Aldosterone Antagonists: Evidence‐Based Yet Underutilized Effective Heart Failure Therapy

Standard therapy for heart failure (HF) consists of β-adrenergic–blocking agents or β-blockers and either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). In symptomatic patients, especially with left ventricular (LV) systolic dysfunction, digitalis is used to improve exercise tolerance and quality of life and reduce hospitalizations, with no beneficial or detrimental effects on survival. For HF with reduced or preserved ejection fraction, diuretics are frequently used to prevent and treat volume overload. A therapy that is too often forgotten, however, is the aldosterone antagonists (AAs), despite impressive data for their clinical benefit.1 Clearly, the activation of mineralocorticoid receptors by both aldosterone and cortisol have deleterious effects on cardiovascular (CV) diseases.2 Activation of these receptors plays an important role in the pathophysiology of HF, with mineralocorticoid receptors being overexpressed in the failing heart. AAs promote cardiac fibrosis and have beneficial effects on extracellular matrix turnover as assessed by measured levels of collagen biomarkers, as well as beneficial effects on several other mechanisms involved in the pathogenesis and prognosis of HF.1-6 Since the placebo-controlled Randomized Aldactone Evaluation Study (RALES)7 was published about 15 years ago, adding the AA spironolactone to other recommended therapies has been sporadically used in patients with systolic HF and moderate to severe symptoms. Since spironolactone was the only AA available for decades, and because of its low cost, it has been the AA of choice, although we believe that this agent was always underutilized. However, because of the substantial off-target effects on testosterone as well as progesterone receptors, spironolactone frequently causes sexual side effects, particularly gynecomastia, which can be especially troublesome to men, but also reduces libido and, occasionally, uterine bleeding, which may limit patient compliance.1 Eplerenone is the other available AA and is much more specific than spironolactone as an AA. Although initially this agent was expensive, it has now become generic, so along with its more favorable side effect profile, it is an attractive alternative to spironolactone for patients with LV dysfunction, HF, and hypertension (HTN). In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS),8 this AA when added to other recommended therapies, reduced the rate of death from any cause and hospitalization for CV reasons among patients with acute myocardial infarction (MI) complicated by LV systolic dysfunction and HF, with the results particularly impressive in the subgroup of patients with diabetes mellitus (DM).9 In the Eplerenone in Mild Patient Hospitalization and Survivals Study in Heart Failure (EMPHASIS-HF),10 eplerenone, compared with placebo, reduced the risk of both death and hospitalization among patients with systolic HF and mild symptoms. In the current issue of Congestive Heart Failure, Bangalore and colleagues11 asked the common clinical question: “When Conventional Heart Failure Therapy Is Not Enough, Which Agent Should Be Added—Angiotensin Receptor Blocker, Direct Renin Inhibitor, or Aldosterone Antagonists?” In order to answer this question, they analyzed data from 16 randomized controlled trials of 31,429 participants. In HF patients typically taking β-blockers and ACE inhibitors, adding ARBs and DRIs did not produce any significant improvements. In fact, ARBs markedly increased hyperkalemia, renal failure, and hypotension when added to ACE inhibitors, whereas AAs increase hyperkalemia (but less so than do ARBs) and DRIs increase hypotension. However, AAs significantly reduce mortality, CV death, HF hospitalizations, and the composite endpoint by 21%, 22%, 26%, and 27%, respectively. Clearly, this meta-analysis supports the addition of AAs over ARBs and DRIs when added to conventional HF therapy. We share the concern of Bangalore and colleagues11 that dual inhibition of the renin-angiotensin-aldosterone system, especially with ARBs or DRIs added to ACE inhibitors, produces considerable concern for safety. In fact, in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trial, hyperkalemia was nearly 5 times more common and elevated creatinine twice as likely when candesartan compared with placebo was added to ACE inhibitors.12 Also, a major meta-analysis of more than 18,000 HF patients demonstrated a high risk of complications when ARBs were added to ACE inhibitors in HF.13 Moreover, the combination of the DRI, aliskiren, to either ACE inhibitor or ARB is particularly contraindicated in patients with DM, and likely isolated renal insufficiency, based on a high risk of renal impairment, hypotension, and hyperkalemia. Additionally, aliskiren was associated with a significant increase in cardiac arrest with resuscitation (P=.04), with trends for increasing the CV composite outcome (P=.09), stroke (fatal or nonfatal) (P=.11), and death caused by CV causes (P=.12), leading to discontinuation of the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), which was halted in December 2011.14 Additionally, in a very recent study of 5887 Medicare patients hospitalized with HF and reduced systolic function (mean age 78 years), 1070 were started on AA therapy during hospitalization.15 Although AA therapy was not independently associated with improved mortality or early CV readmissions, it was associated with a 13% lower HF readmissions at 3 years (P=.02), but at a cost of a doubling of early readmissions for hyperkalemia (2.9% vs 1.2%; P40%]),17 the potential benefits of AAs seem to far outweigh the risks. In our opinion, AAs represent an evidence-based yet greatly underutilized effective therapy for a broad range of patients with HF. Incorporating AAs into standard HF therapy will likely at least lead to reductions in HF hospitalizations and more likely reductions in major CV events.