Effects of Mavacamten on Measures of Cardiopulmonary Exercise Testing Beyond Peak Oxygen Consumption: A Secondary Analysis of the EXPLORER-HCM Randomized Trial

Matthew T Wheeler; Iacopo Olivotto; Perry M Elliott; Sara Saberi; Anjali T Owens; Mathew S Maurer; Ahmad Masri; Amy J Sehnert; Jay M Edelberg; Yu-Mao Chen; Victoria Florea; Rajeev Malhotra; Andrew Wang; Artur Oręziak; Jonathan Myers

doi:10.1001/jamacardio.2022.5099

. 2023 Jan 18;8(3):240–247. doi: 10.1001/jamacardio.2022.5099

Effects of Mavacamten on Measures of Cardiopulmonary Exercise Testing Beyond Peak Oxygen Consumption

A Secondary Analysis of the EXPLORER-HCM Randomized Trial

Matthew T Wheeler ^1,^✉, Iacopo Olivotto ^2,³, Perry M Elliott ⁴, Sara Saberi ⁵, Anjali T Owens ⁶, Mathew S Maurer ⁷, Ahmad Masri ⁸, Amy J Sehnert ⁹, Jay M Edelberg ⁹, Yu-Mao Chen ¹⁰, Victoria Florea ⁹, Rajeev Malhotra ¹¹, Andrew Wang ¹², Artur Oręziak ¹³, Jonathan Myers ^14,¹⁵

¹Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California

²Azienda Ospedaliera Universitaria Careggi, Florence, Italy

³University of Florence, Florence, Italy

⁴Institute of Cardiovascular Science, University College London, London, United Kingdom

⁵Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor

⁶Center for Inherited Cardiovascular Disease, University of Pennsylvania Perelman School of Medicine, Philadelphia

⁷Columbia University Irving Medical Center, New York, New York

⁸Center for Hypertrophic Cardiomyopathy, Knight Cardiovascular Institute, Oregon Health & Science University, Portland

⁹MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, Brisbane, California

¹⁰Bristol Myers Squibb, Princeton Pike, New Jersey

¹¹Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston

¹²Duke University Hospital, Durham, North Carolina

¹³1st Department of Arrhythmia, National Institute of Cardiology, Warsaw, Poland

¹⁴Veterans Affairs Palo Alto Health Care System, Palo Alto, California

¹⁵Stanford University, Stanford, California

Accepted for Publication: November 17, 2022.

Published Online: January 18, 2023. doi:10.1001/jamacardio.2022.5099

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Corresponding Author: Matthew T. Wheeler, MD, PhD, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, 870 Quarry Rd, MC 5406, Palo Alto, CA 94304 (wheelerm@standford.edu).

Author Contributions: Dr Wheeler had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Wheeler, Olivotto, Elliott, Saberi, Masri, Sehnert, Edelberg, Florea, Wang, and Oręziak.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Conflict of Interest Disclosures: Dr Wheeler received grants, in-kind medical writing support and payments as a consultant from MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb. Dr Olivotto received grants from Bayer, MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, Sanofi Genzyme, and Shire, now part of Takeda; personal fees from Bayer, Sanofi Genzyme, and Shire, now part of Takeda; and payments as a consultant from MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb. Dr Elliott received payment as a consultant from DiNAQOR, Freeline, MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, Pfizer, Sanofi, and Sarepta; an unrestricted grant from Pfizer; and lecture fees from PeerVoice, the Radcliffe Group, and Sanofi. Dr Saberi received payments as a consultant from MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb. Dr Owens reported consulting for Cytokinetics and MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb. Dr Maurer received funding from the National Institutes of Health (HL139671-01, AG R21AG058348, and AG K24AG036778) and consulting income from Akcea, Alnylam, Eidos Therapeutics, Pfizer, Prothena, Novo Nordisk, and Intellia; his institution has also received funding for clinical trials for Alnylam, Eidos Therapeutics, Pfizer, and Prothena. Dr Masri received research grants from Akcea, Ionis, Pfizer, Ultromics, and the Wheeler Foundation, and fees (honoraria or consulting) from Alnylam, Attralus, Bristol Myers Squibb, Cytokinetics, Eidos Therapeutics, Ionis, Pfizer, and Tenaya. Drs Sehnert, Chen, and Florea are employees of MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, and own stock in Bristol Myers Squibb. Dr Edelberg was an employee of MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, when this work was carried out and owns stocks of Bristol Myers Squibb. Mr. Chen is an employee of Bristol Myers Squibb. Dr Malhotra received payments as a consultant from MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb. Dr Wang received payments as a consultant and grants from MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, and personal fees from Cytokinetics. Dr Myers received payments as a consultant from MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb. No other disclosures were reported.

Funding/Support: The study was supported by MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, including the medical writing assistance. No honoraria or payments were made for authorship.

Role of the Funder/Sponsor: MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, contributed to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 4.

Additional Contributions: The authors would like to thank the patients and families who made this study possible and the clinical study teams who participated. Writing and editorial assistance was provided by Nicolas Bertheleme, PhD, of Oxford PharmaGenesis, Oxford, United Kingdom, and was funded by MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb.

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Corresponding author.

PMCID: PMC9857843 PMID: 36652223

This study examines the effect of mavacamten on exercise physiology using cardiopulmonary exercise testing.

Key Points

Question

What are the effects of mavacamten on peak and submaximal cardiopulmonary exercise testing (CPET) parameters?

Findings

This prespecified exploratory analysis of the EXPLORER-HCM study shows that mavacamten improved a range of CPET parameters beyond peak oxygen uptake, including measures at both peak and subpeak exercise.

Meaning

The favorable effect of mavacamten on submaximal exertional tolerance provides further insights into the beneficial impact of mavacamten.

Abstract

Importance

Mavacamten, a cardiac myosin inhibitor, improved peak oxygen uptake (pVO₂) in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) in the EXPLORER-HCM study. However, the full extent of mavacamten’s effects on exercise performance remains unclear.

Objective

To investigate the effect of mavacamten on exercise physiology using cardiopulmonary exercise testing (CPET).

Design, Setting, and Participants

Exploratory analyses of the data from the EXPLORER-HCM study, a randomized, double-blind, placebo-controlled, phase 3 trial that was conducted in 68 cardiovascular centers in 13 countries. In total, 251 patients with symptomatic obstructive HCM were enrolled.

Interventions

Patients were randomly assigned in a 1:1 ratio to mavacamten or placebo.

Main Outcomes and Measures

The following prespecified exploratory cardiovascular and performance parameters were assessed with a standardized treadmill or bicycle ergometer test protocol at baseline and week 30: carbon dioxide output (VCO₂), minute ventilation (V_E), peak V_E/VCO₂ ratio, ventilatory efficiency (V_E/VCO₂ slope), peak respiratory exchange ratio (RER), peak circulatory power, ventilatory power, ventilatory threshold, peak metabolic equivalents (METs), peak exercise time, partial pressure of end-tidal carbon dioxide (PETCO₂), and VO₂/workload slope.

Results

Two hundred fifty-one patients were enrolled. The mean (SD) age was 58.5 (11.9) years and 59% of patients were male. There were significant improvements with mavacamten vs placebo in the following peak-exercise CPET parameters: peak V_E/VCO₂ ratio (least squares [LS] mean difference, −2.2; 95% CI, −3.05 to −1.26; P < .001), peak METs (LS mean difference, 0.4; 95% CI, 0.17-0.60; P < .001), peak circulatory power (LS mean difference, 372.9 mL/kg/min × mm Hg; 95% CI, 153.12-592.61; P = .001), and peak PETCO₂ (LS mean difference, 2.0 mm Hg; 95% CI, 1.12-2.79; P < .001). Mavacamten also improved peak exercise time compared with placebo (LS mean difference, 0.7 minutes; 95% CI, 0.13-1.24; P = .02). There was a significant improvement in nonpeak-exercise CPET parameters, such as V_E/VCO₂ slope (LS mean difference, −2.6; 95% CI, −3.58 to −1.52; P < .001) and ventilatory power (LS mean difference, 0.6 mm Hg; 95% CI, 0.29-0.90; P < .001) favoring mavacamten vs placebo.

Conclusions and Relevance

Mavacamten improved a range of CPET parameters beyond pVO₂, indicating consistent and broad benefits on maximal exercise capacity. Although improvements in peak-exercise CPET parameters are clinically meaningful, the favorable effects of mavacamten on submaximal exertional tolerance provide further insights into the beneficial impact of mavacamten in patients with obstructive HCM.

Trial Registration

ClinicalTrials.gov Identifier: NCT03470545

Introduction

Hypertrophic cardiomyopathy (HCM) is a complex disease that is caused by excessive cardiac myosin-actin cross-bridging with core pathophysiologic features that include left ventricular hypertrophy, hypercontractility, and multifactorial diastolic dysfunction.^1,2,3,4,5 Consequently, HCM can be a debilitating disease resulting in impaired functionality and quality of life.⁶ The most common symptoms of HCM are dyspnea, fatigue, palpitations, chest pain, lightheadedness, and syncope.⁷ The burden of disease experienced by patients includes limitations to physical activity and daily activities, negative effects on emotional state, and adverse effects on work productivity.⁷

Cardiopulmonary exercise testing (CPET) is a useful, noninvasive tool to assess functional capacity and understand the underlying mechanisms of exercise intolerance. Given that most patients with HCM do not exercise or exert themselves to peak exercise capacity, the ability of CPET to assess both peak and submaximal exercise responses makes it a unique and powerful indicator of what a patient can physically achieve in their daily activities.^8,9 Furthermore, CPET is a valuable method to estimate prognosis in patients with HCM.¹⁰ Indeed, peak oxygen uptake (pVO₂), and ventilatory efficiency (minute ventilation [V_E]/carbon dioxide output [VCO₂] slope) have been independently associated with overall mortality, death due to heart failure, sudden cardiac death, heart transplant, and functional deterioration.^{11,12,13,14,15} Furthermore, circulatory power has been shown to be an independent predictor of death or hospitalization due to heart failure, heart transplant, and progression to New York Heart Association (NYHA) functional class III or IV.¹⁵

Mavacamten is a first-in-class, small-molecule, selective inhibitor of cardiac myosin that targets the underlying pathophysiology of HCM.^16,17 In the EXPLORER-HCM study (NCT03470545), treatment with mavacamten led to significant and clinically meaningful improvements in symptoms, functional capacity, left ventricular outflow tract (LVOT) gradients, biomarkers, and key aspects of quality of life in patients with symptomatic obstructive HCM.¹⁸ More specifically, mavacamten was associated with a significant improvement in pVO₂ at week 30 compared with placebo.

The objective of this prespecified exploratory analysis of EXPLORER-HCM was to evaluate additional maximal and submaximal parameters from CPET, beyond pVO₂, to examine the effects of mavacamten on exercise physiology in patients with obstructive HCM, and to expand our understanding of this disease.

Methods

Study Design

The details of the EXPLORER-HCM trial design and primary results have been reported elsewhere.^18,19 The trial protocol and statistical analysis plan are available in Supplement 2 and Supplement 3, respectively. In brief, EXPLORER-HCM was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients were randomized 1:1 to receive mavacamten (starting dose, 5 mg) or placebo for 30 weeks. Study drug (mavacamten or matching placebo, which were identical in appearance) was labeled with a unique identifying number that was assigned to a patient through the interactive response system. The principal investigator, site staff, and participants were masked. Randomization was stratified by current β-blocker use (yes or no), NYHA functional class (II or III), ergometer type (treadmill or bicycle), and consent for cardiovascular magnetic resonance imaging substudy (yes or no). Key inclusion criteria included being 18 years of age or older, having a diagnosis of obstructive HCM (unexplained left ventricular hypertrophy with maximal left ventricular wall thickness of 15 mm or more [or 13 mm or more with a family history of HCM]), having at least 1 peak LVOT gradient of 50 mm Hg or higher at rest or with provocation (Valsalva maneuver or after exercise), having a Valsalva LVOT gradient of at least 30 mm Hg, having a left ventricular ejection fraction of at least 55%, and being able to perform upright CPET with a respiratory exchange ratio (RER) of 1.0 or more or between 0.91 and 1.0 if peak exercise was achieved, as assessed by the core laboratory. Key exclusion criteria included a history of syncope or sustained ventricular tachyarrhythmia with exercise in the 6 months before screening, atrial fibrillation present at screening, and treatment or planned treatment with disopyramide, ranolazine, or a combination of β-blockers and nondihydropyridine calcium channel blockers.

Outcomes and Data Collection

CPET was conducted using a standardized treadmill or bicycle ergometer test protocol at screening and at week 30 prior to dosing with the study drug. The same modality (treadmill or upright bicycle) and the same time of day (as much as possible) were used for all CPET assessments conducted for a given patient. The treadmill protocol was a modified Naughton protocol and the cycle ergometer protocol was an incremental protocol with increases in work rate of 25 watts every 2 minutes. Site technicians were trained and certified for the protocol and followed a detailed CPET manual. Supine testing using a recumbent bicycle was not allowed and symptom-limited exercise tests were performed after a 4-hour fast. In addition to pVO₂, which was a component of the composite primary end point and a prespecified secondary efficacy end point, the following prespecified exploratory cardiovascular and performance parameters were assessed: VCO₂, minute ventilation (V_E), peak V_E/VCO₂ ratio, V_E/VCO₂ slope (determined from rest to peak exercise), peak RER, peak circulatory power (pVO₂ × peak systolic blood pressure), ventilatory power (peak systolic blood pressure/V_E/VCO₂ slope), peak metabolic equivalents (METs), partial pressure of end-tidal carbon dioxide (PETCO₂), peak exercise time, ventilatory threshold, and VO₂/workload slope. Per protocol, participants receiving β-blockers or calcium channel blockers should have been receiving the same dose at screening and at the end-of-treatment CPET, whenever possible, and these medications were administered prior to CPET. CPET data were analyzed centrally by the core laboratory (Cardiovascular and Metabolic Disease Research Institute, Mountain View, California). Reference values for some key CPET parameters are presented in eTable 1 in Supplement 1.

Statistical Analysis

The end points were summarized by treatment group and visit using descriptive statistics in the intention-to-treat population, defined as all randomized patients, regardless of whether they received the study drug. The estimates of treatment-group differences of the change from baseline to week 30 and the 95% CIs based on normal approximation were calculated. Between-group comparisons were based on analysis of covariance and all statistical tests were conducted at a 2-sided significance α level of .05. Treatment group (mavacamten vs placebo), baseline value of the corresponding end point of interest, and the 3 stratification factors (β-blocker use, NYHA class, and ergometer type) were treated as fixed effects. Least squares (LS) mean differences of the CPET parameters were tested separately and the P values generated from exploratory analyses were not adjusted for multiplicity and are considered to be nominal (descriptive). Owing to the low rate of discontinuation, missing data were not imputed. Post hoc correlations (pVO₂ vs N-terminal pro-brain natriuretic peptide [NT-proBNP], V_E/VCO₂ slope vs NT-proBNP, and V_E/VCO₂ slope vs Kansas City Cardiomyopathy Clinical Summary Score [KCCQ-CSS]) were analyzed in the intention-to-treat population using changes in mean values from baseline to week 30 for the relevant outcomes. Nominal P values were calculated for the test of correlations. SAS version 9.4 (SAS Institute) was used for statistical analyses.

Results

Patient Population

Patient demographics and baseline characteristics in the EXPLORER-HCM study have been described in detail previously and are presented in Table 1.^18,19 In summary, from May 30, 2018, to July 12, 2019, 429 patients were screened and 251 were randomized to receive mavacamten (n = 123) or placebo (n = 128) (Figure 1). The mean (SD) age of the patient population was 58.5 (11.9) years and 59% of patients were male. Most patients (183 of 251 ) had NYHA class II symptoms at baseline (73%) and most were receiving background HCM therapy (β-blockers: 94 of 123 patients for mavacamten [76%] and 95 of 128 patients for placebo [74%]; calcium channel blockers: 25 of 123 patients for mavacamten [20%] and 17 of 128 patients for placebo [13%]; Table 1). In both treatment arms, 45% of patients performed CPET using an exercise bicycle and 55% using a treadmill (Figure 1). Baseline CPET parameter values were similar for both treatment groups (Table 1) and consistent with values reported previously for patients with HCM.^10,20 Heart rate and systolic blood pressure at rest and at peak exercise are summarized in eTable 2 in Supplement 1.

Table 1. Demographics and Baseline Characteristics^a.

Demographics and baseline characteristics	No. (%)
Demographics and baseline characteristics	Mavacamten (n = 123)	Placebo (n = 128)
Age, mean (SD), y	58.5 (12.2)	58.5 (11.8)
Sex
Male	66 (54)	83 (65)
Female	57 (46)	45 (35)
Background HCM therapy
β-Blocker	94 (76)	95 (74)
Calcium channel blocker	25 (20)	17 (13)
Neither	4 (3)	16 (13)
Heart rate, mean (SD), bpm	63 (10.1)	62 (10.6)
Blood pressure, mean (SD), mm Hg
Systolic	128.4 (16.2)	128.4 (14.6)
Diastolic	75.5 (10.8)	76.1 (9.9)
NYHA functional class
II	88 (72)	95 (74)
III	35 (28)	33 (26)
Peak-exercise CPET parameters, mean (SD)
Peak VO₂, mL/kg/min	18.9 (4.9)	19.9 (4.9)
Peak V_E/VCO₂ ratio	35.4 (5.2)	34.2 (5.5)
Peak METs	5.4 (1.4)	5.7 (1.4)
Peak circulatory power, mL/kg/min × mm Hg	3087.1 (1165.2)	3284.8 (1173.3)
Peak exercise time, min	10.1 (4.0)	10.5 (4.2)
Peak RER	1.1 (0.1)	1.1 (0.1)
Peak PETCO₂, mm Hg	33.7 (4.5)	34.7 (5.1)
Nonpeak-exercise CPET parameters, mean (SD)
V_E/VCO₂ slope	33.6 (6.2)	32.4 (6.2)
Ventilatory power, mm Hg	4.9 (1.4)	5.2 (1.5)
Ventilatory threshold (ie, anaerobic threshold), mL/kg/min	11.5 (2.3)	11.5 (2.6)
PETCO₂ at rest, mm Hg	32.5 (4.2)	33.0 (4.3)
VO₂/workload slope	0.75 (0.25)	0.76 (0.26)
Biomarkers, geometric mean (CV%), ng/L
NT-proBNP	777 (136)	616 (108)
High-sensitivity cardiac troponin I	12.5 (208)	12.5 (373)
Echocardiographic parameters, mean (SD)
LVOT gradient, mm Hg
Rest	52 (29)	51 (32)
Valsalva	72 (32)	74 (32)
Postexercise	86 (34)	84 (36)

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Abbreviations: bpm, beats per minute; CPET, cardiopulmonary exercise testing; CV, coefficient of variation; HCM, hypertrophic cardiomyopathy; LVOT, left ventricular outflow tract; MET, metabolic equivalent; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; PETCO₂, partial pressure of end-tidal carbon dioxide; RER, respiratory exchange ratio; VCO₂, carbon dioxide output; V_E, minute ventilation; VO₂, oxygen uptake.

^{^a}

β-blocker use and NYHA function classification are based on information captured on electronic case report forms. The heart rate and SBP data presented here are from vital signs as opposed to the data presented in eTable 2 in Supplement 1, which present data measured during the CPET assessment.

Figure 1. — All randomized patients received at least 1 dose of study drug and were included in the efficacy analyses. Two patients who discontinued for other reasons (mavacamten, n = 1; placebo, n = 1) did not complete the week-30 visits within the window owing to scheduling issues. CPET indicates cardiopulmonary exercise testing; ECG, electrocardiogram.

^aOne patient discontinued treatment, but performed the CPET assessment at week 30.

CPET Parameters

Peak-Exercise CPET Parameters

Compared with placebo, mavacamten improved peak V_E/VCO₂ ratio (LS mean difference, −2.2; 95% CI, −3.05 to −1.26; P < .001), peak METs (LS mean difference, 0.4; 95% CI, 0.17-0.60; P < .001), peak circulatory power (LS mean difference, 372.9 mL/kg/min × mm Hg; 95% CI, 153.12-592.61 mL/kg/min × mm Hg; P = .001), peak exercise time (LS mean difference, 0.7 minutes; 95% CI, 0.13-1.24 minutes; P = .02), and peak PETCO₂ (LS mean difference, 2.0 mm Hg; 95% CI, 1.12-2.79 mm Hg; P < .001) (Figure 2, Table 2). There was no significant difference between treatment groups in peak RER (LS mean difference, 0.02; 95% CI, −0.003 to 0.040; P = .09).

Figure 2. — LS indicates least squares; MET, metabolic equivalent; PETCO₂, partial pressure of end-tidal carbon dioxide; VCO₂, carbon dioxide output; V_E, minute ventilation.

Table 2. CPET Parameters at Baseline, at Week 30, and Change From Baseline to Week 30.

	Mavacamten			Placebo			Adjusted difference in difference (95% CI)^a	P value
	Mean (SD) [No.]		Absolute difference (SD) [No.]^b	Mean (SD) [No.]		Absolute difference (SD) [No.]^b
	Baseline (n = 123)	Week 30	Absolute difference (SD) [No.]^b	Baseline (n = 128)	Week 30	Absolute difference (SD) [No.]^b
Peak-exercise CPET parameters
Peak V_E/VCO₂ ratio	35.4 (5.2)	33.4 (4.8) [120]	−1.9 (3.7) [120]	34.2 (5.5)	34.7 (5.9) [125]	0.5 (3.8) [125]	−2.2 (−3.05 to −1.26)	<.001
Peak METs	5.4 (1.4)	5.8 (1.5) [120]	0.4 (0.9) [120]	5.7 (1.4)	5.7 (1.5) [125]	−0.02 (0.86) [125]	0.4 (0.17-0.60)	<.001
Peak circulatory power, mL/kg/min × mm Hg	3087.1 (1165.2)	3505.9 (1214.4) [119]	414.1 (972.0) [119]	3284.8 (1173.3)	3300.2 (1208.4) [124]	−17.9 (869.1) [121]	372.9 (153.12-592.61)	.001
Peak exercise time, min	10.1 (4.0)	10.9 (4.5) [120]	0.8 (2.4) [120]	10.5 (4.2)	10.6 (4.3) [125]	0.1 (2.0) [125]	0.7 (0.13-1.24)	.02
Peak RER	1.1 (0.1)	1.1 (0.1) [120]	0.0 (0.1) [120]	1.1 (0.1)	1.1 (0.1) [125]	0.0 (0.1) [125]	0.02 (−0.003 to 0.040)	.09
Peak PETCO₂, mm Hg	33.7 (4.5)	35.5 (4.8) [110]	1.7 (3.4) [106]	34.7 (5.1)	34.4 (5.2) [113]	−0.4 (3.0) [109]	2.0 (1.12-2.79)	<.001
Nonpeak-exercise CPET parameters
V_E/VCO₂ slope	33.6 (6.2)	31.1 (5.0) [120]	−2.4 (4.6) [120]	32.4 (6.2)	32.9 (7.0) [125]	0.4 (4.1) [125]	−2.6 (−3.58 to −1.52)	<.001
Ventilatory power, mm Hg	4.9 (1.4)	5.6 (1.3) [119]	0.7 (1.4) [119]	5.2 (1.5)	5.3 (1.7) [124]	−0.03 (1.23) [121]	0.6 (0.29-0.90)	<.001
Ventilatory threshold (ie, anaerobic threshold), mL/kg/min	11.5 (2.3)	12.2 (2.7) [111]	0.7 (2.5) [106]	11.5 (2.6)	11.6 (2.6) [119]	0.1 (2.6) [116]	0.6 (−0.03 to 1.17)	.06
PETCO₂ at rest, mm Hg	32.5 (4.2)	33.2 (4.2) [109]	0.6 (3.0) [105]	33.0 (4.3)	32.7 (3.7) [113]	−0.3 (3.2) [108]	0.8 (0.07-1.53)	.03
VO₂/workload slope	0.75 (0.25)	0.79 (0.24) [118]	0.04 (0.17) [116]	0.76 (0.26)	0.76 (0.25) [123]	−0.02 (0.20) [123]	0.04 (0.002-0.086)	.04

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Abbreviations: CPET, cardiopulmonary exercise testing; MET, metabolic equivalent; PETCO₂, partial pressure of end-tidal carbon dioxide; RER, respiratory exchange ratio; VCO₂, carbon dioxide output; V_E, minute ventilation; VO₂, oxygen uptake.

^{^a}

The adjusted difference in difference corresponds to the LS mean treatment difference.

^{^b}

The absolute difference corresponds to the change from baseline to week 30.

Nonpeak-Exercise CPET Parameters

Mavacamten was associated with a significant improvement in V_E/VCO₂ slope compared with placebo (LS mean difference, −2.6; 95% CI, −3.58 to −1.52; P < .001). There was a significant increase in ventilatory power (LS mean difference, 0.6 mm Hg; 95% CI, 0.29-0.90 mm Hg; P < .001) and in VO₂/workload slope (LS mean difference, 0.04; 95% CI, 0.002 to 0.09; P = .04), favoring mavacamten over placebo. Mavacamten also improved PETCO₂ at rest (LS mean difference: 0.8 mm Hg; 95% CI, 0.07-1.53 mm Hg; P = .03) compared with placebo. However, although there was no significant difference in VO₂ at the ventilatory threshold (LS mean difference, 0.6 mL/kg/min; 95% CI, −0.03 to 1.17 mL/kg/min; P = .06) between mavacamten and placebo in exploratory analyses that were not adjusted for multiplicity, a numerical trend toward improvement was observed (Figure 3; Table 2).

Figure 3. — LS indicates least squares; PETCO₂, partial pressure of end-tidal carbon dioxide; VCO₂, carbon dioxide output; V_E, minute ventilation; VO₂, oxygen uptake.

Correlation Between CPET Parameters and Other Variables

Additionally, the study team sought to determine the association between change in CPET measures and markers of disease severity, including NT-proBNP (a biomarker of cardiac wall stress) and KCCQ-CSS (a patient-reported outcome symptom score).^18,21 It should be noted that reductions in NT-proBNP levels were statistically significantly greater with mavacamten than with placebo.¹⁸ In the mavacamten group, there was a negative correlation between change in pVO₂ and change in log₂ NT-proBNP at week 30 (Pearson correlation coefficient, −0.30; P = .002), indicating that improvements in pVO₂ were associated with a decrease in NT-proBNP levels (eTable 3 in Supplement 1). Change in pVO₂ and change in log₂ NT-proBNP levels at week 30 were not correlated in the placebo group (Pearson correlation coefficient, 0.064; P = .48). In the mavacamten group, there was a positive correlation between improvements in V_E/VCO₂ slope and reduction in NT-proBNP levels (Pearson correlation coefficient, 0.27; P = .003) (eTable 3 in Supplement 1). There were no significant correlations between improvement in V_E/VCO₂ slope and improvement in symptoms, as measured by the KCCQ-CSS, in either treatment group (eTable 3 in Supplement 1).

Discussion

Mavacamten was previously reported to improve pVO₂ in patients with obstructive HCM.¹⁸ The present results indicate that treatment with mavacamten was also able to improve the exercise capacity of patients on a range of CPET parameters, including peak-exercise independent parameters, allowing us to deepen our understanding of the full extent of mavacamten effects on exercise tolerance. The novelty of our findings resides in the fine characterization of the exercise limitation observed in patients with obstructive HCM. Because CPET parameters represent reproducible clinical surrogates for functional capacity, our findings suggest that mavacamten may potentially be associated with improvements in the ability of patients to perform physical activities.

Several factors have been identified as potential determinants of the exercise limitation in patients with HCM, including left ventricular diastolic and systolic dysfunction, LVOT obstruction, chronotropic incompetence, ventilation-to-perfusion mismatch, abnormal peripheral oxygen utilization, and the inability to increase stroke volume.^{8,22,23,24,25,26,27,28,29} Invasive hemodynamic studies have confirmed left ventricular diastolic dysfunction as a cause of the inability to increase stroke volume, which seems to be exacerbated by LVOT obstruction.^{25,28,30,31,32} The improvements in exercise capacity associated with mavacamten may be mediated by its beneficial effects on measures of diastolic function via an improved ability to increase stroke volume; however, further investigation is needed to confirm this hypothesis.^33,34,35 Furthermore, the reductions associated with mavacamten in peak V_E/VCO₂ ratio and in V_E/VCO₂ slope are indicative of improved ventilatory efficiency at peak and submaximal exercise, respectively. This may be due to a reduction in exercise-induced diastolic pressures and partial correction of the ventilation-to-perfusion mismatch exacerbated during exercise observed in patients with HCM.^13,36 Moreover, in patients with HCM, impaired ventilatory efficiency has been significantly associated with a composite end point of death, heart transplant, and implantation of a ventricular assist device.¹² Indeed, while V_E/VCO₂ slope of 30 or less might be considered normal, values more than 32 were shown to be powerful predictors of progression to heart failure.¹⁰ Consequently, the reduction in mean V_E/VCO₂ slope from 33.6 to 31.1 associated with mavacamten is clinically meaningful. Additionally, a modest improvement was observed in peak PETCO₂ with mavacamten compared with placebo though not to the normal range (eTable 1 in Supplement 1). These associations suggest that mavacamten not only improved symptoms and functional capacity, but also has the potential to improve clinical outcomes.

Given that most patients with HCM do not routinely exercise to peak exercise capacity, submaximal exercise CPET parameters may reflect what patients can typically physically achieve better than peak exercise parameters. In this context, the improvements in V_E/VCO₂ slope, in ventilatory power, in VO₂/workload slope, and in PETCO₂ at rest may better reflect the improvement in submaximal cardiopulmonary efficiency that in turn translates to symptomatic benefits that patients are experiencing after treatment with mavacamten. These parameters could be examined by clinicians when performing CPET in patients with HCM.

Although no significant association between V_E/VCO₂ slope and patient-reported symptoms (KCCQ-CSS) was observed in the present study, Nassif et al³⁷ reported a significant correlation between pVO₂ and KCCQ-CSS in patients enrolled in the EXPLORER-HCM study. Furthermore, mavacamten has been associated with improvements in symptoms and health status in patients with obstructive HCM, as measured by NYHA functional classification and by the KCCQ, respectively.^18,21 These findings, together with the correlation observed between CPET parameters (pVO₂ and V_E/VCO₂ slope) and measures of the neurohormonal effect of disease (NT-proBNP levels) are evidence of the beneficial effect of mavacamten on the patients’ daily lives.

Our findings suggest that the impaired exercise performance observed in patients with obstructive HCM is reversible with relief of the LVOT pressure gradient, which can be achieved following treatment with mavacamten. Indeed, a number of clinically meaningful CPET parameters consistently improved with mavacamten, and these benefits correlated with improvement in a biomarker of cardiac wall stress. Nevertheless, it seems that symptomatic improvement indicated by the change in KCCQ-CSS is more striking than that seen with CPET, suggesting that the pathophysiology of symptoms is not wholly captured by this testing. Thus, the benefits of mavacamten seem to extend beyond improvement in CPET parameters and fully understanding this represents an unmet need, and may help unravel further the pathophysiology of this complex disease. These considerations would be critical for the design of future trials in patients with obstructive or nonobstructive HCM.

Limitations

The results presented here should be interpreted in the context of several limitations. These analyses are exploratory in nature and should be viewed as hypothesis generating. However, it should be noted that most CPET parameters consistently improved with treatment and that no specific parameter was weighed over another, although some are likely correlated, the clinical interpretation of each parameter is conducted separately. Furthermore, the analytical strategy used here was aligned with the EXPLORER-HCM trial. The single–time point CPET measurement after treatment is also a limitation, as is the variability of symptom status in HCM. Another limitation is the lack of direct measures of daily living or energy expenditure. While multiple mechanisms of exercise impairment were assessed, the extent to which they overlap cannot be entirely accounted for. Additionally, the type of ergometer used can affect the measures of the CPET parameters; however, this potential issue was overcome because randomization was stratified by type of ergometer.

Conclusions

In conclusion, mavacamten therapy improved a range of CPET parameters beyond pVO₂, indicating consistent and broad benefits on maximal exercise capacity. The favorable effects of mavacamten on submaximal exertional tolerance provide further insights into the beneficial effect of mavacamten in patients with obstructive HCM.

Supplement 1.

eTable 1. Normal and abnormal values for key CPET parameters

eTable 2. Resting and peak heart rate and systolic blood pressure measured during CPET at Baseline, at Week 30 and Change from Baseline to Week 30

eTable 3. Change in pVO2 and Change in VE/VCO2 Slope Versus Change in Log2 NT-proBNP at Week 30, and Change in VE/VCO2 Slope Versus Change in KCCQ-CSS at Week 30

Click here for additional data file.^{(88.9KB, pdf)}

Supplement 2.

Protocol amendment 5 PCL.

Click here for additional data file.^{(344.7KB, pdf)}

Supplement 3.

SAP2.0.

Click here for additional data file.^{(807.2KB, pdf)}

Supplement 4.

Data sharing statement.

Click here for additional data file.^{(11.3KB, pdf)}

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eTable 1. Normal and abnormal values for key CPET parameters

eTable 2. Resting and peak heart rate and systolic blood pressure measured during CPET at Baseline, at Week 30 and Change from Baseline to Week 30

eTable 3. Change in pVO2 and Change in VE/VCO2 Slope Versus Change in Log2 NT-proBNP at Week 30, and Change in VE/VCO2 Slope Versus Change in KCCQ-CSS at Week 30

Click here for additional data file.^{(88.9KB, pdf)}

Supplement 2.

Protocol amendment 5 PCL.

Click here for additional data file.^{(344.7KB, pdf)}

Supplement 3.

SAP2.0.

Click here for additional data file.^{(807.2KB, pdf)}

Supplement 4.

Data sharing statement.

Click here for additional data file.^{(11.3KB, pdf)}

[hoi220083r1] 1.Maron BJ. Clinical course and management of hypertrophic cardiomyopathy. N Engl J Med. 2018;379:655-668. doi: 10.1056/NEJMra1710575 [DOI] [PubMed] [Google Scholar]

[hoi220083r2] 2.Robert-Paganin J, Auguin D, Houdusse A. Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition. Nat Commun. 2018;9(1):4019. doi: 10.1038/s41467-018-06191-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220083r3] 3.Marian AJ, Braunwald E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res. 2017;121(7):749-770. doi: 10.1161/CIRCRESAHA.117.311059 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220083r4] 4.van der Velden J, Tocchetti CG, Varricchi G, et al. Metabolic changes in hypertrophic cardiomyopathies: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology. Cardiovasc Res. 2018;114(10):1273-1280. doi: 10.1093/cvr/cvy147 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220083r5] 5.Heitner SB, Jacoby D, Lester SJ, et al. Mavacamten treatment for obstructive hypertrophic cardiomyopathy: a clinical trial. Ann Intern Med. 2019;170(11):741-748. doi: 10.7326/M18-3016 [DOI] [PubMed] [Google Scholar]

[hoi220083r6] 6.Borsari W, Davis L, Meiers E, Salberg L, Barbara M. Living with hypertrophic cardiomyopathy: the patient’s perspective. Future Cardiol. 2021;18(1):43-50. doi: 10.2217/fca-2021-0091 [DOI] [PubMed] [Google Scholar]

[hoi220083r7] 7.Zaiser E, Sehnert AJ, Duenas A, Saberi S, Brookes E, Reaney M. Patient experiences with hypertrophic cardiomyopathy: a conceptual model of symptoms and impacts on quality of life. J Patient Rep Outcomes. 2020;4(1):102. doi: 10.1186/s41687-020-00269-8 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220083r8] 8.Sharma S, Elliott P, Whyte G, et al. Utility of cardiopulmonary exercise in the assessment of clinical determinants of functional capacity in hypertrophic cardiomyopathy. Am J Cardiol. 2000;86(2):162-168. doi: 10.1016/S0002-9149(00)00854-7 [DOI] [PubMed] [Google Scholar]

[hoi220083r9] 9.Mezzani A. Cardiopulmonary exercise testing: basics of methodology and measurements. Ann Am Thorac Soc. 2017;14(suppl 1):S3-S11. doi: 10.1513/AnnalsATS.201612-997FR [DOI] [PubMed] [Google Scholar]

[hoi220083r10] 10.Magrì D, Santolamazza C. Cardiopulmonary exercise test in hypertrophic cardiomyopathy. Ann Am Thorac Soc. 2017;14(suppl 1):S102-S109. doi: 10.1513/AnnalsATS.201611-884FR [DOI] [PubMed] [Google Scholar]

[hoi220083r11] 11.Masri A, Pierson LM, Smedira NG, et al. Predictors of long-term outcomes in patients with hypertrophic cardiomyopathy undergoing cardiopulmonary stress testing and echocardiography. Am Heart J. 2015;169(5):684-692.e1. doi: 10.1016/j.ahj.2015.02.006 [DOI] [PubMed] [Google Scholar]

[hoi220083r12] 12.Finocchiaro G, Haddad F, Knowles JW, et al. Cardiopulmonary responses and prognosis in hypertrophic cardiomyopathy: a potential role for comprehensive noninvasive hemodynamic assessment. JACC Heart Fail. 2015;3(5):408-418. doi: 10.1016/j.jchf.2014.11.011 [DOI] [PubMed] [Google Scholar]

[hoi220083r13] 13.Coats CJ, Rantell K, Bartnik A, et al. Cardiopulmonary exercise testing and prognosis in hypertrophic cardiomyopathy. Circ Heart Fail. 2015;8(6):1022-1031. doi: 10.1161/CIRCHEARTFAILURE.114.002248 [DOI] [PubMed] [Google Scholar]

[hoi220083r14] 14.Magrì D, Limongelli G, Re F, et al. Cardiopulmonary exercise test and sudden cardiac death risk in hypertrophic cardiomyopathy. Heart. 2016;102(8):602-609. doi: 10.1136/heartjnl-2015-308453 [DOI] [PubMed] [Google Scholar]

[hoi220083r15] 15.Magrì D, Re F, Limongelli G, et al. Heart failure progression in hypertrophic cardiomyopathy—possible insights from cardiopulmonary exercise testing. Circ J. 2016;80(10):2204-2211. doi: 10.1253/circj.CJ-16-0432 [DOI] [PubMed] [Google Scholar]

[hoi220083r16] 16.Green EM, Wakimoto H, Anderson RL, et al. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science. 2016;351(6273):617-621. doi: 10.1126/science.aad3456 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220083r17] 17.Anderson RL, Trivedi DV, Sarkar SS, et al. Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers. Proc Natl Acad Sci U S A. 2018;115(35):E8143-E8152. doi: 10.1073/pnas.1809540115 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220083r18] 18.Olivotto I, Oreziak A, Barriales-Villa R, et al. ; EXPLORER-HCM study investigators . Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396(10253):759-769. doi: 10.1016/S0140-6736(20)31792-X [DOI] [PubMed] [Google Scholar]

[hoi220083r19] 19.Ho CY, Olivotto I, Jacoby D, et al. Study design and rationale of EXPLORER-HCM: evaluation of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy. Circ Heart Fail. 2020;13(6):e006853. doi: 10.1161/CIRCHEARTFAILURE.120.006853 [DOI] [PubMed] [Google Scholar]

[hoi220083r20] 20.Bayonas-Ruiz A, Muñoz-Franco FM, Ferrer V, et al. Cardiopulmonary exercise test in patients with hypertrophic cardiomyopathy: a systematic review and meta-analysis. J Clin Med. 2021;10(11):2312. doi: 10.3390/jcm10112312 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220083r21] 21.Spertus JA, Fine JT, Elliott P, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2021;397(10293):2467-2475. doi: 10.1016/S0140-6736(21)00763-7 [DOI] [PubMed] [Google Scholar]

[hoi220083r22] 22.Patel V, Critoph CH, Elliott PM. Mechanisms and medical management of exercise intolerance in hypertrophic cardiomyopathy. Curr Pharm Des. 2015;21(4):466-472. doi: 10.2174/138161282104141204142436 [DOI] [PubMed] [Google Scholar]

[hoi220083r23] 23.Hung RK, Al-Mallah MH, Whelton SP, et al. Effect of beta-blocker therapy, maximal heart rate, and exercise capacity during stress testing on long-term survival (from The Henry Ford Exercise Testing Project). Am J Cardiol. 2016;118(11):1751-1757. doi: 10.1016/j.amjcard.2016.08.060 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220083r24] 24.Van Baak MA. Beta-adrenoceptor blockade and exercise. an update. Sports Med. 1988;5(4):209-225. doi: 10.2165/00007256-198805040-00002 [DOI] [PubMed] [Google Scholar]

[hoi220083r25] 25.Lele SS, Thomson HL, Seo H, Belenkie I, McKenna WJ, Frenneaux MP. Exercise capacity in hypertrophic cardiomyopathy. role of stroke volume limitation, heart rate, and diastolic filling characteristics. Circulation. 1995;92(10):2886-2894. doi: 10.1161/01.CIR.92.10.2886 [DOI] [PubMed] [Google Scholar]

[hoi220083r26] 26.Jones S, Elliott PM, Sharma S, McKenna WJ, Whipp BJ. Cardiopulmonary responses to exercise in patients with hypertrophic cardiomyopathy. Heart. 1998;80(1):60-67. doi: 10.1136/hrt.80.1.60 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220083r27] 27.Dybro AM, Rasmussen TB, Nielsen RR, Andersen MJ, Jensen MK, Poulsen SH. Randomized trial of metoprolol in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2021;78(25):2505-2517. doi: 10.1016/j.jacc.2021.07.065 [DOI] [PubMed] [Google Scholar]

[hoi220083r28] 28.Dybro AM, Rasmussen TB, Nielsen RR, et al. Effects of metoprolol on exercise hemodynamics in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2022;79(16):1565-1575. doi: 10.1016/j.jacc.2022.02.024 [DOI] [PubMed] [Google Scholar]

[hoi220083r29] 29.Palau P, Seller J, Domínguez E, et al. Effect of β-blocker withdrawal on functional capacity in heart failure and preserved ejection fraction. J Am Coll Cardiol. 2021;78(21):2042-2056. doi: 10.1016/j.jacc.2021.08.073 [DOI] [PubMed] [Google Scholar]

[hoi220083r30] 30.Sugrue DD, McKenna WJ, Dickie S, et al. Relation between left ventricular gradient and relative stroke volume ejected in early and late systole in hypertrophic cardiomyopathy. Assessment with radionuclide cineangiography. Br Heart J. 1984;52(6):602-609. doi: 10.1136/hrt.52.6.602 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220083r31] 31.Ruzyłło W, Chojnowska L, Demkow M, et al. Left ventricular outflow tract gradient decrease with non-surgical myocardial reduction improves exercise capacity in patients with hypertrophic obstructive cardiomyopathy. Eur Heart J. 2000;21(9):770-777. doi: 10.1053/euhj.1999.1905 [DOI] [PubMed] [Google Scholar]

[hoi220083r32] 32.Critoph CH, Patel V, Mist B, Elliott PM. Cardiac output response and peripheral oxygen extraction during exercise among symptomatic hypertrophic cardiomyopathy patients with and without left ventricular outflow tract obstruction. Heart. 2014;100(8):639-646. doi: 10.1136/heartjnl-2013-304914 [DOI] [PubMed] [Google Scholar]

[hoi220083r33] 33.Ho CY, Mealiffe ME, Bach RG, et al. Evaluation of mavacamten in symptomatic patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2020;75(21):2649-2660. doi: 10.1016/j.jacc.2020.03.064 [DOI] [PubMed] [Google Scholar]

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PERMALINK

Effects of Mavacamten on Measures of Cardiopulmonary Exercise Testing Beyond Peak Oxygen Consumption

Matthew T Wheeler, MD, PhD

Iacopo Olivotto, MD

Perry M Elliott, MD

Sara Saberi, MD

Anjali T Owens, MD

Mathew S Maurer, MD

Ahmad Masri, MD

Amy J Sehnert, MD

Jay M Edelberg, MD, PhD

Yu-Mao Chen, MSc

Victoria Florea, MD

Rajeev Malhotra, MD

Andrew Wang, MD

Artur Oręziak, MD

Jonathan Myers, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design

Outcomes and Data Collection

Statistical Analysis

Results

Patient Population

Table 1. Demographics and Baseline Characteristicsa.

Figure 1. CONSORT Diagram.

CPET Parameters

Peak-Exercise CPET Parameters

Figure 2. Treatment Difference of the Change From Baseline to Week 30 Between Mavacamten and Placebo in Peak-Exercise Cardiopulmonary Exercise Testing (CPET) Parameters.

Table 2. CPET Parameters at Baseline, at Week 30, and Change From Baseline to Week 30.

Nonpeak-Exercise CPET Parameters

Figure 3. Treatment Difference of the Change From Baseline to Week 30 Between Mavacamten and Placebo in Submaximal Exercise Cardiopulmonary Exercise Testing (CPET) Parameters.

Correlation Between CPET Parameters and Other Variables

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Cited by other articles

Links to NCBI Databases

Table 1. Demographics and Baseline Characteristics^a.