Spironolactone for Heart Failure
Abstract & Commentary
By Michael H. Crawford, MD, Editor
Source: Lee KK, et al. Effectiveness and safety of spironolactone for systolic heart failure. Am J Cardiol 2013;112:1427-1432.
In order to assess the safety and efficacy of spironolactone combined with other recommended drugs for systolic heart failure, these investigators from Kaiser Permanente Northern California studied 2358 patients with newly diagnosed heart failure, a left ventricular ejection fraction (LVEF) < 40%, and no previous mineralocorticoid receptor antagonist (MRA) use. Patients were excluded if their serum creatinine was > 2.5 mg/dL or their potassium was > 5.0 mEq/L. Spironolactone was initiated in 521 patients (22%) and they were followed for a median of 2.5 years. The spironolactone cohort was younger, had fewer comorbidities, and was more likely to be on other heart failure therapies, including digoxin and potassium supplementation. Also, they had higher GFR, but lower LVEFs. After adjustments for different patient characteristics and concurrent use of other heart failure therapies, spironolactone was not associated with death (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.60-1.44) or all-cause hospitalization (HR, 0.91; 95% CI, 0.77-1.08). Lower death rates were associated with the use of an angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), and beta-blockers (HR, 0.47; 95% CI, 0.44, 0.38, respectively), as was reduced hospitalization (HR, 0.60; 95% CI, 0.73, 0.52). Spironolactone use adjusted for potential confounders was associated with a higher rate of severe hyperkalemia (HR, 3.46; 95% CI, 1.97-6.06), but not kidney injury (HR, 0.66; 95% CI, 0.42-1.05). Also, lower GFR correlated with acute kidney injury and severe hyperkalemia on spironolactone. The authors concluded that in a diverse, community-based population with new systolic heart failure, spironolactone did not reduce death or hospitalization, but did increase the incidence of hyperkalemia.
This study adds to the current observational literature on the lack of effectiveness of spironolactone for systolic heart failure in real-world settings. As compared to prior studies, it has several strengths. First, it only included patients with a new diagnosis of heart failure, which eliminates the survivor bias. Second, they eliminated patients with prior spironolactone use, which reduces the responder bias. Third, they knew all the drugs each patient was taking and for how long. Finally, they had serial laboratory results on all the patients. Limitations of this study, besides being observational, include a lack of exact knowledge of the dose of spironolactone the patients were on and that the spironolactone patients were sicker than the rest the patients, since guidelines at the time recommended MRAs for class III-IV heart failure patients.
The adverse effects of spironolactone were similar to those in randomized trials, which suggests that they were not the cause of the difference in response. Of the three randomized, placebo-controlled trials, only one (RALES) used spironolactone, the other two used eplerenone. One major difference between this study and RALES is that beta-blocker use was only 11% in RALES vs 82% in this study. Thus, perhaps MRA therapy is more beneficial if patients are not on beta-blockers. The two trials using eplerenone were on guideline-driven therapy, so the beneficial effects of eplerenone cannot be ascribed to deficiencies in other recommended therapies. Also, it is possible that eplerenone is more effective than spironolactone, but to date there have been no head-to-head comparisons of these two MRAs.
What should clinicians do at this point? In patients who meet the entry criteria of the three randomized trials (RALES, EMPHASIS, EPHESUS) and in whom close monitoring of blood pressure, potassium, and creatinine can be accomplished, it would be reasonable to start a MRA. In patients not meeting trial entry criteria, but who have no contraindications to MRAs, it would be reasonable to start a MRA if they are not optimally managed on class I guidelines care. However, all patients started on MRA need careful follow-up. Patients on potassium-sparing diuretics or potassium replacement are at high risk, as are patients with renal impairment or hypotension. MRAs are problematic in such patients and preference should be given to ACEIs/ARBs and beta-blockers, which clearly improve survival.