The "Fantastic Four" for optimal HFrEF therapy

The conclusion of a recent article in the European Heart Journal is that ARNI and SGLT-2 inhibitors should be combined in HFrEF patients. Treatment is most promising when supplemented with a beta blocker and a mineralocorticoid receptor antagonist. This is indicated by recent subanalyses of large cardiovascular outcome studies.

According to current scientific evidence, the four-way combination of ARNI, SGLT-2 inhibitor, beta blocker, and mineralocorticoid receptor antagonist is the best guarantee for maximally reducing deaths and hospitalizations in patients with heart failure and reduced ejection fraction (HFrEF), according to German heart failure expert Prof. Johann Bauersachs, MD, of Hannover Medical School, in a recently published article [1,2].

Additive SGLT-2 inhibitor treatment: proven additional benefit.

According to the European Society of Cardiology (ESC), LVEF<40% is heart failure with reduced ejection fraction (HFrEF). HFrEF requires multimodal treatment with a combination of different medications to achieve symptomatic and prognostic improvement [3,4]. After DAPA-HF, the EMPEROR-Reduced trial also provided evidence that the SGLT-2 inhibitors dapagliflozin and empagliflozin, respectively, significantly reduce cardiovascular mortality and hospitalizations due to heart failure in patients with HFrEF additive to standard therapy [6,7]. Improvements in these outcomes were seen to a similar extent in both diabetic and nondiabetic patients.

Do both patients with vs. without ARNI benefit from empagliflozin?

A subanalysis of the EMPEROR-Reduced trial published this year in the European Heart Journal addressed the question of whether empagliflozin would also prove clinically effective in those HFrEF patients who, in addition to beta-blockers and MRA, had also received ARNI therapy [2,8]. Empagliflozin was shown to significantly reduce cardiovascular deaths and heart failure hospitalizations compared to placebo in both the 727 participants on sacubitril/valsartan therapy (hazard ratio: 0.64; 95% confidence interval: 0.45-0.89; p=0.009) and the 3003 participants not on ARNI therapy (HR: 0.77; 95% CI: 0.66-0.90; p=0.0008). [2,8].

The detailed analyses of two large outcome trials on SGLT-2 inhibitors in HFrEF patients [8,9] support data from previous publications [6,7] as well as the results of the metaanalysis of the DAPA-HF and the EMPEROR-Reduced study, which show that patients treated with ARNI benefit at least as much from add-on treatment with an SGLT-2 inhibitor as patients without ARNI therapy [10].

Literature:

Bauersachs J: Heart failure drug treatment: the fantastic four. European Heart Journal 2021: 42(6): 681-683.
Overbeck P: Optimal heart failure therapy with the “Fantastic Four,” Jan. 20, 2021, www.kardiologie.org/herzinsuffizienz/optimale-herzinsuffizienz-therapie-mit-den–fantastischen-vier-/18782468, (last accessed Apr. 28, 2021).
Ponikowski P, et al: 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur J Heart Fail 2016; 18: 891-975.
Berliner D, Hänselmann A , Bauersachs J: The treatment of heart failure with reduced ejection fraction. Dtsch Arztebl Int 2020; 117: 376-386.
Docherty KF, et al: Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Eur Heart J 2020; 41: 2379-2392.
McMurray JJV, et al: DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381: 1995-2008.
Packer M, et al: EMPEROR Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020; 383: 1413-1424.
Packer M, et al: for the EMPEROR-Reduced Trial Committees and Investigators. Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced Trial. Eur Heart J 2021; 42: 671-680.
Solomon SD, et al: Effect of dapagliflozin in patients with HFrEF treated with sacubitril/valsartan: the DAPA-HF trial. JACC Heart Fail 2020; 8: 811-818.
Zannad F, et al: SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020; 396: 819-829.
Vaduganathan M, et al: Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet 2020; 396: 121-128.