Aldosterone blockade in patients with heart failure and a reduced left ventricular ejection fraction.

Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), b-adrenergic receptor blockers (BBs), and aldosterone blockers (ABs) have been shown to be effective in reducing cardiovascular mortality and the need for hospitalizations for heart failure (HF) in patients with chronic HF and a reduced left ventricular ejection fraction (HFREF) and in patients with HFREF post-myocardial infarction (MI). The use of ACEIs, ARBs, and BBs in appropriate patients in clinical practice has, however, been far greater than for ABs. There are probably a number of reasons for this apparent gap in the application of ABs to clinical practice despite their class 1 indication for patients with severe chronic HFREF and in patients with HF post-MI. In part, the greater use of ACEIs, ARBs, and BBs can be attributed to the greater number of available agents in each of these classes, a greater number of large-scale randomized trials demonstrating their effectiveness in comparison with ABs, and the fact that the available ABs are generic or soon to be generic and hence have not been the focus of intensive marketing in comparison with the newer ARBs and BBs. Another explanation for the relatively low use of ABs in appropriate patients with chronic HFREF in clinical practice relates to the risk of hyperkalaemia and its consequences. In a recent review of the effect of eplerenone on serum potassium in the EPHESUS trial, it was pointed out that despite the occurrence of hyperkalaemia there was not a single death attributable to hyperkalaemia either in EPHESUS or RALES. It should, however, be emphasized that it is necessary to select patients carefully on the basis of their renal function, to monitor serum potassium, and to adjust the dose of the AB accordingly if hyperkalaemia is to be avoided. In patients with an estimated glomerular filtration rate (eGFR) .60 mL/min/1.73 m, there was no significant increase in hyperkalaemia in EPHESUS, whereas in those with an eGFR 60 mL/min/1.73 m2 in whom the risk of hyperkalaemia is increased, serum potassium should be monitored closely over the long term. The mechanisms responsible for the beneficial effects of ABs in patients with HFREF continue to evolve but include: an increase in antioxidant reserves and a decrease in oxygen free radical formation; an increase in the availability of nitric oxide and an improvement in endothelial function; a decrease in vascular and myocardial fibrosis, hypertrophy, and remodelling; a decrease in sympathetic nervous system activation; a decrease in myocardial calcium channel expression; a decrease in myocardial apoptosis; as well as an increase in sodium excretion with a concomitant decrease in plasma volume. The recent meta-analysis by Ezekowitz and McAlister of 19 randomized trials comprising 10 807 patients with either chronic HFREF or HF post-MI randomized to an AB (spironolactone, eplerenone, or canreonate) or placebo focuses attention on the role of ABs in patients with HFREF and shows a 20% reduction in all-cause mortality [95% confidence interval (CI) 0.74–0.87] in patients randomized to an AB. Although the RALES and EPHESUS trials supplied the overwhelming majority of the evidence supporting the effectiveness of AB in these patient populations, the results of the remaining relatively smaller trials are consistent with the results of the larger trials. These beneficial results were associated with an absolute 2.9% increase in hyperkalaemia in patients randomized to an AB. However, the three trials with the highest incidence of hyperkalaemia were dose-finding trials in which doses of spironolactone or eplerenone .50 mg/day were used. They also point out that whereas ABs have shown a significant reduction in all-cause mortality in patients with HFREF when added to an ACEI, ARBs have not. In recent meta-analyses of ACEIs, ARBs, and their combination in patients with HFREF, there was no apparent benefit of adding an ARB to an ACEI, whereas the combination was associated with a significant increase