Ahmad Masri, MD, MS, is the director of the Hypertrophic Cardiomyopathy Center at Oregon Health and Science University. 

Ahmad Masri, MD, MS

non-obstructive hypertrophic cardiomyopathy (nHCM

) who were treated with aficamten saw significant improvements in symptom burden and exercise capacity, according to full results from ACACIA-HCM.

Aficamten Safe, Efficacious in nHCM, Improves Symptoms and Exercise Capacity

European Society of Cardiology (ESC) Congress 2026

 in Munich, Germany, by Ahmad Masri, MD, MS, cardiomyopathy section head at Oregon Health & Science University, director of the OHSU hypertrophic cardiomyopathy center and the OHSU Knight Cardiovascular Institute Cardiac Amyloidosis Program, and co-author of the study.

“Non-obstructive HCM represents a substantial proportion of patients with HCM who arguably have the highest unmet need right now, since they don’t have any therapies available or approved that can actually improve their symptoms and exercise capacity,” Masri told 

ACACIA-HCM was a double-blind phase 3 trial, conducted across 182 sites internationally. Patients were eligible for inclusion if they were between 18 and 85 years of age with a body mass index <40 kg/m2. Additionally, patients were required to have a respiratory exchange ratio ≥1 at screening by cardiopulmonary exercise testing and predicted peak oxygen uptake ≤90% for age and sex. Patients with significant valvular heart disease, infiltrative, genetic, or storage disorder causing cardiac hypertrophy, or unrevascularized coronary artery stenosis of ≥70%, among other criteria, were excluded.

A total of 517 patients were enrolled in the trial and randomly assigned in a 1:1 ratio to aficamten or placebo. Treatment continued for ≤72 weeks. Aficamten doses were adjusted based on LV ejection fraction (LVEF). The trial featured a dual primary endpoint of change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and in maximal exercise performance (pVO2) from baseline to week 36.

At 36 weeks, Masri and colleagues found that KCCQ-CSS had improved by 11.4 in the aficamten group compared to 8.4 in the placebo group (

 = .02). These benefits were noted as early as 12 weeks, according to the team. pVO2 also improved by 0.64 mL/kg/min in the aficamten group while remaining almost fully unchanged in the placebo group (-.03 mL/kg/min) (

Secondary endpoints, such as New York Heart Association functional class, submaximal exercise performance, and NT-proBNP, also saw improvements with aficamten treatment. The trial did display an increased incidence of patients with LVEF <50% with aficamten (10%) compared to placebo (1%), but this was managed through dose adjustment and no patients discontinued treatment.

Ultimately, Masri and colleagues concluded the definitive improvements provided by aficamten in this population, highlighting its clear efficacy in reducing symptoms for nHCM. In the interview, Masri expressed anticipation of results from the trial’s long-term extension, FOREST-HCM, which includes >80% of the patients from ACACIA-HCM following trial completion.

“What we are looking forward to is the long-term extension, FOREST-HCM, which will provide more data on the longer-term exposure to aficamten and what the results could look like for those patients,” Masri said. “We will also at some point report results from the echocardiographic outcomes as well as the cardiac MRI substudy related to that change in structure and function. So, stay tuned.”

Editors’ Note: Masri reports disclosures with Pfizer, Attralus, Lexicon, Ionis, Cytokinetics, BioMarin, and others.

Masri A. ACACIA-HCM: Aficamten for symptomatic nonobstructive hypertrophic cardiomyopathy. Presented at the European Society of Cardiology Congress 2026, Munich, Germany. August 28-31, 2026.

Cytokinetics. A Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy (nHCM) (ACACIA-HCM). ClinicalTrials.gov Identifier: NCT06081894. Updated August 5, 2026. Accessed August 28, 2026. 

https://clinicaltrials.gov/study/NCT06081894

Videos

Ahmad Masri, MD, MS, discusses his presentation of the full results of the ACACIA-HCM trial at the ESC Congress 2026.

ACACIA-HCM: Aficamten Beats Placebo in Non-Obstructive Hypertrophic Cardiomyopathy

Aficamten has outperformed placebo among patients with 

symptomatic non-obstructive hypertrophic cardiomyopathy (nHCM)

, according to topline data from ACACIA-HCM.

These data were announced by parent company Cytokinetics on May 5, 2026, highlighting improvements in both Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and maximal exercise performance (pVO2). These results highlight aficamten’s potential as a treatment for the underlying hypercontractility associated with nHCM.

“Traditionally, we have placed more weight on peak oxygen consumption – it is a very hard endpoint to move,” Ahmad Masri, MD, cardiomyopathy section head at Oregon Health & Science University, director of the OHSU hypertrophic cardiomyopathy center and OHSU Knight Cardiovascular Institute Cardiac Amyloidosis Program, and co-author of the study, told 

 in an exclusive interview. “We’ve shown that the minimal change in peak VO2 that patients perceive as clinically significant is 0.5. Most of the heart failure therapies we use don’t even hit on pVO2, even when they improve mortality and heart failure hospitalizations.”

ACACIA-HCM is a multicenter, randomized, double-blind phase 3 trial comparing aficamten to placebo in adults with symptomatic nHCM. The trial itself was conducted across 180 locations worldwide and included patients with a body mass index (BMI) <40 kg/m2 who had been diagnosed with nHCM and had a screening echocardiogram with end-diastolic left ventricular wall thickness ≥15 mm in ≥1 myocardial segment. Additionally, patients were required to have NYHA class II or III, a respiratory exchange rate of ≥1 at screening, and a KCCQ-CSS score of ≤85, among other criteria.

Patients were excluded from ACACIA-HCM if they presented with significant valvular heart disease, known or suspected infiltrative, genetic, or storage disorders causing cardiac hypertrophy, or a history of LV systolic dysfunction, syncope, symptomatic ventricular arrhythmia, resistant hypertension, or sustained ventricular tachyarrhythmia with exercise, among other criteria.

The study consisted of 2 primary endpoints – change in KCCQ-CSS and change in pVO2 from baseline to week 36. Secondary endpoints included the proportion of patients with ≥1 class improvement in NYHA functional class and changes in the composite z-score of 2 cardiopulmonary exercise testing parameters of sub-maximal exercise performance, NT-proBNP, and left atrial volume index.

A total of 516 patients were enrolled in the trial and randomly assigned in a 1:1 ratio to either aficamten or placebo. Each patient was administered ≤4 escalating doses of aficamten or placebo based on echocardiographic guidance – those in the treatment arm began with 5 mg daily. Echocardiograms were performed at weeks 2, 4, and 6 to determine the safety of up-titrating to doses of 10, 15, or 20 mg. Escalation only occurred in the presence of LVEF ≥60%.

By week 36, patients in the aficamten arm saw improvements in KCCQ-CSS of 11.4 points (95% CI, 9.6 to 13.2) and of 0.64 mL/kg/min in pVO2 (95% CI, 0.32 to 0.95), compared to 8.4 points (95% CI, 6.6 to 10.2) and -0.03 mL/kg/min (95% CI, 0.22 to 1.1), respectively, in the placebo arm (

 = .021 and .003, respectively). The improvement in KCCQ was robust and consistent throughout treatment; however, following washout, it decreased among the aficamten arm to match placebo. pVO2 remained unchanged for patients on placebo despite increasing for those on aficamten, consistent with previous research.

Investigators also reported statistically significant improvements in NYHA functional class, the composite z-score of ventilatory efficiency and pVO2, and NT-proBNP. No new safety signals were identified, and only 2 participants receiving aficamten experienced serious adverse events of heart failure associated with LVEF <50%.

“What we are looking at here is symptom improvement as a continuous variable. You’re looking at the mean average population change,” Masri said. “We all know that there are some patients who might report feeling better, some who report feeling worse, and so you will have to understand, who are the patients who felt better? What is the categorical change of having 5 or more points of improvement in KCCQ? That’s where we don’t have the data yet, and I think that data will help us understand the symptom perspective.”

Editors’ Note: Masri reports disclosures with Pfizer, Attralus, Eidos, Ionis, Cytokinetics, BioMarin, and others.

Cytokinetics. Cytokinetics Announces Positive Topline Results from ACACIA-HCM, the Pivotal Phase 3 Clinical Trial of Aficamten in Patients with Non-Obstructive Hypertrophic Cardiomyopathy. May 5, 2026. Accessed May 8, 2026. 

https://ir.cytokinetics.com/press-releases/press-release-details/2026/Cytokinetics-Announces-Positive-Topline-Results-from-ACACIA-HCM-the-Pivotal-Phase-3-Clinical-Trial-of-Aficamten-in-Patients-with-Non-Obstructive-Hypertrophic-Cardiomyopathy/default.aspx

Cytokinetics. Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic nHCM (ACACIA-HCM). ClinicalTrials.gov Identifier: NCT06081894. Updated February 2, 2026. Accessed May 8, 2026. 

Ahmad Masri, MD, from OHSU, discusses the positive topline results from this phase 3 trial, highlighting a new path forward for nHCM.

To close the discussion, Dr Maron and Dr Masri address how surgical myectomy and alcohol septal ablation fit into a therapeutic ecosystem that now includes potent sarcomere-directed drugs. Masri stresses that clinicians have an obligation to present all reasonable options—medical and invasive—and to individualize decisions through shared decision-making. Although cardiac myosin inhibitors offer a noninvasive, reversible approach that can be maintained long term, patients must understand that therapy is generally chronic, and gradients and symptoms recur when treatment is discontinued. By contrast, septal reduction, particularly surgical myectomy, can offer a more definitive “one-and-done” solution, albeit with higher upfront procedural risk and recovery.

Integrating Myosin Inhibitors With Septal Reduction and Future Directions in Nonobstructive HCM

Maron underscores that a subset of patients with complex LVOT and mitral valve anatomy may have residual obstruction and symptoms despite optimal myosin inhibition. For these individuals, structural intervention remains essential to address anatomic contributors that pharmacologic modulation cannot fully overcome. Younger patients, women planning pregnancy, and individuals strongly averse to lifelong pharmacotherapy and monitoring may also reasonably favor septal reduction, provided they understand and accept procedural risks. The experts agree that myosin inhibitors are unlikely to obviate the need for expert septal reduction centers but will instead complement and refine referral patterns.

Finally, the discussion looks ahead to nonobstructive HCM. Masri cites the neutral ODYSSEY-HCM trial of mavacamten in nonobstructive disease but expresses optimism regarding the ongoing ACACIA-HCM trial evaluating aficamten in this population. Both clinicians regard nonobstructive HCM as a major remaining unmet need, given the lack of targeted therapies that reliably improve exercise capacity and symptoms. Maron concludes that results from trials like ACACIA-HCM will be pivotal in determining whether the benefits of myosin inhibition can extend beyond obstructive physiology, potentially redefining care for an even broader spectrum of patients with HCM.

Maron and Masri define the ongoing role of surgical myectomy and alcohol septal ablation in the myosin inhibitor era and preview emerging trials of aficamten in nonobstructive HCM.

In this segment, Dr Maron poses a key practical question: in newly presenting, treatment-naive patients with symptomatic obstructive HCM, should clinicians still begin with traditional beta-blockers or calcium channel blockers, or has the evidence base matured sufficiently to justify first-line use of cardiac myosin inhibitors? Dr Masri responds by highlighting the MAPLE-HCM trial, in which aficamten, used as first-line monotherapy, outperformed metoprolol in terms of LVOT gradient reduction and symptomatic improvement. Notably, metoprolol was associated with worsening exercise capacity, higher N-terminal pro–brain natriuretic peptide levels, and increased left atrial volume index.

Positioning Cardiac Myosin Inhibitors as First-Line Therapy: Evidence Versus Beta-blockers

Both faculty members emphasize that, while formal head-to-head comparisons of beta-blockers with mavacamten are lacking, the limited and largely nonrandomized evidence for beta-blockers contrasts sharply with the robust phase 3 data for myosin inhibitors. Given the magnitude and consistency of gradient reduction and symptom improvement, Masri explains that in his practice, he moves rapidly toward myosin inhibition in highly symptomatic, markedly obstructed patients rather than spending prolonged periods titrating conventional agents to maximal tolerated doses. Maron argues that, based on current data, it is reasonable to consider aficamten as initial monotherapy in suitable patients.

The clinicians also acknowledge real-world constraints, including payer requirements that may still mandate a trial of traditional negative inotropes before authorizing myosin inhibitors. Maron clarifies that this first-line positioning pertains specifically to treatment of obstruction-related symptoms and does not supersede beta-blocker use when indicated for other conditions such as atrial fibrillation or hypertension. Nonetheless, both experts concur that the totality of evidence now supports consideration of aficamten as a legitimate first-line option for symptomatic obstructive HCM, reflecting a substantial evolution in standard of care.

Maron and Masri discuss whether myosin inhibitors, particularly aficamten, should be considered first-line therapy for symptomatic obstructive HCM in treatment-naive patients, in light of data from trials like MAPLE-HCM.

Ahmad Masri, MD, MS

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