Narrative about one death and permanent drug discontinuation (LVEF <50%, Week 16–56)¹

81-year-old patient with obstructive HCM and a prior history of unsuccessful alcohol septal ablation was originally randomised to placebo. At Week 16, their LVEF was 73% with a Valsalva LVOT of 53.55 mmHg, and was classified as NYHA Class III. They chose to continue in the study and began 5 mg of CAMZYOS. Between weeks 16 and 28, the LVEF ranged from 65–72% and Valsalva LVOT gradient ranged from 12–53 mm Hg. At Week 28, their mavacamten was increased to 10 mg and at Week 32, their LVEF was 57% with a Valsalva LVOT gradient of 6.1 mmHg. They were maintained on 10 mg through Week 44 visit (LVEF of 60% on site-read echocardiogram). At Week 56, the site-read echocardiogram was remarkable for decreased LVEF of 30%, no systolic anterior motion of the mitral valve, LVOT gradient at rest and Valsalva of 0 mmHg and severe mitral regurgitation. Patient was deemed to be asymptomatic without signs of congestive heart failure. CAMZYOS was permanently discontinued, and they were scheduled to return for a follow visit in 2 weeks. However, their baseline HCM medications (disopyramide and verapamil) were continued as directed by the treating cardiologist.

Subsequently, the patient was evaluated by a pulmonologist 3 days later and was found to have mild forced expiratory wheeze consistent with mild asthma. It was considered possibly secondary to mould exposure and they were started on a fluticasone inhaler. The patient died 4 days later in their sleep with cause of death determined to be sudden cardiac death. The autopsy report showed cardiomegaly with an enlarged left ventricle, dilated thoracic ascending aorta, and an area of upper septal scarring (deemed to be due to prior alcohol septal ablation). There was coronary artery sclerosis but narrowing <50%, firm lungs on exam with underlying pulmonary fibrosis. Pneumonia was found (reported difficulty in grossly differentiating lobar versus diffuse pneumonia due to fibrosis). There was no evidence of myocardial infarction and a dilated aortic root was seen with no dissection.

Narrative about one heart failure admission and permanent drug discontinuation (LVEF <50%, Week 16–56)¹

70-year-old patient with obstructive HCM randomised to placebo. During the double-blind period, their LVEF ranged from 61–66% with a Valsalva LVOT of 84.77–106.48 mmHg. At Week 16, they chose to remain in the study and received 5 mg of CAMZYOS. At Week 24, their LVEF was 60% with a Valsalva LVOT of 60.75 mmHg. Their dose was increased to 10 mg. At Week 28, their LVEF was 55% with a Valsalva LVOT of 34.07 mmHg and the dose was increased to 15 mg. Soon after, the subject was diagnosed with new-onset atrial fibrillation, was started on apixaban 5 mg twice daily and referred to electrophysiology. Four weeks later, they underwent an outpatient direct current cardioversion and sinus rhythm was restored. No action was taken with regards to study medication.

Few days later, the subject began experiencing worsening symptoms and had irregular heart rate which was determined to be rapid atrial fibrillation and an LVEF that had decreased to 30%. CAMZYOS was discontinued permanently followed by a second successful cardioversion the next day. Two weeks later, during the subject’s end of treatment study visit, they were found to be in congestive heart failure and hospitalised for acute decompensated HF. They underwent a left heart catheterisation which revealed no obstructive coronary artery disease. They were treated with appropriate guideline directed medical therapy and discharged. At week 56 follow up and beyond, patient has remained in normal sinus rhythm and LVEF has normalised. In the longer-term, their LVOT gradient on Valsalva was > 50 mmHg. However, they have chosen not to undergo SRT and have been managed on commercially approved HCM medical therapy.

Adapted from Desai M et al. 2023.¹
HCM, hypertrophic cardiomyopathy; LVEF, left ventricular ejection fration; LVOT, left ventricular outflow tract; NYHA, New York Heart Association.