The results of the EPHESUS landmark trial Citation[1], a double-blind, placebo-controlled study evaluating the effect of eplerenone, a selective aldosterone blocker, on morbidity and mortality among 6642 patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure were published in 2003. A total of 8 years later, a group of these authors report in the November 2011 issue of the Journal of the American College of Cardiology an elegant post-hoc analysis of the drug’s potential mechanisms of the survival benefit Citation[2].
In the original EPHESUS trial, patients already on standard medical therapy were randomized to eplerenone 25–50 mg daily or placebo within 3–14 days of hospitalization. Statistically significant reductions in favor of the active drug were seen in total mortality (relative risk [RR]: 0.85; 95% CI: 0.75–0.96; p = 0.008) and cardiovascular mortality/hospitalization (RR: 0.87; 95% CI: 0.79–0.95; p = 0.002). Particularly striking was the reduction in sudden cardiac death (RR: 0.79; 95% CI: 0.64–0.97; p = 0.03).
The recent analysis covers the 6080 patients who were alive at the 1-month evaluation and for whom data were available. The purpose of the study was to determine whether a diuretic effect, evaluated by estimated plasma volume and bodyweight reduction, as well as a potassium-sparing activity, may be detectable in patients treated with eplerenone, as compared with placebo, during the first month; and whether these effects were associated with the drug’s beneficial action on long-term cardiovascular outcomes.
At 1 month, the group treated with eplerenone showed a significant – although hardly clinically relevant – reduction in estimated plasma volume. This difference was no longer significant at the third month, despite the per-protocol uptitration to a higher dose of 50 mg daily of eplerenone.
In both study groups, a significant increase in serum potassium concentration was observed after 1 month, and it was of greater magnitude in the eplerenone group. However, values were constantly in normal range, with a small difference between groups (0.15 mmol/l).
In multivariate analyses, diuresis, indirectly calculated using estimated plasma volume decrements, was significantly associated with a 11–19% reductions in the two primary end points (i.e., death from any cause and death from cardiovascular causes or first hospitalization from a cardiovascular event), independently of each other and of the eplerenone clinical benefits seen in the trial’s primary results.
Multivariate analysis also revealed that the potassium-sparing effect, defined as a serum potassium increase greater than the median change in the placebo group (0.11 mmol/l), was also independently associated with a 12–34% reduction in the risk for the same primary outcomes. Of note, there was no statistically significant interaction between the observed beneficial effects of eplerenone (9–17% reductions in risk) on cardiovascular outcomes and the potassium-sparing or diuretic effects.
The authors concluded that their findings provide strong evidence that eplerenone shows a clinical diuretic action as well as a potassium-sparing effect, although clinical gains in terms of outcomes appear to be related to other ‘pleiotropic’ effects of the drug.
As pointed out by the authors themselves, the current study has relevant methodological and conceptual limitations. First, the retrospective nature of the study makes the results valid only for generating hypotheses, not for attributing causal relationships. Second, in the EPHESUS study, the sample size was designed to include at least 1012 deaths to maintain an overall type I error rate of 0.05 with a power of 88.3%. Recruiting only patients with available data after the first month, the present study excluded 552 ‘older and sicker’ patients (∼8% of the whole population) and, among them, deaths occurred in the first month of follow-up, amounting to 25% of the entire study (i.e., 259 out of 1032). Such methodological drawbacks makes it highly probable that a type I error occurred, namely, accepting a difference as true which is actually absent. Third, the retrospective nature of the study justifies the need of estimating the diuretic effect using inaccurate, indirect measures, such as the reduction in bodyweight and the decrease in estimated plasma volume (using a formula never validated in the heart failure setting). Such inaccuracy in the measurement of the variables may have caused a nondifferential misclassification, either diluting the exposure effect (toward the null effect) or producing estimates biased in either direction.
Last, other factors beyond eplerenone could influence the reduction in estimated plasma volume or bodyweight, such as changes in dietary habits, hemodynamic improvement and the concurrent action of other drugs, as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or β-blockers. Failure to account for the effects of variables that could have an important influence on the outcome of interest can cause a confounding bias, threatening the validity of inferences made regarding cause and effect – that is, internal validity.
The study under discussion also contains potential misconceptions that need to be discussed.
As reported in the preceding paper to the EPHESUS study, a relatively low dose of 50 mg of eplerenone daily is expected to induce modest hemodynamic and diuretic effects Citation[3]. Although after the first month, eplerenone dosage was increased from 25 to 50 mg per protocol, the most significant reduction of the estimated plasma volume was seen in the placebo group at 3 months, virtually denying a substantial diuretic effect of the drug.
Based on their retrospective data, the authors made inference that short-term interventions that decrease volemia, may provide long-term benefits on outcomes.
In actual fact, fluid overload is a key pathophysiologic mechanism underlying both the acute decompensation episodes of heart failure and the progression of the syndrome. Nevertheless, the combined results from small and relatively heterogeneous studies provide strong evidence that diuretics relieve symptoms, reduce episodes of decompensation and increase exercise capacity, however, there is weak evidence for an effect on mortality in patients with chronic heart failure Citation[4]. Even studies of mechanical removal of accumulated fluid have failed to demonstrate survival benefit Citation[5]. Although recent small-size observational data seem to indicate that hemoconcentration associated with aggressive fluid removal by diuretics may be linked to an improved survival Citation[6], the evidence is not sufficient to justify a major prognostic influence of diuretics in chronic heart failure, especially with regard to sudden death. Altogether, potential mechanisms linking reduced congestion with improved outcomes may include reduction in preload-dependent functional mitral regurgitation and ventricular remodeling, reduced inflammation due to changes in vascular endothelial cell phenotype, improved renal perfusion associated with reduced renal vein pressures, and reduced peripheral vascular resistance. Many therapies are directed towards neurohormonal systems essential for sodium and water regulation, but little is known regarding their effects on plasma volume. Therefore, it may be desirable to perform a direct assessment of plasma volume as part of the clinical evaluation for patients with chronic heart failure, and combining this with neurohormonal and cytokine profiling.
Regarding the suggested positive link between the serum potassium level at 1 month and the primary end points, a previous retrospective study conducted on the same EPHESUS population was unable to demonstrate any significant effect on all-cause mortality for variation on serum potassium from baseline to day 30 (0.2 mEq/l for both treatment groups) Citation[7,8]. As stated in the present work, how such a potassium variation would bring about a significant reduction in mortality in the long term, is hardly supported.
The most relevant finding of the discussed study is that eplerenone maintains its positive effect on prognosis independently from its diuretic or potassium-sparing actions. As a matter of fact, aldosterone antagonists with diuretic properties (i.e., spironolactone and eplerenone) Citation[1,9,10] have so far shown consistent reductions on mortality and rehospitalization, as long as hyperkalemia is prevented. The mechanism of the clinical benefit appears to stem from the specific aldosterone antagonism action. Eplerenone may reduce myocardial fibrosis by blocking the effects of aldosterone on the formation of collagen, allowing infarct scar healing and preventing reactive fibrosis in areas remote from the infarct zone, which may influence left ventricular remodeling and prognosis Citation[11]. Spironolactone may prevent sudden cardiac death by preventing both potassium loss and increasing myocardial uptake of norepinephrine Citation[12]. In patients with heart failure, aldosterone antagonists improve endothelial dysfunction, increase nitric oxide bioactivity and inhibit vascular Ang I and Ang II. Moreover, they act on myocardial fibrosis, autonomic balance, fibrinolysis, oxidative stress and activation of the NF-κB and AP-1 signaling pathways Citation[13]. In other words, there are numerous plausible ‘pleiotropic’ mechanisms of eplerenone, which may explain its clinical benefits beyond its diuretic and hemodynamic properties.
In conclusion, aldosterone antagonists seem to exert positive effects on outcomes in patients with heart failure, complicating myocardial infarction independently of their weak diuretic action. Certainly, we need prospective studies based on suitable and validated techniques to assess the volemic state of patients and to relate it to prognostic end points.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- Pitt B, Remme W, Zannad F et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med.348, 1309–1321 (2003).
- Rossignol P, Ménard J, Fay R et al. Eplerenone survival benefits in heart failure patients post-myocardial infarction are independent from its diuretic and potassium-sparing effects: insights from an EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) substudy. J. Am. Coll. Cardiol.58, 1958–1966 (2011).
- Pitt B, Williams G, Remme W et al. The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Eplerenone Post-AMI Heart Failure Efficacy and Survival study. Cardiovasc. Drugs Ther.15, 79–87 (2001).
- Faris RF, Flather M, Purcell H, Poole-Wilson PA, Coats AJS. Diuretics for heart failure. Cochrane Database Syst. Rev. doi:10.1002/14651858.CD003838.pub2 (2009) (Epub ahead of print).
- Costanzo MR, Guglin ME, Saltzberg MT et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J. Am. Coll. Cardiol.49, 675–683 (2007).
- Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP. Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation122, 265–272 (2010).
- Pitt B, Bakris G, Ruilope LM et al. Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival study (EPHESUS). Circulation118, 1643–1650 (2008).
- Pitt B, White H, Nicolau J et al. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J. Am. Coll. Cardiol.46, 425–431 (2005).
- Pitt B, Zannad F, Remme W et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N. Engl. J. Med.341, 709–717 (1999).
- Zannad F, McMurray JJV, Krum H et al. Eplerenone in patients with systolic heart failure and mild symptoms. N. Engl. J. Med.364, 11–21 (2011).
- Iraqi W, Rossignol P, Angioi M et al. Extracellular cardiac matrix biomarkers in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival study (EPHESUS). Circulation119, 2471–2479 (2009).
- Rousseau MF, Gurné O, Duprez D et al. Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: results from the RALES neurohormonal substudy. J. Am. Coll. Cardiol.40(9), 1596–1601 (2002).
- Enomoto S, Yoshiyama M, Omura T et al. Effects of eplerenone on transcriptional factors and mRNA expression related to cardiac remodeling after myocardial infarction. Heart91(12), 1595–1600 (2005).