Welcome to PracticeUpdate! We hope you are enjoying temporary access to this content.
Please register today for a free account and gain full access
to all of our expert-selected content.
Already Have An Account? Log in Now
Effect of Aficamten on Cardiac Structure and Function in Patients With Obstructive Hypertrophic Cardiomyopathy
TAKE-HOME MESSAGE
- This substudy of the SEQUOIA-HCM CMR trial evaluated the effect of aficamten, a cardiac myosin inhibitor, on cardiac remodeling compared with placebo in patients with obstructive hypertrophic cardiomyopathy. After 24 weeks of treatment, aficamten led to significant reductions in LV mass index, maximal LV wall thickness, LA volume index, native T1 relaxation time, and indexed extracellular volume fraction, which suggested favorable remodeling. However, no significant changes were observed in LV chamber volume, LV replacement fibrosis, or LV extracellular volume fraction.
- The findings indicate that aficamten may mitigate obstructive hypertrophic cardiomyopathy–related pathology and reduce cardiovascular events, including heart failure and atrial fibrillation, over extended follow-up periods.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular (LV) hypertrophy, LV outflow tract obstruction, and left atrial dilation, which can be associated with progressive heart failure, atrial fibrillation, and stroke. Aficamten is a next-in-class cardiac myosin inhibitor that reduces outflow tract obstruction by modulating cardiac contractility, with the potential to reverse pathological remodeling and, in turn, reduce cardiovascular events.
OBJECTIVES
This study sought to investigate the effect of aficamten on cardiac remodeling compared with placebo using cardiovascular magnetic resonance (CMR) and its association with key clinical endpoints in the SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) CMR substudy.
METHODS
SEQUOIA-HCM was a phase 3 double-blind, placebo-controlled trial for adults with symptomatic oHCM who were randomized 1:1 to 24 weeks of aficamten (dose range: 5-20 mg) or placebo. Eligible participants were offered enrollment in the CMR substudy with studies performed at baseline and week 24. Image analysis was performed in a blinded fashion by a core laboratory.
RESULTS
Of the 282 randomized patients, 57 (20%) participated in the substudy, and of those, 50 (88%) completed both baseline and week 24 CMR. Baseline characteristics of the CMR cohort were similar to the overall study population. Of these 50 patients, 21 received aficamten and 29 received placebo. Relative to placebo, patients receiving aficamten demonstrated significant reductions (Δ least-squares mean) in LV mass index (-15 g/m2; 95% CI: -25 to -6 g/m2; P = 0.001), maximal LV wall thickness (-2.1 mm; 95% CI: -3.1 to -1.1 mm; P < 0.001), left atrial volume index (-13 mL/m2; 95% CI: -19 to -7 mL/m2; P < 0.001), native T1 relaxation time (-37 ms; 95% CI: -69 to -5 ms; P = 0.026), indexed extracellular volume fraction (-3.9 g/m2; 95% CI: -7.0 to -0.9 g/m2; P = 0.014), and indexed myocyte mass (-14 g/m2; 95% CI: -23 to -4 g/m2; P = 0.004), while there were no significant changes in LV chamber volumes, LV replacement fibrosis (late gadolinium enhancement mass -0.7 g; 95% CI: -2.9 to 1.6 g; P = 0.54), or extracellular volume (0.7%; 95% CI: -2.2% to 3.6%; P = 0.61).
CONCLUSIONS
The CMR substudy of SEQUOIA-HCM demonstrated that treatment with aficamten relative to placebo for 24 weeks resulted in favorable cardiac remodeling. These changes, particularly with regard to LV mass, wall thickness, and left atrial size, could potentially lead to reduced cardiovascular events including heart failure and atrial fibrillation with longer follow-up. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818).
Additional Info
Effect of Aficamten on Cardiac Structure and Function in Obstructive Hypertrophic Cardiomyopathy: SEQUOIA-HCM CMR Substudy
J Am Coll Cardiol 2024 Aug 28;[EPub Ahead of Print], A Masri, RN Cardoso, TP Abraham, BL Claggett, CJ Coats, SM Hegde, IJ Kulac, MMY Lee, MS Maron, B Merkely, M Michels, I Olivotto, A Oreziak, DL Jacoby, SB Heitner, S Kupfer, FI Malik, L Meng, SD Solomon, A Wohltman, RY Kwong, CM KramerFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Traditional standard-of-care therapies for obstructive hypertrophic cardiomyopathy (oHCM) are used to improve symptoms and quality of life. Cardiac myosin inhibitors target the underlying hypercontractility driving the oHCM phenotype and its complications. Aficamten, in a pivotal phase III trial (SEQUOIA-HCM), has been shown to improve exercise capacity, symptoms, quality of life, LV outflow tract gradients, and cardiac biomarker levels. Although echocardiography is performed on every single patient enrolled in oHCM trials, cardiac magnetic resonance imaging (CMR) remains the gold standard for assessing cardiac structure and function as well as the disease-modifying potential of novel therapies. Given the low event rate in contemporary-treated patients with oHCM, we rely on these imaging surrogates to study disease progression.
In the current study, patients enrolled in the SEQUOIA-HCM trial were invited to participate in the CMR substudy. A total of 57 patients out of 282 were enrolled, and 50 completed both baseline and 24-week CMRs. The investigators found that aficamten, compared with placebo, demonstrated significant reductions in LV mass index (15 g/m2), LV wall thickness, LA volume index, native T1 relaxation time, indexed extracellular volume fraction, and indexed myocyte mass. Measures of replacement fibrosis (late gadolinium enhancement) and interstitial fibrosis (extracellular volume fraction) remained stable. These results demonstrate the beneficial effects of aficamten on cardiac structure and function, beyond improvements in hemodynamics, biomarker levels, symptoms, and quality of life. The study also provides a comparison to echocardiography-derived treatment effects, further emphasizing the need for CMR substudies in patients with HCM. An ongoing 5-year CMR substudy (FOREST-HCM) involving patients with HCM treated with aficamten will provide additional data on the long-term effects of aficamten on cardiac structure and function.
The take-home message is that favorable myocardial structural changes, observed over just 24 weeks, signal the potential of aficamten in reducing the risk of long-term adverse outcomes associated with progressive adverse LV remodeling in patients with HCM.