Iacopo Olivotto1, Artur Oreziak2, Roberto Barriales-Villa3, Theodore P Abraham4, Ahmad Masri5, Pablo Garcia-Pavia6, Sara Saberi7, Neal K Lakdawala8, Matthew T Wheeler9, Anjali Owens10, Milos Kubanek11, Wojciech Wojakowski12, Morten K Jensen13, Juan Gimeno-Blanes14, Kia Afshar15, Jonathan Myers16, Sheila M Hegde8, Scott D Solomon8, Amy J Sehnert17, David Zhang17, Wanying Li17, Mondira Bhattacharya17, Jay M Edelberg17, Cynthia Burstein Waldman18, Steven J Lester19, Andrew Wang20, Carolyn Y Ho8, Daniel Jacoby21. 1. Cardiomyopathy Unit, Azienda Ospedaliera Universitaria Careggi, Florence, Italy; University of Florence, Florence, Italy. Electronic address: iacopo.olivotto@unifi.it. 2. 1st Department of Arrhythmia, National Institute of Cardiology, Warsaw, Poland. 3. Unidad de Cardiopatías Familiares, Instituto de Investigación Biomédica de A Coruña, A Coruña, Spain; Complexo Hospitalario Universitario de A Coruña, A Coruña, Spain; Servizo Galego de Saúde, A Coruña, Spain; Universidade da Coruña, A Coruña, Spain; Centro de Investigación Biomédica en Red, Madrid, Spain. 4. Division of Cardiology, University of California San Francisco, San Francisco, CA, USA. 5. Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA. 6. Centro de Investigación Biomédica en Red, Madrid, Spain; Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain. 7. Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA. 8. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA. 9. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. 10. University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA. 11. Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. 12. Division of Cardiology and Structural Heart Diseases, Medical University of Silesia, Katowice, Poland. 13. Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark. 14. Inherited Cardiac Disease Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain. 15. Intermountain Medical Center Heart Institute, Intermountain Medical Center, Murray, UT, USA. 16. Division of Cardiology, Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, USA; Stanford University, Palo Alto, CA, USA. 17. MyoKardia, Brisbane, CA, USA. 18. HCMBeat, Los Angeles, CA, USA. 19. Department of Cardiovascular Diseases, Mayo Clinic Arizona, Phoenix, AZ, USA. 20. Duke University School of Medicine, Durham, NC, USA. 21. Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University, New Haven, CT, USA.
Abstract
BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. FUNDING: MyoKardia.
BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. FUNDING: MyoKardia.
Authors: Victor Arévalos; Juan José Rodríguez-Arias; Salvatore Brugaletta; Antonio Micari; Francesco Costa; Xavier Freixa; Mónica Masotti; Manel Sabaté; Ander Regueiro Journal: J Clin Med Date: 2021-05-24 Impact factor: 4.241
Authors: Styliani Vakrou; Yamin Liu; Li Zhu; Gabriela V Greenland; Bahadir Simsek; Virginia B Hebl; Yufan Guan; Kirubel Woldemichael; Conover C Talbot; Miguel A Aon; Ryuya Fukunaga; M Roselle Abraham Journal: Sci Rep Date: 2021-06-23 Impact factor: 4.996
Authors: Isadora Sande Mathias; Jorge Otávio Oliveira Lima Filho; Daniel A Culver; E Rene Rodriguez; Carmela D Tan; Manuel L Ribeiro Neto; Christine L Jellis Journal: Eur Heart J Case Rep Date: 2021-06-26