What's Next: Emerging HF Pharmacotherapies

Presenter: Nasrien E. Ibrahim, MD

There are four pillars of guideline-directed medical therapies (GDMT) for HFrEF, but Nasrien E. Ibrahim, MD, of Inova Heart & Vascular Institute said there are more possibilities.

The four current pillars are the guideline-directed beta-blockers, angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists, and SGLT2 inhibitors. Dr. Ibrahim listed four more: vericiguat, omecamtiv mecarbil, finerenone, and mavacamten.

Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator (myotrope). It was studied in the phase 2 COSMIC trial.1 The primary endpoint was the maximum concentration of OM at week 2 and 12, and the predose concentration of OM at week 2, 8, 12, 16, and 20.

Dr. Ibrahim said the secondary endpoints are what really interested her, which are changes in systolic ejection time, stroke volume, LV end-systolic and end-diastolic diameters, heart rate, and concentration of NT-proBNP in plasma at week 20.

The investigators found patients who received OM had improvement in cardiac structure and function and a reduction in NT-proBNP. Across all parameters, patients who received OM had improvement in systolic ejection time and in stroke volume compared with patients who received placebo, and they had a reduction in LV end-systolic and end-diastolic diameters. Dr. Ibrahim said that what is of most interest to her as a biomarker researcher is that patients who received OM had a reduction in NT-proBNP concentration.

“What was also very exciting,” said Dr. Ibrahim, “was that patients who received OM, compared with patients who received placebo, had improvement in health-related quality of life.”2

The most recent sub-study from the COSMIC trial looked at whether OM can improve right ventricular structure and function in patients with chronic systolic heart failure. Patients receiving OM showed an improvement across RV systolic parameters.3

“So this was great news,” Dr. Ibrahim said, “a phase 2 trial that showed OM improved left ventricular structure and function and right ventricular structure and function. It improved natriuretic peptides as we saw the reduction in NT-proBNP, and it also reduced pulmonary artery systolic pressures. So the question is does OM improve outcomes?”

The phase 3 GALACTIC-HF study4 was performed to answer that question. Dr. Ibrahim noted the systolic blood pressure exclusion criteria of less than 85 mmHg and described this as a “sicker group of patients,” which included patients who had systolic blood pressure in the 90s. They found that a sicker cohort of patients seem to derive some benefit from OM.

Dr. Ibrahim then posed the question, is there a place for OM in the armamentarium of GDMT that already exists for HFrEF, and said it becomes important to know which endpoints are important to patients, staying out of the hospital or longevity. Looking at the study findings, Dr. Ibrahim said, “Do I think there’s a place for OM right now? I’m not sure if we can add it to the guidelines as of yet, but there is potential for a specific group of patients, maybe sicker group of patients, who might benefit from OM.”

Dr. Ibrahim looked at a study of finerenone as well,5 which found patients receiving finerenone had a significant reduction in the composite cardiovascular outcome compared with patients who received placebo. She then asked if the future of finerenone is similar to that of SGLT2i, where a drug being studied for diabetes becomes a cardiovascular drug, but said that question remains to be answered.

The EXPLORER-HCM study6 showed that in patients receiving mavacamten there was a significant improvement in exercise capacity, there was improvement in LVOT obstruction, and an improvement in New York Heart Association functional class and health status.

“In conclusion,” Dr. Ibrahim said, “there are many therapies on the horizon, but I think because of the sub-optimal uptake of the traditional guideline-directed medical therapies, we really must get better at optimizing existing GDMT in patients with HFrEF. And why? Because HFrEF we know reduces morbidity and mortality with a disease that has such a high burden in society.”

Nasrien E. Ibrahim, MD, is a consultant for Cytokinetics and Novartis and receives honoraria from Cytokinetics, Medtronic, Novartis, and Roche.

 

References

  1. Teerlink JR, Felker GM, McMurray JJ, Solomon SD, Adams KF Jr, Cleland JG, Ezekowitz JA, Goudev A, Macdonald P, Metra M, Mitrovic V, Ponikowski P, Serpytis P, Spinar J, Tomcsányi J, Vandekerckhove HJ, Voors AA, Monsalvo ML, Johnston J, Malik FI, Honarpour N; COSMIC-HF Investigators. Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial. Lancet. 2016 Dec 10;388(10062):2895-2903. doi: 10.1016/S0140-6736(16)32049-9. Epub 2016 Dec 1. PMID: 27914656.
  2. Felker GM, Solomon SD, McMurray JJV, Cleland JGF, Abbasi SA, Malik FI, Zhang H, Globe G, Teerlink JR; COSMIC-HF Investigators. Effects of Omecamtiv Mecarbil on Symptoms and Health-Related Quality of Life in Patients With Chronic Heart Failure: Results From the COSMIC-HF Study. Circ Heart Fail. 2020 Dec;13(12):e007814. doi: 10.1161/CIRCHEARTFAILURE.120.007814. Epub 2020 Nov 12. PMID: 33176437; PMCID: PMC7742205.
  3. Biering-Sørensen T, Minamisawa M, Liu J, Claggett B, Papolos AI, Felker GM, McMurray JJV, Legg JC, Malik FI, Honarpour N, Kurtz CE, Teerlink JR, Solomon SD. The effect of the cardiac myosin activator, omecamtiv mecarbil, on right ventricular structure and function in chronic systolic heart failure (COSMIC-HF). Eur J Heart Fail. 2021 Apr 7. doi: 10.1002/ejhf.2181. Epub ahead of print. PMID: 33826209.
  4. Teerlink JR, Diaz R, Felker GM, McMurray JJV, Metra M, Solomon SD, Legg JC, Büchele G, Varin C, Kurtz CE, Malik FI, Honarpour N. Omecamtiv Mecarbil in Chronic Heart Failure With Reduced Ejection Fraction: Rationale and Design of GALACTIC-HF. JACC Heart Fail. 2020 Apr;8(4):329-340. doi: 10.1016/j.jchf.2019.12.001. Epub 2020 Feb 6. PMID: 32035892.
  5. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, Kolkhof P, Nowack C, Schloemer P, Joseph A, Filippatos G; FIDELIO-DKD Investigators. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020 Dec 3;383(23):2219-2229. doi: 10.1056/NEJMoa2025845. Epub 2020 Oct 23. PMID: 33264825.
  6. Ho CY, Olivotto I, Jacoby D, Lester SJ, Roe M, Wang A, Waldman CB, Zhang D, Sehnert AJ, Heitner SB. Study Design and Rationale of EXPLORER-HCM: Evaluation of Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy. Circ Heart Fail. 2020 Jun;13(6):e006853. doi: 10.1161/CIRCHEARTFAILURE.120.006853. Epub 2020 Jun 5. PMID: 32498620.

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