Effect of Mavacamten in Women Compared With Men With Obstructive Hypertrophic Cardiomyopathy: Insights From EXPLORER-HCM
Abstract
BACKGROUND:
Compared with men, women with hypertrophic cardiomyopathy (HCM) have a higher incidence of heart failure and worse outcomes. We investigated baseline clinical and echocardiographic characteristics and response to mavacamten among women compared with men in the EXPLORER-HCM study (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy).
METHODS:
A prespecified post hoc analysis of sex from the blinded, randomized EXPLORER-HCM trial of mavacamten versus placebo in symptomatic patients with obstructive HCM was performed. Baseline characteristics were compared with t tests for continuous variables (expressed as mean values) and χ2 tests for categorical variables. Prespecified primary, secondary, and exploratory end points and echocardiographic measurements from baseline to end of treatment (week 30) were analyzed with ANCOVA for continuous end points and a generalized linear model with binomial distribution for binary end points, with adjustment for each outcome's baseline value, New York Heart Association class, β-blocker use, and ergometer type.
RESULTS:
At baseline, women (n=102) were older (62 years versus 56 years; P<0.0001), had lower peak oxygen consumption (16.7 mL·kg−1·min−1 versus 21.3 mL·kg−1·min−1; P<0.0001), were more likely to be assigned New York Heart Association class III (42% versus 17%; P<0.0001), had worse health status (Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score 64 versus 75; P<0.0001), and had higher baseline plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels (1704 ng/L versus 990 ng/L; P=0.004) than men (n=149). After 30 weeks of mavacamten treatment, similar improvements were observed in women and men in the primary composite end point (percentage difference on mavacamten versus placebo, 22% versus 19%, respectively; P=0.759) and in the secondary end points of change in postexercise left ventricular outflow tract gradient (−42.4 mm Hg versus −33.6 mm Hg; P=0.348), change in peak oxygen consumption (1.2 mL·kg−1·min−1 versus 1.6 mL·kg−1·min−1; P=0.633), and percentage achieving ≥1 New York Heart Association class improvement (41% versus 28%; P=0.254). However, women had greater improvement in health status (Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score 14.8 versus 6.1; P=0.026) and in the exploratory end point of NT-proBNP levels (−1322 ng/L versus −649 ng/L; P=0.0008).
CONCLUSIONS:
Although at baseline women with symptomatic obstructive HCM enrolled in EXPLORER-HCM were older and had worse heart failure and health status than men, treatment with mavacamten resulted in similar improvements in the primary and most secondary EXPLORER-HCM end points and greater improvements in health status and NT-proBNP.
REGISTRATION:
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03470545.
Clinical Perspective
What Is New?
•
In the EXPLORER-HCM trial (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) of patients with symptomatic obstructive hypertrophic cardiomyopathy, women were older and had worse heart failure and worse patient-reported health status at baseline.
•
Mavacamten treatment for 30 weeks produced comparable positive response in men and women for the primary composite end point and in the prespecified secondary end points of mean improvement in postexercise left ventricular outflow tract gradient, peak oxygen consumption, Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness of Breath subscore, and percentage achieving ≥1 New York Heart Association class improvement.
•
After mavacamten treatment for 30 weeks, women had a greater mean improvement in the prespecified secondary Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score health status outcome and in the exploratory end point of NT-proBNP (N-terminal pro-B-type natriuretic peptide) level.
What Are the Clinical Implications?
•
There are sex-related differences in the symptomatic expression of hypertrophic cardiomyopathy.
•
Both men and women with symptomatic obstructive hypertrophic cardiomyopathy show benefits from treatment with mavacamten.
•
Our data show favorable health status outcomes for women with obstructive hypertrophic cardiomyopathy with treatment with mavacamten that may be relevant to clinicians when considering mavacamten treatment.
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disease characterized by left ventricular (LV) hypertrophy.1–4 More than two-thirds of individuals with HCM have LV outflow tract (LVOT) obstruction at rest or with provocation.5 LVOT obstruction has been associated with higher incidence and severity of heart failure and worse outcomes.5 Recent observational studies show that, compared with men, women with HCM have more adverse hemodynamics, more LVOT obstruction, a higher incidence and greater severity of heart failure, and worse outcomes, including mortality.6,7
Mavacamten, a selective, allosteric and reversible cardiac myosin ATPase inhibitor that stabilizes the superrelaxed state of myosin,8 has recently been approved by health authorities in 5 continents, including the United States and Europe, as a first-in-class medical therapy for obstructive HCM (oHCM). In the phase 3, double-blinded, randomized, placebo-controlled EXPLORER-HCM trial (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; ClinicalTrials.gov identifier NCT03470545), mavacamten was shown to significantly reduce LVOT gradients and to improve peak oxygen consumption (pVO2), New York Heart Association (NYHA) class, NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, and patient-reported health status in patients with oHCM and NYHA class II or III symptoms.9,10
We performed a prespecified subgroup and additional post hoc analyses of the EXPLORER-HCM trial (1) to evaluate differences in baseline clinical characteristics between women and men and (2) to assess sex-associated differences in mavacamten response for the primary, secondary, and exploratory end points of EXPLORER-HCM.
METHODS
The EXPLORER-HCM trial has previously been described in detail.9 Briefly, EXPLORER-HCM assessed the effect of mavacamten in patients with HCM and an LVOT gradient of ≥50 mm Hg (at rest or with provocation) and NYHA class II or III symptoms.9 We performed a prespecified subgroup and additional post hoc analyses assessing whether there were differences in response to mavacamten by sex. We assessed 3 categories of end points: (1) the 2 components of the EXPLORER-HCM composite primary end point (≥1.5–mL/kg per minute increase in pVO2 and at least 1 NYHA class reduction or a ≥3.0–mL/kg per minute increase in pVO2 with no worsening of NYHA class)9; (2) changes in the EXPLORER-HCM secondary end points,9 including health status, as well as the prespecified exploratory end point of change in NT-proBNP; and (3) echocardiographic parameters that were previously described in a secondary analysis but not stratified by sex.10 Two measures of patient-reported health status were used as prespecified secondary end points, the Kansas City Cardiomyopathy Questionnaire (KCCQ)–Clinical Summary Score (CSS) and the Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness of Breath (HCMSQ-SoB) subscore. The KCCQ-CSS incorporates the KCCQ Physical Limitation and Total Symptom domains and ranges from 0 to 100 with higher scores indicating better health status. The KCCQ-CSS mirrors the key components that clinicians use to assign the NYHA class from the patient’s perspective.11,12 It has been validated in oHCM, and a difference in scores of 5 points on the KCCQ has been determined to represent a clinically significant change in health status.13,14 The HCMSQ is a more recently developed patient-reported outcome measurement tool for HCM15 that has 4 domains; 1 domain focuses on shortness of breath (range, 0 to 18 with higher score indicating more shortness of breath).15 A change of 1 to 2 points on the HCMSQ-SoB subscore has been determined to represent a clinically significant change.15
Baseline characteristics were compared between women and men with 2-sample t tests for continuous variables and χ2 tests for categorical variables. Geometric means and coefficients of variation were also provided for NT-proBNP and troponin because they represent the measure of central tendency of skewed data, in which the coefficient of variation measures the dispersion of data relative to the mean. ANCOVA was used to estimate treatment differences (mavacamten–placebo) by modeling the change in continuous secondary and exploratory end points from baseline to week 30 using treatment group (mavacamten versus placebo), women versus men, and their interaction. Treatment difference estimates for NT-proBNP were reported with the use of arithmetic means, whereas over-time values were reported with geometric means. The clinical responses of categorical primary and secondary end points at week 30 were analyzed with generalized linear models with binomial distribution and identity link16 on treatment group (mavacamten versus placebo), women versus men, and their interaction to estimate treatment differences. The primary end point in EXPLORER-HCM was a ≥1.5–mL/kg per minute increase in pVO2 and at least 1 NYHA class reduction or a ≥3.0–mL/kg per minute increase in pVO2 with no worsening of NYHA class after treatment with mavacamten for 30 weeks.9 Primary end-point models were adjusted for NYHA class. All other models were adjusted for their corresponding baseline values (eg, baseline KCCQ when examining change in KCCQ, baseline NT-proBNP when examining change in NT-proBNP) and for NYHA class, β-blocker use, and ergometer type (based on IXRS), which were stratification parameters at randomization. Two sensitivity analyses were performed to assess the robustness of the NT-proBNP results: an analysis that excluded observations with extreme values and another that used a robust regression17 that down-weights these observations. Final data for this subgroup analysis included all imputations performed in the EXPLORER-HCM study.9 Nominal P values are provided without multiplicity adjustment. BMS policy on data sharing may be found at https://bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html. The EXPLORER-HCM protocol was approved by site institutional review boards at all participating sites, as previously reported.9
RESULTS
Baseline Characteristics
As shown in Table 1, compared with men (n=149), women (n=102) in EXPLORER-HCM had similar background medical treatment of HCM and similar comorbid conditions but were older and more likely to be in NYHA functional class III and to have lower pVO2. Women had higher baseline plasma levels of NT-proBNP and lower levels of high sensitivity cardiac troponin I. Women had lower KCCQ-CSS and higher HCMSQ-SoB scores, consistent with worse health status and more shortness of breath.
| Characteristic | Men | Women | P value* | ||||
|---|---|---|---|---|---|---|---|
| Mavacamten (n=66) | Placebo (n=83) | Overall (n=149) | Mavacamten (n=57) | Placebo (n=45) | Overall (n=102) | ||
| Age, y, mean (SD) | 55.8 (11.1) | 56.3 (11.8) | 56.1 (11.5) | 61.6 (12.7) | 62.5 (10.7) | 62.0 (11.8) | <0.0001 |
| Age group, n (%) | <0.0001 | ||||||
| ≤60 y | 42 (64) | 51 (61) | 93 (62) | 22 (39) | 16 (36) | 38 (37) | |
| >60 y | 24 (36) | 32 (39) | 56 (38) | 35 (61) | 29 (64) | 64 (63) | |
| Race and ethnicity, n (%) | 0.300 | ||||||
| White | 61 (92) | 76 (92) | 137 (92) | 54 (95) | 38 (84) | 92 (90) | |
| Black or African American | 0 (0) | 3 (4) | 3 (2) | 1 (2) | 2 (4) | 3 (3) | |
| American Indian or Alaska Native | 0 (0) | 1 (1) | 1 (1) | 0 (0) | 0 (0) | 0 (0) | |
| Asian | 4 (6) | 1 (1) | 5 (3) | 0 (0) | 1 (2) | 1 (1) | |
| Unknown | 1 (2) | 2 (2) | 3 (2) | 2 (4) | 4 (9) | 6 (6) | |
| Region, n (%) | 0.470 | ||||||
| United States | 27 (41) | 36 (43) | 63 (42) | 26 (46) | 19 (42) | 45 (44) | |
| Spain | 6 (9) | 12 (14) | 18 (12) | 11 (19) | 4 (9) | 15 (15) | |
| Poland | 11 (17) | 12 (14) | 23 (15) | 5 (9) | 4 (9) | 9 (9) | |
| Other† | 22 (33) | 23 (28) | 45 (30) | 15 (26) | 18 (40) | 33 (32) | |
| HCM genetic testing performed, n (%) | 47 (71) | 68 (82) | 115 (77) | 43 (75) | 32 (71) | 75 (74) | 0.508 |
| Pathogenic or likely pathogenic HCM gene variant, n/N (%) | 13/47 (28) | 14/68 (21) | 27/115 (23) | 15/43 (35) | 8/32 (25) | 23/75 (31) | 0.271 |
| HCM duration, n (%) | 0.650 | ||||||
| ≤5 y | 35 (53) | 38 (46) | 73 (49) | 30 (53) | 17 (38) | 47 (46) | |
| >5 y | 31 (47) | 45 (54) | 76 (51) | 27 (47) | 28 (62) | 55 (54) | |
| Medical history, n (%) | |||||||
| Family history of HCM | 15 (23) | 21 (25) | 36 (24) | 18 (32) | 15 (33) | 33 (32) | 0.153 |
| Atrial fibrillation | 8 (12) | 13 (16) | 21 (14) | 4 (7) | 10 (22) | 14 (14) | 0.934 |
| Septal reduction therapy | 6 (9) | 3 (4) | 9 (6) | 5 (9) | 5 (11) | 10 (10) | 0.268 |
| Hypertension | 31 (47) | 38 (46) | 69 (46) | 29 (51) | 21 (47) | 50 (49) | 0.673 |
| Hyperlipidemia | 12 (18) | 24 (29) | 36 (24) | 15 (26) | 15 (33) | 30 (29) | 0.353 |
| Coronary artery disease | 4 (6) | 4 (5) | 8 (5) | 8 (14) | 2 (4) | 10 (10) | 0.181 |
| Obesity | 7 (11) | 11 (13) | 18 (12) | 8 (14) | 3 (7) | 11 (11) | 0.752 |
| Type 2 diabetes | 2 (3) | 5 (6) | 7 (5) | 4 (7) | 2 (4) | 6 (6) | 0.678 |
| Asthma | 6 (9) | 7 (8) | 13 (9) | 11 (19) | 4 (9) | 15 (15) | 0.139 |
| Chronic obstructive pulmonary disease | 1 (2) | 0 (0) | 1 (1) | 1 (2) | 3 (7) | 4 (4) | 0.070 |
| Background HCM therapy, n (%) | |||||||
| β-Blocker | 51 (77) | 64 (77) | 115 (77) | 43 (75) | 31 (69) | 74 (73) | 0.403 |
| Calcium channel blocker | 14 (21) | 8 (10) | 22 (15) | 11 (19) | 9 (20) | 20 (20) | 0.313 |
| Implantable cardioverter defibrillator | 12 (18) | 19 (23) | 31 (21) | 15 (26) | 10 (22) | 25 (25) | 0.489 |
| Body mass index, kg/m², mean (SD) | 29.4 (4.0) | 29.8 (5.3) | 29.6 (4.8) | 29.9 (5.7) | 28.2 (6.1) | 29.2 (5.9) | 0.149 |
| Baseline heart rate, bpm, mean (SD) | 61 (8.7) | 62 (10.6) | 62 (9.8) | 65 (11.1) | 62 (10.6) | 64 (10.9) | 0.056 |
| Baseline systolic blood pressure, mm Hg, mean (SD) | 129 (13.3) | 129 (12.0) | 129 (12.6) | 128 (19.1) | 127 (18.5) | 128 (18.7) | 0.537 |
| Baseline diastolic blood pressure, mm Hg, mean (SD) | 78 (10.5) | 77 (8.7) | 78 (9.5) | 73 (10.4) | 74 (11.6) | 73 (10.9) | 0.0011 |
| NYHA class, n (%) | <0.0001 | ||||||
| Class II | 55 (83) | 69 (83) | 124 (83) | 33 (58) | 26 (58) | 59 (58) | |
| Class III | 11 (17) | 14 (17) | 25 (17) | 24 (42) | 19 (42) | 43 (42) | |
| NT-proBNP, mean (SD), ng/L | 1094 (1510) | 907 (929) | 990 (1219) | 2014 (2498) | 1317 (1426) | 1704 (2110) | 0.0040 |
| NT-proBNP, geometric mean, ng/L (CV%)‡ | 600 (138) | 553 (102) | 573 (123) | 1056 (124) | 751 (108) | 908 (124) | 0.0023 |
| High-sensitivity cardiac troponin I, mean (SD), ng/L | 30.9 (63.7) | 39.0 (158.7) | 35.3 (124.5) | 18.6 (34.2) | 58.2 (192.0) | 35.5 (129.0) | 0.0084 |
| High-sensitivity cardiac troponin I, geometric mean, ng/L (CV%)‡ | 14.8 (206) | 13.4 (407) | 14.0 (352) | 10.3 (184) | 10.9 (330) | 10.5 (363) | 0.0084 |
| pVO2, mL/kg per minute, mean (SD) | 21.3 (4.5) | 21.3 (4.6) | 21.3 (4.6) | 16.2 (3.6) | 17.3 (4.3) | 16.7 (4.0) | <0.0001 |
| KCCQ-CSS, mean (SD) | 75 (15) | 75 (18) | 75 (17) | 65 (16) | 62 (18) | 64 (17) | <0.0001 |
| HCMSQ-SoB, mean (SD) | 4.5 (2.5) | 3.9 (3.0) | 4.1 (2.8) | 5.3 (2.4) | 5.6 (3.4) | 5.4 (2.9) | 0.0016 |
| Echocardiographic parameters, mean (SD) | |||||||
| LVEF, % | 73 (5) | 74 (6) | 74 (5) | 76 (7) | 74 (6) | 75 (7) | 0.050 |
| Left atrial diameter, mm | 44 (5) | 43 (6) | 44 (6) | 40 (5) | 40 (5) | 40 (5) | <0.0001 |
| Maximum LV wall thickness, mm | 20 (3) | 20 (3) | 20 (3) | 20 (4) | 19 (3) | 19 (4) | 0.033 |
| Posterior or inferolateral wall thickness, mm | 12 (2) | 12 (3) | 12 (2) | 11 (3) | 11 (2) | 11 (2) | 0.024 |
| Interventricular septum thickness, mm | 17 (2) | 17 (3) | 17 (2) | 16 (3) | 16 (3) | 16 (3) | 0.0032 |
| Septal-to-inferolateral wall thickness ratio | 1.5 (0.3) | 1.5 (0.3) | 1.5 (0.3) | 1.5 (0.4) | 1.6 (0.4) | 1.5 (0.4) | 0.468 |
| LA volume index, mL/m² | 41 (12) | 40 (14) | 40 (13) | 39 (12) | 42 (14) | 40 (13) | 0.987 |
| LV mass index, g/m² | 118 (23) | 112 (26) | 114 (25) | 106 (31) | 106 (26) | 106 (29) | 0.0151 |
| Lateral e′, cm/s | 7 (2) | 7 (3) | 7 (2) | 6 (2) | 6 (2) | 6 (2) | 0.0044 |
| Septal e′, cm/s | 5 (1) | 5 (2) | 5 (1) | 4 (1) | 4 (1) | 4 (1) | <0.0001 |
| Lateral E/e′ ratio | 14 (6) | 14 (6) | 14 (6) | 16 (6) | 19 (10) | 17 (8) | 0.0002 |
| Septal E/e′ ratio | 19 (7) | 18 (7) | 19 (7) | 22 (7) | 24 (11) | 23 (9) | <0.0001 |
| Peak E wave velocity, cm/s | 86 (27) | 86 (24) | 86 (26) | 89 (22) | 96 (32) | 92 (27) | 0.0399 |
| Peak A wave velocity, cm/s | 72 (23) | 76 (24) | 74 (23) | 89 (26) | 86 (30) | 87 (28) | <0.0001 |
| LV end-diastolic volume index, mL/m² | 35 (7) | 35 (8) | 35 (7) | 30 (7) | 31 (7) | 30 (7) | <0.0001 |
| LVOT gradient at rest, mm Hg | 51 (29) | 48 (32) | 49 (31) | 53 (30) | 57 (32) | 54 (31) | 0.143 |
| LVOT gradient on Valsalva | 70 (34) | 74 (31) | 72 (32) | 75 (30) | 74 (34) | 75 (31) | 0.525 |
| LVOT gradient, after exercise, mm Hg | 85 (32) | 84 (34) | 84 (33) | 86 (37) | 85 (38) | 86 (38) | 0.741 |
Values are mean (SD) for continuous variables and number (percent) or number/total (percent) for categorical variables.
CV% indicates coefficient of variation; HCM, hypertrophic cardiomyopathy; HCMSQ-SoB, Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness of Breath; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score; LV, left ventricular; LAVI, left atrial volume index; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NHYA, New York Heart Association; and pVO2, peak oxygen consumption.
*
P values are derived from the overall subgroup comparison.
†
Other includes Israel, Germany, France, Czech Republic, Denmark, The Netherlands, Portugal, Italy, Belgium, and the United Kingdom.
‡
NT-proBNP and high-sensitivity cardiac troponin I values are also presented as geometric means (CV%) for appropriate measure of central tendency of skewed data, where CV% measures the dispersion of data relative to the mean.
With respect to echocardiographic parameters, compared with men, women had similar baseline LV ejection fraction (LVEF) and lower maximal LV wall thickness, LV septal thickness, and LV end-diastolic volume index. Women had higher E/e’, consistent with higher LV filling pressures. Although left atrial diameter among women was lower, left atrial volume indexed for body surface area was not significantly different between men and women.
Response to Treatment: EXPLORER-HCM Primary End Point
As shown in Table 2, similar improvements were observed in the percentage of women compared with men who had positive response (ie, percent difference on mavacamten versus placebo) for the primary composite end point. The differences in percentage of women compared with men with positive response for either component of the primary end point were also similar.
| Prespecified primary EXPLORER-HCM end points | Response at week 30, n/N (%) | Difference (95% CI)* Mavacamten–Placebo, % | Interaction P value | |
|---|---|---|---|---|
| Mavacamten | Placebo | |||
| Either ≥1.5 mL/kg per minute increase in pVO2 with ≥1 NYHA class improvement or ≥3.0 mL/kg per minute increase in pVO2 with no worsening of NYHA class | 0.759 | |||
| Men | 26/66 (39) | 17/83 (21) | 19 (4, 34) | |
| Women | 19/57 (33) | 5/45 (11) | 22 (7, 38) | |
| pVO2 increase ≥1.5 mL/kg per minute with ≥1 NYHA class improvement | 0.337 | |||
| Men | 22/66 (33) | 15/83 (18) | 16 (2, 29) | |
| Women | 19/57 (33) | 3/45 (7) | 25 (11, 39) | |
| pVO2 increase ≥3.0 mL/kg per minute with no worsening of NYHA class | 0.169 | |||
| Men | 20/66 (30) | 10/83 (12 | 19 (6, 32) | |
| Women | 9/57 (16) | 4/45 (9) | 6 (−6, 19) | |
EXPLORER-HCM indicates Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NYHA, New York Heart Association; and pVO2, peak oxygen consumption.
*
Model estimates represent the absolute difference in means and are adjusted for NYHA class only because of sample size.
Response to Treatment: Prespecified EXPLORER-HCM Secondary End Points and Exploratory NT-proBNP End Point
As shown in Table 3, after treatment with mavacamten for 30 weeks, compared with men, women in EXPLORER-HCM had similar changes in postexercise LVOT gradient, pVO2, difference between treatments (mavacamten–placebo) in achieving ≥1 improvement in NYHA class, and HCMSQ-SoB scores. There were similar changes in mean Valsalva-induced LVOT gradients in women and men in response to mavacamten treatment (Averages across study visits by treatment and sex are shown in Figure 1). Women had a greater improvement in the secondary health status end point measured by KCCQ-CSS and in the exploratory end point of NT-proBNP. Two sensitivity analyses were performed to assess the robustness of the NT-proBNP results: 1 excluding observations with extreme values and another using a robust regression that down-weights these observations. In both analyses, the interaction remained significant (P=0.0003 and P=0.0002, respectively). Average KCCQ-CSS scores, NT-proBNP levels, and troponin values across study visits by treatment and sex are shown in Figure 2, Figure 3, and Figure S1, respectively.
| Prespecified secondary EXPLORER-HCM end points | Change from baseline to week 30 | Difference (95% CI)* Mavacamten–Placebo | Interaction P value | |
|---|---|---|---|---|
| Mavacamten | Placebo | |||
| Postexercise LVOT gradient, mm Hg | 0.348 | |||
| Men | −46.7 (37.8), n=63 | −13.1 (29.9), n=79 | −33.6 (−45.3, −21.8) | |
| Women | −47.9 (43.5), n=54 | −5.5 (28.7), n=43 | −42.4 (−56.6, −28.2) | |
| pVO2, mL/kg per minute | 0.633 | |||
| Men | 1.6 (3.6), n=65 | −0.0 (2.9), n=82 | 1.6 (0.6, 2.5) | |
| Women | 1.2 (2.4), n=55 | −0.1 (3.3), n=43 | 1.2 (−0.0, 2.4) | |
| ≥1 NYHA class improvement, n/N (%) | 0.254 | |||
| Men | 42/66 (64) | 29/83 (35) | 28 (13, 44) | |
| Women | 38/57 (67) | 11/45 (24) | 41 (25, 58) | |
| KCCQ-CSS | 0.0259 | |||
| Men | 10.0 (12.9), n=52 | 3.9 (13.1), n=59 | 6.1 (1.3, 10.8) | |
| Women | 18.2 (15.1), n=40 | 4.8 (15.1), n=29 | 14.8 (8.7, 20.9) | |
| HCMSQ-SoB subscore | 0.305 | |||
| Men | −2.4 (2.7), n=44 | −0.7 (2.3), n=56 | −1.5 (−2.4, −0.6) | |
| Women | −3.2 (2.6), n=41 | −1.2 (2.5), n=30 | −2.3 (−3.3, −1.2) | |
| NT-proBNP concentration, ng/L† | 0.0008 | |||
| Men | −764.1 (1382.9), n=63 | −13.2 (466.8), n=80 | −649.2 (−893.8, −404.6) | |
| Women | −1649.8 (2194.7), n=53 | 150.3 (667.3), n=41 | −1321.8 (−1626.5, −1017.1) | |
Values are mean (SD); n is the subgroup sample size for continuous end points; and n/N (%) is for indicator end point.
EXPLORER-HCM indicates Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; HCMSQ-SoB, Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness of Breath; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire–Clinical Symptom Score; LVOT, left ventricular outflow tract; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; and pVO2, peak oxygen consumption.
*
Model estimates represent the absolute difference in means and are adjusted for the corresponding baseline values, NYHA class, β-blocker use, and ergometer type (based on IXRS) with the exception of LVOT gradient.
†
NT-proBNP was a pre-specified exploratory end point. While baseline and per visit NT-proBNP values are reported as geometric means, these estimates represent difference in arithmetic means.
There were similar numbers of men and women who had ≥1 serious adverse event (SAEs). Although the numbers of men and women with SAEs were similar, only 1 man and 5 women had ≥2 SAEs. SAEs are specified in Table S1. As reported previously,9 9 subjects had transient LVEF <50% (6 men in the treatment arm, 2 men in the placebo arm, 1 woman in the treatment arm).
Response to Treatment: EXPLORER-HCM Echocardiographic Measures
As shown in Table 4, after treatment with mavacamten for 30 weeks, compared with men, women in EXPLORER-HCM had a lower mean decrease in LVEF from baseline. No other significant interaction between sex group and response to mavacamten was observed for changes in any other EXPLORER-HCM echocardiographic measures. Specifically, women had similar improvements in resting and Valsalva LVOT gradients. There were also similar improvements in LV filling pressures as determined by the change in E/e’. As reported previously,10 the degree of mitral regurgitation was not quantified in EXPLORER-HCM; response of this echocardiographic parameter to mavacamten therefore could not be assessed.
| Echocardiographic end points | Change from baseline to week 30 | Difference (95% CI)* Mavacamten–Placebo | Interaction P value | |
|---|---|---|---|---|
| Mavacamten | Placebo | |||
| LVEF % | 0.0490 | |||
| Men | −4.7 (8.1), n=62 | 0.2 (6.1), n=76 | −5.6 (−7.7, −3.4) | |
| Women | −3.0 (7.1), n=52 | −0.3 (7.9), n=43 | −2.2 (−4.8, 0.4) | |
| Resting LVOT gradient, mm Hg | 0.758 | |||
| Men | −38.9 (28.4), n=64 | −4.1 (28.8), n=81 | −33.3 (−40.4, −26.2) | |
| Women | −38.3 (31.1), n=53 | −8.2 (26.3), n=42 | −31.5 (−40.3, −22.8) | |
| Valsalva LVOT gradient, mm Hg | 0.824 | |||
| Men | −50.5 (34.9), n=64 | −13.9 (32.6), n=81 | −38.9 (−47.6, −30.2) | |
| Women | −47.4 (34.0), n=53 | −8.8 (27.7), n=43 | −37.4 (−48.0, −26.7) | |
| Interventricular septal thickness, mm | 0.118 | |||
| Men | 0.0 (1.5), n=63 | 1.5 (1.9), n=79 | −1.5 (−2.0, −0.9) | |
| Women | 0.3 (1.6), n=51 | 1.0 (1.4), n=41 | −0.8 (−1.5, −0.2) | |
| Inferolateral wall thickness, mm | 0.450 | |||
| Men | −0.6 (1.7), n=62 | 0.3 (1.9), n=72 | −0.9 (−1.4, −0.4) | |
| Women | −0.5 (1.8), n=48 | 0.3 (1.3), n=39 | −0.6 (−1.2, 0.0) | |
| Septal-to-inferolateral wall thickness ratio | 0.885 | |||
| Men | 0.06 (0.23), n=62 | 0.08 (0.27), n=72 | −0.02 (−0.09, 0.06) | |
| Women | 0.06 (0.26), n=47 | 0.06 (0.26), n=38 | −0.01 (−0.10, 0.08) | |
| LVMI, g/m² | 0.348 | |||
| Men | −9.4 (16.9), n=61 | 9.0 (15.0), n=72 | −17.3 (−22.5, −12.2) | |
| Women | −4.7 (18.8), n=47 | 8.5 (15.9), n=38 | −13.4 (−19.9, −6.9) | |
| LAVI, mL/m² | 0.643 | |||
| Men | −7.7 (7.7), n=64 | 0.6 (8.4), n=80 | −7.8 (−10.3, −5.3) | |
| Women | −7.3 (8.0), n=51 | −1.4 (9.1), n=43 | −6.9 (−10.0, −3.7) | |
| Lateral e′, cm/s | 0.696 | |||
| Men | 1.7 (1.9), n=60 | 0.1 (1.7), n=75 | 1.5 (0.9, 2.0) | |
| Women | 1.5 (1.8), n=47 | 0.3 (1.8), n=41 | 1.3 (0.6, 2.0) | |
| Septal e′, cm/s | 0.608 | |||
| Men | 0.6 (1.7), n=63 | 0.0 (1.1), n=79 | 0.5 (0.1, 1.0) | |
| Women | 0.7 (1.3), n=50 | −0.1 (0.9), n=40 | 0.7 (0.2, 1.2) | |
| E/e′ lateral ratio | 0.469 | |||
| Men | −3.6 (4.5), n=59 | −0.0 (4.0), n=71 | −3.5 (−5.2, −1.9) | |
| Women | −3.9 (5.1), n=45 | 0.2 (6.2), n=41 | −4.5 (−6.5, −2.5) | |
| E/e′ septal ratio | 0.362 | |||
| Men | −3.3 (6.5), n=62 | −0.4 (4.0), n=77 | −2.8 (−4.5, −1.1) | |
| Women | −3.9 (5.5), n=49 | −0.0 (5.2), n=40 | −4.1 (−6.2, −2.0) | |
| Peak E-wave velocity, cm/s | 0.857 | |||
| Men | −6.7 (23.1), n=62 | −2.8 (17.6), n=79 | −4.2 (−9.9, 1.5) | |
| Women | −6.1 (18.2), n=49 | −3.0 (18.5), n=43 | −5.0 (−12.0, 2.1) | |
| Peak A-wave velocity, cm/s | 0.271 | |||
| Men | 0.1 (14.7), n=58 | −0.3 (16.0), n=73 | −0.2 (−5.4, 4.9) | |
| Women | −2.6 (14.8), n=51 | 2.9 (18.6), n=42 | −4.7 (−10.8, 1.4) | |
Values are mean (SD); n is subgroup sample size.
LAVI indicates left atrial volume index; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; and LVOT, left ventricular outflow tract.
*
Model estimates represent the absolute difference in means and are adjusted for the corresponding baseline values, New York Heart Association class, β-blocker use, and ergometer type (based on IXRS).
DISCUSSION
It is increasingly important for clinical trials to explicitly examine potential differences in treatment effect for women compared with men.18–21 Our analysis of sex differences in response to 30 weeks of mavacamten treatment in the EXPLORER-HCM trial found no sex-related differences in the primary composite end point, in either of its components, or in the prespecified secondary end points of mean improvement in postexercise LVOT gradient, pVO2, and HCMSQ-SoB subscore or in percentage achieving ≥1 NYHA class improvement. However, women had a greater mean improvement in the prespecified secondary KCCQ-CSS health status outcome and in the exploratory end point of NT-proBNP levels.
At baseline, we found that women compared with men enrolled in EXPLORER-HCM were older, had lower pVO2, were more likely to be assigned NYHA functional class III, and had significantly higher NT-proBNP levels and worse health status as measured by the KCCQ-CSS and the HCMSQ-SoB subscore. With respect to echocardiographic parameters, women were observed to have higher E/e’, consistent with higher LV filling pressures. Our findings confirm and extend those from other studies that have reported that women with HCM are older at the time of diagnosis, have higher rates of LVOT obstruction, are more likely to have heart failure, and have worse outcomes, including mortality.6,7,22–24 Although the presence and magnitude of LVOT obstruction have been proposed to contribute to the higher incidence of heart failure and worse outcomes observed in women with HCM, in EXPLORER-HCM, all patients had LVOT obstruction, and resting, Valsalva, and postexercise LVOT gradients were similar between women and men at baseline. We therefore cannot implicate higher LVOT gradients as a contributor to the sex-related differences we observed at baseline. A recent study combining echocardiographic assessment with tissue histopathology and functional measurements of cardiomyocytes obtained from myectomy samples from the same individuals with oHCM found that, compared with men, women had more severe diastolic dysfunction, decreased capillary density, a change in titin isoform composition, and more fibrosis.25 Such sex-related pathoanatomical differences may help explain the higher filling pressures and worse heart failure we observed in women in EXPLORER-HCM.
Compared with men, women in EXPLORER-HCM had lower pVO2. Given that women in EXPLORER-HCM were older and that pVO2 is known to be lower in women compared with men and is also known to decrease with age,26 the lower pVO2 we observed in women at baseline was an expected finding and supports the sex-related differences observed in a prior study that assessed pVO2 in HCM.6
The higher levels of NT-proBNP at baseline and greater improvement after 30 weeks of treatment with mavacamten we observed in women compared with men in EXPLORER-HCM merit further discussion. Higher baseline NT-proBNP levels have been reported in women in the general population,27 but heart failure populations have not consistently shown this sex-related difference.27,28 In fact, some investigators have proposed that sex differences are overridden in advanced stages of heart failure.28 In patients with HCM, NT-proBNP level has been shown to be an important marker of symptoms and adverse outcomes, including heart failure and sudden cardiac death, and is an independent predictor of survival.29–35 Repeated measures of NT-proBNP in an observational registry of oHCM and nonobstructive HCM showed that, compared with men, women had higher NT-proBNP levels and E/e’ at baseline and that women continued to have higher NT-proBNP levels and higher rates of heart failure hospitalization at the 2-year follow-up.36 In contrast, NT-proBNP has been shown to decrease after successful septal reduction therapy, in parallel with decreased LVOT obstruction and improvement in NYHA class, heart failure symptoms, and KCCQ scores.37,38 We found that treatment with mavacamten for 30 weeks also resulted in a decrease in NT-proBNP levels in women. Although at baseline women in EXPLORER-HCM had significantly higher NT-proBNP levels, after treatment with mavacamten, their NT-proBNP levels improved to levels that were similar to those seen in mavacamten-treated men. Our results therefore demonstrate that the worse hemodynamics and heart failure observed in women with HCM could be significantly improved by mavacamten treatment and that women may have a greater treatment effect compared with men as measured by this end point.
The observation of greater improvement in KCCQ-measured health status from myosin inhibition in women than men also warrants further discussion. The KCCQ has been extensively validated in multiple heart failure populations, including HCM.11,13,39,40 A change of 5 points on the KCCQ has been determined to be a clinically significant change in health status.12–14,41 Changes of 10 and 15 to 20 points represent moderate to large and large to very large clinical changes in patients’ health status.12 At baseline, women in EXPLORER-HCM had lower KCCQ scores, consistent with sex-related differences in health status observed in other heart failure cohorts.42–44 However, even after adjustment for the baseline differences in KCCQ-CS scores between men and women, men had a clinically important 6-point benefit from mavacamten treatment, and women had more than twice as large a benefit. As a prespecified but secondary end point, these results may be considered hypothesis generating. However, we believe that these results are potentially clinically meaningful and deserving of further investigation, especially in light of the fact that improving patients’ health status is a primary treatment goal for patients with oHCM.45–47
Insights into sex-related differences in clinical characteristics and responses to treatment may be gained from clinical trials in other forms of heart failure with preserved ejection fraction. Two recent clinical trials in patients with heart failure with preserved ejection fraction assessed sex-related differences in clinical characteristics and responses to treatment.48,49 The EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction) observed that women had worse baseline health status,48 a finding that has been supported by other studies of patients with heart failure with preserved ejection fraction.50 The PARAGON study (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) also observed that women had worse health status, more heart failure symptoms, and a greater likelihood of being in NYHA class III heart failure at baseline; this study reported that treatment with sacubitril-valsartan (versus valsartan) resulted in fewer heart failure hospitalizations in women compared with men.48,49 These studies, similar to ours, found that although women were in more severe heart failure and had worse health status at baseline, they had a similar or greater response to treatment compared with men.48,49
Our study should be interpreted in the context of several potential limitations. Although the subgroup analysis by sex was prespecified, aspects of this analysis were post hoc. Furthermore, the numbers in each group are small, although this would have decreased our power to detect sex-based interactions in health status and NT-proBNP. In addition, as stated in the Methods section, we did not adjust for multiplicity, and replicating these findings in future studies is needed to validate these observations. Last, given that Black subjects made up only 2.4% of EXPLORER-HCM participants (only 1 Black patient in the mavacamten treatment group), it is unclear whether the sex-related responses we observed in response to mavacamten in EXPLORER-HCM are pertinent to HCM patients of other races or ethnicities, and further studies in more diverse groups are clearly needed.
Conclusions
Our analyses demonstrate that, at baseline in EXPLORER-HCM, women with symptomatic oHCM were older and more likely to have NYHA class III heart failure, higher plasma levels of NT-proBNP, and worse patient-reported health status. Despite these markers of a more severe oHCM clinical syndrome, compared with men, women in EXPLORER-HCM treated with mavacamten had similar improvement in the primary end point and most secondary end points, as well as greater improvement in health status and NT-proBNP levels. These findings have important implications for understanding sex-related differences in the clinical expression of HCM and support patient selection criteria inclusive of women with severe oHCM when considering mavacamten treatment.
ARTICLE INFORMATION
Supplemental Material
Figure S1
Table S1
Footnote
Nonstandard Abbreviations and Acronyms
- HCM
- hypertrophic cardiomyopathy
- HCMSQ-SoB
- Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness of Breath
- KCCQ
- Kansas City Cardiomyopathy Questionnaire
- KCCQ-CSS
- Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score
- LV
- left ventricular
- LVEF
- left ventricular ejection fraction
- LVOT
- left ventricular outflow tract
- NT-proBNP
- N-terminal pro-B-type natriuretic peptide
- NYHA
- New York Heart Association
- oHCM
- obstructive hypertrophic cardiomyopathy
- pVO2
- peak oxygen consumption
- SAE
- serious adverse event
Supplemental Material
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© 2023 American Heart Association, Inc.
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History
Received: 17 May 2023
Accepted: 24 October 2023
Published online: 14 November 2023
Published in print: 13 February 2024
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Disclosures
Disclosures Dr Cresci reports institution research funding for clinical trial from Imbria Pharmaceuticals and serving on the Data Monitoring Committee for Cytokinetics. Dr Bach reports institution research funding for clinical trials from BMS and Cytokinetics. Dr Saberi reports consulting for Cytokinetics and BMS. Dr Owens reports consulting for BMS, Cytokinetics, Pfizer, Tenaya, Renovacor, Stealth, Edgewise, Lexicon, and Biomarin. Dr Spertus reports consulting on patient-reported outcomes and evidence evaluation for Alnylam, AstraZeneca, Bayer, Merck, Janssen, BMS, Edwards, Kineksia, 4DT Medical, Terumo, Cytokinetics, Imbria, and United Healthcare; receiving research grants from BMS, Abbott Vascular, and Janssen; holding copyright to the Seattle Angina Questionnaire, KCCQ, and Peripheral Artery Questionnaire; and serving on the Board of Directors for Blue Cross Blue Shield of Kansas City. Dr Hegde reports fees paid to institution for core laboratory services from Myokardia/BMS. Dr Lakdawala reports consulting for BMS, Cytokinetics, Tenaya, Pfizer, and Akros and receiving research support from BMS and Pfizer. Dr Nilles and D.M. Wojdyla report no conflicts. Dr Sehnert is an employee of BMS and owns stock/stock grants from BMS. Dr Wang reports research grant to institution from BMS and Cytokinetics and serving on the Advisory Board (consultant) for BMS, Cytokinetics, and BioMarin and speakers’ bureau for BMS.
Sources of Funding
MyoKardia Inc, a wholly owned subsidiary of Bristol Myers Squibb (BMS), provided funding for these statistical analyses and the EXPLORER-HCM study. Dr Cresci’s effort is supported in part by the National Institutes of Health (R01HL170079).
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