Risultati per: Diagnosi e trattamento della cardiomiopatia ipertrofica (HCM)

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Circulation, Ahead of Print. Background: In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), VALOR-HCM trial (Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy [URL: https://clinicaltrials.gov; Unique identifier: NCT04349072]) reported that mavacamten reduced the short-term need for septal reduction therapy (SRT). The current report examined the longer-term effect of mavacamten through end of treatment at week 128.Methods: A double-blind randomized placebo-controlled multicenter trial at 19 sites in the United States included symptomatic obstructive HCM patients referred for SRT (enrollment July 2020 through October 2021). The group initially randomized to mavacamten continued the drug for 128 weeks and the placebo to mavacamten group from week 16 to 128 (112-week exposure). Dose titrations were performed using echocardiographic left ventricular outflow tract gradient and left ventricular ejection fraction measurements. The principal end point was proportion of patients proceeding with SRT or remaining guideline-eligible at week 128.Results: At week 128, 17 of 108 (15.7%) patients in the total study sample met the composite end point (7 underwent SRT, 1 was SRT-eligible, and 9 SRT-status unevaluable). Additionally, 87 of 108 (80.5%) patients demonstrated ≥1 New York Heart Association class improvement by week 128, and 52 of 108 (48.1%) demonstrated ≥2, with a sustained reduction in resting and Valsalva left ventricular outflow tract gradients of 38.2 mm Hg and 59.4 mm Hg, respectively. Ninety-five of 108 (88%) patients transitioned to commercial mavacamten. Overall, 15 of 108 (13.8%) patients (5.41 per 100 patient-years) had an left ventricular ejection fraction

Circulation, Volume 150, Issue Suppl_1, Page A4140102-A4140102, November 12, 2024. Introduction:In patients with obstructive hypertrophic cardiomyopathy (oHCM), the SEQUOIA-HCM trial demonstrated that aficamten, a next-in-class cardiac myosin inhibitor, improved exercise capacity, heart failure symptoms and hemodynamics compared with placebo. Aficamten’s impact on overall quality-of-life (QoL) in oHCM has not been reported.Hypothesis:Aficamten, compared with placebo, improves QoL as assessed by the EQ-5D-5L.Aims:To describe EQ-5D-5L changes in patients enrolled in SEQUOIA-HCM.Methods:SEQUOIA-HCM (NCT05186818) is a phase III, placebo-controlled trial of adults with symptomatic oHCM randomized to aficamten (n=142) or placebo (n=140) on top of standard-of-care medical therapy. Participants underwent blinded dose escalation over 6 weeks and were treated for 24 weeks followed by a 4-week washout. EQ-5D-5L (ranges from 0 to 1) and overall QoL using the Visual Analogue Scale (VAS; from 0 to 100) was measured at baseline through week 28 with higher scores indicating better QoL. Aficamten treatment effect on EQ-5D-5L was estimated using linear regression (study visits) and mixed effects regression (overall treatment effect) using all follow-up data with model adjustments for baseline EQ-5D-5L score and randomization stratification variables.Results:Mean age (n=282) was 59.1±12.9 years (40.8% women; 79.1% white). Aficamten baseline EQ-5D-5L index and VAS scores were 0.8±0.19 and 71.2±17.9 (placebo: 0.78±0.2; 68.9±18.6), respectively. Aficamten improved the EQ-5D-5L by 0.026 (95% CI: -0.001, 0.052; p=0.056) and the VAS by 2.8 points (95% CI: 0.8, 4.8; p=0.006) versus placebo with significant differences as early as 8 weeks after treatment initiation (p=0.005). After treatment withdrawal at 24 weeks, QoL benefits in aficamten-treated patients decreased compared with placebo (Figure: Index, p

Circulation, Volume 150, Issue Suppl_1, Page A4139196-A4139196, November 12, 2024. Introduction:The mavaCamten ObservationaL evIdence Global cOnsortium in hypertrophic cardiomyopathy (COLLIGO-HCM; ClinicalTrials.gov ID NCT06372457) is a multinational, multicenter observational research initiative aiming to describe the real-world outcomes of mavacamten for the treatment of obstructive HCM.Aims:Describe the real-world effectiveness and safety of mavacamten, measured by echo measurements and NYHA class.Methods:This retrospective study used data from medical records from two participating HCM centers in the US. Patient-level data was extracted to assess the effectiveness and safety of mavacamten post-treatment initiation through 60 weeks. Patient characteristics and outcomes were described, including echocardiogram measurements, New York Heart Association (NYHA) functional class, and safety.Results:A total of 93 patients were treated with mavacamten (mean age 60.6 ± 13.9 years, 23.7% black, 57.0% female, and 77.4% NYHA class III at baseline) with a mean follow-up of 37.0 ± 28.1 weeks (Table). From baseline to week 60, 3 (3.2%) patients experienced temporary treatment discontinuation, and 3 (3.2%) discontinued mavacamten due to left ventricular ejection fraction (LVEF)

Circulation, Volume 150, Issue Suppl_1, Page A4141030-A4141030, November 12, 2024. Background:There are limited data on the treatment patterns of mavacamten and background therapies in real-world patients with obstructive HCM.Aims:To describe posology, discontinuation, adherence to mavacamten, and the use of HCM background therapies in real-world patients.Methods:This was a retrospective cohort study of adult patients using the Symphony Integrated Dataverse from Apr 28, 2022 to Jan 18, 2024. Patients were included if they had ≥ 1 approved claim for mavacamten and had continuous claims activity during the 12 months (baseline) before the first claim (index date). The stable dose (defined as the dose used for 6 months consecutively), discontinuation (defined as a treatment gap ≥ 95 days without restarting), and adherence (measured as proportion of days covered [PDC]) were described for mavacamten. The use of background therapies (beta blockers, calcium channel blockers and disopyramide) was described at index and during the follow-up.Results:A total of 1867 patients (mean ± SD age 64.7 ± 12.2 years, 63.1% female, median [interquartile range, IQR] follow-up 219 [107, 346] days) were included (Table). Among patients with ≥ 6 (n = 993), ≥ 9 (n = 640), and ≥12 (n = 394) months of treatment, 67.3%, 86.1%, and 93.7% reached stable dose, respectively. Among patients who reached stable dose (n = 691, median [IQR] treatment duration 345 [270, 435] days), 54.8% did not require any dose adjustment, and 33.0% required only one adjustment from treatment initiation. The most commonly used stable dose was 5 mg (49.6%), followed by 2.5 mg (25.0%), 10 mg (20.5%) and 15 mg (4.8%). The discontinuation rate for mavacamten was 10.8% and 8.7% among patients with ≥1 and ≥2 claims, respectively. Mean PDC for mavacamten was 93.7 ± 9.1%. Overall, 25% of patients did not have any claim for background therapy at index. For the remaining patients (n = 1401), 11.6% discontinued and 15.1% down titrated the index HCM background therapy.Conclusions:The vast majority of patients treated with mavacamten reached stable dose with no or only one dose adjustment. Discontinuation rate was 8.7-10.8% and adherence to mavacamten was high. A substantial proportion of patients discontinued or down titrated HCM background therapy.

Circulation, Volume 150, Issue Suppl_1, Page A4141331-A4141331, November 12, 2024. Background:About 45% of identified HCM-causing mutations are in cardiac myosin binding protein C (cMyBP-C). One prevalent missense mutation is R495Q, which is in a positively charged pocket and alters the predicted electrostatic properties of the C3 domain. Many known HCM-causing mutations cause hypercontractility, likely through promoting the disordered relaxed state (DRX), in which myosin heads are more likely to bind to actin to generate contractile force, relative to the super relaxed state (SRX) in which myosin heads fold back on myosin tails. Mavacamten (MAVA), an FDA-approved drug for HCM patients with left ventricular outflow obstruction, is proposed to reduce DRX:SRX toward normal by inhibiting the myosin ATPase. It is unclear if all HCM-causing mutations act via this mechanism.Question:What is the contractile phenotypic timeline ofMYBPC3R495Q in human iPSC-engineered heart tissue (EHT) and can chronic MAVA ameliorate this phenotype?Aim:Define the phenotype progression in EHTs homozygous for the R495Q mutation (QQ), compared to isogenic controls (RR). We will use this timeline, combined with pharmacologic intervention to gain mechanistic insight into the pathogenesis of the R495Q mutation.Methods:3D EHTs were generated from CRISPR/Cas-9 edited QQ and RR human iPSC cardiomyocytes. We used capillary immunoassay to quantify cMyBP-C expression and immunocytochemistry to determine protein localization. Contractile function of EHTs was assessed weekly (weeks 1-6) with chronic treatment of MAVA (100nM) starting at day 8 of EHT culture.Results:QQ EHTs express normal cMyBP-C protein levels with appropriate incorporation into the sarcomere, yet at day 8 show increased twitch force (TF) and fast relaxation (Fig A-B). At day 36, QQs have normalized TF andslowrelaxation. Importantly, MAVA normalizes relaxation time (Fig C,D).Conclusion:These data suggest that R495Q presents with an early hypercontractile phenotype. With prolonged time in culture, TF is reduced, and relaxation time slows. Chronic administration of MAVA quickened relaxation, but reduced total force compared to untreated normal EHT, suggesting that caution may be warranted to ensure that systolic function isn’t impaired.

Circulation, Volume 150, Issue Suppl_1, Page A4143175-A4143175, November 12, 2024. Background:Mavacamten was approved by the US Food and Drug Administration (FDA) in April 2022 for the treatment of adults with New York Heart Association (NYHA) class II-III symptomatic obstructive hypertrophic cardiomyopathy (HCM). Few studies have reported on the long-term real-world effectiveness and safety of mavacamten. We evaluated clinical outcomes in patients on mavacamten in multiple health centers across the United States.Research Questions:This study assessed the real-world effectiveness and safety of mavacamten in patients with symptomatic obstructive HCM.Methods:In this multi-center observational study, we evaluated patient characteristics at baseline, NYHA class, left ventricular outflow tract gradients (LVOTg) at rest and Valsalva, and left ventricular ejection fraction (LVEF) in patients with symptomatic obstructive HCM treated with mavacamten for up to 72 weeks.Results:Mavacamten was initiated in 172 patients across 4 US centers (UCSF, Mayo Arizona, Stanford, and Atlantic Health System/Morristown Medical Center). Baseline characteristics included: 56% female, mean age 64 (standard deviation ±13) years, 47% NYHA class III, mean resting LVOTg of 47 mmHg and mean Valsalva LVOTg of 89 mmHg, and 23% non-White. Comorbidities included hypertension (56%) and atrial fibrillation (25%) at baseline (Table). Patients experienced a notable early response to mavacamten in resting and Valsalva gradients by week 4, which was sustained through week 72 (Figure A). No patients were NYHA class III at week 72, compared to 47% at baseline (Figure B). Mean LVEF did not change substantially between baseline and week 72. No patients experienced an LVEF of

Circulation, Volume 150, Issue Suppl_1, Page A4142906-A4142906, November 12, 2024. Background:Patients (pts) with obstructive hypertrophic cardiomyopathy (oHCM) with severe symptoms despite medical therapy are offered septal reduction therapy (SRT) when available. We report the efficacy and safety of aficamten in SRT-eligible pts in the Phase 2 open-label extension trial FOREST-HCM (NCT04848506).Methods:Pts completing an aficamten parent study were offered participation in FOREST-HCM. Aficamten was initiated in all participants at 5 mg and escalated (10, 15, and 20 mg) at investigators’ discretion with protocol guidance according to left ventricular ejection fraction (LVEF) and left ventricular outflow obstruction (LVOT) criteria. SRT eligibility was defined per guidelines as both New York Heart Association (NYHA) class III/IV and any peak LVOT-G ≥50 mmHg.Results:Of 180 oHCM pts (mean age 60.8±13.1 years, 54% male) enrolled in FOREST-HCM from May 28, 2021 to March 15, 2024 with ≥24 weeks of follow-up, 57 (31.6%) were SRT-eligible at baseline. By week 24, only 2 (3.5%) pts remained SRT eligible (32 [56.1%] met neither criteria, 20 [35.1%] had LVOT-G ≥50 mmHg but were NYHA class I/II, and 2 (3.5%) had NYHA III/IV but LVOT-G

Circulation, Volume 150, Issue Suppl_1, Page A4146512-A4146512, November 12, 2024. Background:Recent heart failure studies show that post-exercise VO2recovery (VO2Rec) patterns track closely with exercise cardiac output and outcomes, but not with peripheral oxygen (O2) extraction. In patients with obstructive hypertrophic cardiomyopathy (oHCM), studies of VO2Rec changes with effective cardio-specific interventions are lacking. We hypothesized that treatment with aficamten, a next-in-class cardiac myosin inhibitor, would shorten VO2Rec in patients with oHCM.Methods:SEQUOIA-HCM is the pivotal phase 3 trial of aficamten in symptomatic patients with oHCM (New York Heart Association functional class [NYHA FC] II-III, peak VO2[pVO2] ≤90% predicted, respiratory exchange ratio ≥1.05). Patients were randomized 1:1 to aficamten or placebo for 24 weeks with the primary endpoint of change from baseline (BL) in pVO2. For this analysis, VO2Rec was measured as the time taken after exercise cessation for VO2to decline by 12.5% (t12.5%), 25%, or 50% of pVO2. Response rates for achieving clinically meaningful threshold reductions ( >15 seconds) in t12.5%, and correlations with changes in cardiac function (echocardiographic parameters/cardiac biomarkers) were assessed.Results:Among 282 randomized patients (mean age 59.1±12.9 years, 115 female [41%]), 263 (93%) had CPETs at BL and W24 with VO2Rec values as shown (Table). At W24, t12.5%improved by 8sec (95% CI, -12, -5sec, p

Circulation, Volume 150, Issue Suppl_1, Page A4132223-A4132223, November 12, 2024. Background:While most current treatments can improve symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM), they may be poorly tolerated and do not target the underlying pathophysiology. Mavacamten is the first and only cardiac myosin inhibitor approved for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive HCM but has not been evaluated in a pediatric age group. SCOUT-HCM (Study of MavaCamten in AdOlescents with Symptomatic ObstrUcTive HCM; NCT06253221) will evaluate the efficacy, safety, and pharmacokinetics of mavacamten in adolescents with symptomatic obstructive HCM.Methods:SCOUT-HCM is a randomized, double-blind, placebo-controlled, international phase 3 clinical trial that will enroll 40 adolescents (age 12 to

Circulation, Volume 150, Issue Suppl_1, Page A4139663-A4139663, November 12, 2024. Background:Atrial fibrillation (AF) is the most common arrhythmia associated with hypertrophic cardiomyopathy (HCM), and patients with HCM complicated by AF are known to have a poor prognosis. Although many studies have reported the efficacy of catheter ablation (CA) for AF in various events, a few have shown its efficacy in HCM patients. Moreover, no large-scale, long-term follow-up studies have been conducted. Therefore, we performed a subgroup analysis of the REVEAL-HCM study to evaluate the long-term efficacy of CA for AF in HCM patients.Methods:The REVEAL-HCM study was a retrospective, multicenter, observational longitudinal cohort study that enrolled 3611 consecutive HCM patients aged ≥ 16 years at 23 centers in Japan between January 2006 and December 2018. Of these, patients who either had a medical history of AF or developed AF during the study period were included, excluding those previously treated with CA for AF. Patients were divided into two groups based on whether they received CA post-enrollment. The primary outcome measured was a composite of all-cause death, heart failure hospitalization, and thromboembolism, while the secondary outcomes assessed each of these events individually.Results:Among 1131 HCM patients with AF (67±12 years, 472 females), CA was performed in 284 patients (25%). During a median follow-up of 4.4 years, 455 composite events were observed. Univariate Cox regression analysis showed significantly fewer composite events in the CA group compared to the No-CA group (hazard ratio [HR]: 0.30; 95% confidence interval [CI]: 0.23-0.41; P < 0.001) (Figure). Multivariate Cox regression analysis also demonstrated a significant reduction in composite events (HR: 0.35; 95% CI: 0.25-0.49; P < 0.001). Multivariate Cox regression analysis of the secondary outcomes also revealed significantly fewer events in the CA group for all-cause death (HR: 0.58; 95% CI: 0.34-0.99; P = 0.044), heart failure hospitalization (HR: 0.33; 95% CI: 0.21-0.50; P < 0.001) and thromboembolism (HR: 0.23; 95% CI: 0.10-0.49; P < 0.001).Conclusion:Our study suggests that CA for AF may reduce major clinical events in HCM patients.