COMMENTARY

Surgery Still Best Option in Obstructive HCM Despite EXPLORER-HCM Results

Patrick O. Myers, MD; Eduard Quintana, MD, PhD

Disclosures

October 15, 2020

Among the landmark presentations at the recent European Society of Cardiology virtual congress was the presentation on the EXPLORER-HCM randomized controlled trial. In this study, simultaneously published in The Lancet, the investigational drug mavacamten improved symptoms and functional status in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM).

We hope mavacamten can enhance the quality of life for patients with disease that is currently managed conservatively. However, we fear that overenthusiasm for the drug may lead to acceptance of inferior outcomes for patients better treated with surgery.

Unambitious Goals

The research on mavacamten is an excellent example of how drug development should work: studied in successive phases and culminating in a four-way blinded, placebo-controlled trial. Blinding is particularly important because the outcomes assessed included symptoms and quality of life. But a closer look at the results finds that the definition of success in EXPLORER-HCM was not particularly ambitious: minimal peak oxygen consumption gains and a decrease of at least one New York Heart Association (NYHA) functional class.

NYHA functional class did not improve in a third of patients treated with mavacamten. More than a quarter of patients in the mavacamten group had a postexercise gradient > 50 mm Hg, which is the usual threshold for septal reduction therapy. Close to half of the treated patients had gradients > 30 mm Hg at study end, a level associated with suboptimal outcomes. Rather than striving for no residual gradient, the researchers tepidly defined complete response as achieving NYHA functional class I and gradient < 30 mm Hg.

The peak oxygen consumption (pVO2) gain threshold was especially weak at an increase of just 1.5 mL/kg/min (or 3 mL/kg/min if symptoms didn't improve). In contrast, surgical myectomy and alcohol septal ablation are associated with increases in the range of 3-7 mL/kg/min.

The Case of the Half Marathoner

To illustrate our concerns, imagine a 48-year-old man who is referred to your clinic with a first episode of syncope during his Sunday morning long run (10 miles/16 km). He competes in half marathons every 6 months, and he runs a few times a week (30-40 km in total). His primary care physician excluded any neurologic or vagal cause of the syncope. Physical examination and transthoracic echocardiogram show mild to moderate mitral regurgitation and significant outflow obstruction with a moderately enlarged left atrium. What treatment would you propose for this patient? After a trial of beta-blockers with no significant changes in echocardiographic results, would you suggest lifelong treatment with mavacamten or surgical management?

Septal myectomy, developed in the 1960s, is a low-risk operation indicated in patients with symptomatic HCM in whom medical management has failed. It effectively abolishes left ventricular outflow tract obstruction and systolic anterior motion of the mitral valve. Longitudinal studies show sustained clinical improvement, with 85%-90% of patients remaining asymptomatic over an average of 8 years (extending up to 25 years).

Myectomy also results in a lifespan similar to that of an age-matched population without HCM, largely due to the normalization of left ventricular pressure. Most patients experience symptom relief and can forgo medication after myectomy, which is not a minor achievement in terms of quality of life. Despite these excellent results, surgery remains underused in the management of obstructive HCM because of outdated fears of operative risk and the specialized nature of treatment.

The patients enrolled in EXPLORER-HCM had significant obstruction but minimal symptoms (mostly NYHA class II) and wouldn't meet indications for septal reduction under current guidelines. Mavacamten was largely effective at reducing symptoms of obstructive HCM, which beta-blockers, verapamil, and disopyramide fail to target specifically. However, the very modest improvements in gradients and pVO2 with this drug fall short of those seen with surgical myectomy.

Indication creep, with extension from this less sick group of patients with obstructive HCM to those suited to septal reduction, is a worry. Who wouldn't want to take a pill and avoid surgery, if possible? As surgeons, we want to offer an invasive option only to patients who will derive a significant benefit from the procedure.

Long-term Safety Questions

Safety is always an issue with novel treatments, and the data so far reassure us that mavacamten is associated with a very low rate of adverse events. However, only 272 patients were enrolled in the two main studies to date, PIONEER-HCM and EXPLORER-HCM, and follow-up remains very short. This is a concern because mavacamten is targeted to young patients who will require lifelong treatment (mean age of patients was 56 and 58 years in PIONEER-HCM and EXPLORER-HCM, respectively). Some patients treated with mavacamten experienced a transient drop in left ventricular ejection fraction below 50%; two required medication discontinuation. Although the incidence was not significantly higher compared with placebo (seven vs two cases), this is a troublesome finding for a lifelong therapy.

If our half marathoner chose to undergo septal myectomy as recommended by leading HCM practices, he could expect relief from exercise-induced syncope, increased exercise capacity, freedom from medications, and he would avoid progressive left atrial dilatation that can lead to atrial fibrillation. Should we trade this superb outcome for lifelong medications with uncertain effects and restrict his ability to exercise?

Heart Team

We understand the fervor surrounding mavacamten. This new therapeutic agent could offer a pathophysiology-targeted and noninvasive option for patients who aren't yet surgical candidates, and it could help them avoid disease progression and delay surgery. However, current European and US guidelines for the management of HCM are out of date and don't match contemporary practice at centers of excellence where patients with NYHA class II symptoms with obstruction are routinely treated with surgery.

As surgeons who perform myectomy, we are aware of our potential bias, and that the supporting evidence for invasive septal reduction is predominantly observational data from centers of excellence. That is why we agree with Barry J. Maron, MD, an expert in HCM who proposed managing patients with an integrated team approach at expert centers. A heart team approach seems like the best way to consider all treatment options — medical treatment, myectomy, and alcohol septal ablation — free of conflicts. Treatment choice should reflect the best strategy for the patient and not the easiest option.

Patrick Myers, MD, is a cardiovascular surgeon who trained in both adult and pediatric cardiac surgery in the United States before returning to his hometown of Geneva, Switzerland. He is associate editor of several scientific publications, secretary of the European Board of Cardiothoracic Surgery, and chair of Adult Cardiac Surgery within the European Association for Cardio-Thoracic Surgery. He is a believer in open science and critical appraisal of evidence. He enjoys running and spending time with his family.

Eduard Quintana, MD, PhD, is a cardiovascular surgery fellowship and residency program director in Barcelona, Spain. He learned septal myectomy at the Mayo Clinic and has worked on expanding its availability in Spain through a national referral service for patients with obstructive hypertrophic cardiomyopathy. He is a believer in public-funded research in medicine. A native Catalan, Eduard loves cooking, swimming, and spending time with his family.

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