What is the recommended treatment plan for patients with symptomatic obstructive hypertrophic cardiomyopathy using Mavacamten (mavacamten)?

Mavacamten Treatment Plan for Symptomatic Obstructive Hypertrophic Cardiomyopathy

Treatment Positioning

Mavacamten is a second-line therapy for adults with symptomatic NYHA class II-III obstructive HCM who remain symptomatic despite first-line beta-blockers or nondihydropyridine calcium channel blockers (verapamil/diltiazem). 1

Treatment Algorithm

First-Line Therapy:

• Initiate nonvasodilating beta-blockers, titrated to resting heart rate <60-65 bpm 1
• Alternative: Verapamil or diltiazem (up to 480 mg/day) if beta-blockers are ineffective, contraindicated, or poorly tolerated 1
• Eliminate medications that worsen obstruction: dihydropyridine calcium channel blockers, ACE inhibitors, ARBs, and high-dose diuretics 1

Second-Line Therapy (for persistent symptoms):

• Mavacamten (adult patients only) 1
• Alternative options: Disopyramide (combined with AV nodal blocking agent) or septal reduction therapy at experienced HCM centers 1

Mavacamten Dosing Protocol

Initiation Requirements

• Confirm LVEF ≥55% before starting 2
• Confirm absence of pregnancy and effective contraception in females of reproductive potential 2
• Starting dose: 5 mg orally once daily 2
• Enrollment in mandatory REMS program required 1, 2

Dose Titration Strategy

Allowable doses: 2.5 mg, 5 mg, 10 mg, or 15 mg once daily (maximum 15 mg) 2

Titration is guided by two parameters:

1. LVEF (priority parameter) 2, 3
2. Valsalva LVOT gradient and clinical status 2, 3

Monitoring Schedule:

• Weeks 4,8,12: Echocardiography with LVEF and Valsalva LVOT gradient 2
• After week 12: Every 12 weeks during maintenance 2
• Consider dose increase if Valsalva LVOT gradient ≥30 mmHg and LVEF ≥55% 2
• Reduce dose if Valsalva LVOT gradient <20 mmHg 2

Critical Safety Monitoring

Mandatory interruption criteria:

• LVEF <50% at any visit 1, 2
• Heart failure symptoms or worsening clinical status 2
• Intercurrent illness (serious infection, uncontrolled arrhythmia) 2

Interruption protocol when LVEF <50%:

• Stop mavacamten immediately 1, 2
• Repeat echocardiography in 2 weeks 2
• If LVEF recovers to ≥50%: May restart at reduced dose 1, 2
• If LVEF remains <50% after 4 weeks: Discontinue permanently 2

Expected Clinical Outcomes

Efficacy data demonstrates:

• 30-60% of patients achieve improvement in LVOT gradients, symptoms, and functional capacity 1
• 37% meet composite endpoint (≥1.5 mL/kg/min pVO2 increase + ≥1 NYHA class improvement) versus 17% with placebo 4
• Mean reduction in post-exercise LVOT gradient: 36 mmHg 4
• 34% more patients improve by ≥1 NYHA class compared to placebo 4
• Effects sustained beyond 3 years in long-term studies 5

Real-world data confirms:

• 72% of patients improve by ≥1 NYHA class after ≥6 months 6
• 79% eliminate hemodynamically significant LVOT obstruction 6
• Mean Valsalva LVOT gradient decreases from 72 mmHg to 29-30 mmHg by 4-12 weeks 7

Critical Safety Considerations

LVEF reduction risk:

• 5.7% develop LVEF <50% attributable to drug alone 1
• Up to 7-10% when considering other clinical conditions 1
• Most cases are reversible with dose reduction or temporary discontinuation 7, 5

Absolute contraindications:

• Pregnancy (teratogenic effects) 1, 2
• Moderate-to-strong CYP2C19 inhibitors or strong CYP3A4 inhibitors 2
• Moderate-to-strong CYP2C19 or CYP3A4 inducers 2

Drug interaction management:

• Weak CYP2C19 or moderate CYP3A4 inhibitors: Reduce mavacamten dose by one level 2
• Delay dose increases during intercurrent illness or arrhythmia 2

Special Populations

Patients with obesity (BMI ≥35 kg/m²):

• May experience attenuated symptomatic relief despite similar gradient reduction 6
• Still appropriate to trial, but set realistic expectations 6

Racial diversity:

• Effectiveness and safety similar across White and non-White populations 6

Common Pitfalls to Avoid

• Do not initiate if LVEF <55% 2
• Do not combine with moderate-to-strong CYP2C19/CYP3A4 inhibitors or inducers 2
• Do not uptitrate during intercurrent illness 2
• Do not continue if LVEF persistently <50% 1, 2
• Do not use in pregnancy 1, 2
• Do not skip mandatory REMS enrollment 1, 2