What are the treatment options for a patient with Hypertrophic Obstructive Cardiomyopathy (HOCM) who is not responding to current medications?

Treatment Options for HOCM Refractory to Current Medications

For patients with symptomatic obstructive HCM who fail first-line therapy with beta-blockers or calcium channel blockers, the 2024 ACC/AHA guidelines recommend escalation to mavacamten (a cardiac myosin inhibitor), disopyramide, or septal reduction therapy performed at comprehensive HCM centers. 1

First-Line Therapy Optimization Before Escalation

Before declaring treatment failure, ensure adequate trials of first-line agents have been completed:

• Beta-blockers (nonvasodilating) should be titrated to achieve resting heart rate <60-65 bpm, up to maximum recommended doses, as physiologic evidence of beta-blockade must be demonstrated before declaring failure 1
• Verapamil or diltiazem (up to 480 mg/day) are reasonable alternatives if beta-blockers are ineffective, contraindicated, or cause intolerable side effects 1
• Combination therapy of beta-blockers with calcium channel blockers for HCM-directed treatment is unsupported by evidence, though may have a role for concurrent hypertension management 1

Critical Step: Eliminate Medications Worsening Obstruction

Discontinue all vasodilators immediately as they worsen LVOT obstruction and can precipitate hemodynamic collapse 2:

• ACE inhibitors and ARBs decrease systemic vascular resistance, reducing afterload and worsening the outflow gradient 2
• Dihydropyridine calcium channel blockers (e.g., nifedipine) are potentially harmful 1
• High-dose diuretics should be avoided, though low-dose diuretics may be cautiously added for persistent congestive symptoms 1

Second-Line Treatment Options for Refractory Symptoms

Option 1: Mavacamten (Cardiac Myosin Inhibitor)

Mavacamten is recommended as second-line therapy for adult patients with NYHA class II-III symptoms despite maximally tolerated first-line therapy 3:

• Efficacy: 30-60% of patients achieve improvement in LVOT gradients, symptoms, and functional capacity 1, 3
• Critical safety requirement: Mandatory interruption if LVEF drops <50% at any visit 3
• Risk profile: LVEF reduction occurs in 5.7% due to drug alone, up to 7-10% when considering other clinical conditions 1, 3
• Absolute contraindication: Pregnancy due to teratogenic effects; negative pregnancy test mandatory before initiation in women of childbearing potential 3
• Monitoring: Risk evaluation and mitigation strategy (REMS) required in the United States 1

Option 2: Disopyramide

Disopyramide combined with a beta-blocker or verapamil is reasonable for patients who fail first-line monotherapy 1:

• Provides symptomatic benefit in patients with obstructive HCM 1
• Critical caveat: Must be used in combination with AV nodal blocking agents (beta-blocker, verapamil, or diltiazem) to prevent rapid ventricular response if atrial fibrillation develops 1
• Anticholinergic side effects may limit tolerability 4

Option 3: Septal Reduction Therapy (SRT)

For patients with persistent severe symptoms despite optimal medical therapy, SRT should be performed only by experienced operators at comprehensive HCM centers 1:

Surgical Septal Myectomy

• Gold standard septal reduction therapy 5
• Generally preferred for younger patients with extreme hypertrophy 4
• Requires multidisciplinary HCM program with demonstrated excellence in clinical outcomes 1

Alcohol Septal Ablation

• Less invasive alternative to surgery 5
• Typically directed toward older patients and those with significant comorbidities 4
• Must be performed at centers with expertise in the procedure 1

Treatment Algorithm for Refractory HOCM

1. Verify adequate first-line therapy: Confirm beta-blocker titrated to HR <60-65 bpm or maximum dose verapamil/diltiazem (480 mg/day) 1

2. Eliminate harmful medications: Discontinue ACE inhibitors, ARBs, dihydropyridine calcium channel blockers, and high-dose diuretics 2

3. Consider low-dose diuretics: May cautiously add for persistent congestive symptoms while on first-line therapy 1

4. Escalate to second-line therapy through comprehensive discussion with patient about success rates, benefits, and risks 1:

   • Mavacamten (adults only): If patient accepts REMS monitoring and LVEF surveillance 3
   • Disopyramide: Add to existing beta-blocker or calcium channel blocker 1
   • Septal reduction therapy: Refer to comprehensive HCM center for evaluation 1

Critical Pitfalls to Avoid

• Do not continue ACE inhibitors or ARBs "for renal protection" or concurrent hypertension in obstructive HCM—the risk of worsening obstruction outweighs theoretical benefits 2
• Do not use verapamil in patients with systemic hypotension, severe dyspnea at rest, very high resting gradients (>100 mmHg), or severe left ventricular dysfunction 1, 6
• Do not declare beta-blocker failure without documented physiologic beta-blockade (resting HR <60-65 bpm) 1
• Do not combine beta-blockers with verapamil for HCM-directed therapy due to risk of excessive bradycardia and AV block 6
• Do not use digitalis for dyspnea in HCM patients without atrial fibrillation—it is potentially harmful 1

Special Considerations for High-Risk Scenarios

In patients with severe LVOT obstruction and acute hypotension who do not respond to fluid administration, intravenous phenylephrine (pure vasoconstrictor) is recommended 1. In the setting of hypertrophic cardiomyopathy specifically, alpha-adrenergic agents (phenylephrine, metaraminol, or methoxamine) should be used to maintain blood pressure rather than isoproterenol or norepinephrine 6.

For patients who develop systolic dysfunction (LVEF <50%) with loss of obstruction, transition to guideline-directed medical therapy for heart failure with reduced ejection fraction, which may include ACE inhibitors or ARBs in this non-obstructive context 2.