Abstract 3021: Revisiting the Impact of Aldosterone Antagonism in Chronic Heart Failure: Insights From the AF-CHF Trial
BACKGROUND: The RALES trial (N=1663) demonstrated a significant reduction in mortality in patients with advanced heart failure (HF) randomized to spironolactone (Spr) therapy (N=822; only 11% on beta-blockers). In the current era, it remains uncertain whether patients with chronic HF on optimal medical therapy may benefit from aldosterone blockade. We assessed the effect of Spr therapy on mortality in patients enrolled in the contemporary AF-CHF trial.
METHODS: The AF-CHF trial (N=1376; mean follow-up 37 months) randomized patients with optimal HF therapy, left ventricular ejection fraction (LVEF) ≤35%, NYHA class II–IV, and a history of atrial fibrillation (AF) to rhythm versus rate control strategies. The effect of Spr therapy on all-cause mortality and cardiovascular mortality was assessed in multivariate Cox regression models (including demographic variables, NYHA functional class, LVEF, creatinine, rhythm versus rate control strategies, and medical therapy).
RESULTS: Patients on Spr (N=616) were younger (66.1±11.2 vs 67.3±10.9 years, P=0.0410) and more likely to have advanced HF symptoms, hospitalizations for HF, persistent AF, a wider QRS, digoxin therapy, and ACE inhibitors compared to patients not on Spr (N=760). LVEF was lower in patients on Spr (26.1±6.1 vs 27.4±5.9%, P<0.0001) whereas beta-blocker use was comparable (78.9% overall). In multivariate analyses, Spr was associated with a 1.4-fold increase in total mortality [95% CI (1.1, 1.8), P=0.0035] and a 1.6-fold increase in cardiovascular mortality [95% CI (1.2, 2,0), P=0.0015]. The latter was driven by sudden cardiac death of presumed arrhythmic etiology [hazard ratio 1.9, 95% CI (1.3, 2.8), P=0.0018], with no effect on non-arrhythmic death. Spr therapy had no appreciable impact on worsening HF [HR 1.0, 95% CI (0.8, 1.3)].
CONCLUSIONS: Our results suggest that, in patients with chronic HF and a history of AF, aldosterone blockade may increase cardiovascular mortality due to arrhythmic deaths when added to currently recommended medical therapy. These hypothesis-generating observations highlight the need for additional randomized trials to clarify the impact of multiple renin-angiotensin-aldosterone inhibitors when combined with beta-blocker therapy in HF.