Expanding Treatment Options: Novel Drug Therapies in the Pipeline for Heart Failure With Reduced Ejection Fraction

Marat Fudim, MD, MHS, is an assistant professor of medicine and a member of the Duke Clinical Research Institute at Duke University School of Medicine in Durham, North Carolina. His research and clinical efforts focus on HF, including advanced therapies such as mechanical assist devices and heart transplantation. He also performs cardiac catheterizations to better understand a patient’s disease state.

The GALACTIC-HF study (ClinicalTrials.gov Identifier: NCT02929329) found that selective cardiac myosin activators, such as omecamtiv mecarbil, result in modest yet statistically significant reductions in initial hospitalizations for HF, especially in the setting of reduced LVEF.¹ Do you believe this class of drug, after further study, may become incorporated into standard of care treatment options for patients with HFrEF?    

I think that following the GALACTIC-HF study, without any need for further studies, the drug has earned itself a place in the treatment algorithm. Once approved, I can imagine that the drug will be, as of now, the sixth-line agent for patients with HFrEF. Given its mechanism of action and the benefit seen in the subgroup of patients with reduced LVEF, this drug will preferentially be used in patients who had been started and up-titrated on 4 or 5 agents and now have borderline low blood pressure, reduced range of ejection fraction, and remain at increased risk for rehospitalization and death. Certainly, more investigation with this drug that solidifies the benefit in certain subgroups will increase its adoption in clinical practice.

The GALACTIC-HF study reported a small increase in troponin I levels when compared with placebo, although it was noted there were no differences in rates of ischemic or ventricular arrhythmic events.¹ How should this finding be interpreted in the context of the study’s findings?

Given the mechanism of action of omecamtiv mecarbil,² increased troponin levels are not a surprise. However, as part of the approval process across a number of studies, the signal of troponin elevation was closely monitored and, as the overall positive results of the trials suggest, the very small elevation in troponin does not appear to be clinically relevant.³

A post-hoc analysis of the GALACTIC-HF trial identified that a subset of patients with more severe HF may have more clinically meaningful outcomes with cardiac myosin activators.⁴ What role could this type of drug class play in these patients who have higher baseline risk and also are more likely to have intolerance to β-blockers, renin-angiotensin-aldosterone system (RAAS) modulators, or mineralocorticoid receptor antagonists due to potential hypotension and renal insufficiency?

I think that is exactly the group of patients most likely to benefit from this drug and likely to be the group in which this drug is first initiated clinically. With time, providers will gain more experience and confidence with the drug and start using it in a broader population.

When might a clinician make the decision not to prescribe a selective cardiac myosin activator?

Good question. The side effect profile of the drug is very good: There is no contraindication in patients with renal dysfunction, it does not lower blood pressure, etc. A key limitation in its uptake will be cost; cost will prevent a broader uptake right from the get-go.

Can you describe your process of risk-benefit determinations when considering an update to HFrEF treatment regimens, especially in patients with severe HFrEF?

My approach to medical management of HFrEF is centered around symptoms and hospitalizations. If patients with HFrEF remain symptomatic with New York Heart Association (NYHA) class II to IV HF symptoms despite guideline-directed medical therapy (GDMT), I discuss with patients their willingness to try something new. This might be a drug that just made it on the market (vericiguat⁵ and soon omecamtiv mecarbil), device therapies, or participation in clinical trials. The biggest mistake we tend to make is to accept ongoing and persistent HF symptoms as the norm and refuse to consider additional therapies instead of presenting additional options to patients. Of course, hospitalizations for HF tend to trigger or accelerate discussion and initiations of therapies given the very apparent deterioration of the clinical course. 

Can you put into context the potential clinical utility of omecamtiv mecarbil as opposed to older inotropic agents, such as dobutamine or milrinone, in the setting of severe HFrEF?

While all the above noted agents have inotropic properties, they achieve the inotropy via different mechanisms. The inotropic properties for agents such as dobutamine and milrinone are more pronounced and are associated with more side effects,⁶ which give the inotropic agents the “bad” reputation. As mentioned earlier, the fear of troponin release and adverse outcomes was not substantiated with omecamtiv mecarbil. In regard to outcomes, it was quite the opposite.

You mentioned GDMT in reference to risk-benefit discussions with patients. Current clinical guidelines recommend that in patients with HFrEF, angiotensin converting enzyme (ACE) inhibitors and β-blockers should be titrated to maximally-tolerated doses. How might newer therapies, including direct myosin activators, be integrated into these guidelines?

Certainly, as it is typical for newer agents, omecamtiv mecarbil will likely be added after the other 4 or 5 drug classes have been started or at least contemplated. I can envision that, for the previously outlined phenotypes of reduced LVEF and low blood pressure, the use of drugs such as omecamtiv mecarbil might move more upstream as providers anticipate (or already have seen patients experience at low doses) side effects with the more established GDMT agents.

You touched upon issues related to accepting persistent HF symptoms as the norm. Can you expound on what clinical endpoints are used in HF trials and what role alternative patient-centered endpoints may have in HFrEF drug development?

The traditional concept is to focus on HF hospitalization and death as the main clinical endpoints. It has now been increasingly recognized that “softer” clinical endpoints, such as QOL — symptom burden or functional status — might matter to patients just as much if not more. There are broad efforts underway to “promote” patient-centered outcomes, such as using QOL as key endpoints. Now we commonly see QOL metrics as clinical endpoints in HF device and drug trials. While the US Food and Drug Administration (FDA) does not accept QOL improvement as the primary endpoint to approve a therapy at this time, we have made great strides in the last decade to promote QOL as a valid clinical endpoint.

This Q&A was edited for clarity and length.

Disclosure

Marat Fudim, MD, reported affiliations with Edwards Lifesciences Corporation; VisCardia, Inc.; NXT Pharma; Axon Therapies Inc.; Daxor Corporation; Foundry Innovation & Research 1, Ltd. (FIRE1); Bodyport Inc.; ZOLL Medical Corporation; CVRx, Inc.; Boston Scientific Corporation; and Bayer HealthCare Pharmaceuticals Inc.

References

1. Teerlink JR, Diaz R, Felker GM, et al; for the GALACTIC-HF Investigators. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med. 2021;384(2):105-116. doi:10.1056/NEJMoa2025797
 
2. Kaplinsky E, Mallarkey G. Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil. Drugs Context. 2018; 7:212518. doi:10.7573/dic.212518
 
3. Mahajan VS, Jarolim P. How to interpret elevated cardiac troponin levels. Circulation. 2011;124(21):2350-2354. doi:10.1161/CIRCULATIONAHA.111.023697
 
4. Felker MG, Solomon SD, Claggett B, et al. Assessment of omecamtiv mecarbil for the treatment of patients with severe heart failure: a post hoc analysis of data from the GALACTIC-HF randomized clinical trial. JAMA Cardiol. 2022;7(1):26–34. doi:10.1001/jamacardio.2021.4027
 
5. Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in patients with heart failure and reduced ejection faction. N Engl J Med. 2020;382(20):1883-1893. doi:10.1056/NEJMoa1915928
 
6. Dubin A, Lattanzio B, Gatti L. The spectrum of cardiovascular effects of dobutamine – from healthy subjects to septic shock patients. Rev Bras Ter Intensiva. 2017;29(4):490-498. doi:10.5935/0103-507X.20170068

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