Treatment of HF in an Era of Multiple Therapies: Statement From the HF Collaboratory

Statement From the HF Collaboratory

Ankeet S. Bhatt, MD, MBA; William T. Abraham, MD; JoAnn Lindenfeld, MD; Michael Bristow, MD; Peter E. Carson, MD; G. Michael Felker, MD, MHS; Gregg C. Fonarow, MD; Stephen J. Greene, MD; Mitchell A. Psotka, MD, PHD; Scott D. Solomon, MD; Norman Stockbridge, MD, PHD; John R. Teerlink, MD; Muthiah Vaduganathan, MD, MPH; Janet Wittes, PHD; Mona Fiuzat, PHARMD; Christopher M. O'Connor, MD; Javed Butler, MD, MPH, MBA


JACC Heart Fail. 2021;9(1):1-12. 

In This Article

Recent Advances and Complexities With Clinical Decision-making

Clinical decision-making has become even more complicated in the current era of HFrEF therapeutics.[16] Enhanced biological insights and renewed investments have led to the development of multiple agents that have or are currently being independently being evaluated in trials enrolling simultaneously (Figure 1). The sodium-glucose cotransporter 2 (SGLT2) inhibitors dapagliflozin and empagliflozin reduced first cardiovascular death or hospitalization for HF in large outcome trials in HFrEF in well-treated patients regardless of baseline type 2 diabetes status.[17–19] The soluble guanylate cyclase stimulator vericiguat has been shown to modestly reduce the same composite endpoint in a population of 5,050 patients with recently worsening HFrEF.[20] A trial with omecamtiv mecarbil (NCT02929329), a novel activator of cardiac myosin, enrolled >8,000 patients with HFrEF with modest reductions in the primary endpoint.[21] Ongoing trials are expected to have a relative minority of ARNI use due to slow uptake of this therapy in clinical practice[22] (Table 1). In addition, these trials will not have recruited significant proportions of patients on an SGLT2 inhibitor given the simultaneous nature of ongoing trials.

Figure 1.

Current and Potential New Drug Therapies in the Treatment of Heart Failure
This figure describes the current and potential therapies for the treatment of heart failure with reduced ejection fraction (HFrEF). Core disease-modifying pathways are depicted as the spokes surrounded by therapies under investigation and approved in particular situations. Early comprehensive therapy modifying 5 core mechanistic pathways should be a central goal in current HFrEF care. Hydral = hydralazine; ISDN = isosorbide dinitrate; IV = intravenous; sGC = soluble guanylate cyclase; SGLT2 = sodium-glucose cotransporter 2; SNS = sympathetic nervous system.

Finally, ongoing large Phase III trials are assessing the impact of intravenous iron in morbidity and mortality in patients with chronic HFrEF and iron deficiency (NCT03037931 and NCT03036462). The AFFIRM-AHF (A Randomised, Double-Blind Placebo Controlled Trial Comparing the Effect of Intravenous Ferric Carboxymaltose on Hospitalisations and Mortality in Iron Deficient Patients Admitted for Acute Heart Failure) trial[23] found reductions in HF hospitalizations in acute HF patients treated with IV iron, but no significant effect on cardiovascular death.

Because ARNI, dapagliflozin or empagliflozin, and vericiguat and omecamtiv mecarbil (and potentially others) have not been evaluated either incrementally or directly against each other, clinicians must decide on how to use and sequence multiple new therapeutics. In an effort to provide a decision-making framework in the current era of multiple newly proven and emerging HF therapies, the Heart Failure Collaboratory convened a multi-stakeholder group including patients, clinicians, clinical investigators, the U.S. Food and Drug Administration, industry, and payers who met at the US Food and Drug Administration campus on March 6, 2020, to discuss these issues and propose considerations for these approaches. The goal of the current paper was to capture the pertinent discussions of this meeting that addressed the following objectives: 1) offer practical guidance to clinicians making therapeutic choices for patients with HFrEF; 2) explore strategies in which existing data and technologies may be leveraged to inform better therapeutic decision-making; and 3) discuss novel trial designs to inform the development of a robust implementation science framework.