Patients with cardiovascular disease often face severe exercise intolerance, which can significantly hinder their physical capabilities and overall quality of life. To address this issue, researchers are exploring cardiac myosin inhibitors (CMIs) to assist those suffering from hypertrophic obstructive cardiomyopathy (HOCM). This condition causes thickening of the heart muscle, which restricts blood flow from the heart.
A recent analysis by researchers at Mass General Brigham examined various exercise responses before and after treatment with the CMI aficamten in the SEQUIOA-HCM trial. The findings were published in JAMA Cardiology. This phase-3, placebo-controlled, randomized clinical trial, funded by Cytokinetics, Inc., assessed the impact of aficamten on exercise capacity and heart function. The primary goal was to measure changes in peak oxygen uptake, evaluated through cardiopulmonary exercise testing.
The study reported significant improvements in peak oxygen uptake, as previously highlighted in the New England Journal of Medicine.
Additionally, measures of cardiac structure and function showed notable enhancements, as confirmed by the Echocardiography Core Laboratory at Brigham and Women’s Hospital.
The research team evaluated 263 patients who underwent exercise testing at the beginning of the trial and again after 24 weeks. They observed substantial improvements in various metrics, including workload achieved, breathing efficiency, and cardiac power generated during exercise. They also introduced a new measurement that combined submaximal and maximal exercise capacity to assess overall improvements in exercise performance. The investigators noted that changes in exercise responses were linked to improvements in cardiac structure and function, extending beyond just the obstruction of blood flow.
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These findings hold significant clinical implications for treating HOCM and may also be relevant for broader populations with non-obstructive hypertrophic cardiomyopathy.
In a presentation at the European Society of Cardiology’s Heart Failure 2024 Congress, the SEQUIOA-HCM trial results revealed that patients treated with aficamten experienced statistically significant and clinically meaningful enhancements in peak oxygen uptake and other health markers compared to those receiving a placebo. The treatment led to an increase of 1.7 mL/kg/min in peak oxygen uptake over 24 weeks, a change that exceeds the threshold typically considered clinically meaningful.
Lead investigator Martin S. Maron, MD, emphasized the robustness of these results, noting that even a 1 mL/kg/min increase in exercise capacity is significant for patients. He stated, “Everything kind of moved in the right direction,” highlighting the consistency of improvements across various measures.
Heart failure specialist Justin Ezekowitz, who commented on the study, described the increase in peak oxygen uptake as a “massive change.” He explained that patients starting with a peak oxygen uptake of 18 or 19 mL/kg/min are severely limited in their physical activities.
An increase of just 1 mL/kg/min can enable a patient to climb a flight of stairs, which they could not do before.
The SEQUIOA-HCM trial involved 282 patients with obstructive HCM, randomly assigned to receive either aficamten or a placebo. All participants had a left ventricular ejection fraction of at least 60% and a left ventricular outflow tract (LVOT) gradient of at least 30 mm Hg at rest.
The study’s results revealed that the average change in peak oxygen uptake at 24 weeks was 1.8 mL/kg/min for the aficamten group, while the placebo group showed no change. The difference between the two groups was statistically significant.
Before aficamten, treatment options for HOCM included beta-blockers, calcium channel blockers, and invasive procedures like alcohol septal ablation or surgical myectomy. Aficamten, similar to another myosin inhibitor called mavacamten, works by reducing left ventricular contractility, thereby alleviating LVOT obstruction.
The SEQUIOA-HCM trial results underscore the potential of aficamten to improve exercise capacity and quality of life for patients with obstructive HCM. As the study indicates, these advancements in treatment could lead to better outcomes for patients, paving the way for further research and development in managing this condition.