =25 )

Eligibility

Screening

Records aer duplicates removed (n = 2217 )

Records screened (n =2217)

Full-text ar
cles assessed for eligibility (n = 36)

Included

Studies included in qualita
ve synthesis (n = 16)

Records excluded (n =2181 )(non RCT, lab studies, preven
on studies, dosing pharmacologic studies) Full-text ar
cles excluded, for not conforming to inclusion/exclusion criteria (n =20)(presence of ac
ve comparator group, non repor
ng of clinical endpoints, crossover studies, subset analyses)

Studies included in quan
ta
ve synthesis (meta-analysis) (n = 16 )

Figure 1 Search strategy according to PRISMA guidelines/statement. RCT ⫽ randomized clinical trial.

AAs]) ⫽ var (ln [OR eplerenone vs comparator]) ⫹ var (ln [OR other AAs vs comparator]), where ln is the natural logarithm, and var is the variance.

studies), followed by canrenone (3 studies), and eplerenone (3 studies) (Table 1).1,2,13-27

Trial Quality RESULTS Our MEDLINE search returned 2237 studies. After elimination of duplicate results, the EMBASE and Cochrane registries did not return any additional studies; leaving 2217 studies for evaluation. Through a review of titles and abstracts, 2181 studies were rejected for relevance. The remaining 36 articles were reviewed and assessed for satisfaction of the inclusion or exclusion criteria. The 16 studies that met all criteria were included in this analysis (Figure 1).

Study Characteristics Trials were fairly homogenous with respect to inclusion and exclusion criteria, with a few key differences. Four studies evaluated effect of aldosterone antagonist post-acute myocardial infarction left ventricular dysfunction,2,13-15 while others randomized heart failure patients. Duration of follow-up varied from 2 months to 24 months. Spironolactone was the most commonly used aldosterone antagonist (10

We used the published standard criteria for reporting of randomized clinical trials studies (PRISMA)11 to select the studies selected for this review (Figure 1). Among the 16 trials included, 8 were low bias risk trials, 7 were intermediate risk, and one was at high risk of bias—as assessed by Cochrane (section 8.5 in the Cochrane Handbook10) metrics for risk of bias (Table 2).1,2,13-27

Primary Outcome We identified 16 articles, accounting for 12,505 subjects (3016 for aldosterone antagonist other than eplerenone and 9489 for eplerenone) that met our inclusion and exclusion criteria. There was a significant reduction of mortality with all aldosterone antagonists in heart failure and post-myocardial infarction left ventricular dysfunction, but eplerenone (15% mortality reduction; relative risk [RR] 0.85; 95% CI, 0.77-0.93; P ⫽ .0007) (Figure 2) was far outperformed by the other aldosterone antagonists, namely spironolactone and canrenone (26% mortality reduction; RR 0.74; 95% CI,

820 Table 1

The American Journal of Medicine, Vol 125, No 8, August 2012 Baseline Characteristics of Studies

Trial Name 18

Agostoni et al Akbulut et al19 Barr et al20 Boccanelli et al21 Chan et al22 Cicoira et al23 Di Pasquale et al13 Gao et al24 Modena et al14 Pitt-SARA25 Pitt - RALES27 RALES16 Rodriguez et al15 Pitt - EPHESUS2,17,28 Zannad - EMPHASIS - HF1 Study 40226

Intervention

Comparator

Age (Years)

% Males

Follow-up

Spironolactone 25 mg Spironolactone 25 mg Spironolactone 50 mg (titrated to 100 mg) Canrenone 25 mg Spironolactone ⫹ candesartan Spironolactone 25 mg (titrated to 50 mg) Canrenoate IV 1 mg/h then oral 25 mg daily ⫹ 6.25 mg captopril Spironolactone 20 mg Canrenoate 50 mg Spironolactone 25 mg, Eplerenone 25 mg, 25 mg BID, 50 and 100 mg Spironolactone 12.5, 25, 50, 75 mg Spironolactone 25 mg (titrated to 50 mg) Spironolactone 25 mg TID Eplerenone 25 mg (titrated to 50 mg) Eplerenone 25 mg (titrated to 50 mg) Eplerenone 25, 50, 100 mg

Placebo Metoprolol 12.5 mg Placebo Placebo Placebo ⫹ candesartan Usual care 6.25 mg captopril

60.3 ⫾ 9.4 58.9 ⫾ 6.1 68 ⫾ 3 63 ⫾ 9 61.4 ⫾ 12.3 62.5 ⫾ 7.9 62.6 ⫾ 6

66 54 79 84 87 85 71

6 3 2 12 12 12 6

Placebo Placebo Placebo

55 ⫾ 13 59 ⫾ 10 61 (31-87)

64 71 78

6 months 12 months 3 months

Placebo Placebo Ramipril 2.5 mg BID Placebo Placebo Placebo

62 ⫾ 12 65 ⫾ 12 58.8 ⫾ 10.8 64 ⫾ 11 68.7 ⫾ 7.7 64(29-88)

80 75 78 72 77.3 84

3 24 6 16 21 3

months months months months months months months

months months months months months months

BID ⫽ twice a day; EMPHASIS-HF ⫽ Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; EPHESUS ⫽ Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; IV ⫽ intravenous; RALES ⫽ Randomized Aldactone Evaluation Study; SARA ⫽ Selective Aldosterone Receptor Antagonist; TID ⫽ 3 times a day.

0.66-0.83; P ⬍.0001)—without any evidence of statistical heterogeneity for either. Also, publication bias was assessed by constructing a funnel plot and an Egger’s test with

Table 2

Assessment of Risk of Bias in Studies

Trial Name

Sequence Generation: Yes (Y), No (N), Unclear (UC)

Agostoni et al18 Akbulut et al19 Barr et al20 Boccanelli et al21 Chan et al22 Cicoira et al23 Di Pasquale et al13 Gao et al24 Modena et al14 Pitt - SARA25 Pitt - RALES27 RALES16 Rodriguez et al15 Pitt - EPHESUS2,17,28 Zannad EMPHASIS - HF1 Study 40226

2-tailed P-value (P ⫽ .43). Indirect comparison OR favored other aldosterone antagonists over eplerenone in mortality reduction (P ⫽ .0094).

Use of ITT: Yes, No, Unclear

Free of Incomplete Outcome Data: Yes, No, Unclear

Free of Selective Outcome Reporting: Yes, No, Unclear

Quality Score (1 ⫽ High Risk, 2 ⫽ Intermediate Risk, 3 ⫽ Low Risk)

N N Y Y Y N Y UC N N Y Y Y Y Y

N Y Y Y Y Y Y Y N Y Y Y Y Y Y

Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y

UC Y Y Y Y Y Y Y Y Y Y Y Y Y Y

1 2 3 3 3 2 3 2 2 2 3 3 2 3 3

UC

Y

UC

Y

2

Allocation Concealment: Yes, No, Unclear

Blinding of Participants, Personnel and Outcome Assessors

N Y Y Y Y Y Y Y Y Y Y Y Y Y Y

UC N Y Y Y UC Y UC UC UC Y Y UC Y Y

Y

Y

EMPHASIS-HF ⫽ Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; EPHESUS ⫽ Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; ITT ⫽ intention to treat; RALES ⫽ Randomized Aldactone Evaluation Study; SARA ⫽ Selective Aldosterone Receptor Antagonist.

Chatterjee et al

Eplerenone versus Older Aldosterone Antagonists

Study or Subgroup

Eplerenone Control Risk Ratio Events Total Events Total Weight M-H, Random, 95% CI

EMPHASIS-HF EPHESUS

171 1364 478 3319

Total (95% CI)

4683

213 1373 554 3313

26.6% 73.4%

0.81 [0.67, 0.97] 0.86 [0.77, 0.96]

4686 100.0%

0.85 [0.77, 0.93]

649 767 Total events Heterogeneity: Tau² = 0.00; Chi² = 0.33, df = 1 (P = 0.57); I² = 0% Test for overall effect: Z = 3.38 (P = 0.0007)

Study or Subgroup Agostoni 2005 Akbulut Barr Bocanelli Chan Cicoira Di Pasquale Gao Modena Pitt-A Pitt-RALES B Rodriguez et al 1997

821 Risk Ratio M-H, Random, 95% CI

0.5 0.7 1 1.5 2 Favours experimental Favours control

Aldosterone Antagonists Control Risk Ratio Events Total Events Total Weight M-H, Fixed, 95% CI 0 0 0 6 0 3 22 0 0 0 284 1

15 35 20 231 23 54 341 58 24 174 822 23

Total (95% CI)

0 0 0 12 0 4 32 0 2 0 386 2

1820

Total events 316 Heterogeneity: Chi² = 1.63, df = 5 (P = 0.90); I² = 0% Test for overall effect: Z = 5.15 (P < 0.00001)

15 70 20 236 2.7% 25 52 0.9% 346 7.3% 58 22 0.6% 40 841 88.0% 24 0.5%

Not estimable Not estimable Not estimable 0.51 [0.19, 1.34] Not estimable 0.72 [0.17, 3.07] 0.70 [0.41, 1.18] Not estimable 0.18 [0.01, 3.63] Not estimable 0.75 [0.67, 0.85] 0.52 [0.05, 5.37]

1749 100.0%

0.74 [0.66, 0.83]

Risk Ratio M-H, Fixed, 95% CI

438 0.5 0.7 1 1.5 2 Favours experimental Favours control

Figure 2 Risk of all-cause mortality with eplerenone and spironolactone/canrenone. CI ⫽ confidence interval; EMPHASIS-HF ⫽ Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; EPHESUS ⫽ Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; RALES ⫽ Randomized Aldactone Evaluation Study.

Study or Subgroup

Eplerenone Control Risk Ratio Events Total Events Total Weight M-H, Fixed, 95% CI

EMPHASIS-HF EPHESUS

147 1364 407 3319

Total (95% CI)

4683

185 1373 483 3313

27.6% 72.4%

0.80 [0.65, 0.98] 0.84 [0.74, 0.95]

4686 100.0%

0.83 [0.75, 0.92]

Total events 554 668 Heterogeneity: Chi² = 0.17, df = 1 (P = 0.68); I² = 0% Test for overall effect: Z = 3.48 (P = 0.0005)

Study or Subgroup Bocanelli Cicoira Pitt-A Pitt-B Total (95% CI)

Risk Ratio M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2 Favours Eplerenone Favours control

Aldosterone Antagonists Control Risk Ratio Events Total Events Total Weight M-H, Random, 95% CI 6 3 9 284

231 54 263 822 1370

12 4 1 386

236 52 54 841

1.5% 0.7% 0.3% 97.5%

0.51 [0.19, 1.34] 0.72 [0.17, 3.07] 1.85 [0.24, 14.28] 0.75 [0.67, 0.85]

1183 100.0%

0.75 [0.67, 0.84]

Total events 302 403 Heterogeneity: Tau² = 0.00; Chi² = 1.36, df = 3 (P = 0.71); I² = 0% Test for overall effect: Z = 4.78 (P < 0.00001)

Risk Ratio M-H, Random, 95% CI

0.01 0.1 1 10 100 Favours experimental Favours control

Figure 3 Risk of cardiovascular mortality with eplerenone and spironolactone/canrenone. CI ⫽ confidence interval; EMPHASIS-HF ⫽ Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; EPHESUS ⫽ Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study.

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The American Journal of Medicine, Vol 125, No 8, August 2012

Study or Subgroup

Eplerenone Control Risk Ratio Events Total Events Total Weight M-H, Random, 95% CI

EMPHASIS-HF EPHESUS Study 402

109 1360 180 3307 4 114

Total (95% CI)

4781

50 1369 126 3301 1 38

43.6% 53.6% 2.7%

2.19 [1.58, 3.04] 1.43 [1.14, 1.78] 1.33 [0.15, 11.57]

4708 100.0%

1.72 [1.19, 2.47]

177 293 Total events Heterogeneity: Tau² = 0.05; Chi² = 4.61, df = 2 (P = 0.10); I² = 57% Test for overall effect: Z = 2.91 (P = 0.004)

Study or Subgroup Akbulut Barr Chan Cicoira Di Pasquale Gao Modena Pitt SARA Pitt-A Pitt-RALES B

Risk Ratio M-H, Random, 95% CI

0.01 0.1 1 10 100 Favours experimental Favours control

Aldosterone Antagonists Control Risk Ratio Events Total Events Total Weight M-H, Random, 95% CI 2 4 1 3 18 1 3 2 14 27

Total (95% CI)

70 20 23 54 341 58 24 54 822 174

1 0 0 0 4 0 2 58 10 2

1640

7.3% 5.6% 4.8% 5.3% 16.1% 4.7% 11.0% 13.4% 18.6% 13.2%

1.00 [0.09, 10.65] 9.00 [0.52, 156.91] 3.25 [0.14, 76.01] 6.75 [0.36, 127.48] 4.57 [1.56, 13.35] 3.00 [0.12, 72.15] 1.38 [0.25, 7.47] 0.17 [0.04, 0.67] 1.43 [0.64, 3.21] 3.10 [0.77, 12.52]

1702 100.0%

1.80 [0.83, 3.91]

35 20 25 52 346 58 22 263 841 40

Total events 75 77 Heterogeneity: Tau² = 0.67; Chi² = 18.13, df = 9 (P = 0.03); I² = 50% Test for overall effect: Z = 1.49 (P = 0.14)

Risk Ratio M-H, Random, 95% CI

0.01 0.1 1 10 100 Favours experimental Favours control

Figure 4 Risk of hyperkalemia with eplerenone and spironolactone/canrenone. CI ⫽ confidence interval; EMPHASIS-HF ⫽ Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; EPHESUS ⫽ Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; RALES ⫽ Randomized Aldactone Evaluation Study; SARA ⫽ Selective Aldosterone Receptor Antagonist.

Study or Subgroup

Eplerenone Control Risk Ratio Events Total Events Total Weight M-H, Random, 95% CI

EMPHASIS-HF EPHESUS

10 1360 13 3319

Total (95% CI)

4679

14 1369 17 3313

44.3% 55.7%

0.72 [0.32, 1.61] 0.76 [0.37, 1.57]

4682 100.0%

0.74 [0.43, 1.27]

23 31 Total events Heterogeneity: Tau² = 0.00; Chi² = 0.01, df = 1 (P = 0.91); I² = 0% Test for overall effect: Z = 1.08 (P = 0.28)

Study or Subgroup Agostoni 2005 Cicoira Gao Pitt SARA Pitt-RALES B Rodriguez et al 1997 Total (95% CI)

Risk Ratio M-H, Random, 95% CI

0.01 0.1 1 10 100 Favours experimental Favours control

Aldosterone Antagonists Control Risk Ratio Events Total Events Total Weight M-H, Random, 95% CI 1 2 3 6 61 2

15 54 58 263 822 23 1235

0 0 0 0 9 0

15 3.9% 52 4.2% 58 4.4% 54 4.6% 841 78.7% 24 4.2%

3.00 [0.13, 68.26] 4.82 [0.24, 98.03] 7.00 [0.37, 132.56] 2.71 [0.15, 47.37] 6.93 [3.47, 13.87] 5.21 [0.26, 102.98]

1044 100.0%

6.26 [3.38, 11.57]

Total events 75 9 Heterogeneity: Tau² = 0.00; Chi² = 0.68, df = 5 (P = 0.98); I² = 0% Test for overall effect: Z = 5.84 (P < 0.00001)

Risk Ratio M-H, Random, 95% CI

0.01 0.1 1 10 100 Favours experimental Favours control

Figure 5 Risk of gynecomastia with eplerenone and spironolactone/canrenone. CI ⫽ confidence interval; EMPHASIS-HF ⫽ Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; EPHESUS ⫽ Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; RALES ⫽ Randomized Aldactone Evaluation Study; SARA ⫽ Selective Aldosterone Receptor Antagonist.

Chatterjee et al

Eplerenone versus Older Aldosterone Antagonists

Study or Subgroup

823

Eplerenone Control Risk Ratio Events Total Events Total Weight M-H, Random, 95% CI

EMPHASIS-HF EPHESUS

408 1364 1493 3319

Total (95% CI)

4683

45.2% 54.8%

0.84 [0.75, 0.93] 0.98 [0.93, 1.03]

4686 100.0%

0.91 [0.78, 1.06]

491 1373 1526 3313

1901 Total events 2017 Heterogeneity: Tau² = 0.01; Chi² = 6.46, df = 1 (P = 0.01); I² = 85% Test for overall effect: Z = 1.21 (P = 0.23)

Risk Ratio M-H, Random, 95% CI

0.5 0.7 1 1.5 2 Favours experimental Favours control

Figure 6 Pooled risk of rehospitalization with eplerenone. CI ⫽ confidence interval; EMPHASIS-HF ⫽ Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; EPHESUS ⫽ Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study.

Secondary Outcomes

with the other aldosterone antagonists it was 6.26 (95% CI, 3.38-11.57, P ⬍.0001). In an exploratory subanalysis, eplerenone did not even reduce rehospitalization rates (RR 0.91; 95% CI, 0.78-1.06, P ⫽ .23) (Figure 6). Publication bias (Figure 7) was assessed by constructing individual funnel plots.30

Reduction in cardiovascular mortality with eplerenone was 17% (RR 0.83; 95% CI, 0.75-0.92; P ⫽ .0005) (Figure 3), while that with other aldosterone antagonists was 25% (RR 0.75; 95% CI, 0.67-0.84; P ⬍.0001). Rate of serious hyperkalemia for eplerenone was high RR 1.72 (95% CI, 1.192.47, P ⫽ .004) (Figure 4) and for other aldosterone antagonists was RR 1.80 (95% CI, 0.83-3.91; P ⫽ .14), being statistically significant for eplerenone only. Rate of gynecomastia was similar to comparator group with eplerenone: RR 0.74 (95% CI, 0.43-1.27; P ⫽ .28) (Figure 5), while

0

DISCUSSION Eplerenone has been hailed as a major therapeutic advancement in the management of patients with mildly symptom-

SE(log[RR])

0.5

1

1.5

2

RR 0.5

0.7

1

1.5

2

Figure 7 Funnel plot to assess publication bias for studies assessing all-cause mortality with spironolactone and canrenone. RR ⫽ relative risk.

824 atic heart failure; however, it was studied in only one randomized trial for the same. Other aldosterone antagonists like spironolactone and canrenone have been evaluated over the years as a time-tested option for advanced heart failure management. The trials of eplerenone with a significantly different study group and concomitant factors and medications cannot effectively be compared with those of aldosterone antagonists like spironolactone directly.29 However, we postulated that their efficacy in preventing hard clinical events could be assessed— especially in a broad population having left ventricular dysfunction. A pooled analysis of eplerenone also did not reveal any benefit in reducing rehospitalization rates. Another indicator of the fact that eplerenone might be inferior to other aldosterone antagonists in preventing mortality and especially cardiovascular mortality, could be extrapolated from the fact that it was tested in a generally healthier population with poorer outcomes. We arrived at this conclusion by also looking at the mortality in the control groups for the pooled eplerenone studies (16.37%), while that in the control group of the pooled “other aldosterone antagonist” group was 28.79%. So eplerenone had more events in a healthier population. Hence, pending a direct head-to-head comparison of eplerenone with other aldosterone antagonists in terms of mortality reduction and other hard clinical endpoints, and also a detailed pharmacoeconomic evaluation using patient-level data, it might be prudent to hold off on over-prescribing eplerenone—notwithstanding the scant economic evidence in favor for it.30 In fact, our review indicates that eplerenone may have a reduced risk of development of gynecomastia, but this was not statistically significant. Our systematic review of the literature indicates that eplerenone has yet to prove the justification of its expense in terms of reducing clinical endpoints. Only a direct head-to-head comparison between the 2 agents can determine true differences in efficacy.

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