What negative inotropic agent can be administered to a patient with obstructive hypertrophic cardiomyopathy?

Quick Takes

• Mavacamten is a first in class myosin inhibitor which can reduce left ventricular (LV) outflow tract gradients in patients with obstructive HCM by decreasing myocardial contractility. In principle, interventions that decrease or abolish outflow gradients in HCM patients can improve heart failure symptoms.
• In the phase III EXPLORER HCM clinical trial, mavacamten lowered gradients in many symptomatic obstructive HCM patients, with 37% of these patients achieving the primary endpoint of ≥1 improvement in subjective heart failure symptoms (NYHA class) and/or improvement in functional capacity (peak VO2) versus 17% on placebo. On the other hand, 50% of patients on mavacamten had residual NYHA class II-III symptoms at the end of the study period. Notable, by virtue of its negative inotropic mechanism, approximately10% of patients did experience a significant transient decrease in ejection fraction to <50%, underscoring the need for longer follow-up to better understand the safety profile of mavacamten.
• EXPLORER-HCM data provide support for considering mavacamten (if FDA approved) as an additional drug therapy option in mild to moderately symptomatic obstructive HCM patients. Of note, mavacamten was not directly compared with the well-established and highly effective invasive septal reduction therapies (surgical myectomy and alcohol septal ablation) for relieving symptoms in obstructive HCM. However, historical comparison suggest that these invasive treatments appear to provide greater reduction in gradient and more symptomatic improvement compared to mavacamten. For these reasons, at this time, mavacamten should not be considered a replacement to invasive septal reduction therapy for severely symptomatic obstructive HCM patients.

Over the last two decades, hypertrophic cardiomyopathy (HCM) has evolved to a highly treatable genetic heart disease associated with normal longevity and excellent quality of life for the majority of patients.1 However, unmet treatment needs remain, including the priority for additional medication options to improve symptom burden in obstructive HCM patients. This point is underscored by the fact that it has been nearly 35 years since a novel drug therapy has been advanced in HCM.2 However, this has recently changed, with the emergence of mavacamten, a myosin inhibitor, which reduces myocardial contractility by decreasing the number of available actin-myosin cross-bridges.3 Mavacamten is associated with a dose dependent reduction in contractility, which decreases mitral valve-septal contact duration and as a result lowers outflow tract gradients. In principle, interventions that lower outflow gradient in HCM can be expected to improve symptoms.

Proof of this concept was demonstrated in the recently published phase III randomized clinical trial EXPLORER-HCM.3 Over 30 weeks, many of the 123 obstructive HCM patients receiving mavacamten demonstrated a substantial reduction in outflow tract gradients. Clinical efficacy of this hemodynamic effect was assessed using a combined primary endpoint of subjective symptom improvement (NYHA class) and/or functional improvement assessed by peak VO2. A significantly greater number of patients on mavacamten met this primary endpoint compared to placebo (37% vs. 17%), with 27% of patients on mavacamten experiencing both complete relief of symptoms (class I) and outflow gradients to ≤30mmHg.3

Before understanding how mavacamten (if ultimately FDA approved) may be integrated into the current treatment algorithm of obstructive HCM patients, it is worth noting several points. It is important to understand that EXPLORER-HCM did not directly compare mavacamten to any of the currently available medical or invasive therapies which are known to be effective at lowering outflow gradients in HCM (Figure 1), including disopyramide or invasive septal reduction therapies.4-6 Indeed, when myectomy or alcohol ablation are performed in expert centers, outflow gradients are eliminated in almost all patients, resulting in >70% of severely symptomatic patients improving to class I.4,5 The impressive clinical benefit of invasive septal reduction therapies can be attributable to complete normalization of intracavitary pressures and elimination of mitral valve regurgitation by directly intervening on the abnormal anatomy responsible for mechanical impedance to LV outflow, and in experienced centers can be performed with very low procedural risk (<1.0%).1 It is unlikely that drug therapy can effectively address the full spectrum of various anatomical issues which contribute to outflow obstruction in HCM and this was noted in the EXPLORER-HCM study in which over the 30 week treatment period 50% of patients on mavacamten remained symptomatic with class II or III symptoms, likely due to residual outflow gradients which persisted in a substantial proportion of patients (43%), including 25% with gradients >50 mmHg. This early experience with mavacamten is not unlike what occurs with disopyramide, another negative inotropic drug which has been used safely and effectively to treat symptomatic obstructive HCM patients for almost 30 years, but for which residual gradients are common and responsible for limited long-term efficacy in some patients.2 Data from open label extension of EXPLORER-HCM will aid in better understanding how residual gradients impact longer term efficacy of mavacamten.

In addition, the proven efficacy of surgical myectomy and alcohol septal ablation have largely been demonstrated in cohorts of obstructive HCM patients who are much more limited in symptom burden than the patient population studied in EXPLORER-HCM.4-6 Indeed, the potential for myectomy to improve patients from NYHA class III to I is well established.4,5 In this regard, efficacy of mavacamten was largely demonstrated by showing symptom reduction from NYHA class II to I in a subset of patients. Therefore, it is unknown if the benefit of mavacamten can be reliably translated to patients with more advanced symptoms (class III) who are otherwise candidates for invasive septal reduction therapy. Additional insights into this issue may be provided by the currently enrolling VALOR-HCM trial.

It is also worth noting that nearly all drugs have unwanted side effects and mavacamten appears no different in this regard. Safety issues relate to the potential for excessive reduction in LV contractility, with mavacamten producing transient systolic dysfunction with ejection fraction (EF) <50% in approximately10% of patients with drops in EF to as low as 35%, including two who developed clinical heart failure.3 The clinical implications of systolic dysfunction induced by mavacamten is currently unresolved but represents an important issue that will require substantially longer follow-up of patient cohorts from the open label extension program to clarify but nevertheless underscores that this drug will ultimately require close surveillance using likely a combination of echocardiography and serum concentrations to monitor outpatient safety.

In summary, the emergence of novel drug therapy for HCM represents an exciting time for this disease. At this still early juncture, EXPLORER-HCM data appear to provide support for considering mavacamten as an additional drug therapy option in symptomatic obstructive HCM patients, with a similar role to other negative inotropic drugs that have been used effectively to improve symptoms, including disopyramide. However, the efficacy of mavacamten in decreasing gradients and symptoms does not appear as substantial compared to surgical myectomy or alcohol septal ablation, suggesting that mavacamten should not at this time be considered a replacement for invasive septal reduction therapies in most severely symptomatic obstructive HCM patients. We anticipate that additional forthcoming studies with substantially more follow-up will provide more insights on safety and tolerability of mavacamten, particularly related to suppression of EF, as well as a more precise understanding of this therapy in the context of currently available and highly effective therapies for patients with obstructive HCM.

References

1. Maron BJ. Clinical course and management of hypertrophic cardiomyopathy. N Engl J Med 2018;379:655-68.
2. Sherrid MV, Barac I, McKenna WJ, et al. Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2005;45:1251-8.
3. Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2020;Aug 29:[Epub ahead of print].
4. Ommen SR, Maron BJ, Olivotto I, et al. Long term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2005;45:470-76.
5. Hodges K, Rivas CG, Aguilera J, et al. Surgical management of left ventricular outflow tract obstruction in a specialized hypertrophic obstructive cardiomyopathy center. J Thorac Cardiovasc Surg 2019;157:2289-99.
6. Kimmelstiel C, Zisa DC, Kuttab JS, et al. Guideline-based referral for septal reduction therapy in obstructive hypertrophic cardiomyopathy is associated with excellent outcomes. Circ Cardiovasc Interv 2019;12:e007673.

Keywords: Heart Failure, Mitral Valve, Disopyramide, Mitral Valve Insufficiency, Actins, Electric Impedance, Outpatients, Quality of Life, Longevity, Stroke Volume, Follow-Up Studies, Cardiomyopathy, Hypertrophic, Echocardiography, Benzylamines, ESC Congress, ESC20

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