Publications of the Week, June 29

Lifetime benefits of comprehensive therapies in heart failure with reduced EF

In patients with heart failure and reduced ejection fraction (HFrEF), optimizing management to reduce mortality and hospitalizations has been anchored in a therapy triad that combines an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), a beta-blocker, and a mineralocorticoid receptor antagonist (MRA). More recently, 2 new classes of pharmacologic agents have shown benefit in patients with HFrEF: angiotensin receptor-neprilysin inhibitors (ARNIs) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors. Each of these treatments can affect one or more mechanisms or pathways that can reduce morbidity and mortality from HErHF.

This across-trial analysis assessed, in an indirect manner that was extrapolated over time, the effects of a more comprehensive disease-modifying pharmacologic therapy, comprising an ARNI, a beta-blocker, an MRA, and an SGLT-2 inhibitor, as compared with conventional therapy, comprising ACE inhibitor/ARB and beta-blocker therapy in patients with chronic HFrEF. Indirect comparisons of these two management approaches were made using data from 3 large randomized trials: EMPHASIS-HF (2737 patients; assessed eplerenone), PARADIGM-HF (8399 patients; assessed sacubitril/valsartan) and DAPA-HF (4744 patients; assessed dapagliflozin). The primary outcome was a composite of cardiovascular death or first hospital admission for heart failure. Secondary outcomes were each of these endpoints and all-cause mortality.

The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive versus conventional therapy on the outcome of cardiovascular death or hospital admission for heart failure was 0.38 (95% CI, 0.30-0.47). The comprehensive management approach also conferred clinical benefit for the outcomes of cardiovascular death (HR, 0.50; 95% CI, 0.37-0.67), hospital admission for heart failure (HR, 0.32; 95% CI, 0.24-0.43), and all-cause mortality (HR, 0.53; 95% CI, 0.40-0.70). In terms of benefit as compared with conventional therapy, the comprehensive management approach was estimated to confer between 2.7 additional years (for an 80-year-old) and 8.3 additional years (for a 55-year-old) of event-free survival for the outcomes of cardiovascular death or first hospital admission for heart failure and between 1.4 additional years (for an 80-year-old) and 6.3 additional years (for a 55-year-old) of overall survival.

The authors concluded that in patients with HFrEF the treatment benefits of a comprehensive disease-modifying pharmacologic therapy approach, comprising an ARNI, a beta-blocker, an MRA, and an SGLT-2 inhibitor, are substantial and support the implementation of this regimen as a new therapeutic standard for HFrEF. There are important cautions when interpreting the findings from this study. First, the proposed comprehensive therapy approach was not compared against the guideline-recommended standard of triple therapy (ACE inhibitor/ARB, beta-blocker, and MRA). Second, the analyses were indirect comparisons across trials and were based on long-term modeling using relatively short-term data from the original randomized trials.