Importance: Impaired exercise capacity is a cardinal manifestation of obstructive hypertrophic cardiomyopathy (HCM). The Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) is a pivotal study characterizing the treatment effect of aficamten, a next-in-class cardiac myosin inhibitor, on a comprehensive set of exercise performance and clinical measures. Objective: To evaluate the effect of aficamten on exercise performance using cardiopulmonary exercise testing with a novel integrated measure of maximal and submaximal exercise performance and evaluate other exercise measures and clinical correlates. Design, Setting, and Participants: This was a prespecified analysis from SEQUOIA-HCM, a double-blind, placebo-controlled, randomized clinical trial. Patients were recruited from 101 sites in 14 countries (North America, Europe, Israel, and China). Individuals with symptomatic obstructive HCM with objective exertional intolerance (peak oxygen uptake [pVO2] ≤90% predicted) were included in the analysis. Data were analyzed from January to March 2024. Interventions: Randomized 1:1 to aficamten (5-20 mg daily) or matching placebo for 24 weeks. Main Outcomes and Measures: The primary outcome was change from baseline to week 24 in integrated exercise performance, defined as the 2-component z score of pVO2 and ventilatory efficiency throughout exercise (minute ventilation [VE]/carbon dioxide output [VCO2] slope). Response rates for achieving clinically meaningful thresholds for change in pVO2 and correlations with clinical measures of treatment effect (health status, echocardiographic/cardiac biomarkers) were also assessed. Results: Among 282 randomized patients (mean [SD] age, 59.1 [12.9] years; 115 female [40.8%], 167 male [59.2%]), 263 (93.3%) had core laboratory-validated exercise testing at baseline and week 24. Integrated composite exercise performance improved in the aficamten group (mean [SD] z score, 0.17 [0.51]) from baseline to week 24, whereas the placebo group deteriorated (mean [SD] z score, -0.19 [0.45]), yielding a placebo-corrected improvement of 0.35 (95% CI, 0.25-0.46; P <.001). Further, aficamten treatment demonstrated significant improvements in total workload, circulatory power, exercise duration, heart rate reserve, peak heart rate, ventilatory efficiency, ventilatory power, and anaerobic threshold (all P <.001). In the aficamten group, large improvements (≥3.0 mL/kg per minute) in pVO2 were more common than large reductions (32% and 2%, respectively) compared with placebo (16% and 11%, respectively). Improvements in both components of the primary outcome, pVO2 and VE/VCO2 slope throughout exercise, were significantly correlated with improvements in symptom burden and hemodynamics (all P <.05). Conclusions and Relevance: This prespecified analysis of the SEQUOIA-HCM randomized clinical trial found that aficamten treatment improved a broad range of exercise performance measures. These findings offer valuable insight into the therapeutic effects of aficamten. Trial Registration: ClinicalTrials.gov Identifier: NCT05186818.

Aficamten and Cardiopulmonary Exercise Test Performance / Lee, Matthew M. Y.; Masri, Ahmad; Nassif, Michael E.; Barriales-Villa, Roberto; Abraham, Theodore P.; Claggett, Brian L.; Coats, Caroline J.; Gimeno, Juan Ramón; Kulac, Ian J.; Landsteiner, Isabela; Ma, Changsheng; Maron, Martin S.; Olivotto, Iacopo; Owens, Anjali T.; Solomon, Scott D.; Veselka, Josef; Jacoby, Daniel L.; Heitner, Stephen B.; Kupfer, Stuart; Malik, Fady I.; Meng, Lisa; Wohltman, Amy; Lewis, Gregory D.; null, null; Wang, Andrew; Sherrid, Mark V; Kelly, Jacob P; Marian, Ali J; Owens, Anjali Tiku; Wever-Pinzon, Omar; Owens, David; Wheeler, Matthew T; Nagueh, Sherif F; Rader, Florian; McGrew, Frank A; Wong, Timothy; O'Neill, Thomas; Bach, Richard G; Martinez, Matthew; Lakdawala, Neal K; Collado, Elias; Turer, Aslan; Desai Y, Milind; Hussain, Zainal; Tower-Rader, Albree F; Hannawi, Bashar; Geske, Jeffrey; Saberi, Sara; Phelan, Dermot; Kramer, Christopher; Sarswat, Nitasha; Ahmad, Ferhaan; Choudhury, Lubna; Markowitz, Jeremy S; Sen, Sounok; Bering, Patrick; Maron, Martin S; Jani, Sandeep; Brinkley, Douglas; Naidu, Srihari; Maurer, Mathew S; Moss, Noah; Bilen, Ozlem; Silva Enciso, Jorge; Fraser, Robert; Akinboboye, Olakunle; Asher, Craig; Emani, Sitaramesh; Sharma, Abhinav; Fermin, David; Lyle, Melissa; Raymer, David; Darlington, Andrew; Resnic, Frederic; Nielsen, Christopher D; Metra, Marco; Musumeci, Beatrice; Emdin, Michele; Targetti, Mattia; Canepa, Marco; Michels, Michelle; Knackstedt, Christian; Amin, Ahmad S.; Barriales Villa, Roberto; Garcia Pavia, Pablo; Gimeno Blanes, Juan Ramon; Hidalgo Urbano, Rafael Jesus; Rincon Diaz, Luis Miguel; Ripoll Vera, Tomas Vicente V; Garcia Alvarez, Ana; Zemanek, David; Jensen, MortenK; Mogensen, Jens; Thune, Jens J; Bundgaard, Henning; Charron, Philippe; Trochu, Jean-Noel; Habib, Gilbert; Lhermusier, Thibault; Reant, Patricia; Hagege, Albert A; Logeart, Damien; Mitrovic, Veselin; Edelmann, Frank; Seidler, Tim; Meder, Benjamin; Schulze, Paul Christian; Stoerk, Stefan; Bekfani, Tarek; Rassaf, Tienush; Merkely, Bela; Arad, Michael; Halabi, Majdi; Zwas, Donna; Piltz, Xavier; Paz, Offir; Habib, Manhal; Dudek, Dariusz; Oreziak, Artur; Wojakowski, Wojciech; Toste Batista, Alexandra M; Mesquita Bastos, Jose Adelino; Elliott, Perry M; Mahmod, Masliza; Coats, Caroline; Cooper, Robert; Bradlow, William; Pantazis, Antonios; Tome Esteban, Maria Teresa; McGinnis, Shaina; Campain, Joseph; Cocca-Spofford, Diane; Giverts, Ilya; Griskowitz, Catherine; Newlands, Chloe; Moreno, Fabely Moreno. - In: JAMA CARDIOLOGY. - ISSN 2380-6583. - ELETTRONICO. - 9:(2024), pp. 11.990-11.1000. [10.1001/jamacardio.2024.2781]

Aficamten and Cardiopulmonary Exercise Test Performance

Olivotto, Iacopo;Targetti, Mattia;Cooper, Robert;
2024

Abstract

Importance: Impaired exercise capacity is a cardinal manifestation of obstructive hypertrophic cardiomyopathy (HCM). The Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) is a pivotal study characterizing the treatment effect of aficamten, a next-in-class cardiac myosin inhibitor, on a comprehensive set of exercise performance and clinical measures. Objective: To evaluate the effect of aficamten on exercise performance using cardiopulmonary exercise testing with a novel integrated measure of maximal and submaximal exercise performance and evaluate other exercise measures and clinical correlates. Design, Setting, and Participants: This was a prespecified analysis from SEQUOIA-HCM, a double-blind, placebo-controlled, randomized clinical trial. Patients were recruited from 101 sites in 14 countries (North America, Europe, Israel, and China). Individuals with symptomatic obstructive HCM with objective exertional intolerance (peak oxygen uptake [pVO2] ≤90% predicted) were included in the analysis. Data were analyzed from January to March 2024. Interventions: Randomized 1:1 to aficamten (5-20 mg daily) or matching placebo for 24 weeks. Main Outcomes and Measures: The primary outcome was change from baseline to week 24 in integrated exercise performance, defined as the 2-component z score of pVO2 and ventilatory efficiency throughout exercise (minute ventilation [VE]/carbon dioxide output [VCO2] slope). Response rates for achieving clinically meaningful thresholds for change in pVO2 and correlations with clinical measures of treatment effect (health status, echocardiographic/cardiac biomarkers) were also assessed. Results: Among 282 randomized patients (mean [SD] age, 59.1 [12.9] years; 115 female [40.8%], 167 male [59.2%]), 263 (93.3%) had core laboratory-validated exercise testing at baseline and week 24. Integrated composite exercise performance improved in the aficamten group (mean [SD] z score, 0.17 [0.51]) from baseline to week 24, whereas the placebo group deteriorated (mean [SD] z score, -0.19 [0.45]), yielding a placebo-corrected improvement of 0.35 (95% CI, 0.25-0.46; P <.001). Further, aficamten treatment demonstrated significant improvements in total workload, circulatory power, exercise duration, heart rate reserve, peak heart rate, ventilatory efficiency, ventilatory power, and anaerobic threshold (all P <.001). In the aficamten group, large improvements (≥3.0 mL/kg per minute) in pVO2 were more common than large reductions (32% and 2%, respectively) compared with placebo (16% and 11%, respectively). Improvements in both components of the primary outcome, pVO2 and VE/VCO2 slope throughout exercise, were significantly correlated with improvements in symptom burden and hemodynamics (all P <.05). Conclusions and Relevance: This prespecified analysis of the SEQUOIA-HCM randomized clinical trial found that aficamten treatment improved a broad range of exercise performance measures. These findings offer valuable insight into the therapeutic effects of aficamten. Trial Registration: ClinicalTrials.gov Identifier: NCT05186818.
2024
9
990
1000
Goal 3: Good health and well-being
Lee, Matthew M. Y.; Masri, Ahmad; Nassif, Michael E.; Barriales-Villa, Roberto; Abraham, Theodore P.; Claggett, Brian L.; Coats, Caroline J.; Gimeno, ...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1404612
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