What can we expect from future HF trials?

Upcoming heart failure (HF) trials are exploring precision medicine, tailored therapies, and de-prescribing strategies. Emphasis is also placed on implementation studies and simplified trial designs to improve therapy uptake and accelerate practice change, ultimately aiming to personalise treatment and improve patient outcomes.

Prof. John McMurray (University of Glasgow, UK) discussed the trials that are on the horizon in HF and shared his vision on how to move the field forward [1]. In his opinion, personalised treatment, implementation studies, and de-prescribing trials are needed to optimise outcomes for patients.

“Precision-based medicine is not really done in regular HF,” Prof. McMurray stated. “It is done in transthyretin amyloid cardiomyopathy [ATTR-CM] and hypertrophic cardiomyopathy [HCM], and there may be one example of a precision medicine trial in regular HF.” Omecamtiv mecarbil is designed specifically to enhance cardiac-myosin binding, therefore targeting the contractility of the heart directly. The results of the GALACTIC trial, which tested this agent in a population of patients with heart failure and reduced ejection fraction (HFrEF), were somewhat disappointing, with a modest and significant effect. However, a subgroup analysis showed that participants with an LVEF ≤28% had a greater benefit from this treatment than those with an LVEF >28% (P_interaction=0.03) [2]. As a result, the COMET-HF trial (NCT06736574) is recruiting patients with HF and an LVEF <30% to further evaluate omecamtiv mecarbil. “The opposite is also interesting,” said Prof. McMurray. Cardiac myosin inhibitors may be used in patients with HFpEF, something that is currently being tested in the AMBER-HFpEF trial (NCT06793371).

What other types of trials are on the horizon? Some studies are aiming for a personalised medicine approach. The best example is probably cardiac resynchronisation therapy for patients with HFrEF who have a specific ECG morphology. Another example is the HERMES study (NCT05636176), which investigates the anti-inflammatory agent ziltivekimab in patients with HFmrEF/HFpEF (n=5,600). “This study is targeted at a well-known biomarker, namely hsCRP ≥2 mg/L,” added Prof. McMurray. Next, PARACHUTE-HF (NCT04023227) is designed for patients with a specific parasitic cause of HF, Chagas disease, caused by a Trypanosoma cruzi infection.

Tailored treatment is another point of focus. “Many of the current second-line therapies are used for persisting symptoms, specific subgroups, or particular comorbidities,” according to Prof. McMurray. For example, the soluble guanylate cyclase stimulator vericiguat is currently being tested in a different HFrEF patient population (VICTOR: NCT05093933) than in the previous trial (VICTORIA; [3]) to see whether the drug is not very effective or whether it is only effective in a specific population. Also, GLP-1 receptor agonists are used to treat a specific comorbidity in HF or, one could argue, a specific type of HF.

Incremental trials aim to expand or improve upon something that we already know works. Renin inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRAs), and aldosterone synthase inhibitors are examples of this. “One specific example is vicadrostat, an agent that is being tested in the large HFmrEF/HFpEF trial called EASi-HF (n=6,000; NCT06424288) as a therapy to add to empagliflozin,” said Prof. McMurray. “And many more trials are investigating these anti-aldosterone therapies.”

Another type of trial Prof. McMurray addressed is the so-called de-prescribing trial, which questions whether certain therapies are (still) needed. A small trial demonstrated that removing a beta-blocker in patients with HFpEF and chronotropic incompetence has a positive impact on these patients’ quality-of-life and functional capacity [4]. Another example is that 2 large trials (PROFID-EHRA: NCT05665608; CONTEMP-ICD: NCT06543446) are questioning the need for a primary prevention implantable cardioverter defibrillator.

“Furthermore, we have all these wonderful therapies, but they are not being used properly,” Prof. McMurray continued. “Therefore, we need implementation trials.” It currently takes about 17 years for evidence to change practice [5]. According to Prof. McMurray, one way to speed up this process is to get patients involved. The Danish EMAIL-HF trial is an example of a trial involving patients in therapeutic decision-making [6]. Another option to facilitate the delivery of guideline-directed medical therapy for HF is to develop a polypill; the COMBO-HF-X study (NCT06029712) is currently investigating this approach.

Ultimately, conducting simplified trials is crucial for moving forward. “In Denmark, there are many of these trials running, such as the APPLE TREE study (NCT06642272), comparing empagliflozin and dapagliflozin, or the CROWD-ASPECT trial (NCT03984591), comparing eplerenone and spironolactone,” Prof. McMurray finished.

1. McMurray JJV. What can we expect from future clinical trials in heart failure? What’s on the horizon in heart failure: precision medicine and tailored treatment, Heart Failure 2025, 17–20 May, Belgrade, Serbia.
2. Teerlink JR, et al. N Engl J Med 2021;384:105-116.
3. Armstrong PW, et al. N Engl J Med 2020;382:1883-1893.
4. Palau P, et al. J Am Coll Cardiol. 2021;78(21):2042-2056.
5. Rubin R. JAMA. 2023;329(16):1333-1336.
6. Elmegaard M, et al. Eur Heart J. 2024;45(supp_1):ehae666.3641.

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Posted on 17 July 2025