Sherrid, Mark

Once considered rare and essentially untreatable with a grim prognosis and reduced life expectancy, hypertrophic cardiomyopathy (HCM) has evolved substantially over 6 decades. Ultimately, HCM has become a contemporary global disease with pharmacologic and interventional options offering effective personalized treatment for all adverse disease pathways. Striking reduction in HCM‐related mortality to ≤0.5%/year in optimally treated cohorts is now comparable to that expected in the US general population, lower than most other disease risks to living, and 10‐fold less than the earliest estimates. The few deaths directly related to HCM are now largely attributable to advanced (end‐stage) heart failure in patients with nonobstructive HCM. Determinants of this transformation to a lower risk disease are evident in hallmark clinical inflection points and breakthroughs, including dedicated HCM programs assembling large clinical databases in which focused (and unfunded) physician‐investigators have derived data directly from patients in clinical practice. Evidence‐based observational studies report emergence of contemporary treatment strategies enhancing survival: implantable defibrillators prevent arrhythmic sudden death globally with 95% sensitive patient selection using an American Heart Association/American College Cardiology risk stratification algorithm; low‐risk, high‐benefit surgical myectomy reverses outflow obstruction and heart failure in >90% with a long‐term survival benefit; and aggressive anticoagulation has reduced embolic strokes. Recent novel pharmacologic alternatives (cardiac myosin inhibitors) are proving effective in relieving obstruction/symptom burden and changing disease management. These principles and time‐tested patient‐centered research strategies uniquely tailored to the heterogeneous HCM clinical spectrum are pivotal in providing practice insights, offering a vulnerable population more optimistic prognosis including opportunity to achieve normal longevity not available to prior generations of patients.

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 <50% (2 with left ventricular ejection fraction ≤30%; 1 death). Of these, 12 of 15 (80%) continued treatment. New-onset atrial fibrillation occurred in 11 (10.2%) patients (4.55 per 100 patient-years). CONCLUSIONS: In severely symptomatic obstructive HCM patients, sustained freedom from SRT was observed at 128 weeks, with nearly 90% patients remaining on long-term mavacamten. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04349072.

BACKGROUND: In severely symptomatic patients with obstructive hypertrophic cardiomyopathy, VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) demonstrated that mavacamten reduces the need for septal reduction therapy with sustained improvement in left ventricular (LV) outflow tract gradients and symptoms. Global longitudinal strain (GLS), a measure of regional myocardial function, is a more sensitive marker of systolic function. In VALOR-HCM, we assessed serial changes in LV and right ventricular (RV) strain. METHODS: VALOR-HCM included 112 patients with symptomatic obstructive hypertrophic cardiomyopathy (mean, 60 years; 51% male; LV ejection fraction, 68%). Patients assigned to mavacamten at baseline continued the drug for 56 weeks (n=56) and those assigned to placebo (n=52) transitioned to mavacamten from weeks 16 to 56 (40-week exposure). LV-GLS and RV-GLS assessment was performed using a vendor-neutral software. Non-foreshortened apical (4-, 3-, and 2-chamber) views were used to obtain peak LV-GLS. RV focused 4-chamber view was used to calculate RV 4-chamber and free wall strain. A more negative strain value is favorable. RESULTS: At baseline, the mean LV-GLS, RV 4-chamber, and free wall strain values were −14.7%, −22.2%, and −16.8%, respectively (all worse than reported normal means). In the total study sample, LV-GLS significantly improved from baseline to week 56 ( P =0.02). Twelve patients had transient reduction in LV ejection fraction (<50%) requiring temporary drug interruption (including 3 permanent discontinuations). The LV-GLS in this subgroup was worse at baseline versus total study population (−11.4%), with no significant worsening from baseline through week 56 ( P =0.64). Both free wall and 4-chamber RV-GLS remained unchanged from baseline to week 56 ( P =0.62 and P =0.56, respectively). CONCLUSIONS: In VALOR-HCM, treatment with mavacamten improved LV-GLS from baseline through week 56 (with no significant worsening of LV-GLS in patients with a reduction in LV ejection fraction ≤50%), suggesting a favorable long-term impact on regional LV systolic function. Additionally, there was no detrimental impact on RV systolic function. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04349072.

Background: In the randomized phase 3 VALOR-HCM study (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) of patients with obstructive hypertrophic cardiomyopathy, mavacamten reduced the need for septal reduction therapy. Because mavacamten improves ventricular compliance, this sub-study examined the effects of treatment with this cardiac myosin inhibitor on diastolic function. Methods: Symptomatic obstructive hypertrophic cardiomyopathy patients on maximally tolerated medical therapy referred for septal reduction therapy were randomized 1:1 to mavacamten or placebo. At baseline and week 16, a resting and stress echocardiogram was performed with interpretation by a core laboratory. In this exploratory substudy, the principal end point was the change in parameters used to define the grade of diastolic function in patients treated with mavacamten and placebo. A related objective was to assess the proportion of patients with an improvement in diastolic function grade. A secondary aim was to assess for correlation between diastolic function parameters and the secondary end points from VALOR-HCM: New York Heart Association class, quality of life, and cardiac biomarkers. Results: Diastolic dysfunction grade was evaluable in 98 patients at baseline and week 16. Among patients treated with mavacamten, 29.4% (15 of 51) demonstrated improvement in diastolic function grade compared with 12.8% (6 of 47) patients with placebo ( P =0.05). Average E/e’ ratio decreased significantly in patients treated with mavacamten (−3.4±5.3) compared with placebo (0.57±3.5; P <0.001). Indexed left atrial volumes (mL/m 2 ) also decreased significantly in patients who received mavacamten (−5.2±7.8) compared with placebo (−0.51±8.1; P =0.005). After adjustment for change in left ventricular outflow tract gradient and mitral regurgitation, mavacamten was significantly associated with a decrease in average E/e’ ratio and indexed left atrial volumes. Change in average E/e’ ratio was significantly correlated with the secondary end points from VALOR-HCM. Conclusions: In this exploratory substudy, after 16 weeks of therapy, mavacamten improved diastolic function, and this change correlated with improvement in clinical and biomarker end points. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04349072.

Background: Septal reduction therapy (SRT) in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy (oHCM) is associated with variable morbidity and mortality. The VALOR-HCM trial (A Study to Evaluate Mavacamten in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) examined the effect of mavacamten on the need for SRT through week 32 in oHCM. Methods: A double-blind randomized placebo-controlled multicenter trial at 19 US sites included patients with oHCM on maximal tolerated medical therapy referred for SRT with left ventricular outflow tract gradient ≥50 mm Hg at rest or provocation (enrollment, July 2020–October 2021). The group initially randomized to mavacamten continued the drug for 32 weeks, and the placebo group crossed over to dose-blinded mavacamten from week 16 to week 32. Dose titrations were based on investigator-blinded echocardiographic assessment of left ventricular outflow tract gradient and left ventricular ejection fraction. The principal end point was the proportion of patients proceeding with SRT or remaining guideline eligible at 32 weeks in both treatment groups. Results: From the 112 randomized patients with oHCM, 108 (mean age, 60.3 years; 50% men; 94% in New York Heart Association class III/IV) qualified for week 32 evaluation (56 in the original mavacamten group and 52 in the placebo cross-over group). After 32 weeks, 6 of 56 patients (10.7%) in the original mavacamten group and 7 of 52 patients (13.5%) in the placebo cross-over group met SRT guideline criteria or elected to undergo SRT. After 32 weeks, a sustained reduction in resting left ventricular outflow tract gradient (−33.0 mm Hg [95% CI, −41.1 to −24.9]) and Valsalva left ventricular outflow tract gradient (−43.0 mm Hg [95% CI, −52.1 to −33.9]) was observed in the original mavacamten group. A similar reduction in resting (−33.7 mm Hg [95% CI, −42.2 to −25.2]) and Valsalva (−52.9 mm Hg [95% CI, −63.2 to −42.6]) gradients was quantified in the cross-over group after 16 weeks of mavacamten. After 32 weeks, improvement by ≥1 New York Heart Association class was observed in 48 of 53 patients (90.6%) in the original mavacamten group and 35 of 50 patients (70%) after 16 weeks in the cross-over group. Conclusions: In severely symptomatic patients with oHCM, 32 weeks of mavacamten treatment showed sustained reduction in the proportion proceeding to SRT or remaining guideline eligible, with similar effects observed in patients who crossed over from placebo after 16 weeks. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04349072.