Tale of three services: early UK experience with mavacamten treatment for hypertrophic cardiomyopathy with left ventricular outflow tract obstruction

Current evidence and treatment guidelines

Mavacamten, a small molecule allosteric inhibitor of cardiac myosin ATPase, reduces actin-myosin cross bridging, attenuating the hypercontractile state seen in HCM.13 14 Multicentre, phase III randomised controlled trials have demonstrated improved exercise capacity, symptoms and LVOT gradients in oHCM patients treated with Mavacamten versus placebo.15 16

EXPLORER-HCM included patients with significant LVOT obstruction (mean postexercise LVOT gradient 86±34 mm Hg) and New York Heart Association (NYHA) class II–III symptoms. At 30 weeks, there was significant improvement in exercise tolerance and symptom profile. 37% patients on mavacamten met the primary endpoint, a composite of improvement in NYHA class and pVO2 (37% mavacamten vs 17% placebo, p<0.0005). More recent results from the long-term extension study (MAVA-LTE) have demonstrated sustained benefit to 180 weeks.17 18

VALOR-HCM assessed patients eligible for SRT. Participants were more symptomatic (93% NYHA class III–IV) than in EXPLORER-HCM but had similar baseline provokable LVOT gradients (84±35 mm Hg). After treatment, 17.9% of patients on mavacamten still met criteria for SRT at 16 weeks compared with 76.8% in the placebo group (p<0.001). These effects were sustained in a follow-up study to 32 weeks.19

In both studies, secondary endpoints demonstrated improved LVOT gradients, cardiac biomarkers and patient-reported symptom outcomes. Cardiac MRI and echocardiography substudies have suggested positive effects on cardiac remodelling, including changes in LV wall thickness, myocardial mass and markers of diastolic dysfunction.20 21 Discontinuation of mavacamten results in rapid loss of symptomatic improvement as measured by the Hypertrophic Cardiomyopathy Symptom Questionnaire-Shortness of Breath Domain (HCMSQ-SoB).

Treatment algorithms for oHCM in Europe and North America recommend mavacamten for treatment of symptomatic patients with oHCM as a second line agent, once optimised on beta-blockers or non-dihydropyridine (DHP) calcium channel blockers.8 9 In the UK, the National Institute for Health and Care Excellence (NICE) recommends mavacamten for oHCM patients who remain symptomatic on disopyramide or who are intolerant of this medication,22 acknowledging low patient uptake for disopyramide, citing poor tolerance and/or supply chain difficulties (see figure 1).

Introducing mavacamten into UK clinical care: treatment requirements

Three major cautions for mavacamten use include (1) LV systolic dysfunction; (2) drug–drug interactions and (3) embryonic-fetal toxicity. As a result, intensive monitoring after initiating treatment, pretreatment CYP2C19 testing (in Europe) and pretreatment reproductive counselling is required.

Dosing regimen and monitoring requirements

A small decrease in LV systolic function is expected with mavacamten (mean left ventricular ejection fraction (LVEF) reduction 3.9% vs 0.1% with placebo in EXPLORER-HCM). Approximately 5% of patients experienced significant LV systolic dysfunction (LVEF <50%), which was reversible following mavacamten cessation within 4 weeks.15 Greatest caution should be taken for patients with intercurrent illness or atrial arrhythmia who appear to be at greater risk of developing LV dysfunction.23

Treatment-related LV systolic impairment is minimised through a multistep dosing algorithm with frequent echocardiographic monitoring of LVEF and LVOT gradients. This includes three phases: initiation, titration and maintenance (see figure 2). Symptom assessment and echocardiography are performed at set intervals. Although these intervals appear predetermined, the speed of treatment response varies between patients and unpredictable dose reduction and/or treatment interruption may change the timing of subsequent appointments. Therefore, flexibility and resilience in service provision are vital to provide safe care.

Figure 2

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Summary of treatment Schedules. Initiation: Starting dose 5 mg or 2.5 mg (poor or unknown CYP2C19 metaboliser status). The initiation covers the first 12 weeks with clinical review and echocardiography required on a 4 weekly basis. *At weeks 4 and 8, if LVEF <50% or provokable LVOT gradient <20 mm Hg, dose reduction or treatment interruption occurs, with reassessment after 4 weeks. Dose titration: At week 12, if LVEF is >55% and the provokable LVOT gradient remains >30 mm Hg, mavacamten dose can be increased in a stepwise fashion to a maximum of 15 mg daily (5 mg in poor metabolisers). Maintenance: Patient enters maintenance with 12 weekly assessment once max LVOT gradient <30 mm Hg and/or at maximum dose for CYP2C19 status, providing LV ejection fraction remains >50%. Interruption or treatment cessation: If LVEF <50% at any stage, treatment should be interrupted, and reassessment at 4-week intervals is reinitiated. **Treatment cessation may be necessary if there are multiple interruptions for LV systolic dysfunction. LVEF, left ventricular ejection function; LVOT, left ventricular outflow tract.

Example models of care from three UK centres

Here, we present our experience of care models designed to meet the challenges outlined above from three centres: Guy’s and St Thomas’ Hospital London, Liverpool Heart and Chest Hospital and the Essex Cardiothoracic centre. Each centre has made use of local infrastructure and departmental experience to address the complex needs of this patient group (pathways presented in figure 3).

Across all three centres, a strong emphasis is placed on multidisciplinary working, with a team that encompasses physicians, clinical scientists/physiologists, specialist nurses, specialised cardiovascular pharmacists and clinical co-ordinators. Patients are often assessed for eligibility and alternative therapeutic options explored in specialised departmental multidisciplinary team (MDT) meetings.

Direct clinical assessment is carried out in either physician or clinical scientist led clinics depending on departmental strengths, with routine assessment common across all three pathways. This includes clinical assessment, ECG and focused echocardiography. Cardiac biomarkers (high sensitivity troponins, NT-proBNP) and patient-reported outcome measures are collected. Clinics are typically ‘block booked’ at weeks 0, 4, 8 and 12, with a more reactive approach for the titration and maintenance period.

Prescreening is either undertaken in specific clinics, using clinical nurse specialists or during routine cardiologist clinical review, with CYP2C19 testing performed ahead of treatment initiation. Early involvement of specialised cardiovascular pharmacists for medication review and to ensure appropriate National Health Service specialist commissioning reimbursement protocols are completed for eligible patients prior to Mavacamten initiation occurs in all three centres.

Study design and setting

This retrospective study included patients with symptomatic oHCM treated with mavacamten at three UK centres: Guy’s and St Thomas’ Hospitals, Essex Cardiothoracic Centre and Liverpool Heart and Chest Hospital between December 2023 and November 2024. The aim was to evaluate outcomes from mavacamten treatment in a real-world setting.

Patient selection

Eligible oHCM patients had NYHA class II–III symptoms, peak LVOT gradient >30 mm Hg and LVEF >55% LVEF was assessed by Simpson’s Biplane Method, 3DEF or AutoEF (GE Healthcare). All were established on standard oHCM therapies (beta-blockers, calcium channel blockers or disopyramide). Mavacamten was introduced in accordance with NICE guidance.22 Exclusion criteria included LVEF <55% and comorbid conditions that could interfere with required safety monitoring.

Interventions

Patients had CYP2C19 genotyping, and mavacamten dosing was guided by the metaboliser phenotype. Poor metabolisers or patients with unknown CYP2C19 status received an initial dose of 2.5 mg daily; other patients received 5 mg daily. The initiation phase comprised follow-up at weeks 0, 4, 8 and 12, including clinical assessment, echocardiography and biomarker testing. Treatment titration and maintenance were in accordance with recommendations from the summary of product characteristics.23 Treatment optimisation was defined as the assessment where the patient entered the maintenance phase without further treatment titration.

Statistical analysis

Data were collected at each assessment and changes in clinical and echocardiographic parameters were analysed. Descriptive statistics were used to summarise baseline characteristics and paired t-tests to compare pretreatment and post-treatment values. Results were expressed as mean±SD or median and IQR with CIs.

Learning from the early experience

These are the first real-world data from UK use of mavacamten for oHCM. The improvement in symptoms and echocardiographic outcomes was comparable to that seen in the EXPLORER-HCM and VALOR-HCM trials. At dose optimisation, mean LVOT gradients were <30 mm Hg, which is in keeping with resolution of LVOT obstruction. Similar to data from MAVA-LTE, over half of the patients were symptom-free (NYHA class I) at treatment optimisation.18

A modest reduction in LV function was expected and in keeping with that seen in trial data,15 20 with LVEF reduction of approximately 4% seen in our population. No patients had permanent discontinuation due to left ventricular dysfunction, and temporary discontinuation due to LVEF <50% or heart failure symptoms occurred in 4.3% of patients, similar to that observed in trial data.15 Patients initiated on mavacamten required a minimum of seven clinical assessments during the first 12 months of treatment, when mapped against the recommended follow-up intervals as of December 2024. Patients in our cohort were estimated to require eight assessments in the first year on average. This predominantly relates to patients who require higher treatment doses, with a longer initiation phase, and approximately 50% of patients in our cohort were optimised on 10–15 mg mavacamten. This impacts service requirements, and although early identification of those likely to require additional monitoring can help with resource allocation, services need flexibility, particularly in echocardiography provision.

One key area where clinical practice differs in the UK compared with North America is the need for CYP2C19 testing. Clinical service development to provide a pipeline for CYP testing can be challenging for new centres, particularly as routine pharmacogenetic testing is in its infancy during day-to-day clinical practice. In our population, mavacamten dose adjustment following CYP testing was rare (2% of patients were poor metabolisers), but recognising metaboliser status was helpful to guide dose adjustments for other potential drug–drug interactions.

Hypertension and atrial fibrillation were common comorbidities in our patients (present in 38% and 23% of patients, respectively). Importantly, however, other than non-DHP calcium channel blockers, most common antihypertensive medications and anticoagulants are not known to have significant pharmacokinetic interactions with mavacamten via CYP2C19 or CYP3A4 pathways.23

There are several limitations to our retrospective analysis. In this real-world setting, patients were often referred for treatment following assessment in consultant clinics or after MDT consensus, where it was felt the patient was most likely to benefit from treatment, and this selection process introduces bias. In addition, despite a well-defined dosing regimen and follow-up framework, clinical practice differed in each site, for example, in echocardiography protocols, which may influence reported outcomes.

We have described three different but effective clinical pathways, which use local experience, whether through consultant or clinical scientist-led services. During service establishment, centres are encouraged to assess and leverage their local strengths to devise local protocols. Our pathways have evolved and developed over time to meet the clinical monitoring, CYP2C19 testing and patient counselling requirements.

There are similarities between pathways: (1) involvement of the MDT according to local strengths, (2) pretreatment assessment and (3) early involvement of cardiovascular pharmacists. Pretreatment assessment provides an opportunity for medication reconciliation, assessment of potential drug–drug interactions, instructions for transition to mavacamten, counselling for use of effective contraception where applicable and CYP2C19 testing. A pretreatment visit helps to minimise delays in treatment initiation and can be used to identify additional needs such as diagnostic HCM genomic testing if not previously performed. Involving cardiovascular pharmacists early in the patient journey is also important in managing the logistical aspects of drug stock and supporting local commissioning applications for mavacamten, which has ‘high cost’ drug restrictions.

Future pathway development

Recognising the importance of equitable patient access to treatment and long-term drug monitoring, the future for mavacamten is likely to require ‘hub-and-spoke’ networks and shared care prescribing agreements to facilitate provision of expert care and medication availability closer to patients’ homes.27 28 With increased real-world data to add to the existing trial data, we expect that knowledge and confidence around drug safety will increase, potentially leading to a reduction in the frequency of clinical and echocardiographic assessments.