Research
JAMA Cardiology | Original Investigation
Aficamten and Cardiopulmonary Exercise Test Performance A Substudy of the SEQUOIA-HCM Randomized Clinical Trial
Matthew M. Y. Lee, PhD, MBChB; Ahmad Masri, MD; Michael E. Nassif, MD, MS; Roberto Barriales-Villa, MD, PhD;
Theodore P. Abraham, MD; Brian L. Claggett, PhD; Caroline J. Coats, MD, PhD; Juan Ramón Gimeno, MD, PhD; Ian J. Kulac, MS; Isabela Landsteiner, MD; Changsheng Ma, MD; Martin S. Maron, MD; Iacopo Olivotto, MD; Anjali T. Owens, MD; Scott D. Solomon, MD; Josef Veselka, MD, PhD; Daniel L. Jacoby, MD; Stephen B. Heitner, MD; Stuart Kupfer, MD; Fady I. Malik, MD, PhD; Lisa Meng, PhD; Amy Wohltman, ME; Gregory D. Lewis, MD; for the SEQUOIA-HCM Investigators
IMPORTANCE Impaired exercise capacity is a cardinal manifestation of obstructive hypertrophic cardiomyopathy (HCM). The Phase 3 Trial to Evaluate the Efficacy
and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) is a pivotal study characterizing the treatment effect of aficamten,
a next-in-class cardiac myosin inhibitor, on a comprehensive set of exercise performance and clinical measures.
OBJECTIVE To evaluate the effect of aficamten on exercise performance using cardiopulmonary exercise testing with a novel integrated measure of maximal and submaximal exercise performance and evaluate other exercise measures and clinical correlates.
DESIGN, SETTING, AND PARTICIPANTS This was a prespecified analysis from SEQUOIA-HCM,
a double-blind,placebo-controlled, randomized clinical trial. Patients were recruited from 101 sites in 14 countries (North America, Europe, Israel, and China). Individuals with symptomatic obstructive HCM with objective exertional intolerance (peak oxygen uptake [pVO2] ≤90% predicted) were included in the analysis. Data were analyzed from January to March 2024.
INTERVENTIONS Randomized 1:1 to aficamten (5-20 mg daily) or matching placebo for 24 weeks.
MAIN OUTCOMES AND MEASURES The primary outcome was change from baseline to week 24 in integrated exercise performance, defined as the 2-componentz score of pVO2 and ventilatory efficiency throughout exercise (minute ventilation [VE]/carbon dioxide output [VCO2] slope). Response rates for achieving clinically meaningful thresholds for change in pVO2 and correlations with clinical measures of treatment effect (health status, echocardiographic/cardiac biomarkers) were also assessed.
RESULTS Among 282 randomized patients (mean [SD] age, 59.1 [12.9] years; 115 female [40.8%], 167 male [59.2%]), 263 (93.3%) had core laboratory-validated exercise testing at baseline and week 24. Integrated composite exercise performance improved in the aficamten group (mean [SD] z score, 0.17 [0.51]) from baseline to week 24, whereas the placebo group deteriorated (mean [SD] z score, −0.19 [0.45]), yielding a placebo-corrected improvement of
0.35 (95% CI, 0.25-0.46;P <.001). Further, aficamten treatment demonstrated significant improvements in total workload, circulatory power, exercise duration, heart rate reserve, peak heart rate, ventilatory efficiency, ventilatory power, and anaerobic threshold
(all P <.001). In the aficamten group, large improvements (≥3.0 mL/kg per minute) in pVO2 were more common than large reductions (32% and 2%, respectively) compared with
placebo (16% and 11%, respectively). Improvements in both components of the primary
outcome, pVO2 and VE/VCO2 slope throughout exercise, were significantly correlated with improvements in symptom burden and hemodynamics (all P <.05).
CONCLUSIONS AND RELEVANCE This prespecified analysis of the SEQUOIA-HCM randomized clinical trial found that aficamten treatment improved a broad range of exercise performance measures. These findings offer valuable insight into the therapeutic effects of aficamten.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT05186818
JAMA Cardiol. doi:10.1001/jamacardio.2024.2781
Published online September 4, 2024.
Author Affiliations: Author affiliations are listed at the end of this article.
Group Information: The members of the SEQUOIA-HCMInvestigators appear in Supplement 4.
Corresponding Author: Gregory D. Lewis, MD, Division of Cardiology, Department of Medicine, Massachusetts General Hospital,
55 Fruit St, Bigelow 800, Boston, MA
02114 (glewis@mgb.org).
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Research Original Investigation |
Aficamten and Cardiopulmonary Exercise Test Performance |
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cardinal clinical feature of obstructive hypertrophic car- diomyopathy (HCM) is exercise intolerance. Cardio-
specific mechanisms underlying exercise intolerance
are thought to arise from the following: (1) dynamic left ventricular outflow tract (LVOT) obstruction, (2) diastolic dys- function, (3) dynamic mitral regurgitation, and (4) myocar- dial oxygen supply-demand mismatch resulting in ischemia.1 The evaluation of patients with obstructive HCM during the physiologic stress of exercise with cardiopulmonary exercise testing (CPET) can ascertain the extent to which these cardio- specific limitations impair exercise performance and serve to evaluate potential functional improvements with treatment. CPET also enables an objective and reproducible assessment of all stages of exercise performance. Importantly, peak oxygen uptake (pVO2) and other exercise physiology metrics measured by CPET have already been shown to predict clinical events in obstructive HCM.2
Cardiac myosin inhibitors (CMIs) have been developed as a therapeutic option for patients with obstructive HCM by targeting the underlying etiopathology of the disease. They act by directly reducing excessive actin-myosin crossbridges at the level of the sarcomere and mitigate cardiac hypercontrac- tility. Mavacamten, the first-in-class CMI, has shown efficacy by improving pVO2 and other CPET parameters.3 Aficamten, a next-in-class CMI, was designed with unique physicochemi- cal properties. Aficamten doses can be adjusted to achieve an individualized target dose rapidly (within 6 weeks) as a result of a wide therapeutic window (modest reductions in left ventricular ejection fraction [LVEF] with each dose-level incre- ment) and plasma half-life of 3.4 days. Additionally, minimal drug-drug interactions and rapid reversibility are safety features that allow for precision dosing and relatively infrequent low LVEF excursions less than 50% that can be managed with dose reduction without the need for treatment interruption.1 Aficamten treatment has been demonstrated to relieve obstruction and improve symptoms, cardiac biomarkers, and measures of diastolic function in the phase 2 and open-label extension studies (REDWOOD-HCM4,5 and FOREST-HCM), and was recently shown to improve pVO2, symptoms, health status, and LVOT gradients (LVOT-G) and reduce eligibility for septal reduction therapy in the SEQUOIA-HCM trial.6
In this prespecified analysis of the SEQUOIA-HCM randomized clinical trial, we hypothesized that aficamten would improve a novel measure of integrated exercise performance that combines complementary measures previously independently related to obstructive HCM prognosis and incorporates both submaximal and maximal exercise capacity.7 We further hypothesized that changes in pVO2 would relate to changes in symptoms and cardiac biomarkers, as well as in LVOT-G and other echocardiographic measures.
Methods
Study Oversight
All study participants provided written informed consent before enrollment. The study was conceived, designed, and conducted by an academic steering committee in conjunction with
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Key Points
Question Does aficamten treatment improve exercise response beyond peak oxygen uptake (pVO2) measured by cardiopulmonary exercise testing in obstructive hypertrophic cardiomyopathy (HCM)?
Findings In the Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) randomized clinical trial,
282 patients with symptomatic obstructive HCM received aficamten or placebo for 24 weeks. Aficamten treatment resulted in significant improvement in multiple exercise measures, including a novel composite of exercise performance during peak and submaximal exercise.
Meaning Aficamten treatment improves several exercise performance measures in patients with obstructive HCM, and improvements in these measures were correlated with other important clinical responses.
the study sponsor (Supplement 1). All patients provided written informed consent, and the study was carried out in accordance with the provisions of the Declaration of Helsinki and the International Council for Harmonisation Guideline for Good Clinical Practice. An independent data monitoring committee had access to unblinded data for monitoring. Study personnel remained blinded to treatment assignments, dosing, and echocardiogram results through database lock. Results were generated based on a prespecified statistical analysis plan (Supplement 2) that was finalized before database lock. The trial was approved by the regulatory agencies in the participating countries and by the institutional review board or ethics committee at each trial center. This study followed Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
Study Design
The rationale for and design of the SEQUOIA-HCM trial have been previously described.1 In brief, this was a phase 3, placebo- controlled, double-blind, multicenter, randomized clinical trial in participants with obstructive HCM. Patients with LVOT-G greater than or equal to 30 mm Hg (resting) and greater than or equal to 50 mm Hg (after Valsalva), New York Heart Association (NYHA) functional class II to III symptoms, baseline pVO2 of 90% or less of predicted, and respiratory exchange ratio (RER) of 1.05 or greater were eligible to participate. Individuals were excluded if they had a history of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months before screening or inability to exercise on a treadmill or cycle. Participants self-identified with the following races and ethnicities: Asian, Black or African American, White, and other, which included American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander; multiracial; or not reported. Race and ethnicity information was included in this study to permit appropriate interpretation of the data and generalize the research.
Randomization
Participants who met screening criteria underwent baseline studies, including history, physical examination, vital signs,
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Aficamten and Cardiopulmonary Exercise Test PerformanceOriginal Investigation Research
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echocardiography, CPET, laboratory assessments, and symp- |
[VO2 × systolic blood pressure], exercise duration, peak RER, |
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tom assessments (NYHA functional class, Kansas City Cardi- |
heart rate reserve, peak heart rate, oxygen pulse at peak ex- |
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omyopathy Questionnaire Clinical Summary Score [KCCQ- |
ercise, proportionate pulse pressure) and (2) during submaxi- |
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CSS], patient and clinical global impression scales), and they |
mal exercise (preanaerobic threshold VE/VCO2 slope from |
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were then randomly assigned 1:1 to receive either aficamten |
the onset of exercise up until and including the first ventila- |
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or matching placebo using an interactive Web Response |
tory anaerobic threshold, derived from the V-slope method, |
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System (Signant Health). Central randomization was strati- |
VE/VCO2 slope throughout exercise [from rest to peak exer- |
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fied by use of β-blockers (yes or no) and CPET exercise modal- |
cise], ventilatory power, ventilatory anaerobic threshold, |
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ity (treadmill or cycle). |
and aerobic efficiency). |
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Interventions |
Sample Size Calculation |
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Patients receiving aficamten were assigned 5 mg, 10 mg, 15 mg, |
Sample size calculations for the SEQUOIA-HCM trial as- |
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or 20 mg orally once daily based on site-read echocardiogram- |
sumed a between-group difference in change from baseline in |
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guided titration.1 Aficamten doses were individualized to |
pVO2 of 1.5 mL/kg per minute for aficamten vs placebo, |
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achieve the lowest effective dose resulting in a Valsalva LVOT-G |
a common SD of 3.5 mL/kg per minute, and 10% missing data |
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of less than 30 mm Hg while maintaining an LVEF of 50% or |
for the primary end point. A sample size of 270 patients at a |
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greater over the first 8 weeks of the study starting at 5 mg. |
randomization ratio of 1:1 (approximately 135 randomized to |
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Patients, investigators, and the study sponsor were masked |
aficamten and approximately 135 to placebo) was estimated |
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to the echocardiogram results and N-terminalpro-brain na- |
to provide greater than or equal to 90% power to detect a dif- |
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triuretic peptide (NT-proBNP) level. |
ference of 1.5 mL/kg per minute in pVO2 change from base- |
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line to week 24 with a 2-sided type I error of 0.05. |
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CPET |
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The CPET core laboratory (Massachusetts General Hospital |
Statistical Analysis |
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and Harvard University) certified study sites according to |
The full statistical analysis plan for CPET analyses is pro- |
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their having demonstrated appropriate and reproducible |
vided in Supplement 2. Unless otherwise specified, efficacy |
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conduct of qualification CPETs in accordance with the CPET |
analyses were performed on the full analysis set, which in- |
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manual of operating procedures, version 1.3 (Supplement 1 |
cludes all randomized patients who received 1 or more doses |
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and eAppendix in Supplement 3). To achieve within- |
of study drug and had 1 or more postbaseline efficacy assess- |
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participant consistency, where possible, CPET was per- |
ments. The primary analysis was performed using an analy- |
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formed on the same equipment, using the same protocol, |
sis of covariance model that included terms of treatment, ran- |
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and was administered by the same staff, at both baseline and |
domization stratification factors (β-blocker use status and |
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week 24. All CPETs were transferred electronically to the |
CPET modality), baseline value of the outcome, and baseline |
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core laboratory, where they were interpreted in a blinded |
body weight as covariates. Missing data were imputed 100 |
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fashion. Prespecified criteria for valid CPETs included the |
times according to the missing at random (MAR) paradigm. |
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absence of equipment malfunction, major CPET protocol |
Least squares mean (LSM) treatment difference and SE were |
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deviation, or transient illness/injury unrelated to HCM |
combined using Rubin rules to produce an LSM estimate of the |
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symptoms that precluded valid CPET completion. |
treatment difference, its 95% CI, and P value for the test of null |
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hypothesis of no treatment effect. Secondary exercise testing |
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CPET End Points |
efficacy end points were analyzed using the same methodol- |
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The primary analysis was change from baseline to week 24 |
ogy as used for the primary end points. |
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in integrated exercise performance, normalized to a compos- |
Additional analyses included the following: (1) a sensitiv- |
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ite of z scores for pVO2 and minute ventilation (VE)/carbon |
ity analysis using an alternate z score with the VE/VCO2 slope |
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dioxide output (VCO2) slope throughout exercise to capture |
preanaerobic threshold (rather than throughout exercise), (2) |
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physiologic responses to maximal and submaximal exercise. |
a responder analysis for the proportional achievement of |
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The z score was derived by reversing the directionality of |
clinically meaningful thresholds for shifts in pVO2 (small [0 to |
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the VE/VCO2 slope such that increases in both z score com- |
<1.5 mL/kg per minute], moderate [≥1.5 to <3 mL/kg per min- |
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ponents indicate benefit, and equal weights were used for |
ute], or large [≥3.0 mL/kg per minute]) by treatment group and |
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each component. For each patient, the composite z score |
correlations between change in pVO2 and other measures of |
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was defined as (z1 + z2) / 2, where z1 is the patient's pVO2 |
treatment effect (symptoms, hemodynamics, biomarkers), |
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change minus the trial-level mean pVO2 change, divided by |
and (3) an evaluation of how change in the z score and its com- |
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the trial-level SD of pVO2 change, and z2 was defined simi- |
ponents relates to change in other SEQUOIA-HCM CPET, |
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larly for VE/VCO2 slope, then multiplied by −1, such that |
symptom-based, echocardiographic, and biomarker end points |
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positive values of both z1 and z2 represent changes from |
by correlation and multivariate regression analysis. |
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baseline that are better than average. |
Baseline data are presented as number (%), mean (SD), and |
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Secondary end points included assessments for changes |
median (IQR). Two-sidedP values <.05 were considered sta- |
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from baseline to week 24 in CPET-derived measures during 2 |
tistically significant. Missing CPET end points at week 24, re- |
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phases of exercise performance: (1) peak exercise (pVO2, peak |
gardless of type of intercurrent events, were imputed using |
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workload, peak metabolic equivalents, peak circulatory power |
multiple imputation methodology under the MAR assump- |
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Aficamten and Cardiopulmonary Exercise Test Performance |
tion for the primary analysis of the primary estimate because the proportion of patients with week 24 CPET missing was expected to be very low.
Statistical analyses were performed from January to March 2024 by the Brigham and Women's Hospital Clinical Trials Outcomes Center.
Results
Patient Population
Between February 1, 2022, and May 15, 2023, 282 eligible patients were randomized to aficamten or placebo at 101 sites in 14 countries. Baseline characteristics have been previously published and are shown in Table 1.1,6 The mean (SD) age of participants was 59.1 (12.9) years, 115 (40.8%) were female, and 167 (59.2%) were male. Patients self-identified with the following races and ethnicities: 54 Asian (19.1%), 3 Black or African American (1.1%), 223 White (79.1%), and 2 other (0.7%). Background HCM therapy included 173 participants (61.3%) receiving β-blockers, 81 (28.7%) receiving nondihydropyridine calcium channel blockers, 36 (12.8%) receiving disopyramide, and 41 (14.5%) not taking any HCM medication. Exercise capacity was reduced as evidenced by the baseline mean (SD) pVO2 of 18.5 (4.5) mL/kg per minute, representing a mean (SD) of 56.9% (11.8%) of age- and sex- predicted pVO2,8 and a reduced VE/VCO2 slope throughout exercise mean (SD) of 33.0 (6.1). Other key baseline CPET parameters included workload (mean [SD], 122.5 [40.1] W) and metabolic equivalents (mean [SD], 5.3 [1.3] mL/kg per minute), both of which were impaired.
Patient Disposition
At least 1 dose of study medication was received by all randomized patients (eFigure in Supplement 3). At week 24, the number (%) of patients taking each aficamten dose was 5 (3.6), 21 (15.3), 48 (35), and 63 (46) for 5 mg, 10 mg, 15 mg, and 20 mg, respectively. Of those randomized, 263 patients (93.3%) completed both baseline and week 24 CPETs that were deemed physiologically interpretable and valid by the core labora- tory. Of the 19 patients (7%; 9 aficamten and 10 placebo) who did not have a core laboratory-interpretable week 24 CPET available for analysis, 6 (2.1%; 3 aficamten and 3 placebo) terminated early from the study before week 24 CPET, and 13 (4.6%; 6 aficamten and 7 placebo) were determined by the core laboratory to have an invalid week 24 CPET (3 did not follow the CPET manual of operations, and 10 were technical failures).
Primary and Secondary End Points
The change from baseline to week 24 in the integrated composite for exercise performance demonstrated improvement in the aficamten group (mean [SD] z score, 0.17 [0.51]) compared with a deterioration in the placebo group (mean [SD] z score, −0.19 [0.45]), yielding a significant placebo- corrected increase (mean [SD] z score, 0.35; 95% CI, 0.25- 0.46; P <.001) (Figure 1 and Table 2). Aficamten improved peak exercise performance as measured by the total workload (LSM
difference, 12 W; 95% CI, 6-18 W; P <.001), circulatory power (LSM difference, 586 mm Hg × mL/kg/min; 95% CI, 379-793
-
Hg × mL/kg/min; P <.001), exercise duration (LSM differ- ence, 1.0 minute; 95% CI, 0.5-1.4 minutes; P <.001), heart rate reserve (LSM difference, 6 beats per minute; 95% CI, 3-9 beats per minute; P <.001), and peak heart rate (LSM difference, 9 beats per minute; 95% CI, 6-12 beats per minute; P <.001) (Table 2). Aficamten also improved submaximal exercise per- formance as measured by ventilatory efficiency (both prean- aerobic threshold: LSM difference, −1.5; 95% CI, −2.5 to −0.6; P =.002 and throughout exercise: LSM difference, −2.3; 95% CI, −3.2 to −1.4; P <.001), increased ventilatory power (LSM difference, 0.9 mm Hg; 95% CI, 0.6-1.1 mm Hg; P <.001), and increased ventilatory anaerobic threshold (LSM difference, 59 mL per minute; 95% CI, 33-85 mL per minute; P <.001) (Table 2). As anticipated, aficamten treatment was not associated with improvements in oxygen pulse at peak exercise, proportion- ate pulse pressure at peak or rest, or aerobic efficiency, and there were no between-group differences in peak RER.
In a sensitivity analysis using an alternate z score using the VE/VCO2 slope preanaerobic threshold (rather than through- out exercise), the change from baseline to week 24 in this al- ternate z score also showed improvement in the aficamten group (mean [SD] z score, 0.15 [0.63]) compared with a dete- rioration in the placebo group (mean [SD] z score, −0.18 [0.57]), resulting in a significant placebo-corrected increased (mean [SD] z score, 0.32; 95% CI, 0.18-0.45;P < .001).
Responder Analysis
Large pVO2 improvements (≥3.0 mL/kg per minute) were more frequent with aficamten treatment compared with placebo (32% vs 16%, respectively), and large pVO2 deteriorations (≤−3.0 mL/kg per minute) were less frequent with aficamten treatment vs placebo (2% vs 11%, respectively) (Figure 2). The odds ratios (ORs) for achieving any improvement (OR, 3.09; 95% CI, 1.88-5.09), moderate to large improvements greater than or equal to 1.5 mL/kg per minute (OR, 2.44; 95% CI, 1.50-3.96), and large improvements greater than or equal to 3.0 mL/kg per minute (OR, 2.44; 95% CI, 1.38-4.29) all favor aficamten treatment and correspond with a number needed to treat of 3.8, 4.7, and 6.3 patients, respectively (eTable 1 in Supplement 3).
Clinical Correlations
Cubic spline graphs and univariate correlation analyses revealed significant associations between improvements in pVO2 and improvements in KCCQ-CSS score, NYHA functional class, septal E/e′ (peak E-wave velocity divided by peak e′ velocity, an estimate of left ventricular end-diastolic pressure), resting and Valsalva LVOT-G,NT-proBNP level, and high-sensitivity cardiac troponin I (hs-cTnI) level (Figure 3 and eTable 2 in Supplement 3). Sequential regression multivariate analyses revealed that changes in NT-proBNP level accounted for the greatest amount of variance in change in pVO2, whereas changes in E/e′ and KCCQ-CSS score also significantly added to the observed variance (eTable 3 in Supplement 3). In a univariate analysis, improvements in VE/VCO2 slope throughout exercise were associated with changes in many of the same clini-
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Aficamten and Cardiopulmonary Exercise Test Performance
Table 1. Baseline Characteristicsa
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Characteristic |
Aficamten (n = 142) |
Placebo (n = 140) |
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Age, y |
59.2 (12.6) |
59.0 (13.3) |
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Sex, No. (%) |
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Female |
56 |
(39.4) |
59 |
(42.1) |
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Male |
86 |
(60.6) |
81 |
(57.9) |
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Race, No. (%) |
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Asian |
29 |
(20.4) |
25 |
(17.9) |
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Black or African American |
3 (2.1) |
0 |
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White |
108 (76.1) |
115 (82.1) |
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Otherb |
2 (1.4) |
0 |
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Geographic region, No. (%) |
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North America |
49 |
(34.5) |
45 |
(32.1) |
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China |
24 |
(16.9) |
22 |
(15.7) |
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Europe and Israel |
69 |
(48.6) |
73 |
(52.1) |
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Medical history, No. (%) |
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Hypertension |
75 |
(52.8) |
70 |
(50.0) |
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Family history or known gene variant |
47 |
(33.1) |
44 |
(31.4) |
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Family history of HCM |
41 |
(28.9) |
34 |
(24.3) |
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Pathogenic sarcomere variant |
24 |
(16.9) |
25 |
(17.9) |
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Paroxysmal atrial fibrillation |
21 |
(14.8) |
20 |
(14.3) |
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Coronary artery disease |
19 |
(13.4) |
16 |
(11.4) |
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Diabetes |
14 |
(9.9) |
9 (6.4) |
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Permanent atrial fibrillation |
2 (1.4) |
1 (0.7) |
||
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Background HCM therapy, No. (%) |
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β-Blocker |
86 |
(60.6) |
87 |
(62.1) |
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Calcium channel blocker |
45 |
(31.7) |
36 |
(25.7) |
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Disopyramide |
16 |
(11.3) |
20 |
(14.3) |
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None |
19 |
(13.4) |
22 |
(15.7) |
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Symptoms |
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KCCQ-CSS |
76 |
(18) |
74 |
(18) |
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NYHA functional class, No. (%) |
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II |
108 (76.1) |
106 (75.7) |
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III |
34 |
(23.9) |
33 |
(23.6) |
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IV |
0 |
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1 (0.7) |
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Cardiac biomarkers |
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Median NT-proBNP (IQR), pg/mL |
818 (377-1630) |
692 (335-1795) |
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Median hs-cTnl (IQR), ng/L |
12.9 (7.6-33.6) |
11.5 (7.7-25.0) |
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Echocardiographic parameters |
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Valsalva LVOT-G, mm Hg |
83 |
(32) |
83 |
(33) |
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Resting LVOT-G, mm Hg |
55 |
(27) |
55 |
(32) |
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LVEF, % |
75 |
(5.5) |
75 |
(6.3) |
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LAVI, mL/m2 |
40.1 (12.7) |
40.9 (15.1) |
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Maximal wall thickness, cm |
2.1 (0.3) |
2.1 (0.3) |
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Cardiopulmonary exercise test parameters |
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Integrated 2-component exercise performance metric |
−0.01 (0.82) |
0.02 (0.75) |
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pVO2, mL/kg/min |
18.4 (4.5) |
18.6 (4.6) |
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Workload, W |
120 (40) |
126 (43) |
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Metabolic equivalents, METS |
5.3 (1.3) |
5.3 (1.3) |
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Ventilatory efficiency throughout exercise (VE/VCO2 slope) |
33.2 (6.4) |
32.9 (6.0) |
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Original Investigation Research
Abbreviations: HCM, hypertrophic cardiomyopathy; hs-cTnI,high-sensitivity cardiac troponin I; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; LAVI, left atrial volume index; LVEF, left ventricular ejection fraction; LVOT-G, left ventricular outflow tract gradient; NT-proBNP,N-terminalpro-brain natriuretic peptide; NYHA, New York Heart Association; pVO2, peak oxygen uptake;
VCO2, carbon dioxide output; VE, minute ventilation.
SI conversion factors: To convert hs-cTnI to micrograms per liter, divide by 1000 and multiply by 1; NT-proBNP to nanograms per liter, multiply by 1.
- Percentages may not total 100 because of rounding. Value in parenthesis represents the SD unless otherwise specified.
- Race was denoted by the patient as part of baseline characteristics. Other ethnic groups included American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander; multiracial; and not reported.
cal measures as change in pVO2. However, change in VE/ VCO2 slope demonstrated higher correlation with changes in LVOT-G (rest and Valsalva) and left atrial volume index (LAVI) and lower correlation with changes in E/e′ and hs-cTnI level.
In the multivariate analysis, changes in NT-proBNP level, LAVI, and mitral regurgitation significantly explained variance in VE/VCO2 slope (eTable 3 in Supplement 3). In addition to distinct correlates for pVO2 and VE/VCO2 slope, only a modest
|
(Reprinted) JAMA Cardiology Published online September 4, 2024 |
E5 |
Downloaded from jamanetwork.com by guest on 09/05/2024
|
Research Original Investigation |
Aficamten and Cardiopulmonary Exercise Test Performance |
Figure 1. Baseline and Week 24 Values and Changes in Integrated Exercise Performance and Its Component Variables
- z Score values, aficamten vs placebo, individual patients
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z scores |
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Patients aficamten
- pVO2 values, aficamten vs placebo, individual patients
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mL/kg/min |
40 |
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mL/kg/min |
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uptake,oxygen |
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uptake,oxygen |
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Patients aficamten
50 100 150
Patients placebo
50 100 150
Patients placebo
- z Score values, aficamten vs placebo, mean (SD) changes
|
scorez |
1.5 |
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0.35 (0.25 to 0.46); P <.001 |
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Adjusted difference (95% CI): |
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component-2 |
1.0 |
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standardizedin |
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−0.5 |
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Change |
−1.0 |
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Placebo |
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Aficamten |
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Baseline |
Week 24 |
Baseline |
Week 24 |
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−0.01 (0.8) |
0.16 (0.8) |
0.02 (0.08) |
−0.17 (0.7) |
Mean (SD)
- pVO2 values, aficamten vs placebo, mean (SD) changes
|
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10 |
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Adjusted difference (95% CI): |
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24 |
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1.7 (1.0 to 2.4); P <.001 |
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weekto |
mL/kg/min |
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baseline |
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Changefrom |
in pVO |
−5 |
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Aficamten |
Placebo |
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|
Baseline |
Week 24 |
Baseline |
Week 24 |
|
18.4 (4.5) |
20.2 (5.2) |
18.6 (4.6) |
18.6 (4.7) |
Mean (SD)
E Ventilatory efficiency, aficamten vs placebo, individual patients
|
F Ventilatory efficiency, aficamten vs placebo, |
|
mean (SD) values |
Ventilatory efficiency
70
60
50
40
30
20
10
050 100
Patients aficamten
Ventilatory efficiency
150
70
60
50
40
30
20
10
0
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Change from baseline to week |
inventilatory efficiency |
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Adjusted difference (95% CI): |
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−2.3 (−3.2 to −1.4); P <.001 |
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−15 |
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100 |
150 |
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Aficamten |
Placebo |
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Baseline |
Week 24 |
Baseline |
Week 24 |
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33.2 (6.4) |
30.9 (5.7) |
32.9 (6.0) |
32.9 (6.4) |
Mean (SD)
Baseline and week 24 values, connected by vertical lines, are shown for individual patients receiving aficamten (left) and placebo (right) for z score values (A), peak oxygen uptake (pVO2) values (C), and ventilatory efficiency values (E). Integrated exercise performance and its component variables (standardized 2-componentz score of pVO2 and VE as measured by minute ventilation [VE]/carbon dioxide output [VCO2] slope throughout all of exercise). The z score was derived by
reversing the directionality of VE/VCO2 slope values such that increases in both z score components indicate benefit; equal weights were used for each component. Changes in values (median and IQR) from baseline to week 24 are shown in panels B, D, and F. Box edges indicate the IQRs; the horizontal lines in between the edges indicate the median values. Whiskers extend to the upper and lower adjacent values, and dots represent outside values.
|
E6 |
JAMA Cardiology Published online September 4, 2024 |
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Aficamten and Cardiopulmonary Exercise Test PerformanceOriginal Investigation Research
Table 2. Cardiopulmonary Exercise Testing (CPET) Parameters by Treatment Assignment
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Aficamten, mean (SD) (n = 133) |
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Placebo, mean (SD) (n = 130) |
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Absolute |
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Absolute |
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Adjusted difference |
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CPET variable |
Baseline |
Week 24 |
difference (SD)a |
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Baseline |
Week 24 |
difference (SD)a |
(95% CI)b |
P value |
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Integrated |
−0.01 (0.82) |
0.16 (0.76) |
0.17 (0.51) |
0.02 |
(0.75) |
−0.17 (0.74) |
−0.19 (0.45) |
0.35 (0.25 to 0.46) |
<.001 |
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2-component |
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z score metricc |
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pVO2, mL/kg/min |
18.4 (4.5) |
20.2 (5.2) |
1.8 (3.1) |
18.6 |
(4.6) |
18.6 (4.7) |
0 (2.7) |
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1.7 (1.0 to 2.4) |
<.001 |
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Peak workload, W |
120 (40) |
134 (50) |
14 (27) |
126 (43) |
127 (44) |
1 (21) |
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12 (6 to 18) |
<.001 |
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Peak METS, |
5.3 (1.3) |
5.8 (1.5) |
0.51 (0.89) |
5.3 (1.3) |
5.3 (1.3) |
0 (0.78) |
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0.49 (0.29 to 0.69) |
<.001 |
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metabolic |
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equivalents |
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Peak circulatory |
3013 (924) |
3550 (1140) |
537 (995) |
3160 (1136) |
3074 (1152) |
−86 (731) |
586 (379 to 793) |
<.001 |
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power, mm |
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Hg × mL/kg/min |
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Exercise duration, |
11.2 (3.0) |
12.4 (3.9) |
1.2 (2.1) |
11.5 |
(3.0) |
11.7 (3.2) |
0.1 (1.5) |
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1.0 (0.5 to 1.4) |
<.001 |
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min |
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Peak RER |
1.19 (0.10) |
1.20 (0.11) |
0.01 (0.10) |
1.18 |
(0.09) |
1.19 (0.10) |
0.01 (0.10) |
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0.00 (−0.02 to 0.02) |
.84 |
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Heart rate reserve, |
59 (18) |
66 (22) |
7 (15) |
57 (19) |
59 (20) |
1 (10) |
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6 (3 to 9) |
<.001 |
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beats/min |
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