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

Abstract and Introduction


The treatment of heart failure with reduced ejection fraction (HFrEF) has changed considerably over time, particularly with the sequential development of therapies aimed at antagonism of maladaptive biologic pathways, including inhibition of the sympathetic nervous system and the renin-angiotensin aldosterone system. The sequential nature of earlier HFrEF trials allowed the integration of new therapies tested against the background therapy of the time. More recently, multiple heart failure therapies are being evaluated simultaneously, and the number of therapeutic choices for treating HFrEF has grown considerably. In addition, implementation science has lagged behind discovery science in heart failure. Furthermore, given there are currently >200 ongoing clinical trials in heart failure, further complexities are anticipated. In an effort to provide a decision-making framework in the current era of expanding therapeutic options in HFrEF, 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 U.S. Food and Drug Administration campus on March 6, 2020. This paper summarizes the discussions and expert consensus recommendations.


The trajectory of heart failure with reduced ejection fraction (HFrEF) has been favorably altered with the demonstrated efficacy of multiple drug therapies. This progress began with vasodilators[1] followed by trials that established angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) as the mainstay of HFrEF medical therapy.[2,3] Beta-blockers[4–6] and mineralocorticoid receptor antagonists (MRAs) showed incremental benefits for patients well treated with renin-angiotensin system blockade with ACE inhibitors or ARBs.[7,8] In Black patients with persistent advanced symptoms, the majority of whom were on ACE inhibitors and a beta-blockade, a combination of hydralazine and isosorbide dinitrate was shown to reduce mortality.[9] In patients with normal sinus rhythm and persistently elevated heart rate, the potassium/sodium hyperpolarization–activated cyclic nucleotide-gated channel 4 blocker ivabradine has reduced heart failure (HF) hospitalizations.[10] More recently, angiotensin receptor neprilysin inhibitor (ARNI) therapy was shown to be superior to enalapril in further improving outcomes.[11] Despite substantial benefits with these incremental therapies, patients with HFrEF still have considerable persistent risk, necessitating the further development of novel drug therapies.[12]

Until recently, the sequential timing of the landmark clinical efficacy trials allowed for the evaluation of each new class on the background of the optimal medical therapy current at the time (Table 1). Initial beta-blocker trials were conducted largely with ACE inhibitor–treated patients. Although the RALES (Randomized Aldactone Evaluation Study) trial largely did not include beta-blockers, subsequent MRA trials enrolled patients well treated with ACE inhibitors or ARBs and beta-blockers. ARNI therapy was evaluated in a cohort on ACE inhibitor/ARB treatment with >90% on beta-blockers and ~50% on MRA therapy.[11] Although target doses in these trials were rarely achieved, patients were largely receiving therapeutic classes of contemporaneous background drug therapy. The use of clearly defined background medical regimens in these trials provided strong evidence for the incremental benefit of novel drug therapies to well-treated patients.

Nonetheless, the development of practice guidelines that address sequencing and optimal dosing has been challenging. Patients are rarely prescribed the target doses of all evidence-based therapies, and uptitration in clinical practice is infrequent.[13,14] A framework for drug initiation and uptitration may be available for each agent individually but rarely integrates the multitude of clinical decisions physicians face in the clinic when deciding how to implement multidrug regimens. Intensification programs to facilitate up-titration have had mixed results, often without incremental improvements.[15] The recommended sequencing of drugs in practice has generally followed the order in which the landmark trials were conducted and has been typically related to historic precedence of drug development.