What is the role of sacubitril (Angiotensin Receptor-Neprilysin Inhibitor) valsartan in the management of hypertrophic cardiomyopathy (HCM)?

Role of Sacubitril/Valsartan in Hypertrophic Cardiomyopathy

Sacubitril/valsartan is not recommended for the management of hypertrophic cardiomyopathy (HCM) as it has shown no significant benefit in exercise capacity, cardiac structure, or function in patients with non-obstructive HCM. 1

Current Pharmacological Management of HCM

First-Line Therapy

• Beta-blockers are the first-line pharmacological therapy for symptomatic obstructive HCM

  • Should be titrated to a resting heart rate of <60-65 bpm or maximally tolerated dose 2
  • Aim to reduce early LV ejection acceleration and systolic pushing force on mitral leaflet
  • Most effective for managing symptoms such as dyspnea and angina

• Calcium channel blockers (verapamil or diltiazem) are reasonable alternatives when:

  • Beta-blockers are ineffective
  • Patient has side effects or contraindications to beta-blockers 2
  • Should be used with caution in patients with high gradients, advanced heart failure, or sinus bradycardia

Advanced Therapy Options for Persistent Symptoms

For patients who don't respond to first-line therapy, options include:

1. Cardiac myosin inhibitors (mavacamten) - for adult patients only

   • Shown to improve LVOT gradients, symptoms, and functional capacity in 30-60% of patients with obstructive HCM 2
   • Requires risk evaluation and mitigation strategy due to potential decrease in LVEF

2. Disopyramide - in combination with beta-blockers or calcium channel blockers

   • Should not be used alone in patients with AF 2

3. Septal reduction therapy - when performed by experienced operators

Evidence Against Sacubitril/Valsartan in HCM

The SILICOFCM trial (2024) specifically evaluated sacubitril/valsartan in non-obstructive HCM and found:

• No significant change in peak oxygen consumption (primary endpoint)
• No clinically significant changes in blood pressure, cardiac structure and function, plasma biomarkers, or quality of life
• While well-tolerated, it demonstrated no therapeutic benefit 1

Potential Role of Valsartan Alone

While sacubitril/valsartan is not recommended, valsartan alone may have a limited role:

• For younger patients (≤45 years) with non-obstructive HCM due to pathogenic cardiac sarcomere genetic variant and mild phenotype 3
• The VANISH trial showed valsartan may attenuate disease evolution in early-stage sarcomeric HCM 4
• Valsartan has been shown to reduce type I collagen synthesis in HCM patients, potentially improving myocardial fibrosis 5
• Recent CMR substudy of VANISH demonstrated valsartan reduced intracellular volume progression and improved biventricular remodeling 6

Cautions and Contraindications

• Vasodilators (including ARBs) should be used with caution in obstructive HCM as they can potentially worsen LVOT gradient 2
• The 2011 ACC/AHA guidelines specifically note that ARBs are "potentially harmful for treatment of symptoms in patients with HCM who have resting or provocable LVOT obstruction" 2

Clinical Algorithm for HCM Management

1. First determine if obstructive or non-obstructive HCM

   • If obstructive: Start with beta-blockers
   • If non-obstructive: Beta-blockers or calcium channel blockers based on comorbidities

2. If symptoms persist despite first-line therapy:

   • For obstructive HCM: Consider cardiac myosin inhibitor, disopyramide, or septal reduction
   • For non-obstructive HCM: Consider adding low-dose diuretics

3. Special case - early sarcomeric HCM in younger patients:

   • Consider valsartan to potentially slow disease progression
   • Not recommended for established disease

4. Avoid in all HCM patients:

   • Dihydropyridine calcium channel blockers
   • Positive inotropic agents
   • Sacubitril/valsartan (no proven benefit)

The evidence clearly shows that while valsartan alone may have a role in early disease modification for specific HCM subgroups, sacubitril/valsartan combination therapy has not demonstrated benefits in HCM management.