Aldosterone Blockade: Another Winner

Abstract & Commentary

Synopsis: When RALES and EPHESUS are considered together, one clearly can recommend the use of an aldosterone receptor blocker for all very ill patients with congestive heart failure and significant LV dysfunction, whether or not related to acute myocardial infarction.

Source: Pitt B, et al. N Engl J Med. 2003;348:1309-1321.

Following on the heels of the RALES trial, which successfully tested spironolactone in patients with severe heart failure, Pitt and associates announced the results of EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) at a late-breaking trial session at the American College of Cardiology Scientific Sessions. Simultaneously, it was published on the New England Journal of Medicine web site and as the lead article in the April 3, 2003, issue. Eplerenone (EPL) is a new aldosterone antagonist that selectively blocks the mineral corticoid receptor, but not the receptors for glucocorticoids, progesterone, or androgen. This drug was used in a high-risk population of post-acute MI patients with congestive heart failure. A total of 6642 patients were randomized to EPL 20-50 mg per day vs placebo and were followed for a mean of 16 months (range, 0-33). Eligible subjects were randomized between 3 and 14 days after an acute infarction; they had to demonstrate left ventricular dysfunction (LVEF of < 40%), as well as clinical heart failure, as confirmed by rales, congestion on x-ray, or a third heart sound. Diabetics could be enrolled with asymptomatic LV dysfunction only. Patients received optimal medical therapy, including ACE inhibitors (86%), beta-blockers (75%), diuretics (60%), aspirin (88%), and statins (47%). Careful potassium boundaries were followed for safety reasons; EPL was decreased or discontinued if potassium rose above 5.5. Two primary end points were used: all-cause mortality, as well as time to cardiovascular death or first hospitalization for a cardiovascular (CV) event. A multiplicity of statistical analyses were used. The study was halted by design when 1012 deaths occurred. This was an international trial involving almost 700 centers in 37 countries, with enrollment occurring during the years 2000 and 2001. The baseline cohorts consisted of 3313 evenly matched individuals. Discontinuation rates were equal in EPL and placebo. The average study medication dose was 43 mg. The primary end point of all-cause death favored EPL, with a 15% risk reduction (P = 0.008). The other primary end point of cardiovascular death or hospitalization for CV events was also reduced by 15% (P = 0.002). Sudden cardiac death was decreased by 21% (P = 0.03), and hospitalizations for heart failure were reduced by EPL by 15% (P = 0.03). The reductions were consistent across a wide variety of sub-groups as well as geographic regions.

Safety data indicated that an incidence of serious hyperkalemia (potassium > 6.0 mE/L) with EPL was 5.5% vs 3.9% in placebo patients (P = 0.002). A low baseline creatinine clearance was a risk factor for hyperkalemia, which resulted in 15 EPL and 3 placebo patients requiring hospitalization.

Pitt et al conclude that EPL added to an optimal treatment regimen after acute MI "resulted in additional reduction in overall mortality and the rate of death from CV causes or hospitalization for CV events among patients with acute MI complicated by left ventricular dysfunction and heart failure." The 1-year mortality rate in placebo patients was 13.6%, which is in the mid-range for the major beta-blocker heart failure trials and greater than the recent CAPRICORN study of post-MI patients treated with carvedilol. Thus, this was a relatively high-risk post-MI population. The mortality in EPHESUS compared to RALES, which used Class III - IV patients with left ventricular dysfunction (mean EF 25%), was higher in RALES, presumably because of worse LV function (mean EF in EPHESUS was 33%) and possibly some recovery of LV function in the acute MI patients in EPHESUS. A major component of the reduction of cardiovascular mortality in EPHESUS was a 21% decrease in sudden cardiac death. Pitt et al emphasize the need to "monitor serum potassium and adjust the dose of EPL accordingly." Of note, hypokalemia was more common than hyperkalemia, and EPL reduced this risk. A potassium < 3.5 mE/L was observed in 8.4% on EPL and 13.1% on placebo (P < 0.001). No sexual side effects were noted with EPL (gynecomastia, impotence), presumably because of the selective nature of this aldosterone antagonist. Pitt et al conclude that 1 life would be saved by treatment of 50 individuals in a year; the number needed to decrease cardiovascular death or hospitalization at 1 year is 33.

Comment by Jonathan Abrams, MD

The idea that aldosterone is a significant adverse player in patients with left ventricular dysfunction is relatively new and somewhat surprising to many physicians. In fact, aldosterone blockade reduces coronary vascular inflammation and attenuates fibrosis in animals. EPL has been shown to decrease oxidative stress, improve endothelial function, decrease platelet aggregation, increase endothelin, decrease matrix metaloproteinase activation, and to improve post-MI remodeling in animal models. Sympathetic drive and heart rate variability are favorably affected by aldosterone blockers; free radicals are reduced. Thus, it is obvious that aldosterone is more than a hormone that solely affects sodium retention. Aldosterone causes increased tissue ACE and angiotensin II, as well as NFKB activation and enhanced oxidative stress. Elevated aldosterone levels have been shown to be adverse in animals, as well as humans with depressed left ventricular systolic function, in part related to stimulation of increased fibrosis within the myocardium. When RALES and EPHESUS are considered together, one clearly can recommend the use of an aldosterone receptor blocker for all very ill patients with congestive heart failure and significant LV dysfunction, whether or not related to acute myocardial infarction. Whether these compounds will be more beneficial in subjects with less severe heart failure and better LV function than these 2 studies remains to be determined. Furthermore, it must be stressed that the efficacy of EPL in the EPHESUS trial is in addition to an ACE inhibitor and a beta-blocker. There is no role for aldosterone receptor blockade without "best medical therapy" for heart failure and major LV dysfunction. Aside from hyperkalemia, potentially a greater problem with subjects on an ACE inhibitor and poor renal function, there is little downside with these drugs. Furthermore, we have had a very long experience with spironolactone, which has a relatively benign safety record other than its estrogen and androgen actions. Pitt et al are to be congratulated for championing the aldosterone hypothesis, as well as designing and completing 2 major trials in the period of 4 years that have favorably impressed the medical community. 

Dr. Abrams is Professor of Medicine Division of Cardiology, University of Virginia, Charlottesville. 

A to Z Trial (Aggrastat to Zocor)

This long-awaited investigation reported on the heparin anticoagulation therapy (A phase) of the A to Z Trial at the ACC Annual Meeting; the statin component is still ongoing. This is a trial of 4000 individuals with an acute coronary syndrome (ACS). Two questions were asked: which is the more effective antithrombotic therapy, the low-molecular-weight heparin (LMWH) enoxaparin (ENOX) or unfractionated heparin (UFH); and is aggressive statin therapy in ACS more beneficial than later statin initiation? Patients with ACS, characterized by chest pain within 24 hours of at least 10 minutes duration, associated with ST changes and/or positive biomarkers. Patients could not have had been on lipid-lowering therapy within 6 weeks. They were randomized to a heparin within 24 hours. Exclusion criteria included a creatinine of > 2.0 mg/dL or abnormal liver function tests. Enrollment took place from December 1999 to May 2002. Approximately 2000 patients were randomized to each of the 2 strategies. All patients received tirofiban. The heparin regimen included ENOX 1 mg per kg every 12 hours vs UFH for 24-48 hours. The primary end point was 7-day CAD death, recurrent myocardial infarction, or refractory ischemia associated with ECG changes or positive biomarkers. The main goal was to demonstrate noninferiority of ENOX over UFH. More than half the patients underwent early PCI. The use of

ACE inhibitors and beta-blockers was robust. The event rates were ENOX 8.4% and UFH 9.4%, (P = non significant for superiority and equivalent for noninferiority).

All secondary end points, including death, MI, or refractory ischemia, were nonsignificant, but trended positive for ENOX. Mortality was 0.9% UFH and 1.1% ENOX, (P = not significant). Bleeding events were low, 3.1% for ENOX and 2.2% for UFH (P = non significant). Major bleeds were 0.4% for UH and 0.9% for ENOX, with a < 1% requirement for transfusions. Most of the major bleeds were associated with invasive procedures. This study concludes that enoxaparin is an attractive alternative to the use of unfractionated heparin with efficacy end points trending in favor of the LMWH. Both agents were found to be quite safe. The statin arm is continuing.

Comment by Jonathan Abrams, MD

This trial does not unequivocally support superior efficacy for LMWH. Nevertheless, the composite triple end point of death, MI, or refractory ischemia is favorable for ENOX when the ESSENCE, TIMI IIB, INTERACT, and A to Z trials are combined.

This study was the first to include a large number of ACS patients receiving a IIb/IIIa inhibitor and an invasive approach was used in 60% of patients, clearly increasing bleeding rates. Another ongoing trial, SYNERGY (ACS patients who undergo early angiography and are randomized to LMWH or UFH) should provide more data on bleeding risks. In the meantime, physicians can use either ENOX or UFH, according to preferences. The ACC ACS Guidelines rate ENOX as a IIa indicator. 

Dr. Abrams is Professor of Medicine Division of Cardiology, University of Virginia, Charlottesville.