Antagonizing aldosterone: another approach to congestive heart failure

Commentary by
James B Young MD
The Kaufman Center for Heart Failure
Department of Cardiology
The Cleveland Clinic Foundation
Cleveland, Ohio
Pitt, B, Zannad, F, Remme, WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators [see comments] N Engl J Med 1999 Sep 2; 709-17

Treating patients with heart failure is a complicated affair, and polypharmacy is necessary for most patients. Data from the recently published Randomized Aldosterone Evaluation Study (RALES) suggest that yet another drug, an aldosterone blocker, should be included in the routine pharmacologic approach to heart failure. The RALES trial, led by Dr Bertram Pitt from the University of Michigan, randomized 1663 patients with NYHA class III or IV congestive heart failure symptoms to receive either 25 mg spironolactone once daily (or even once every other day) or placebo. Background therapy included an ACE inhibitor, a loop diuretic, and usually digoxin. Beta blockers were neither required nor were an exclusion factor.

Spironolactone significantly lowered risk of all-cause mortality and, in particular, death from worsening heart failure and sudden cardiac death. All-cause mortality fell from 46% to 35% in this quite ill population of heart failure patients. Indeed, the magnitude of benefit of spironolactone was comparable to early observations made with ACE inhibitors in severe heart failure, but in this case it was additive to the ACE drug class. Using low doses of spironolactone, serious hyperkalemia or azotemia was rare; the only significant problem was gynecomastia or breast pain in 10% of treated patients, most commonly reported by men.

Aldosterone as culprit

As our attention has turned to blocking detrimental neurohumoral perturbation in heart failure, the use of agents such as ACE inhibitors, beta blockers and, now, an aldosterone antagonist demonstrates the impact of pharmacologic blockade on the well-known physiologic responses to ventricular dysfunction. Aldosterone appears to be detrimental in the setting of cardiac failure because it is associated with perivascular and interstitial cardiac fibrosis, which likely contributes to diastolic as well as to systolic dysfunction. Aldosterone may also precipitate cardiac arrhythmias by inhibiting cardiac noradrenaline reuptake, impairing baroreceptor-mediated parasympathetic heart rate variability and augmenting sympathetic activity generally.

Furthermore, the potassium and magnesium depletion induced by aldosterone is likely related to cardiac arrhythmias in the heart failure setting. It should be stressed that the diuretic and hemodynamic effects of spironolactone in the RALES trial were not greatly significant: there was no change in body weight, systemic blood pressure, or sodium retention.

Although it is likely that many of today's stable congestive heart failure patients are also receiving beta blockers, it should be pointed out that few RALES patients were receiving concomitant beta adrenergic receptor blocking drugs (only 11% overall). Nonetheless, in the beta blocker subgroup of the RALES treatment arm the same reduction in mortality took place as in those patients not receiving a beta blocker.

One might raise the question of why aldosterone is elevated in heart failure patients treated with ACE inhibitors. Aldosterone production is linked to angiotensin II receptor activation. It has been demonstrated that ACE inhibitor-treated heart failure patients may have persistently raised concentrations of serum aldosterone that are likely caused by angiotensin II stimulation resulting from tissue chymase conversion pathways. It is now well known that the simple blockade of angiotensin-converting enzyme, which primarily occurs in the lung, is insufficient to completely stop angiotensin II production.

Clinical implications

The initial observation above is linked to the RALES treatment strategy and to the reported favorable outcomes. This has important clinical implications. Patients with significant congestive heart failure (NYHA class III and IV) should likely receive spironolactone in addition to an ACE inhibitor, loop diuretic, and digoxin. Dosing strategies should follow the scheme developed in RALES. If plasma potassium is less than or equal to 5.0 mmol/L and serum creatinine is less than 0.22 mmol/L, then 25 mg/day spironolactone should be tried. Low doses are reasonable, as the frequency of hyperkalemia and azotemia in the trial increased with spironolactone doses above 50 mg/day. The problem of gynecomastia and breast tenderness is likely to be resolved with development of aldosterone antagonists with greater receptor specificity.

It should also be stressed that the RALES study focused on systolic left ventricular dysfunction; patients were required to have a left ventricular ejection fraction of 35% or less. Though spironolactone may theoretically provide benefit in patients with diastolic dysfunction and myocardial fibrosis, it would be speculative to recommend spironolactone to these patients today. Rather, one should consider prescribing spironolactone for symptomatic congestive heart failure patients having left ventricular systolic dysfunction with a baseline ACE inhibitor and loop diuretic already in place. Stable patients should also be considered candidates for beta blocker therapy.

Although such drug regimes are coming into focus for stable CHF patients, to date little information supports the use of beta blockers in unstable congested patients. Thus their prescription for NYHA class IV congestive heart failure patients remains contentious.

Future drug treatments in CHF

Agents specifically designed to block aldosterone in the heart failure setting will have to be evaluated in conjunction with other strategies in the future. Indeed, studies with endothelin antagonists, ACE and endopeptidase inhibitors, the combination of ACE inhibitors and angiotensin receptor blockers, and agents that attack inflammatory perturbation are all ongoing. Unfortunately, a simplified pharmacologic approach to treating patients with heart failure is unlikely without identifying more objective markers of therapeutic response, a key to choosing among the different emerging strategies.