Evaluating the efficacy and safety of mavacamten in hypertrophic cardiomyopathy: A systematic review and meta-analysis focusing on qualitative assessment, biomarkers, and cardiac imaging.

BACKGROUND: Hypertrophic Cardiomyopathy (HCM) is a complex cardiac condition characterized by hypercontractility of cardiac muscle leading to a dynamic obstruction of left ventricular outlet tract (LVOT). Mavacamten, a first-in-class cardiac myosin inhibitor, is increasingly being studied in randomized controlled trials. In this meta-analysis, we aimed to analyse the efficacy and safety profile of Mavacamten compared to placebo in patients of HCM. METHOD: We carried out a comprehensive search in PubMed, Cochrane, and clinicaltrials.gov to analyze the efficacy and safety of mavacamten compared to placebo from 2010 to 2023. To calculate pooled odds ratio (OR) or risk ratio (RR) at 95% confidence interval (CI), the Mantel-Haenszel formula with random effect was used and Generic Inverse Variance method assessed pooled mean difference value at a 95% CI. RevMan was used for analysis. P<0.05 was considered significant. RESULTS: We analyzed five phase 3 RCTs including 609 patients to compare mavacamten with a placebo. New York Heart Association (NYHA) grade improvement and KCCQ score showed the odds ratio as 4.94 and 7.93 with p<0.00001 at random effect, respectively. Cardiac imaging which included LAVI, LVOT at rest, LVOT post valsalva, LVOT post-exercise, and reduction in LVEF showed the pooled mean differences for change as -5.29, -49.72, -57.45, -36.11, and -3.00 respectively. Changes in LVEDV and LVMI were not statistically significant. The pooled mean difference for change in NT-proBNP and Cardiac troponin-I showed 0.20 and 0.57 with p<0.00001. The efficacy was evaluated in 1) A composite score, which was defined as either 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 and 2) changes in pVO2, which was not statistically significant. Similarly, any treatment-associated emergent adverse effects (TEAE), treatment-associated serious adverse effects (TSAE), and cardiac-related adverse effects were not statistically significant. CONCLUSION: Mavacamten influences diverse facets of HCM comprehensively. Notably, our study delved into the drug's impact on the heart's structural and functional aspects, providing insights that complement prior findings. Further large-scale trials are needed to evaluate the safety profile of Mavacamten.

Impact of Left Ventricular Outflow Tract Obstruction on Coronary Physiological Assessment.

Hypertrophic cardiomyopathy which is known to occasionally have coronary artery disease as concomitant disease may require coronary physiological assessment (Okayama et al., 2015; Shin et al., 2019 [1,2]). However, no study clarified the impact of left ventricular outflow tract obstruction on coronary physiological assessment. Herein, a case of hypertrophic obstructive cardiomyopathy concomitant with moderate coronary lesion was reported, in which dynamic change of physiological values was observed during pharmacological intervention. Specifically, fractional flow reserve (FFR) and resting full-cycle ratio (RFR) changed in an opposite fashion when the left ventricular outflow tract pressure gradient was decreased by intravenous propranolol and cibenzoline: in FFR from 0.83 to 0.79 and in RFR from 0.73 to 0.91. Cardiologists should pay attention to the presence of concomitant cardiovascular disorders in interpreting coronary physiological data.

Considerations for managed care pharmacy in evaluating mavacamten, a novel agent for obstructive hypertrophic cardiomyopathy.

DISCLOSURES: Dr Taddei-Allen was a PRIME Education Moderator on Hypertrophic Cardiomyopathy CE at AMCP Nexus 2021; AJMC article on managed care considerations for hypertrophic cardiomyopathy. No funding was contributed toward the writing of this commentary.

Projecting the Long-term Clinical Value of Mavacamten for the Treatment of Obstructive Hypertrophic Cardiomyopathy in the United States: An Assessment of Net Health Benefit.

PURPOSE: The aim of the study was to project the long-term net health benefits of mavacamten for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (HCM) in the United States. METHODS: A Markov model with 4 mutually exclusive health states (New York Heart Association [NYHA] functional classes I, II, and III/IV and death) was developed to project the life-years (LYs) and quality-adjusted life-years (QALYs) over a lifetime horizon for patients with symptomatic obstructive HCM receiving mavacamten with or without ß-blocker (BB) or calcium channel blocker (CCB) monotherapy or placebo with or without BB or CCB monotherapy. The model simulated a patient cohort with a starting age of 59 years and 41% women. Transition probabilities across NYHA functional classes were estimated using data from the Phase III Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy (EXPLORER-HCM) and the EXPLORER long-term extension (EXPLORER-LTE) cohort from the Long-term Safety Extension Study of Mavacamten in Adults who Have Completed MAVERICK-HCM or EXPLORER-HCM (MAVA-LTE) trial and were extrapolated after week 30. The mortality risks of NYHA functional class I were assumed to be the age- and sex-specific mortality risks of the US general population. The mortality risks for NYHA class II and III/IV were estimated using those for class I in conjunction with the relative mortality risks derived using patients with obstructive HCM from a large real-world registry. Health state utilities for each treatment were estimated from EXPLORER-HCM. Both LYs and QALYs were aggregated over a lifetime for each treatment arm, discounted at 3% annually, and compared between the 2 arms. Sensitivity analyses were conducted to evaluate the robustness of the model findings. FINDINGS: Over a lifetime, treatment with mavacamten with or without BB or CCB monotherapy was associated with 3.67 incremental LYs compared with placebo with or without BB or CCB monotherapy (13.00 vs 9.33 LYs). Compared with individuals in the placebo group, patients in the mavacamten group were projected to spend 6.17 additional LYs in NYHA functional class I and 0.04 and 2.46 fewer LYs in NYHA functional classes II and III/IV, respectively. With utilities incorporated, mavacamten with or without BB or CCB monotherapy was associated with 4.17 additional QALYs compared with placebo with or without BB or CCB monotherapy (11.74 vs 7.57 QALYs). In the sensitivity analyses, incremental benefits ranged from 1.55 to 6.21 LYs and from 2.48 to 6.19 QALYs across the scenarios. IMPLICATIONS: This model projected substantial net health benefits associated with mavacamten for symptomatic obstructive HCM owing to improved patient survival and quality of life. The projected QALY gain underscored the likely long-term clinical value of mavacamten in symptomatic obstructive HCM.

Sex differences in cardiac magnetic resonance features in patients with hypertrophic cardiomyopathy.

Whether sex differences exist in cardiac magnetic resonance (CMR) findings in patients with hypertrophic cardiomyopathy (HCM) remain unknown. We sought to assess and compare CMR characteristics in male and female patients with HCM. From January-2006 to October-2017, 165 consecutive HCM patients evaluated with CMR were included. All clinical and complementary test information was prospectively collected. At the time of CMR evaluation women were older (70 [57-75] vs. 61 [47-72] years, p = 0.02) and more symptomatic in terms of dyspnea (New York Heart Association class II-IV 47.2 vs. 24.1%, p = 0.003) and palpitations (19.6 vs. 4.6%, p = 0.006) and received more frequently treatment with diuretics (49.1% vs. 23.4%, p = 0.001). On echocardiographic examination more women had obstructive physiology (45.1 vs. 20.6%, p = 0.002). On CMR evaluation, women showed smaller left ventricular end-systolic volume index (13 [10-15] vs. 16 [13-21] ml/m2, p < 0.001), higher left ventricular ejection fraction (77 [74-80] vs. 72 [66-78]%, p = 0.004), more marked left ventricular outflow tract acceleration (54.7 vs. 26.4%, p < 0.001) and mitral regurgitation (33.3 vs. 12.7%, p = 0.002). In multivariable analysis, female sex [OR 2.44 (1.04-5.73), p = 0.04] and left ventricular end-systolic volume index [OR 1.60 (1.08-2.38), p = 0.018] were independently associated with obstructive physiology. Women with HCM have more frequently obstructive physiology, a finding that could be related to the smaller left ventricular end-systolic volume.

Assessment of myocardial function in obstructive hypertrophic cardiomyopathy cats with and without response to medical treatment by carvedilol.

BACKGROUND: Inconsistency of treatment response in cats with obstructive hypertrophic cardiomyopathy is well recognized. We hypothesized that the difference in response to beta-blockers may be caused by myocardial functional abnormalities. This study was designed to compare myocardial function in cats with obstructive hypertrophic cardiomyopathy with and without response to beta-blockers. Twenty-one, client-owned, hypertrophic cardiomyopathy cats treated with carvedilol were analyzed. After carvedilol treatment, cats with decreased left ventricular outflow tract velocity were categorized as responders (n = 10); those exhibiting no response (no decrease in the left ventricular outflow tract velocity) were categorized as non-responders (n = 11). The cats were examined using layer-specific assessment of the myocardial function (whole, endocardial, and epicardial layers) longitudinally and circumferentially by two-dimensional speckle-tracking echocardiography, before and after carvedilol treatment. RESULTS: The non-responder cats had a significantly higher age, end-diastolic left ventricular posterior-wall thickness, peak velocity of left ventricular outflow tract, and dose of carvedilol than the responders (p = 0.04, p < 0.01, p < 0.01, and p < 0.01, respectively). The circumferential strain in the epicardial layer was lower and circumferential endocardial to epicardial strain ratio was higher in non-responders than responders (p < 0.001 and p = 0.006). According to the multivariate analysis, circumferential strain in the epicardial layer was the only independent correlate of treatment response with carvedilol. CONCLUSIONS: Myocardial function, assessed by two-dimensional speckle-tracking echocardiography, differed in cats with hypertrophic cardiomyopathy with and without response to beta-blockers. The determination of layer-specific myocardial function may facilitate detailed pathophysiologic assessment and treatment response in cats with hypertrophic cardiomyopathy.

Refined echocardiographic assessment and contemporary medical treatment of obstructive hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a complex cardiac disease, relatively common among genetic disorders. The prevalence is about 1:500 in the general population. Obstructive type occurs in about 25% of the cases. The clinical course is heterogeneous due to the large variety of genetic-based phenotypes with different prognostic impact. Primary HCM is one of the most important causes of sudden death in young people and may be a medical problem in athletes with physiologic left ventricular hypertrophy. In the last decade, however, several studies reported normal longevity. Echocardiography has emerged as the most important noninvasive method to make diagnosis and provide classifications of the disease. In this commentary, some out of the most recent and sophisticated applications of this method in HCM are reported. The most common pathophysiologic aspects and a proposal of classification of the obstruction-causing mechanisms, like systolic anterior motion of the mitral valve, papillary hypertrophy and dislocation, chordal slack, mid-cavity obliteration, are described. Some recent studies on coronary blood flow velocity and coronary reserve, performed by sophisticated Doppler echocardiography, have demonstrated important pathophysiological insights on microcirculatory impairment in patients with HCM. At present, advanced echocardiography surely improves the clinical management of these patients, and contributes to optimize the therapeutic strategies. However, the most appropriate framework of tests to be performed in the majority of them still remains a challenging clinical matter.

Assessment of coronary blood flow in hypertrophic cardiomyopathy using thrombolysis in myocardial infarction frame count method.

BACKGROUND: Coronary microvascular dysfunction has been reported to be present in patients with hypertrophic cardiomyopathy (HCM) despite normal epicardial coronary arteries. In this study we aimed to evaluate coronary blood flow in patients with HCM by means of Thrombolysis In Myocardial Infarction (TIMI) frame count. METHODS: Thirty-two patients with HCM (22 male, 10 female; mean age=48+/-7 years) and 36 healthy control subjects (23 male, 13 female; mean age=49+/-7 years) without any cardiovascular disease were included in the study. All patients and control subjects were selected from individuals who underwent coronary angiography and left heart catheterization in our hospital and were found to have angiographically normal coronary arteries. All patients had an asymmetrically hypertrophic nondilated left ventricle and a basal intraventricular pressure gradient>30 mmHg recorded in the left ventricular outflow tract. A complete transthoracic echocardiographic examination including two-dimensional, M-mode, pulse and continuous Doppler was performed in all patients and control subjects. Coronary flow rates of all subjects were documented by the TIMI frame count method. To obtain corrected TIMI frame count for the left anterior descending (LAD) coronary artery, TIMI frame count for this vessel was divided by 1.7. RESULTS: Corrected TIMI frame count for the LAD coronary artery was found to be significantly higher in patients with HCM compared to control subjects (35+/-8 vs. 25+/-6, p<0.001). However, we found no significant difference between patients and control subjects regarding TIMI frame counts for the left circumflex (LCx) coronary artery and the right coronary artery (RCA) (LCx: 28+/-6 vs. 26+/-6, p=0.07 and RCA: 26+/-6 vs. 24+/-5, p=0.09). Besides, the corrected TIMI frame count for the LAD coronary artery was found to be significantly correlated with interventricular septal wall thickness (r=0.546, p=0.001) and interventricular septal/posterior wall thickness ratio (r=0.490, p=0.004). However, no significant correlation was detected between the corrected TIMI frame count for the LAD coronary artery and other echocardiographic variables. CONCLUSION: We show that patients with HCM had significantly higher corrected TIMI frame counts for the LAD compared to the control subjects. No such difference was detected between the two groups regarding TIMI frame counts for the LCx and RCA, suggesting the presence of regional (interventricular septal) rather than global impairment of coronary blood flow in patients with HCM.

Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, crossover study (M-PATHY).

BACKGROUND: Dual-chamber pacing (DDD) has been proposed as a treatment alternative to surgery for severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), based largely on uncontrolled studies. METHODS AND RESULTS: This prospective, multicenter trial assessed pacing in 48 symptomatic HCM patients with >/=50 mm Hg basal gradient, refractory to drug therapy. Patients were randomized to 3 months each of DDD pacing and pacing backup (AAI-30) in a double-blind, crossover study design, followed by an uncontrolled and unblinded 6-month pacing trial. With randomization, no significant differences were evident between pacing and no pacing for subjective or objective measures of symptoms or exercise capacity, including NYHA functional class, quality of life score, treadmill exercise time or peak oxygen consumption. After 6 additional months of unblinded pacing, functional class and quality of life score were improved compared with baseline (P<0.01), but peak oxygen consumption was unchanged. Outflow gradient decreased 40%, 82+/-32 mm Hg to 48+/-32 mm Hg (P<0. 001), and was reduced in 57% of patients but showed no change or an increase in 43%. At 12 months, 6 individual patients (12%) showed improved functional capacity; each was 65 to 75 years of age. Left ventricular wall thicknesses in the overall study group showed no remodeling between baseline (22+/-5 mm) and 12 months (21+/-5 mm; P=NS). CONCLUSIONS: (1) Pacing cannot be regarded as a primary treatment for obstructive HCM; (2) with randomization, perceived symptomatic improvement was most consistent with a substantial placebo effect; (3) longer, uncontrolled pacing periods were associated with some subjective benefit but unaccompanied by objective improvement in cardiovascular performance and should be interpreted cautiously; (4) modest reduction in outflow gradient was achieved in most patients; and (5) a small subset (12%) >/= 65 years of age showed a clinical response, suggesting that DDD pacing could be a therapeutic option for some elderly patients.

Prognostic value of non-sustained ventricular tachycardia and the potential role of amiodarone treatment in hypertrophic cardiomyopathy: assessment in an unselected non-referral based patient population.

BACKGROUND: Amiodarone has been reported to reduce the likelihood of sudden death in patients with hypertrophic cardiomyopathy (HCM). However, data regarding the clinical course in HCM have traditionally come from selected referral populations biased toward assessment of high risk patients. AIMS: To evaluate antiarrhythmic treatment for sudden death in an HCM population not subject to tertiary referral bias, closely resembling the true disease state present in the community. METHODS: Cardiovascular mortality was assessed in relation to the occurrence of non-sustained ventricular tachycardia (NSVT) on 24 or 48 hour ambulatory Holter recording, a finding previously regarded as a marker for sudden death, particularly when the arrhythmia was frequent, repetitive or prolonged. 167 consecutive patients were analysed by multiple Holter ECG recordings (mean (SD) 157 (129) hours) and followed for a mean of 10 (5) years. Only patients with multiple repetitive NSVT were treated with amiodarone, and in relatively low. doses (220 (44) mg/day). RESULTS: Nine HCM related deaths occurred: 8 were the consequence of congestive heart failure, but only 1 was sudden and unexpected. Three groups of patients were segregated based on their NSVT profile: group 1 (n = 39), multiple (> or = 2 runs) and repetitive bursts (on > or = 2 Holters) of NSVT, or prolonged runs of ventricular tachycardia, included 4 deaths due to heart failure; group 2 (n = 38), isolated infrequent bursts of NSVT, included 1 sudden death; group 3 (n = 90), without NSVT, included 4 heart failure deaths. Kaplan-Meier survival analysis showed no significant differences in survival between the three groups throughout follow up. CONCLUSIONS: In an unselected patient population with HCM, isolated, non-repetitive bursts of NSVT were not associated with adverse prognosis and so this arrhythmia does not appear to justify chronic antiarrhythmic treatment. Amiodarone, administered in relatively low doses, did not carry an independent and additive risk for cardiac mortality. Amiodarone may have contributed to the absence of sudden cardiac death in patients believed to be at higher risk because of multiple repetitive NSVT.

Ambulatory assessment of the QT interval in patients with hypertrophic cardiomyopathy: risk stratification and effect of low dose amiodarone.

This study aims to assess the dynamics of the QT interval in patients with hypertrophic cardiomyopathy (HCM). Three consecutive QT intervals and the preceding RR intervals were measured on 24 hour ambulatory electrocardiograms at 30-minute intervals in ten high risk patients with HCM (sudden cardiac death [SCD] and/or documented ventricular fibrillation), aged 29 +/- 17 years, compared with ten age and sex matched low risk patients with HCM (no syncope, no adverse family history, and no ventricular tachycardia on Holter monitoring), and ten normal subjects. Another ten patients who were on amiodarone therapy (200-mg daily) were also studied. Patients with intraventricular conduction defects were excluded. There were 4,424 pairs of QT intervals and their preceding RR intervals were measured in this study. A nonsignificant prolongation in the QT interval and a significant prolongation in QTc values (Bazett's and Fridericia's formulas) were demonstrated in patients with HCM compared with normals. There were no significant differences in the QT and QTc between high and low risk patients. The slope of regression line for the QT against RR interval was significantly different between normals and HCM (0.1583 +/- 0.040 vs. 0.2017 +/- 0.043, P < 0.05), but not between high and low risk patients. Amiodarone significantly prolonged the QT and QTc without significantly altering the slope of the regression line (0.2017 +/- 0.043 vs 0.2099 +/- 0.037, NS). Our findings support the observations that there is a prolonged QT interval in patients with HCM and that there is no significant use dependent effect of amiodarone on ventricular repolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Disopyramide in hypertrophic cardiomyopathy. I. Hemodynamic assessment after intravenous administration.

The hemodynamic effects of intravenous disopyramide were determined in 43 patients with hypertrophic cardiomyopathy and pressure gradients at rest (resting obstruction). The basal subaortic pressure gradient decreased in all patients by a mean of 61 mm Hg (range 16 to 123); in 35 patients the gradient was abolished (less than 20 mm Hg). The reduction in pressure gradient was achieved through a decrease in left ventricular systolic pressure, from 178 to 135 mm Hg (p less than 0.0001), and a rise in aortic systolic pressure, from 105 to 123 mm Hg (p less than 0.0001). Left ventricular ejection time was reduced from 326 to 273 ms (p less than 0.0001). Left ventricular end-diastolic pressure decreased from 19 to 16 mm Hg (p less than 0.0001). In a subgroup of 13 patients, cardiac output was unchanged after disopyramide, despite a prolongation of the pre-ejection period from 104 to 137 ms (p less than 0.0001) indicating a decrease in contractility. The maintenance of cardiac output, despite a decrease in contractility, may reflect a decrease in mitral regurgitation resulting from the reduction of systolic anterior motion of the mitral valve by disopyramide. These results indicate that disopyramide produces predictably favorable hemodynamic effects in patients with hypertrophic cardiomyopathy and resting obstruction to left ventricular outflow.

Disopyramide in hypertrophic cardiomyopathy. II. Noninvasive assessment after oral administration.

The effects of oral disopyramide 150 mg 4 times a day were compared with propranolol 40 mg 4 times a day and placebo in 10 patients with hypertrophic cardiomyopathy and resting obstruction (7 patients) or latent obstruction (3 patients), in a randomized double-blind crossover design; each drug was given for a period of 4 days. As determined from echocardiographic evaluation of systolic anterior motion of the mitral valve, the subaortic pressure gradient was decreased from 61 +/- 20 mm Hg with placebo to 5 +/- 15 mm Hg with disopyramide (p less than 0.01), and 30 +/- 30 mm Hg with propranolol (p less than 0.01). Disopyramide was more effective than propranolol (p less than 0.01). Disopyramide and propranolol both shortened left ventricular ejection time from 352 +/- 51 ms with placebo to 314 +/- 26 and 322 +/- 41 ms, respectively (p less than 0.01). Preejection period was lengthened from 93 +/- 35 ms with placebo to 119 +/- 25 ms with disopyramide, but was unchanged by propranolol at 98 +/- 23 ms. Disopyramide increased exercise duration versus placebo (10.4 +/- 2 vs 9.6 +/- 2 minutes, respectively (p less than 0.05), whereas propranolol produced no significant change (8.8 +/- 2 minutes).

Effects of disopyramide on left ventricular function: assessment by radionuclide cineangiography.

To determine the effects of disopyramide on resting systolic left ventricular (LV) function and LV functional reserve, gated equilibrium radionuclide cineangiography was performed at rest and during maximal symptom-limited supine bicycle exercise in 12 patients after a single 300 mg oral loading dose of disopyramide, and in 22 patients (including the 12 patients just mentioned) after they received disopyramide 150 mg 4 times daily for 5 to 10 days (average 7). The oral loading dose (average serum level 3.6 +/- 1.3 micrograms/ml [standard deviation] produced decreases in ejection fraction in 9 of 12 patients with a decrease in average resting ejection fraction from 40 +/- 15% to 33 +/- 11% (p less than 0.005). However, the lower, sustained dosage of disopyramide was associated with a lower average serum level of 2.5 +/- 0.8 micrograms/ml and with smaller but significant decreases in ejection fraction in 3 of 22 patients during exercise only. At this dosage there was no significant decrease in average ejection fraction for the group at rest or during exercise. Adverse effects of disopyramide on ejection fraction occurred even in patients with previously normal LV function at rest. Hence, disopyramide may be associated with significant decreases in LV systolic function, particularly when given in high, oral "loading" doses. However, sustained therapy with lower dosages as well as lower drug levels is also associated with less depression of LV function.

Non-invasive assessment of diastolic function in hypertrophic cardiomyopathy on and off beta adrenergic blocking drugs.

Beta adrenergic blocking drugs in hypertrophic cardiomyopathy provide symptomatic relief but their effect on long-term prognosis is uncertain. Thirty patients were studied non-invasively by simultaneous recordings of echocardiogram, apex-cardiogram, phonocardiogram, and electrocardiogram in order to assess diastolic abnormalities on and off oral beta adrenergic blocking drugs. While on treatment these patients had a mean dose of propranolol 200 mg/day. The treatment was stopped for one week and then non-invasive assessment was repeated. The following diastolic time intervals were studied: isovolumic relaxation period (A2-mitral valve opening); rapid relaxation period (A2-O point of the apexcardiogram), and the period from mitral valve opening to the O point of the apexcardiogram (Mo-O) when most of the filling of the left ventricle occurs. The prolongation of the rapid relaxation period reflects a reduced rate of fall of the left ventricular pressure when the pressure differential does not change between A2 and the O point of the apexcardiogram, and in this study this period was prolonged in 19, shortened in eight, and remained the same in three patients after beta blockade. The Mo-O point was prolonged in 22, shortened in seven, and was unchanged in one patient after beta adrenergic blocking drugs. All these results were independent of heart rate. In conclusion the response of diastolic time intervals to beta blocking drugs in hypertrophic cardiomyopathy was variable but there was a significant number of patients in whom the time available for filling of the left ventricle was prolonged, suggesting better filling possibly because of improved distensibility of the left ventricle after beta adrenergic blocking drugs.