Effect of beta-blockade on improvements associated with cardiac myosin inhibitor in obstructive HCM
Effect of beta-blocker therapy on the response to mavacamten in patients with symptomatic obstructive hypertrophic cardiomyopathy
Introduction and methods
Mavacamten is a selective inhibitor of cardiac myosin that reduces cardiac muscle contractility by inhibiting excessive myosin-actin cross-bridge formation [1,2]. In the EXPLORER-HCM trial, mavacamten improved exercise capacity and symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM) . Mavacamten effects on the primary composite endpoint of peak oxygen consumption (VO2) and NYHA class were greater in patients not receiving background beta-blockers than in those receiving beta-blockers . Beta-blockers may selectively affect the beneficial effects of mavacamten with regard to peak VO2 increase (heart-rate dependent), but not of other important, non-heart rate-dependent study endpoints.
Aim of the study
This post hoc analysis of data from EXPLORER-HCM and interim data from MAVA-LTE studied the effects of concomitant beta-blocker use on the response to mavacamten in patients with symptomatic oHCM.
The EXPLORER-HCM, a phase 3, double-blind, randomized, placebo-controlled, parallel group trial of mavacamten in patients with symptomatic oHCM enrolled a total of 251 adults with NYHA class II or III obstructive HCM with LVEF ≥55% and left ventricular outflow tract (LVOT) peak gradient ≥50 mmHg at baseline. Patients were randomized (1:1) to receive either mavacamten or placebo once daily for 30 weeks.
MAVA-LTE is an ongoing, 5-year study of mavacamten in patients who had completed either EXPLORER-HCM or the MAVERICK-HCM study ; 231 of 244 patients who completed EXPLORER-HCM enrolled in MAVA-LTE. All patients in MAVA-LTE received mavacamten irrespective of background HCM medication received in the original study. Patients and investigators were blinded to mavacamten dose and prior assigned treatment. In the present subgroup analyses only patients who enrolled into MAVA-LTE from the EXPLORER-HCM study, referred to as the EXPLORER-LTE cohort, were included.
In the EXPLORER-HCM, 189 patients (75.3%) received beta-blockers and 62 patients (24.7%) calcium channel blockers or no background medications. 224 patients were enrolled in the EXPLORER-LTE cohort of the MAVA-LTE study and received mavacamten. Overall, 169 patients (75.4%) were receiving concomitant beta-blockers; the remaining patients were prescribed calcium channel blockers (n=37) or neither background medication (n=18).
The main outcomes for this post-hoc analysis included change in peak VO2, peak metabolic equivalents (MET), peak heart rate, peak exercise time, ventilatory efficiency, LVOT gradient, LVEF, proportion of patients with a ≥1 class of NYHA improvement, change in KCCQ clinical summary score, and change in biomarkers. Analyses for EXPLORER-HCM were performed at week 30 and for the ongoing MAVA-LTE interim data from week 12 were used.
- At week 30 in the EXPLORER-HCM, improvements in peak VO2 with mavacamten versus placebo were greater in patients without beta-blockers (mean difference 2.69, 95%CI:1.29-4.09 mL/kg/min), than those in patients with beta-blockers (mean difference 1.04, 95%CI:0.12-1.95) mL/kg/min).
- In the EXPLORER-HCM, at week 30, improvements of METs with mavacamten versus placebo were greater in those without beta blockers (mean difference 0.77, 95%CI:0.38-1.17), whereas than in those with beta-blockers (mean difference 0.30, 95%CI:0.04-0.56).
- At week 30 in the EXPLORER-HCM, the effect of mavacamten compared with placebo on mean peak exercise time was greater in those without beta blockers (mean difference 1.9, 95%CI:0.7 to 3.1), than in those with beta-blockers (mean difference 0.34, 95%CI:-0.28 to 0.96). A similar pattern was seen for mean peak heart rate with maximal exercise.
- At week 30 in the EXPLORER-HCM, mavacamten improved the heart-rate independent parameter, ventilatory efficiency (VE/VCO2 slope), regardless of beta-blocker.
- Benefits by mavacamten on LVOT gradient at rest, after Valsalva manoeuvre or exercise were independent of beta-blocker use.
- Effects of mavacamten on LVEF were irrespective of beta-blocker use. Mean absolute change from baseline in LVEF was 5.0% (SD 7.6) compared with 1.3% (SD 5.8) in patients with mavacamten vs. placebo in patients without beta-blockers (mean difference of −3.7%, 95%CI:−7.3 to 0.0). For those using beta-blockers, mavacamten decreased the mean LVEF by 3.6% (SD 7.7) compared with 0.5% (SD 7.1) with placebo (mean difference of −4.0%, 95%CI:−6.2 to −1.8).
- Interim analysis of the EXPLORER-LTE cohort showed similar results on LVOT gradients and LVEF.
- At week 30 in the EXPLORER-HCM study, the proportion of patients with ≥1 NYHA class improvement was 65.5% with mavacamten and 21.2% with placebo in patients without beta-blockers, and 64.9% with mavacamten and 34.7% with placebo in patients with beta-blockers.
- At 30 weeks in the EXPLORER-HCM study, mavacamten improved patient-reported quality of life and symptom burden. Mean (SD) change in KCCQ score was 11.0 (15.0) with mavacamten compared with 6.3 (13.8) with placebo in patients without beta-blockers (mean difference was 4.7, 95%CI: −4.0 to 13.4), and 14.2 (14.3) compared with 3.3 (13.7), respectively (mean difference was 11.0, 95%CI: 6.2-15.7), in patients with beta-blockers.
- In the EXPLORER-LTE cohort, improvements in NYHA functional class with mavacamten vs. placebo at 12 weeks were independent of beta-blocker use.
- cTnI concentrations were 40% and 60% greater with mavacamten than those with placebo at 30 weeks in patients with and without beta-blocker use.
- Reductions in NT-proBNP concentration with mavacamten were 80% greater than that with placebo irrespective of beta-blocker usage. These reductions were maintained in the EXPLORER-LTE cohort.
Results from both EXPLORER-HCM and EXPLORER-LTE showed that treatment with mavacampten improved measures of functional capacity, LVOT gradients, symptom burden and serum NT proBNP levels in patients with HCM regardless of beta-blocker use. Beta-blocker use was often linked to chronotropic incompetence, affecting peak VO2 and other heart rate-dependent measures, but had minimal impact on heart-rate independent measures.
The authors conclude: “The potential adverse effects of chronotropic incompetence related to beta-blocker use in oHCM requires critical reappraisal in clinical practice”.
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