Safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy: A 36-week analysis from FOREST-HCM.

AIMS: The aim of this study was to report safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy (nHCM) over 36 weeks in the ongoing FOREST-HCM trial. METHODS AND RESULTS: Patients were started on aficamten 5 mg daily, with doses adjusted in 5-mg increments (5-20 mg) at ≥2-week intervals according to site-read left ventricular ejection fraction (LVEF). Aficamten dose was increased if LVEF ≥55%, maintained if LVEF 50-54%, decreased if LVEF 40-<50%, and temporarily interrupted if LVEF <40%. Safety and efficacy were assessed over 36 weeks. Overall, 34 patients were enrolled (mean age 57.2 ± 15.3 years, 62% female, 41% in New York Heart Association [NYHA] class III). Over 36 weeks, 82.3% achieved 15-20 mg daily dose and there was a modest reduction in LVEF by -4.3% ± 5.2 from 70% ± 6.1 (p < 0.0001). At Week 36, NYHA class improved by ≥1 class in 27 (79.4%) patients. Mean Kansas City Cardiomyopathy Questionnaire clinical summary score improved by 13.8 ± 12.5 points relative to baseline. Median (interquartile range) levels of N-terminal pro-B-type natriuretic peptide were significantly improved from baseline (-665.5 pg/ml [-1244.0, -232.0]; p < 0.0001), while high-sensitivity cardiac troponin I was unchanged (-2.7 ng/L [-11.3, 1.6]; p = 0.25). There were no drug discontinuations due to adverse events. LVEF <50% occurred in 2 (5.9%) patients, one following pulmonary vein isolation and one associated with atrial fibrillation. CONCLUSIONS: Over 36 weeks, aficamten appeared safe and effective in the studied patients with nHCM.

Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.

BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation. CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

Efficacy and Safety of Aficamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results From the REDWOOD-HCM Trial, Cohort 4.

BACKGROUND: This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with nonobstructive hypertrophic cardiomyopathy (nHCM). METHODS: Patients with symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤ 30 mmHg, left ventricular ejection fraction [LVEF] ≥ 60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] > 300 pg/mL) received aficamten 5-15 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks. RESULTS: We enrolled 41 patients (mean ± SD age 56 ± 16 years; 59% female). At Week 10, 22 (55%) patients experienced an improvement of ≥ 1 New York Heart Association class; 11 (29%) became asymptomatic. Clinically relevant improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores occurred in 22 (55%) patients. Symptom relief was paralleled by reductions in NT-proBNP levels (56%; P < 0.001) and high-sensitivity cardiac troponin I (22%; P < 0.005). Modest reductions in LVEF (mean ± SD) of -5.4% ± 10 to 64.6% ± 9.1 were observed. Three (8%) patients had asymptomatic reduction in LVEF < 50% (range: 41%-48%), all returning to normal after 2 weeks of washout. One patient with prior history of aborted sudden cardiac death experienced a fatal arrhythmia during the study. CONCLUSIONS: Aficamten administration for symptomatic nHCM was generally safe and was associated with improvements in heart failure symptoms and cardiac biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04219826.

Tricuspid Regurgitation and Clinical Outcomes in Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Tricuspid regurgitation (TR) is common and is associated with poor outcomes in patients with heart failure (HF). However, data with adjudicated events from fully characterized patients with heart failure with reduced ejection fraction (HFrEF) are lacking. OBJECTIVES: This study sought to explore the association between mild or moderate/severe TR and clinical outcomes of patients with HFrEF. METHODS: GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) was a double-blind, placebo-controlled randomized trial comparing omecamtiv mecarbil vs placebo in patients with symptomatic HFrEF. RESULTS: Among the 8,232 patients analyzed in the GALACTIC-HF trial, 8,180 (99%) had data regarding baseline TR (none: n = 6,476 [79%], mild: n = 919 [11%], and moderate/severe: n = 785 [10%]). The primary composite outcome of a first HF event or cardiovascular death occurred in 2,368 (36.6%) patients with no TR, 353 (38.4%) patients with mild TR, and 389 (49.6%) patients with moderate/severe TR. Moderate/severe TR was independently associated with a higher relative risk of the primary composite outcome compared with either no TR (adjusted HR: 1.12 [95% CI: 1.01-1.26]; P = 0.046) or no/mild TR (adjusted HR: 1.14 [95% CI: 1.02-1.27]; P = 0.025) driven predominantly by HF events. The association between moderate/severe TR and clinical outcomes was more pronounced in outpatients with worse renal function, higher left ventricular ejection fraction, and lower N-terminal pro-B-type natriuretic peptide and bilirubin levels. The beneficial treatment effect of omecamtiv mecarbil vs placebo on clinical outcomes was not modified by TR. CONCLUSIONS: In symptomatic patients with HFrEF, baseline moderate/severe TR was independently associated with cardiovascular death or HF events driven predominantly by HF events. The beneficial treatment effect of omecamtiv mecarbil on the primary outcome was not modified by TR.

Cardiac Troponin and Treatment Effects of Omecamtiv Mecarbil: Results From the GALACTIC-HF Study.

BACKGROUND: Omecamtiv mecarbil improves outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined the relationship between baseline troponin levels, change in troponin levels over time and the treatment effect of omecamtiv mecarbil in patients enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial (NCT02929329). METHODS: GALACTIC-HF was a double-blind, placebo-controlled trial that randomized 8256 patients with symptomatic HFrEF to omecamtiv mecarbil or placebo. High-sensitivity troponin I (cTnI) was measured serially at a core laboratory. We analyzed the relationship between both baseline cTnI and change in cTnI concentrations with clinical outcomes and the treatment effect of omecamtiv mecarbil. RESULTS: Higher baseline cTnI concentrations were associated with a risk of adverse outcomes (hazard ratio for the primary endpoint of time to first HF event or CV death = 1.30; 95% CI 1.28, 1.33; P < 0.001 per doubling of baseline cTnI). Although the incidence of safety outcomes was higher in patients with higher baseline cTnI, there was no difference between treatment groups. Treatment with omecamtiv mecarbil led to a modest increase in cTnI that was related to plasma concentrations of omecamtiv mecarbil, and it peaked at 6 weeks. An increase in troponin from baseline to week 6 was associated with an increased risk of the primary endpoint (P < 0.001), which was similar, regardless of treatment assignment (P value for interaction = 0.2). CONCLUSIONS: In a cohort of patients with HFrEF, baseline cTnI concentrations were strongly associated with adverse clinical outcomes. Although cTnI concentrations were higher in patients treated with omecamtiv mecarbil, we did not find a differential effect of omecamtiv mecarbil on either safety or efficacy based on baseline cTnI status or change in cTnI.

Exercise Capacity in Patients With Obstructive Hypertrophic Cardiomyopathy: SEQUOIA-HCM Baseline Characteristics and Study Design.

Patients with obstructive hypertrophic cardiomyopathy (oHCM) have increased risk of arrhythmia, stroke, heart failure, and sudden death. Contemporary management of oHCM has decreased annual hospitalization and mortality rates, yet patients have worsening health-related quality of life due to impaired exercise capacity and persistent residual symptoms. Here we consider the design of clinical trials evaluating potential oHCM therapies in the context of SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). This large, phase 3 trial is now fully enrolled (N = 282). Baseline characteristics reflect an ethnically diverse population with characteristics typical of patients encountered clinically with substantial functional and symptom burden. The study will assess the effect of aficamten vs placebo, in addition to standard-of-care medications, on functional capacity and symptoms over 24 weeks. Future clinical trials could model the approach in SEQUOIA-HCM to evaluate the effect of potential therapies on the burden of oHCM. (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM [SEQUOIA-HCM]; NCT05186818).

The Effect of Omecamtiv Mecarbil in Hospitalized Patients as Compared With Outpatients With HFrEF: An Analysis of GALACTIC-HF.

BACKGROUND: In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil, compared with placebo, reduced the risk of worsening heart failure (HF) events, or cardiovascular death in patients with HF and reduced ejection fraction. The primary aim of this prespecified analysis was to evaluate the safety and efficacy of omecamtiv mecarbil by randomization setting, that is, whether participants were enrolled as outpatients or inpatients. METHODS AND RESULTS: Patients were randomized either during a HF hospitalization or as an outpatient, within one year of a worsening HF event (hospitalization or emergency department visit). The primary outcome was a composite of worsening HF event (HF hospitalization or an urgent emergency department or clinic visit) or cardiovascular death. Of the 8232 patients analyzed, 2084 (25%) were hospitalized at randomization. Hospitalized patients had higher N-terminal prohormone of B-type natriuretic peptide concentrations, lower systolic blood pressure, reported more symptoms, and were less frequently treated with a renin-angiotensin system blocker or a beta-blocker than outpatients. The rate (per 100 person-years) of the primary outcome was higher in hospitalized patients (placebo group = 38.3/100 person-years) than in outpatients (23.1/100 person-years); adjusted hazard ratio 1.21 (95% confidence interval 1.12-1.31). The effect of omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients (hazard ratio 0.89, 95% confidence interval 0.78-1.01) and outpatients (hazard ratio 0.94, 95% confidence interval 0.86-1.02) (interaction P = .51). CONCLUSIONS: Hospitalized patients with HF with reduced ejection fraction had a higher rate of the primary outcome than outpatients. Omecamtiv mecarbil decreased the risk of the primary outcome both when initiated in hospitalized patients and in outpatients.

EstimATTR: A Simplified, Machine-Learning-Based Tool to Predict the Risk of Wild-Type Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM), an increasingly recognized cause of heart failure (HF), often remains undiagnosed until later stages of the disease. METHODS AND RESULTS: A previously developed machine learning algorithm was simplified to create a random forest model based on 11 selected phenotypes predictive of ATTRwt-CM to estimate ATTRwt-CM risk in hypothetical patient scenarios. Using U.S. medical claims datasets (IQVIA), International Classification of Diseases codes were extracted to identify a training cohort of patients with ATTRwt-CM (cases) or nonamyloid HF (controls). After assessment in a 20% test sample of the training cohort, model performance was validated in cohorts of patients with International Classification of Diseases codes for ATTRwt-CM or cardiac amyloidosis vs nonamyloid HF derived from medical claims (IQVIA) or electronic health records (Optum). The simplified model performed well in identifying patients with ATTRwt-CM vs nonamyloid HF in the test sample, with an accuracy of 74%, sensitivity of 77%, specificity of 72%, and area under the curve of 0.82; robust performance was also observed in the validation cohorts. CONCLUSIONS: This simplified machine learning model accurately estimated the empirical probability of ATTRwt-CM in administrative datasets, suggesting it may serve as an easily implementable tool for clinical assessment of patient risk for ATTRwt-CM in the clinical setting. BRIEF LAY SUMMARY: Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM for short) is a frequently overlooked cause of heart failure. Finding ATTRwt-CM early is important because the disease can worsen rapidly without treatment. Researchers developed a computer program that predicts the risk of ATTRwt-CM in patients with heart failure. In this study, the program was used to check for 11 medical conditions linked to ATTRwt-CM in the medical claims records of patients with heart failure. The program was 74% accurate in identifying ATTRwt-CM in patients with heart failure and was then used to develop an educational online tool for doctors (the wtATTR-CM estimATTR).

Clinical Profile, Health Care Costs, and Outcomes of Patients Hospitalized for Heart Failure With Severely Reduced Ejection Fraction.

Background Many patients with heart failure (HF) have severely reduced ejection fraction but do not meet threshold for consideration of advanced therapies (ie, stage D HF). The clinical profile and health care costs associated with these patients in US practice is not well described. Methods and Results We examined patients hospitalized for worsening chronic heart failure with reduced ejection fraction ≤40% from 2014 to 2019 in the GWTG-HF (Get With The Guidelines-Heart Failure) registry, who did not receive advanced HF therapies or have end-stage kidney disease. Patients with severely reduced EF defined as EF ≤30% were compared with those with EF 31% to 40% in terms of clinical profile and guideline-directed medical therapy. Among Medicare beneficiaries, postdischarge outcomes and health care expenditure were compared. Among 113 348 patients with EF ≤40%, 69% (78 589) had an EF ≤30%. Patients with severely reduced EF ≤30% tended to be younger and were more likely to be Black. Patients with EF ≤30% also tended to have fewer comorbidities and were more likely to be prescribed guideline-directed medical therapy ("triple therapy" 28.3% versus 18.2%, P<0.001). At 12-months postdischarge, patients with EF ≤30% had significantly higher risk of death (HR, 1.13 [95% CI, 1.08-1.18]) and HF hospitalization (HR, 1.14 [95% CI, 1.09-1.19]), with similar risk of all-cause hospitalizations. Health care expenditures were numerically higher for patients with EF ≤30% (median US$22 648 versus $21 392, P=0.11). Conclusions Among patients hospitalized for worsening chronic heart failure with reduced ejection fraction in US clinical practice, most patients have severely reduced EF ≤30%. Despite younger age and modestly higher use of guideline-directed medical therapy at discharge, patients with severely reduced EF face heightened postdischarge risk of death and HF hospitalization.

Omecamtiv Mecarbil in Black Patients With Heart Failure and Reduced Ejection Fraction: Insights From GALACTIC-HF.

BACKGROUND: Omecamtiv mecarbil improves cardiovascular outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Consistency of drug benefit across race is a key public health topic. OBJECTIVES: The purpose of this study was to evaluate the effect of omecamtiv mecarbil among self-identified Black patients. METHODS: In GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) patients with symptomatic HF, elevated natriuretic peptides, and left ventricular ejection fraction (LVEF) ≤35% were randomized to omecamtiv mecarbil or placebo. The primary outcome was a composite of time to first event of HF or cardiovascular death. The authors analyzed treatment effects in Black vs White patients in countries contributing at least 10 Black participants. RESULTS: Black patients accounted for 6.8% (n = 562) of overall enrollment and 29% of U.S. enrollment. Most Black patients enrolled in the United States, South Africa, and Brazil (n = 535, 95%). Compared with White patients enrolled from these countries (n = 1,129), Black patients differed in demographics, comorbid conditions, received higher rates of medical therapy and lower rates of device therapies, and experienced higher overall event rates. The effect of omecamtiv mecarbil was consistent in Black vs White patients, with no difference in the primary endpoint (HR = 0.83 vs 0.88, P-interaction = 0.66), similar improvements in heart rate and N-terminal pro-B-type natriuretic peptide, and no significant safety signals. Among endpoints, the only nominally significant treatment-by-race interaction was the placebo-corrected change in blood pressure from baseline in Black vs White patients (+3.4 vs -0.7 mm Hg, P for interaction = 0.02). CONCLUSIONS: GALACTIC-HF enrolled more Black patients than other recent HF trials. Black patients treated with omecamtiv mecarbil had similar benefit and safety compared with White counterparts.

Limitations of gene editing assessments in human preimplantation embryos.

Range of DNA repair in response to double-strand breaks induced in human preimplantation embryos remains uncertain due to the complexity of analyzing single- or few-cell samples. Sequencing of such minute DNA input requires a whole genome amplification that can introduce artifacts, including coverage nonuniformity, amplification biases, and allelic dropouts at the target site. We show here that, on average, 26.6% of preexisting heterozygous loci in control single blastomere samples appear as homozygous after whole genome amplification indicative of allelic dropouts. To overcome these limitations, we validate on-target modifications seen in gene edited human embryos in embryonic stem cells. We show that, in addition to frequent indel mutations, biallelic double-strand breaks can also produce large deletions at the target site. Moreover, some embryonic stem cells show copy-neutral loss of heterozygosity at the cleavage site which is likely caused by interallelic gene conversion. However, the frequency of loss of heterozygosity in embryonic stem cells is lower than in blastomeres, suggesting that allelic dropouts is a common whole genome amplification outcome limiting genotyping accuracy in human preimplantation embryos.

Efficacy of omecamtiv mecarbil in heart failure with reduced ejection fraction according to N-terminal pro-B-type natriuretic peptide level: insights from the GALACTIC-HF trial.

AIM: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is predictive of both outcomes and response to treatment in patients with heart failure with reduced ejection fraction (HFrEF). The aim of this study was to examine the effect of the cardiac myosin activator omecamtiv mecarbil according to baseline NT-proBNP level in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure trial (GALACTIC-HF). METHODS AND RESULTS: The primary outcome was the composite of a worsening heart failure event (urgent clinic visit, emergency department visit, or hospitalization) or cardiovascular death. We prespecified analysis of the effect of treatment according to baseline NT-proBNP (≤ median, > median), excluding individuals with atrial fibrillation/flutter (AF/AFL). Of the 8232 patients analysed, 8206 had an available baseline NT-proBNP measurement. Among the 5971 patients not in AF/AFL, the median (Q1-Q3) NT-proBNP level was 1675 (812-3579) pg/ml. Hazard ratios (HR) for the effect of omecamtiv mecarbil, compared with placebo, for the primary endpoint in patients without AF/AFL were: ≤ median 0.94 (95% confidence interval [CI] 0.80-1.09), > median 0.81 (0.73-0.90) (p-interaction = 0.095); for the overall population (including patients with AF/AFL) the HRs were ≤ median 1.01 (0.90-1.15) and > median 0.88 (0.80-0.96) (p-interaction = 0.035). There was an interaction between treatment and NT-proBNP, examined as a continuous variable, with greater effect of omecamtiv mecarbil on the primary outcome in patients with a higher baseline NT-proBNP (p-interaction = 0.086). CONCLUSIONS: In GALACTIC-HF, the benefit of omecamtiv mecarbil appeared to be larger in patients with higher baseline NT-proBNP levels, especially in patients without AF/AFL. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02929329; EudraCT number, 2016-002299-28.

Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients. OBJECTIVES: This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM. METHODS: Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout. RESULTS: From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: -40 ± 27 mm Hg, and -43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (-36 ± 27 mm Hg and -53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (-6% ± 7.5% and -12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro-B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms. CONCLUSIONS: Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.

Myocardial contrast echocardiography assessment of perfusion abnormalities in hypertrophic cardiomyopathy.

BACKGROUND: Perfusion defects during stress can occur in hypertrophic cardiomyopathy (HCM) from either structural or functional abnormalities of the coronary microcirculation. In this study, vasodilator stress myocardial contrast echocardiography (MCE) was used to quantify and spatially characterize hyperemic myocardial blood flow (MBF) deficits in HCM. METHODS: Regadenoson stress MCE was performed in patients with septal-variant HCM (n = 17) and healthy control subjects (n = 15). The presence and spatial distribution (transmural diffuse, patchy, subendocardial) of perfusion defects was determined by semiquantitative analysis. Kinetic analysis of time-intensity data was used to quantify MBF, microvascular flux rate (ß), and microvascular blood volume. In patients undergoing septal myectomy (n = 3), MCE was repeated > 1 years after surgery.  RESULTS: In HCM subjects, perfusion defects during stress occurred in the septum in 80%, and in non-hypertrophied regions in 40%. The majority of septal defects (83%) were patchy or subendocardial, while 67% of non-hypertrophied defects were transmural and diffuse. On quantitative analysis, hyperemic MBF was approximately 50% lower (p < 0.001) in the hypertrophied and non-hypertrophied regions of those with HCM compared to controls, largely based on an inability to augment ß, although hypertrophic regions also had blood volume deficits. There was no correlation between hyperemic MBF and either percent fibrosis on magnetic resonance imaging or outflow gradient, yet those with higher degrees of fibrosis (≥ 5%) or severe gradients all had low septal MBF during regadenoson. Substantial improvement in hyperemic MBF was observed in two of the three subjects undergoing myectomy, both of whom had severe pre-surgical outflow gradients at rest. CONCLUSION: Perfusion defects on vasodilator MCE are common in HCM, particularly in those with extensive fibrosis, but have a different spatial pattern for the hypertrophied and non-hypertrophied segments, likely reflecting different contributions of functional and structural abnormalities. Improvement in hyperemic perfusion is possible in those undergoing septal myectomy to relieve obstruction.  TRIAL REGISTRATION: ClinicalTrials.gov NCT02560467.

Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction: The METEORIC-HF Randomized Clinical Trial.

Importance: Exercise limitation is a cardinal manifestation of heart failure with reduced ejection fraction (HFrEF) but is not consistently improved by any of the current guideline-directed medical therapies. Objective: To determine whether omecamtiv mecarbil, a novel direct myosin activator that improves cardiac performance and reduces the risk for cardiovascular death or first HF event in HFrEF, can improve peak exercise capacity in patients with chronic HFrEF. Design, Setting, and Participants: Phase 3, double-blind, placebo-controlled randomized trial of patients with HFrEF (left ventricular ejection fraction ≤35%), New York Heart Association class II-III symptoms, N-terminal pro-B-type natriuretic peptide level of 200 pg/mL or greater, and baseline peak oxygen uptake (V̇o2) of 75% or less of predicted. Patients were randomized in a 2:1 ratio (omecamtiv mecarbil to placebo) between March 2019 and May 2021 at 63 sites in North America and Europe, with the last patient visit occurring on November 29, 2021. Interventions: Omecamtiv mecarbil (n = 185) or matching placebo (n = 91), given orally twice daily at a dose of 25 mg, 37.5 mg, or 50 mg based on target plasma levels, for 20 weeks. Main Outcomes and Measures: The primary end point was a change in exercise capacity (peak V̇o2) from baseline to week 20. Secondary end points included total workload, ventilatory efficiency, and daily physical activity as determined by accelerometry. Results: Among 276 patients who were randomized (median age, 64 years; IQR, 55-70 years; 42 women [15%]), 249 (90%) completed the trial. The median left ventricular ejection fraction was 28% (IQR, 21-33) and the median baseline peak V̇o2 was 14.2 mL/kg/min (IQR, 11.6-17.4) in the omecamtiv mecarbil group and 15.0 mL/kg/min (IQR, 12.0-17.2) in the placebo group. Mean change in peak V̇o2 did not differ significantly between the omecamtiv mecarbil and placebo groups (mean, -0.24 mL/kg/min vs 0.21 mL/kg/min; least square mean difference, -0.45 mL/kg/min [95% CI, -1.02 to 0.13]; P = .13). Adverse events included dizziness (omecamtiv mecarbil: 4.9%, placebo: 5.5%), fatigue (omecamtiv mecarbil: 4.9%, placebo: 4.4%), heart failure events (omecamtiv mecarbil: 4.9%, placebo: 4.4%), death (omecamtiv mecarbil: 1.6%, placebo: 1.1%), stroke (omecamtiv mecarbil: 0.5%, placebo: 1.1%), and myocardial infarction (omecamtiv mecarbil: 0%, placebo: 1.1%). Conclusions and Relevance: In patients with chronic HFrEF, omecamtiv mecarbil did not significantly improve exercise capacity over 20 weeks compared with placebo. These findings do not support the use of omecamtiv mecarbil for treatment of HFrEF for improvement of exercise capacity. Trial Registration: ClinicalTrials.gov Identifier: NCT03759392.

Effects of omecamtiv mecarbil in heart failure with reduced ejection fraction according to blood pressure: the GALACTIC-HF trial.

AIM: Patients with heart failure with reduced ejection fraction and low systolic blood pressure (SBP) have high mortality, hospitalizations, and poorly tolerate evidence-based medical treatment. Omecamtiv mecarbil may be particularly helpful in such patients. This study examined its efficacy and tolerability in patients with SBP ≤100 mmHg enrolled in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF). METHODS AND RESULTS: The GALACTIC-HF enrolled patients with baseline SBP ≥85 mmHg with a primary outcome of time to cardiovascular death or first heart failure event. In this analysis, patients were divided according to their baseline SBP (≤100 vs. >100 mmHg). Among the 8232 analysed patients, 1473 (17.9%) had baseline SBP ≤100 mmHg and 6759 (82.1%) had SBP >100 mmHg. The primary outcome occurred in 715 (48.5%) and 2415 (35.7%) patients with SBP ≤100 and >100 mmHg, respectively. Patients with lower SBP were at higher risk of adverse outcomes. Omecamtiv mecarbil, compared with placebo, appeared to be more effective in reducing the primary composite endpoint in patients with SBP ≤100 mmHg [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.70-0.94] compared with those with SBP >100 mmHg (HR, 0.95; 95% CI, 0.88-1.03; P-value for interaction = 0.051). In both groups, omecamtiv mecarbil did not change SBP values over time and did not increase the risk of adverse events, when compared with placebo. CONCLUSION: In GALACTIC-HF, risk reduction of heart failure outcomes with omecamtiv mecarbil compared with placebo was large and significant in patients with low SBP. Omecamtiv mecarbil did not affect SBP and was well tolerated independent of SBP values.

Developments in Exercise Capacity Assessment in Heart Failure Clinical Trials and the Rationale for the Design of METEORIC-HF.

Heart failure with reduced ejection fraction (HFrEF) is a highly morbid condition for which exercise intolerance is a major manifestation. However, methods to assess exercise capacity in HFrEF vary widely in clinical practice and in trials. We describe advances in exercise capacity assessment in HFrEF and a comparative analysis of how various therapies available for HFrEF impact exercise capacity. Current guideline-directed medical therapy has indirect effects on cardiac performance with minimal impact on measured functional capacity. Omecamtiv mecarbil is a novel selective cardiac myosin activator that directly increases cardiac contractility and in a phase 3 cardiovascular outcomes study significantly reduced the primary composite end point of time to first heart failure event or cardiovascular death in patients with HFrEF. The objective of the METEORIC-HF trial (Multicenter Exercise Tolerance Evaluation of Omecamtiv Mecarbil Related to Increased Contractility in Heart Failure) is to assess the effect of omecamtiv mecarbil versus placebo on multiple components of functional capacity in HFrEF. The primary end point is to test the effect of omecamtiv mecarbil compared with placebo on peak oxygen uptake as measured by cardiopulmonary exercise testing after 20 weeks of treatment. METEORIC-HF will provide state-of-the-art assessment of functional capacity by measuring ventilatory efficiency, circulatory power, ventilatory anaerobic threshold, oxygen uptake recovery kinetics, daily activity, and quality-of-life assessment. Thus, the METEORIC-HF trial will evaluate the potential impact of increased myocardial contractility with omecamtiv mecarbil on multiple important measures of functional capacity in ambulatory patients with symptomatic HFrEF. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT03759392.