Two recent randomized trials show success with metoprolol and mavacamten

Results from two randomized clinical trials demonstrated the efficacy of metoprolol and mavacamten in treating obstructive hypertrophic cardiomyopathy (oHCM).

In the TEMPO trial, metoprolol—a beta blocker—reduced left ventricular outflow tract obstruction at rest and during exercise, and improved symptoms and quality of life in these patients. In the EXPLORER-HCM study, mavacamten—a cardiac myosin inhibitor—improved both left ventricular diastolic function and systolic anterior motion.

Results of both studies are published in the Journal of the American College of Cardiology.

In an accompanying editorial entitled “A new dawn in HCM: Rise of the RCTs,” Ahmad Masri, MD, MS, of the Knight Cardiovascular Institute, Division of Cardiology, School of Medicine, Oregon Health and Science University, Portland, offered a brief history.

“Sixty-three years have passed since Donald Teare’s seminal report on asymmetrical septal hypertrophy—which he described as a benign tumor—in the heart of young adults. Despite being a visionary, Donald Teare would not have expected that one-half century later, we are still treating hypertrophic cardiomyopathy (HCM) as if it were a benign tumor, by using simple medical therapy for mild symptoms, and offering invasive ’debulking’ treatments for severe symptoms,” he wrote.

In the TEMPO trial, researchers led by Anne M. Dybro, MD, of Aarhus University Hospital, Aarhus N, Denmark, assessed the effects of metoprolol on left ventricular outflow tract (LVOT) obstruction, symptoms, and exercise capacity in 29 patients with obstructive hypertrophic cardiomyopathy (HCM). TEMPO was a double-blind, placebo-controlled, randomized crossover trial.

All patients had obstructive HCM and NYHA functional class II or higher symptoms. Dybro et al found that patients treated with metoprolol had lower LVOT gradients compared with placebo patients as follows:

  • At rest: 25 versus 72 mmHg, respectively (P=0.007).
  • At peak exercise: 28 versus 62 mmHg (P<0.001).
  • Postexercise: 45 versus 115 mmHg (P<0.0001).

They also found that fewer patients were in NYHA functional class III or higher during treatment with metoprolol compared with placebo (14% versus 38%, respectively; P˂0.01), and that no patients treated with metoprolol were in CCS class III or higher compared with 10% of placebo patients (P˂0.01). Higher KCCQ-OSS in patients treated with metoprolol compared with placebo confirmed these results (76.2 versus 73.8, respectively; P=0.039).

Researchers found no between-group differences in exercise capacity, peak oxygen consumption, and N-terminal pro-B-type natriuretic peptide.

In the multicenter, double-blind, placebo-controlled, randomized, phase III EXPORER-HCM study, Sheila M. Hegde, MD, of Brigham and Women’s Hospital, Boston, and colleagues assessed the effects of mavacamten on cardiac structure and function and other clinical measures using serial echocardiograms taken over 30 weeks in 251 patients with symptomatic oHCM treated with mavacamten and comparing them with patients treated with placebo.

They found that complete resolution of mitral valve systolic anterior motion occurred more often in patients treated with mavacamten compared with placebo (80.9% versus 34.0%, respectively; difference: 46.8%; P˂0.0001). Patients treated with mavacamten also had significantly greater improvements in measures of diastolic function compared with placebo, including the following:

  • Left atrial volume index (LAVI): mean change from baseline: −7.5 versus −0.09 mL/m2, respectively (P<0.0001)
  • Lateral E/e’: change from baseline: −3.8 versus 0.04 (P<0.0001)

In addition, mavacamten patients showed improvements in resting, Valsalva, and post-exercise left ventricular outflow tract (LVOT) gradients, LAVI, and lateral E/e’ that were associated with reductions in N-terminal pro-B-type natriuretic peptide (P≤0.03 for all).

Finally, Hedge et al found that reductions in LAVI were associated with improved peak exercise oxygen consumption (P=0.04).

“Dybro et al should be congratulated for conducting the first comprehensive RCT of BB in oHCM in over one-half century after their initial use for this disease,” Masri commented, adding that the results from Hedge and colleagues are also valuable.

“It is important to note that the majority of subjects were treated with either BB (75%) or calcium channel blockers (17%), which makes EXPLORER-HCM a trial of mavacamten versus placebo on the background of BB and/or calcium channel blockers, without prespecified dosages. The significant change in markers of diastolic function appeared as early as 18 weeks of mavacamten treatment, which was not observed in the standard of care group. There was also a significant interaction between higher baseline LVOT gradients and more reduction in left atrial volume index and NT-proBNP as compared to placebo, reflective of favorable remodeling, particularly in patients with more advanced oHCM,” noted Masri.

“Collectively, these findings highlight that a successful treatment strategy in oHCM should achieve significant reduction in LVOT gradient, combined with functional improvement and favorable remodeling,” he added.

“Pharmacotherapy for HCM continues to evolve, with novel therapies directly targeting the molecular pathophysiology of the disease, leading to reappraisal of our current standard of care therapies. Robust RCTs, such as those in this issue of the Journal, will be necessary and helpful in guiding HCM providers and patients to navigate the expanding set of therapeutic options,” Masri concluded.

Limitations of the TEMPO study include that it was conducted at a single center in a small cohort of patients, the short treatment period (only 2 weeks in each arm), and that the study was designed to assess responses to treatment on echocardiographic measures and symptoms and not the long-term reduction of LVOT gradients and symptoms.

Limitations of the EXPLORER-HCM study include the exclusion of patients with mild symptoms, those treated with disopyramide, and those with LV ejection fractions less than 55%. The number of patients from ethnic minorities and those less than 50 years old was also small, limiting generalizability of the findings. Researchers also noted the lack of accuracy and reliable quantification of mitral regurgitation and the short duration of the study.

  1. In the TEMPO trial, treatment with the beta-blocker metoprolol effectively reduced left ventricular outflow tract obstruction at rest and during exercise, and improved symptoms and quality of life in patients with obstructive hypertrophic cardiomyopathy.

  2. In EXPLORER-HCM, mavacamten—a cardiac myosin inhibitor—improved measures of left ventricular diastolic function and systolic anterior motion.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

The TEMPO study was supported by the Novo Nordic Foundation and by Skibsreder Per Henriksen, R. og hustrus Foundation. The manufacturer of metoprolol succinate (Hexal) was neither involved in nor funded the study.

Dybro reported no disclosures.

Study funding for the EXPLORER-HCM study was provided by MyoKardia, Inc, Brisbane, CA, a wholly owned subsidiary of Bristol Myers Squibb.

Hegde serves on the faculty of the Cardiovascular Imaging Core Laboratory at Brigham and Women’s Hospital; and her institution has received payments for her consulting work from MyoKardia.

Masri has received research grants from Pfizer, Ionis, Akcea, and Ultromics; and has received fees from Eidos, Pfizer, Ionis, Akcea, Alnylam, Cytokinetics, and Attralus.

Cat ID: 914

Topic ID: 74,914,730,914,192,925