Effect of Mavacamten in Women Compared With Men With Obstructive Hypertrophic Cardiomyopathy: Insights From EXPLORER-HCM.

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, ß-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.

Sex Differences in Characteristics, Outcomes, and Treatment Response With Dapagliflozin Across the Range of Ejection Fraction in Patients With Heart Failure: Insights From DAPA-HF and DELIVER.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors have emerged as a key pharmacotherapy in heart failure (HF) with both reduced and preserved ejection fraction. The benefit of other HF therapies may be modified by sex, but whether sex modifies the treatment effect and safety profile of sodium-glucose cotransporter-2 inhibitors remains unclear. Our analyses aim to assess the effect of sex on the efficacy and safety of dapagliflozin. METHODS: In a prespecified patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), clinical outcomes were compared by sex (including the composite of cardiovascular death or worsening HF events, cardiovascular death, all-cause death, total events [first and recurrent HF hospitalization and cardiovascular death], and Kansas City Cardiomyopathy Questionnaire scores) across the spectrum of left ventricular ejection fraction. RESULTS: Of a total of 11 007 randomized patients, 3856 (35%) were women. Women with HF were older and had higher body mass index but were less likely to have a history of diabetes and myocardial infarction or stroke and more likely to have hypertension and atrial fibrillation compared with men. At baseline, women had higher ejection fraction but worse Kansas City Cardiomyopathy Questionnaire scores than men did. After adjustment for baseline differences, women were less likely than men to experience cardiovascular death (adjusted hazard ratio, 0.69 [95% CI, 0.60-0.79]), all-cause death (adjusted hazard ratio, 0.69 [95% CI, 0.62-0.78]), HF hospitalizations (adjusted hazard ratio, 0.82 [95% CI, 0.72-0.94]), and total events (adjusted rate ratio, 0.77 [95% CI, 0.71-0.84]). Dapagliflozin reduced the primary end point in both men and women similarly (Pinteraction=0.77) with no sex-related differences in secondary outcomes (all Pinteraction>0.35) or safety events. The benefit of dapagliflozin was observed across the entire ejection fraction spectrum and was not modified by sex (Pinteraction>0.40). There were no sex-related differences in serious adverse events, adverse events, or drug discontinuation attributable to adverse events. CONCLUSIONS: In DAPA-HF and DELIVER, the response to dapagliflozin was similar between men and women. Sex did not modify the treatment effect of dapagliflozin across the range of ejection fraction.

Monitoring treatment with cardiac myosin inhibitors in symptomatic obstructive hypertrophic cardiomyopathy.

PURPOSE OF REVIEW: Cardiac myosin inhibitors (CMIs) represent a major milestone in the treatment of patients with symptomatic obstructive hypertrophic cardiomyopathy. The objective of this review is to discuss the mechanisms of action, clinical trial evidence, safety profile and monitoring of CMIs, which are important to the implementation of these drugs in clinical practice. RECENT FINDINGS: Mavacamten and aficamten have both been shown to substantially improve left ventricular outflow tract gradients, biomarkers and symptoms in patients with obstructive hypertrophic cardiomyopathy. Both agents are well tolerated with few adverse events in clinical trial follow up. Transient reductions in left ventricular ejection fraction may be associated with both mavacamten and aficamten but respond to dose reduction. SUMMARY: There is now robust clinical trial evidence base to support the use of mavacamten for patients with symptomatic obstructive hypertrophic cardiomyopathy. Generation of long-term safety and efficacy data and exploring applications of CMI to nonobstructive cardiomyopathy and heart failure with preserved ejection fraction represent important next steps.

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. FUNDING: MyoKardia.

Effect of High-Dose Trivalent vs Standard-Dose Quadrivalent Influenza Vaccine on Mortality or Cardiopulmonary Hospitalization in Patients With High-risk Cardiovascular Disease: A Randomized Clinical Trial.

Importance: Influenza is temporally associated with cardiopulmonary morbidity and mortality among those with cardiovascular disease who may mount a less vigorous immune response to vaccination. Higher influenza vaccine dose has been associated with reduced risk of influenza illness. Objective: To evaluate whether high-dose trivalent influenza vaccine compared with standard-dose quadrivalent influenza vaccine would reduce all-cause death or cardiopulmonary hospitalization in high-risk patients with cardiovascular disease. Design, Setting, and Participants: Pragmatic multicenter, double-blind, active comparator randomized clinical trial conducted in 5260 participants vaccinated for up to 3 influenza seasons in 157 sites in the US and Canada between September 21, 2016, and January 31, 2019. Patients with a recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor were eligible. Interventions: Participants were randomly assigned to receive high-dose trivalent (n = 2630) or standard-dose quadrivalent (n = 2630) inactivated influenza vaccine and could be revaccinated for up to 3 seasons. Main Outcomes and Measures: The primary outcome was the time to the composite of all-cause death or cardiopulmonary hospitalization during each enrolling season. The final date of follow-up was July 31, 2019. Vaccine-related adverse events were also assessed. Results: Among 5260 randomized participants (mean [SD] age, 65.5 [12.6] years; 3787 [72%] men; 3289 [63%] with heart failure) over 3 influenza seasons, there were 7154 total vaccinations administered and 5226 (99.4%) participants completed the trial. In the high-dose trivalent vaccine group, there were 975 primary outcome events (883 hospitalizations for cardiovascular or pulmonary causes and 92 deaths from any cause) among 884 participants during 3577 participant-seasons (event rate, 45 per 100 patient-years), whereas in the standard-dose quadrivalent vaccine group, there were 924 primary outcome events (846 hospitalizations for cardiovascular or pulmonary causes and 78 deaths from any cause) among 837 participants during 3577 participant-seasons (event rate, 42 per 100 patient-years) (hazard ratio, 1.06 [95% CI, 0.97-1.17]; P = .21). In the high-dose vs standard-dose groups, vaccine-related adverse reactions occurred in 1449 (40.5%) vs 1229 (34.4%) participants and severe adverse reactions occurred in 55 (2.1%) vs 44 (1.7%) participants. Conclusions and Relevance: In patients with high-risk cardiovascular disease, high-dose trivalent inactivated influenza vaccine, compared with standard-dose quadrivalent inactivated influenza vaccine, did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations. Influenza vaccination remains strongly recommended in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT02787044.

Influenza Vaccine in Heart Failure.

BACKGROUND: Influenza infection is a serious event for patients with heart failure (HF). Little knowledge exists about the association between influenza vaccination and outcome in patients with HF. This study sought to determine whether influenza vaccination is associated with improved long-term survival in patients with newly diagnosed HF. METHODS: We performed a nationwide cohort study including all patients who were >18 years of age and diagnosed with HF in Denmark in the period of January 1, 2003, to June 1, 2015 (n=134 048). We collected linked data using nationwide registries. Vaccination status, number, and frequency during follow-up were treated as time-varying covariates in time-dependent Cox regression. RESULTS: Follow-up was 99.8% with a median follow-up time of 3.7 years (interquartile range, 1.7-6.8 years). The vaccination coverage of the study cohort ranged from 16% to 54% during the study period. In unadjusted analysis, receiving ≥1 vaccinations during follow-up was associated with a higher risk of death. After adjustment for inclusion date, comorbidities, medications, household income, and education level, receiving ≥1 vaccinations was associated with an 18% reduced risk of death (all-cause: hazard ratio, 0.82; 95% CI, 0.81-0.84; P<0.001; cardiovascular causes: hazard ratio, 0.82; 95% CI, 0.81-0.84; P<0.001). Annual vaccination, vaccination early in the year (September to October), and greater cumulative number of vaccinations were associated with larger reductions in the risk of death compared with intermittent vaccination. CONCLUSIONS: In patients with HF, influenza vaccination was associated with a reduced risk of both all-cause and cardiovascular death after extensive adjustment for confounders. Frequent vaccination and vaccination earlier in the year were associated with larger reductions in the risk of death compared with intermittent and late vaccination.

Six-Year Changes in Physical Activity and the Risk of Incident Heart Failure: ARIC Study.

BACKGROUND: Higher physical activity (PA) is associated with lower heart failure (HF) risk; however, the effect of changes in PA on HF risk is unknown. METHODS: We evaluated 11 351 ARIC study (Atherosclerosis Risk in Communities) participants (mean age 60 years) who attended visit 3 (1993-1995) and did not have a history of cardiovascular disease. Exercise PA was assessed using a modified Baecke questionnaire and categorized according to American Heart Association guidelines as recommended, intermediate, or poor. We used Cox regression models to characterize the association of 6-year changes in PA between the first (1987-1989) and third ARIC visits and HF risk. RESULTS: During a median of 19 years of follow-up, 1750 HF events occurred. Compared with those with poor activity at both visits, the lowest HF risk was seen for those with persistently recommended activity (hazard ratio, 0.69; 95% confidence interval, 0.60-0.80). However, those whose PA increased from poor to recommended also had reduced HF risk (hazard ratio, 0.77; 95% confidence interval 0.63-0.93). Among participants with poor baseline activity, each 1 SD higher PA at 6 years (512.5 METS*minutes/week, corresponding to ≈30 minutes of brisk walking 4 times per week) was associated with significantly lower future HF risk (hazard ratio, 0.89, 95% confidence interval, 0.82-0.96). CONCLUSIONS: Although maintaining recommended activity levels is associated with the lowest HF risk, initiating and increasing PA, even in late middle age, are also linked to lower HF risk. Augmenting PA may be an important component of strategies to prevent HF.

Physical Activity and Prognosis in the TOPCAT Trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist).

BACKGROUND: Physical activity (PA) is inversely associated with adverse cardiovascular outcomes in healthy populations, but the impact of physical activity in patients with heart failure (HF) with preserved ejection fraction is less well characterized. METHODS: The baseline self-reported PA of 1751 subjects enrolled in the Americas region of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) was categorized as poor, intermediate, or ideal PA with American Heart Association criteria. PA was related to the primary composite outcome (HF hospitalization, cardiovascular mortality, or aborted cardiac arrest), its components, and all-cause mortality with the use of multivariable Cox models. RESULTS: The mean age at enrollment was 68.6±9.6 years. Few patients met American Heart Association criteria for ideal activity (11% ideal, 14% intermediate, 75% poor). Over a median follow-up of 2.4 years, the primary composite outcome occurred in 519 patients (397 HF hospitalizations, 222 cardiovascular deaths, and 6 aborted cardiac arrests). Compared with those with ideal baseline PA, poor and intermediate baseline PA was associated with a greater risk of the primary outcome (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.28-3.28; HR, 1.95; 95% CI, 1.15-3.33, respectively), HF hospitalization (HR, 1.93; 95% CI, 1.16-3.22; HR, 1.84; 95% CI, 1.02-3.31), cardiovascular mortality (HR, 4.36; 95% CI, 1.37-13.83; HR, 4.05; 95% CI, 1.17-14.04), and all-cause mortality (HR, 2.95; 95% CI, 1.44-6.02; HR, 2.05; 95% CI, 0.90-4.67) after multivariable adjustment for potential confounders. CONCLUSIONS: In patients with HF with preserved ejection fraction, both poor and intermediate self-reported PA were associated with higher risk of HF hospitalization and mortality. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT00094302.

Cardiac structure and function and leisure-time physical activity in the elderly: The Atherosclerosis Risk in Communities Study.

AIMS: Adults who engage in leisure-time physical activity (LTPA) have a reduced risk of developing heart failure. We hypothesized that high levels of LTPA are associated with diminished adverse age-related changes in cardiac structure and function. METHODS AND RESULTS: We studied 4342 Atherosclerosis Risk in Communities Study participants free of cardiovascular disease who underwent standardized echocardiography. In a cross-sectional analysis, we related LTPA (poor, intermediate, or ideal) to cardiac structure and function. We also related cumulative average LTPA over 24 years and changes in LTPA categories to echocardiographic measures. Cross-sectional analysis demonstrated that ideal LTPA, compared with poor LTPA, was associated with better diastolic function [prevalence of normal diastolic function: 39.8% vs. 31.5%, P < 0.001; mean E/E' ratio (95% CI): 9.8 (9.6, 9.9) vs. 10.4 (10.2, 10.5), P = 0.001] and better systolic function [left-ventricular (LV) longitudinal strain: -18.3 (-18.4, -18.2) vs. -17.9 (-18.0, -17.8), P < 0.001] after adjusting for age, sex, race, and centre. Higher cumulative average LTPA over 24 years or an improvement in LTPA category were also, respectively, related to a more favourable E/E' ratio (P < 0.0001, P = 0.004) and longitudinal LV strain (P = 0.0002, P = 0.002). CONCLUSION: Ideal LTPA, higher average levels of LTPA over a 24-year period, and an improvement in LTPA even later in life were associated with more favourable indices of LV diastolic and systolic function in older adults. Sustaining higher levels of LTPA, and even increasing physical activity later in life, may be beneficial for older adults in attenuating expected age-related changes in cardiac structure and function.

Influence of Physical Activity on Hypertension and Cardiac Structure and Function.

The global burden of hypertension is rising and accounts for substantial morbidity and mortality. Lifestyle factors such as diet and physical inactivity contribute to this burden, further highlighting the need for prevention efforts to curb this public health epidemic. Regular physical activity is associated with lower blood pressure, reduced cardiovascular risk, and cardiac remodeling. While exercise and hypertension can both be associated with the development of left ventricular hypertrophy (LVH), the cardiac remodeling from hypertension is pathologic with an associated increase in myocyte hypertrophy, fibrosis, and risk of heart failure and mortality, whereas LVH in athletes is generally non-pathologic and lacks the fibrosis seen in hypertension. In hypertensive patients, physical activity has been associated with paradoxical regression or prevention of LVH, suggesting a mechanism by which exercise can benefit hypertensive patients. Further studies are needed to better understand the mechanisms underlying the benefits of physical activity in the hypertensive heart.

Long-Term Safety and Efficacy of Mavacamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Interim Results of the PIONEER-OLE Study.

BACKGROUND: The phase 2 PIONEER-HCM (Phase 2 Open-label Pilot Study Evaluating Mavacamten in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction) study showed that mavacamten improved left ventricular outflow tract gradients, exercise capacity, and symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM), but the results of longer-term treatment are less well described. We report interim results from the PIONEER-OLE (PIONEER Open-Label Extension) study, the longest-term study of mavacamten in patients with symptomatic obstructive HCM. METHODS AND RESULTS: Patients who previously completed PIONEER-HCM (n=20) were eligible to enroll in PIONEER-OLE. Patients received oral mavacamten, 5 mg once daily (starting dose), with individualized dose titration at week 6. Evaluations included serial monitoring of safety, echocardiography, Kansas City Cardiomyopathy Questionnaire-Overall Summary Score, and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Thirteen patients enrolled and received mavacamten (median study duration at data cutoff, 201 weeks). Most patients (92.3%) received ß-blockers concomitantly. Treatment-emergent adverse events were predominantly mild/moderate. One patient had an isolated reduction in left ventricular ejection fraction to 47%, which recovered and remained normal with continued treatment at a reduced dose. At week 180, mavacamten was associated with New York Heart Association class improvements from baseline (class II to I, n=9; class III to II, n=1; and unchanged, n=2), sustained reductions in left ventricular outflow tract gradients (mean [SD] change from baseline: resting, -50 [55] mm Hg; Valsalva, -70 [41] mm Hg), and serum NT-proBNP levels (median [interquartile range] change from baseline: -498 [-2184 to -76] ng/L), and improved Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (mean [SD] change from baseline: +17 [16]). CONCLUSIONS: This long-term analysis supports the continued safety and effectiveness of mavacamten for >3 years in obstructive HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03496168.

Influenza Vaccine Immune Response in Patients With High-Risk Cardiovascular Disease: A Secondary Analysis of the INVESTED Randomized Clinical Trial.

Importance: High-dose trivalent compared with standard-dose quadrivalent influenza vaccine did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations in patients with high-risk cardiovascular disease in the INVESTED trial. Whether humoral immune response to influenza vaccine is associated with clinical outcomes is unknown. Objective: To examine the antibody response to high-dose trivalent compared with standard-dose quadrivalent inactivated influenza vaccine and its associations with clinical outcomes. Design, Setting, and Participants: This secondary analysis is a prespecified analysis of the immune response substudy of the randomized, double-blind, active-controlled INVESTED trial, which was conducted at 157 sites in the United States and Canada over 3 influenza seasons between September 2016 and January 2019. Antibody titers were determined by hemagglutination inhibition assays at randomization and 4 weeks during the 2017-2018 and 2018-2019 seasons. Eligibility criteria included recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor. Data were analyzed from February 2023 to June 2023. Main Outcomes and Measures: Mean antibody titer change, seroprotection (antibody titer level ≥1:40) and seroconversion (≥4-fold increase in titer) at 4 weeks, and the association between seroconversion status and the risk for adverse clinical outcomes. Interventions: High-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine, with revaccination up to 3 seasons. Results: Antibody data were available for 658 of 5260 randomized participants (12.5%; mean [SD] age, 66.2 [11.4] years; 507 male [77.1%], 151 female [22.9%]; 348 with heart failure [52.9%]). High-dose vaccine was associated with an increased magnitude in antibody titers for A/H1N1, A/H3N2, and B-type antigens compared with standard dose. More than 92% of all participants achieved seroprotection for each of the contained antigens, while seroconversion rates were higher in participants who received high-dose vaccine. Seroconversion for any antigen was not associated with the risk for cardiopulmonary hospitalizations or all-cause mortality (hazard ratio, 1.09; 95% CI, 0.79-1.53; P = .59), irrespective of randomized treatment (P = .38 for interaction). Conclusions and Relevance: High-dose vaccine elicited a more robust humoral response in patients with heart failure or prior myocardial infarction enrolled in the INVESTED trial, with no association between seroconversion status and the risk for cardiopulmonary hospitalizations or all-cause mortality. Vaccination to prevent influenza remains critical in high-risk populations. Trial Registration: ClinicalTrials.gov Identifier: NCT02787044.

Mavacamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy: Interim Results From the MAVA-LTE Study, EXPLORER-LTE Cohort.

BACKGROUND: Data assessing the long-term safety and efficacy of mavacamten treatment for symptomatic obstructive hypertrophic cardiomyopathy are needed. OBJECTIVES: The authors sought to evaluate interim results from the EXPLORER-Long Term Extension (LTE) cohort of MAVA-LTE (A Long-Term Safety Extension Study of Mavacamten in Adults Who Have Completed EXPLORER-HCM; NCT03723655). METHODS: After mavacamten or placebo withdrawal at the end of the parent EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545), patients could enroll in MAVA-LTE. Patients received mavacamten 5 mg once daily; adjustments were made based on site-read echocardiograms. RESULTS: Between April 9, 2019, and March 5, 2021, 231 of 244 eligible patients (94.7%) enrolled in MAVA-LTE (mean age: 60 years; 39% female). At data cutoff (August 31, 2021) 217 (93.9%) remained on treatment (median time in study: 62.3 weeks; range: 0.3-123.9 weeks). At 48 weeks, patients showed improvements in left ventricular outflow tract (LVOT) gradients (mean change ± SD from baseline: resting: -35.6 ± 32.6 mm Hg; Valsalva: -45.3 ± 35.9 mm Hg), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (median: -480 ng/L; Q1-Q3: -1,104 to -179 ng/L), and NYHA functional class (67.5% improved by ≥1 class). LVOT gradients and NT-proBNP reductions were sustained through 84 weeks in patients who reached this timepoint. Over 315 patient-years of exposure, 8 patients experienced an adverse event of cardiac failure, and 21 patients had an adverse event of atrial fibrillation, including 11 with no prior history of atrial fibrillation. Twelve patients (5.2%) developed transient reductions in site-read echocardiogram left ventricular ejection fraction of <50%, resulting in temporary treatment interruption; all recovered. Ten patients discontinued treatment due to treatment-emergent adverse events. CONCLUSIONS: Mavacamten treatment showed clinically important and durable improvements in LVOT gradients, NT-proBNP levels, and NYHA functional class, consistent with EXPLORER-HCM. Mavacamten treatment was well tolerated over a median 62-week follow-up.

Feasibility and Findings of Including Self-Identified Adult Congenital Heart Disease Patients in the INVESTED Trial.

Background: Adult congenital heart disease (ACHD) patients have significant morbidity and rise in cardiac admissions. Their outcome with high-dose influenza vaccination is unknown in comparison to those without ACHD. Objectives: The purpose of this study was to compare all-cause mortality or cardiopulmonary hospitalizations in self-identified ACHD versus non-ACHD patients receiving high- or low-dose influenza vaccination within the INfluenza Vaccine to Effectively Stop cardioThoracic Events and Decompensated heart failure trial. Methods: We prospectively included ACHD patients in the INVESTED (INfluenza Vaccine to Effectively Stop cardioThoracic Events and Decompensated heart failure) trial. The primary endpoint was all-cause death or hospitalization for cardiovascular or pulmonary causes. Results: Of the 272 ACHD patients, 132 were randomly assigned to receive high-dose trivalent and 140 to standard-dose quadrivalent influenza vaccine. Compared to the non-ACHD cohort (n = 4,988), ACHD patients were more likely to be younger, women, smokers, have atrial fibrillation, and have a qualifying event of heart failure. The primary outcome was 49.8 events versus 42.8 events per 100 person-years (adjusted HR: 1.17; 95% CI: 0.95-1.45; P = 0.144) in the ACHD group and non-ACHD group, respectively. The interaction between ACHD status and randomized treatment effect was not significant for the primary outcome (P = 0.858). Vaccine-related adverse events were similar in both groups. Conclusions: Patients who self-identify as being ACHD had similar primary outcome of all-cause death or hospitalization for cardiovascular or pulmonary causes compared to non-ACHD cohort. High-dose influenza vaccination was similar to standard-dose influenza vaccination on the primary outcome in patients who self-identify as ACHD.

Cardiovascular-kidney-metabolic overlap in heart failure with preserved ejection fraction: Cardiac structure and function, clinical outcomes, and response to sacubitril/valsartan in PARAGON-HF.

AIMS: Cardiovascular-kidney-metabolic (CKM) multimorbidity is prevalent among individuals with heart failure (HF), but whether cardiac structure and function, clinical outcomes, and treatment response to sacubitril/valsartan vary in relation to CKM status is unknown. METHODS AND RESULTS: In this PARAGON-HF post-hoc analysis, we evaluated the impact of CKM multimorbidity (atherosclerotic cardiovascular [CV] disease, chronic kidney disease, and type 2 diabetes) on cardiac structure and function, clinical outcomes, and treatment effects of sacubitril/valsartan versus valsartan. The primary outcome was a composite of total HF hospitalizations and CV death. Secondary outcomes included the individual components of the primary outcome and a composite kidney outcome (sustained estimated glomerular filtration rate reduction of ≥50%, end-stage kidney disease, or kidney-related death). At baseline, 35.2% had one CKM condition, 33.3% had two, 15.9% had three, and only 15.6% had HF alone. CKM multimorbidity was associated with higher septal and posterior wall thickness, lower global longitudinal strain, higher E/e', and worse right ventricular function. Total HF hospitalizations or CV death increased with greater CKM multimorbidity, with the highest relative risk observed with three CKM conditions (rate ratio 3.06, 95% confidence interval 2.33-4.03), compared with HF alone. Treatment effects of sacubitril/valsartan were consistent irrespective of the number of CKM conditions for the primary endpoint (pinteraction = 0.75), CV death (pinteraction = 0.82), total HF hospitalizations (pinteraction = 0.67), and the composite kidney endpoint (pinteraction = 0.99). CONCLUSIONS: Cardiovascular-kidney-metabolic multimorbidity was common in PARAGON-HF and associated with adverse changes in cardiac structure and function and with a stepwise increase in risk of clinical outcomes. Treatment effects of sacubitril/valsartan were consistent irrespective of CKM burden. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01920711.

Intervention for critical aortic stenosis in Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare genetic premature aging disease that is historically fatal in teenage years, secondary to severe accelerated atherosclerosis. The only approved treatment is the farnesyltransferase inhibitor lonafarnib, which improves vascular structure and function, extending average untreated lifespan of 14.5 years by 4.3 years (30%). With this longer lifespan, calcific aortic stenosis (AS) was identified as an emerging critical risk factor for cardiac death in older patients. Intervention to relieve critical AS has the potential for immediate improvement in healthspan and lifespan. However, HGPS patient-device size mismatch, pervasive peripheral arterial disease, skin and bone abnormalities, and lifelong failure to thrive present unique challenges to intervention. An international group of experts in HGPS, pediatric and adult cardiology, cardiac surgery, and pediatric critical care convened to identify strategies for successful treatment. Candidate procedures were evaluated by in-depth examination of 4 cases that typify HGPS clinical pathology. Modified transcatheter aortic valve replacement (TAVR) and left ventricular Apico-Aortic Conduit (AAC) placement were deemed high risk but viable options. Two cases received TAVR and 2 received AAC post-summit. Three were successful and 1 patient died perioperatively due to cardiovascular disease severity, highlighting the importance of intervention timing and comparative risk stratification. These breakthrough interventions for treating critical aortic stenosis in HGPS patients could rewrite the current clinical perspective on disease course by greatly improving late-stage quality of life and increasing lifespan. Expanding worldwide medical and surgical competency for this ultra-rare disease through expert information-sharing could have high impact on treatment success.

Effect of beta-blocker therapy on the response to mavacamten in patients with symptomatic obstructive hypertrophic cardiomyopathy.

AIMS: In the EXPLORER-HCM trial, mavacamten improved exercise capacity and symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten effects on the primary endpoint, a composite of peak oxygen consumption (VO2 ) and New York Heart Association (NYHA) class, were greater in patients not receiving background beta-blockers than in those receiving beta-blockers. We sought to determine if the effect of background treatment was consistent across other clinically meaningful parameters. METHODS AND RESULTS: Subgroup analyses by beta-blocker use were performed in patients with oHCM from the EXPLORER-HCM and mavacamten long-term extension (MAVA-LTE) studies. In EXPLORER-HCM, 189 patients (75.3%) were receiving beta-blockers, and 62 (24.7%) were receiving non-dihydropyridine calcium channel blockers or no background HCM medication; 170 patients (90.4%) receiving beta-blockers had chronotropic incompetence. Improvements in peak VO2 at week 30 with mavacamten versus placebo were lower with beta-blockers (mean difference [95% confidence interval (CI)]: 1.04 [0.12, 1.95] ml/kg/min) than without beta-blockers (mean difference [95% CI]: 2.69 [1.29, 4.09] ml/kg/min); improvements in non-heart rate-dependent parameters (VE /VCO2 slope) appeared unaffected by beta-blockers. Improvements in functional capacity parameters at week 30 with mavacamten versus placebo were independent of beta-blockade for post-exercise left ventricular outflow tract gradient (mean difference [95% CI]: -37.9 [-48.0, -27.9] mmHg with beta-blockers; -33.5 [-53.6, -13.3] mmHg without beta-blockers), proportion of patients with reduction of ≥1 NYHA class, Kansas City Cardiomyopathy Questionnaire clinical summary scores and N-terminal pro-B-type natriuretic peptide. Mavacamten benefits were reproduced and maintained in MAVA-LTE regardless of beta-blockade. CONCLUSION: Mavacamten improved measures of functional capacity, left ventricular outflow tract obstruction, symptom burden and biomarkers in patients with HCM regardless of beta-blocker use. Beta-blocker use was often associated with chronotropic incompetence, affecting peak VO2 and other heart rate-dependent measures, but had minimal impact on heart rate-independent measures.

Temporal Association Among Influenza-Like Illness, Cardiovascular Events, and Vaccine Dose in Patients With High-Risk Cardiovascular Disease: Secondary Analysis of a Randomized Clinical Trial.

Importance: Influenza-like illness (ILI) activity has been associated with increased risk of cardiopulmonary (CP) events during the influenza season. High-dose trivalent influenza vaccine was not superior to standard-dose quadrivalent vaccine for reducing these events in patients with high-risk cardiovascular (CV) disease in the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial. Objective: To evaluate whether high-dose trivalent influenza vaccination is associated with benefit over standard-dose quadrivalent vaccination in reducing CP events during periods of high, local influenza activity. Design, Setting, and Participants: This study was a prespecified secondary analysis of INVESTED, a multicenter, double-blind, active comparator randomized clinical trial conducted over 3 consecutive influenza seasons from September 2016 to July 2019. Follow-up was completed in July 2019, and data were analyzed from September 21, 2016, to July 31, 2019. Weekly Centers for Disease Control and Prevention (CDC)-reported, state-level ILI activity was ascertained to assess the weekly odds of the primary outcome. The study population included 3094 patients with high-risk CV disease from participating centers in the US. Intervention: Participants were randomized to high-dose trivalent or standard-dose quadrivalent influenza vaccine and revaccinated for up to 3 seasons. Main Outcomes and Measures: The primary outcome was the time to composite of all-cause death or CP hospitalization within each season. Additional measures included weekly CDC-reported ILI activity data by state. Results: Among 3094 participants (mean [SD] age, 65 [12] years; 2309 male [75%]), we analyzed 129 285 person-weeks of enrollment, including 1396 composite primary outcome events (1278 CP hospitalization, 118 deaths). A 1% ILI increase in the prior week was associated with an increased risk in the primary outcome (odds ratio [OR], 1.14; 95% CI, 1.07-1.21; P < .001), CP hospitalization (OR, 1.13; 95% CI, 1.06-1.21; P < .001), and CV hospitalization (OR, 1.12; 95% CI, 1.04-1.19; P = .001), after adjusting for state, demographic characteristics, enrollment strata, and CV risk factors. Increased ILI activity was not associated with all-cause death (OR, 1.00; 95% CI, 0.88-1.13; P > .99). High-dose compared with standard-dose vaccine did not significantly reduce the primary outcome, even when the analysis was restricted to weeks of high ILI activity (OR, 0.88; 95% CI, 0.65-1.20; P = .43). Traditionally warmer months in the US were associated with lower CV risk independent of local ILI activity. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, ILI activity was temporally associated with increased CP events in patients with high-risk CV disease, and a higher influenza vaccine dose did not significantly reduce temporal CV risk. Other seasonal factors may play a role in the coincident high rates of ILI and CV events. Trial Registration: ClinicalTrials.gov Identifier: NCT02787044.

Association of post-vaccination adverse reactions after influenza vaccine with mortality and cardiopulmonary outcomes in patients with high-risk cardiovascular disease: the INVESTED trial.

AIMS: Influenza vaccination is associated with reduced cardiopulmonary morbidity and mortality among patients with heart failure or recent myocardial infarction. The immune response to vaccination frequently results in mild adverse reactions (AR), which leads to vaccine hesitancy. This post hoc analysis explored the association between vaccine-related AR and morbidity and mortality in patients with high-risk cardiovascular disease. METHODS AND RESULTS: The INVESTED trial randomized 5260 patients with recent heart failure hospitalization or acute myocardial infarction to high-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine. We examined the association between vaccine-related AR and adverse clinical outcomes across both treatment groups in propensity-adjusted models. Among 5210 participants with available information on post-vaccination symptoms, 1968 participants (37.8%) experienced a vaccine-related AR. Compared to those without AR, post-vaccination AR, most commonly injection site pain (60.3%), were associated with lower risk for the composite of all-cause death or cardiopulmonary hospitalization (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.75-0.92, p < 0.001), cardiopulmonary hospitalizations (HR 0.85 [95% CI 0.76-0.95], p = 0.003), all-cause death (HR 0.77 [95% CI 0.62-0.96], p = 0.02), cardiovascular hospitalizations (HR 0.88 [95% CI 0.78-0.99], p = 0.03) and non-cardiopulmonary hospitalizations (HR 0.80 [95% CI 0.69-0.92], p = 0.003). While mild (76.4%) and moderate (20.6%) AR were most common and together associated with lower risk for the primary outcome (HR 0.81 [95% CI 0.74-0.90], p < 0.001), severe AR (2.9%) were related to increased risk (HR 1.68 [95% CI 1.17-2.42], p = 0.005). CONCLUSION: Mild to moderate post-vaccination reactions after influenza vaccine were associated with reduced risk of cardiopulmonary hospitalizations and all-cause mortality in patients with high-risk cardiovascular disease, while severe reactions may indicate increased risk. Mild to moderate AR to influenza vaccination may be a marker of immune response and should not deter future vaccinations.