Heart failure drug treatment: the fantastic four

Abstract

Heart failure with reduced ejection fraction (HFrEF) requires a multimodal treatment with combination of several drugs as the cornerstone for symptomatic and prognostic improvement in all patients. Drug therapies such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor/neprilysin inhibitors (ARNIs; sacubitril/valsartan), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) provide incremental benefit with marked reduction in allcause mortality, cardiovascular mortality, all-cause hospitalizations, and hospitalizations for heart failure. Recently, the sodium–glucose co-transporter 2 (SGLT2) inhibitors dapagliflozin (DAPA-HF) and empagliflozin (EMPEROR-Reduced) showed a highly significant and clinically relevant reduction in mortality and heart failure hospitalizations, and improvement of quality of life when added to current standard drugs in patients with HFrEF. Importantly, outcomes were ameliorated to a similar extent in patients with and without diabetes. The question remained, however, of whether the nominally ‘standard’ heart failure drug treatment in the SGLT2 inhibitor trials corresponded to a ‘real’ modern guideline-directed medical therapy. While in both DAPA-HF and EMPEROR-Reduced the majority of patients received a combination of ACE inhibition, beta-blockade, and an MRA, only 10.7% of patients enrolled in DAPA-HF were treated with sacubitril/valsartan at baseline. The benefit of dapagliflozin on the primary endpoint of cardiovascular death or worsening heart failure and the secondary endpoints was identical in patients treated with or without sacubitril/valsartan. In the current issue of the European Heart Journal, Packer et al. provide a detailed analysis of the influence of ARNI pre-treatment on the effects of SGLT2 inhibition with empagliflozin in patients with HFrEF included in EMPEROR-Reduced. In this trial, 19.5% of the patients received sacubitril/valsartan at baseline. The remarkable reduction of the primary endpoint (cardiovascular death or first heart failure hospitalization) and secondary endpoint of total heart failure hospitalizations was similar in patients with and without ARNI at baseline. Also the secondary renal endpoint (slope of the change in estimated glomerular filtration rate supported by an analysis of a composite of serious adverse renal outcomes) was markedly reduced in patients treated both with and without sacubitril/valsartan. In particular, the hazard ratios for all the primary and key secondary endpoints all tended to be even smaller in patients on an ARNI vs. the patients without an ARNI. The current analysis goes far beyond the initial report and includes corrections for important covariates and baseline differences. Patients taking a neprilysin inhibitor at baseline, for example, had slightly lower blood pressure, and were more likely to be treated with implantable cardioverter-defibrillator and/or cardiac resynchronization therapy. Side effects were similar in patients taking or not taking an ARNI; symptomatic hypotension non-significantly tended to be more frequent in patients on sacubitril/ valsartan. Thus, the detailed analyses from two large outcome trials in HFrEF with SGLT2 inhibitors now substantiate the first crude data already reported in the original publications as well as in the meta-analysis of DAPA-HF and EMPEROR-Reduced showing that patients treated with an ARNI derive at least the same benefit from additional SGLT2 inhibitor treatment as patients not on an ARNI. Taken together, these results derived from a considerable number of patients with ARNI pre-treatment now provide fundamental evidence that physicians caring for patients with HFrEF should not consider prescribing either an ARNI or an SGLT2 inhibitor, but rather both therapeutic principles in combination as default strategy. Thus, in clinical practice, patients without contraindications appear to gain most benefit from combined treatment with the ‘fantastic four’: an