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

Novel Trials to Inform Future Decisions

Sequencing Trials

Adequately powered sequencing trials may aid clinicians to evolve from the traditional chronological order of initiating therapies. In the PIONEER-HF (Comparison of Sacubitril-Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode) trial, the safety and benefit of initiation of ARNI in patients previously naive to ACE inhibitor/ARB therapy were similar to those on pre-existing ACE inhibitor/ARB therapy.[44] The CIBIS III trial evaluated whether initial therapy with an ACE inhibitor or beta-blocker is preferred in HFrEF.[11] Similar approaches can be applied to new therapies. Sequencing trials could combine clinical and echocardiographic endpoints with those evaluating adherence, tolerability of additional guideline-directed medical therapy (GDMT), and compliance. For example, assessing the impact of sequencing strategies to time to ejection fraction recovery may inform optimal sequencing efforts; however, these analyses should then be coupled with prospective evaluations of the potential benefits of incremental GDMT in those with HF with recovered EF. In addition, given the robust evidence base supporting use and well-characterized safety profiles, large simple trials to assess sequencing could cost-effectively and feasibly provide insights that are broadly generalizable.

N Minus 1/Knockout Trials

N minus 1 or knockout trials aim to understand the effect of subtracting therapy. Data from the PROVED (Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin)[45] and RADIANCE (Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme)[46] trials showed that on the background of ACE inhibitors and diuretics, withdrawal of digoxin therapy resulted in worsening HF and reduced exercise performance. Similarly, withdrawal of quinapril in patients with HFrEF led to steady deterioration in functional status and quality of life in patients with chronic HFrEF.[47] More recently, the TRED-HF (Therapy Withdrawal in Recovered Dilated Cardiomyopathy–Heart Failure)[48] investigators found that withdrawal of GDMT in patients with dilated cardiomyopathy and recovered ejection fraction led to higher rates of relapsed HF. This study laid the foundation for the insight that HF with recovered EF may actually be HF "in remission",[40] although this interpretation is limited because the trial included a highly selected and small number of patients. Knockout trials may be more effective in specialized conditions in which cardiac dysfunction is believed to be recoverable by the natural history of the disease. Examples may include peri-partum or tachycardia-mediated cardiomyopathy.

Specific Disease–Oriented Trials

Specific disease–oriented trials might provide opportunities to study combinations and/or withdrawal of therapies in particular well-characterized HF states. For example, little is known about the disease-modifying effects of conventional HFrEF therapy on conditions such as stress-induced, tachycardia-mediated, or alcoholic cardiomyopathy. Current practice is limited to expert opinion and patient tolerability. These trials, although narrower in scope, may afford the ability to establish niche indications for HF therapy in these populations.

Trials in De Novo HF

De novo HF represents an opportunity to study new therapy sequencing without complicating issues of pre-existing background therapy. The PIONEER-HF trial, in which 34% of patients had de novo HF, provided important insights, with similar treatment effects seen in those with de novo HF compared with those with established HF.[49] In planned trials, such as DAPA ACT HF-TIMI 68 (Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure–Thrombolysis In Myocardial Infarction 68; NCT04363697), patients with de novo HF are eligible. In addition, registry randomization trials offer a unique opportunity to study de novo HF if large-scale registries capturing incident HFrEF are collated. Novel therapies can be compared with placebo in addition to protocolized standard of care in both arms. Moreover, given that de novo HF patients are receiving little to no evidence-based HF therapy at time of diagnosis, this population may be ideal for sequencing trials in which patients are randomized to different protocols of initiation and titration of evidence-based HF therapies. Such trials may identify advantages of the upfront use of particular therapies that may actually aid in further GDMT optimization by mitigating risks of hypotension and renal failure, among other considerations.