Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial
Jazyk angličtina Země Anglie, Velká Británie Médium print-electronic
Typ dokumentu klinické zkoušky, fáze III, časopisecké články, multicentrická studie, randomizované kontrolované studie, práce podpořená grantem
Grantová podpora
IK6 RX002477
RRD VA - United States
PubMed
32871100
DOI
10.1016/s0140-6736(20)31792-x
PII: S0140-6736(20)31792-X
Knihovny.cz E-zdroje
- MeSH
- benzylaminy škodlivé účinky terapeutické užití MeSH
- beta blokátory terapeutické užití MeSH
- blokátory kalciových kanálů terapeutické užití MeSH
- dvojitá slepá metoda MeSH
- hemodynamika fyziologie MeSH
- hodnocení výsledků pacienta MeSH
- hypertrofická kardiomyopatie farmakoterapie patofyziologie MeSH
- kardiovaskulární látky terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- spotřeba kyslíku fyziologie MeSH
- srdeční myosiny antagonisté a inhibitory MeSH
- tolerance zátěže fyziologie MeSH
- uracil škodlivé účinky analogy a deriváty terapeutické užití MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- benzylaminy MeSH
- beta blokátory MeSH
- blokátory kalciových kanálů MeSH
- kardiovaskulární látky MeSH
- MYK-461 MeSH Prohlížeč
- srdeční myosiny MeSH
- uracil MeSH
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.
1st Department of Arrhythmia National Institute of Cardiology Warsaw Poland
Department of Cardiology Aarhus University Hospital Aarhus Denmark
Department of Cardiology Institute for Clinical and Experimental Medicine Prague Czech Republic
Department of Cardiovascular Diseases Mayo Clinic Arizona Phoenix AZ USA
Department of Internal Medicine Section of Cardiovascular Medicine Yale University New Haven CT USA
Division of Cardiology and Structural Heart Diseases Medical University of Silesia Katowice Poland
Division of Cardiology University of California San Francisco San Francisco CA USA
Division of Cardiovascular Medicine Brigham and Women's Hospital Boston MA USA
Duke University School of Medicine Durham NC USA
Inherited Cardiac Disease Unit University Hospital Virgen de la Arrixaca Murcia Spain
Intermountain Medical Center Heart Institute Intermountain Medical Center Murray UT USA
Knight Cardiovascular Institute Oregon Health and Science University Portland OR USA
University of Pennsylvania Perelman School of Medicine Philadelphia PA USA
Citace poskytuje Crossref.org
Relationship Between Genotype Status and Clinical Outcome in Hypertrophic Cardiomyopathy
Clinical Features and Natural History of Preadolescent Nonsyndromic Hypertrophic Cardiomyopathy
ClinicalTrials.gov
NCT03470545
