What are the treatment options for patients with symptomatic obstructive Hypertrophic Cardiomyopathy (HCM) who have not responded to traditional therapies?

Treatment Options for Symptomatic Obstructive Hypertrophic Cardiomyopathy Refractory to Traditional Therapies

For patients with symptomatic obstructive HCM who have not responded to traditional therapies, advanced treatment options include cardiac myosin inhibitors (mavacamten), disopyramide, or septal reduction therapy (SRT), with the choice depending on individual factors and availability at experienced centers. 1

First-Line Therapies (For Context)

Before considering advanced options, ensure first-line therapies have been optimized:

• Beta-blockers are first-line therapy for symptomatic obstructive HCM and should be titrated to achieve heart rate suppression before declaring treatment failure 1
• Non-dihydropyridine calcium channel blockers (verapamil, diltiazem) are reasonable alternatives when beta-blockers are ineffective or not tolerated 1
• Caution with verapamil in patients with severe dyspnea at rest, hypotension, very high resting gradients (>100 mm Hg), or in children <6 weeks of age 1, 2

Advanced Treatment Options for Refractory Cases

1. Cardiac Myosin Inhibitors

• Mavacamten is now indicated for adult patients with obstructive HCM who remain symptomatic despite first-line therapy 1
• Benefits include:
  • Improves LVOT gradients, symptoms, and functional capacity in 30-60% of patients 1
  • Significantly reduces the need for septal reduction therapy in eligible patients 3
  • Recent evidence shows aficamten (another cardiac myosin inhibitor) may be superior to metoprolol as monotherapy 4
• Important considerations:
  • Requires risk evaluation and mitigation strategy due to potential decrease in LVEF <50% in 5.7-10% of patients 1
  • Regular echocardiographic monitoring is essential 5
  • Not approved for pediatric patients 1

2. Disopyramide

• Effective for symptom relief in patients who have failed first-line therapy 1
• Must be used in combination with beta-blockers, verapamil, or diltiazem to prevent enhanced AV conduction during atrial fibrillation 1
• Dosing should be titrated based on symptom response 1

3. Septal Reduction Therapy (SRT)

• Indicated for patients with severe persistent symptoms despite medical therapy 1
• Two main approaches:
  • Surgical myectomy: Preferred for younger patients or those with associated cardiac abnormalities requiring surgical correction 1
  • Alcohol septal ablation: Reasonable alternative for older patients or those with significant comorbidities making surgery high-risk 1
• Should only be performed at comprehensive or primary HCM centers with demonstrated excellence in clinical outcomes 1
• Very effective for relieving LVOT obstruction when performed by experienced operators 1

Treatment Algorithm for Refractory Obstructive HCM

1. Confirm optimization of first-line therapy:

   • Ensure beta-blockers have been titrated to physiologic effect (resting HR <60-65 bpm) 1
   • If ineffective, try non-dihydropyridine calcium channel blockers 1

2. For persistent symptoms despite optimized first-line therapy:

   • Consider cardiac myosin inhibitors (mavacamten) in adult patients 1
   • OR disopyramide (combined with beta-blocker or calcium channel blocker) 1
   • OR referral for SRT evaluation at an experienced center 1

3. Treatment selection factors:

   • Patient age and comorbidities
   • Severity of symptoms and LVOT gradient
   • Presence of other cardiac abnormalities requiring intervention
   • Patient preference after comprehensive discussion of risks/benefits 1

Additional Management Considerations

• Discontinue medications that may worsen LVOT obstruction:
  • Vasodilators (ACE inhibitors, ARBs, dihydropyridine calcium channel blockers) 1
  • Digoxin 1
• Low-dose diuretics may be cautiously used in patients with persistent dyspnea and volume overload 1
• For acute hypotension, use intravenous phenylephrine or other pure vasoconstrictors without inotropic activity 1
• Avoid positive inotropic drugs (dopamine, dobutamine, norepinephrine) as they can worsen obstruction 1

Emerging Therapies

• Aficamten, a next-generation cardiac myosin inhibitor with shorter half-life and fewer drug interactions than mavacamten, shows promising results in clinical trials 6, 5
• Recent data from the MAPLE-HCM trial suggests aficamten monotherapy may be superior to metoprolol monotherapy for improving exercise capacity and reducing symptoms 4