What are the therapies for cardiac amyloidosis due to Transthyretin (TTR)?

Therapies for Cardiac Amyloidosis Due to Transthyretin (TTR)

Tafamidis is the first-line therapy for TTR cardiac amyloidosis, demonstrating significant reduction in all-cause mortality (29.5% vs 42.9%) and cardiovascular-related hospitalizations (0.48 vs 0.70 per year) compared to placebo. 1

TTR Stabilizers

First-Line Therapy

• Tafamidis (Vyndaqel/Vyndamax): FDA-approved for ATTR cardiomyopathy
  • Mechanism: Binds to thyroxin-binding site of TTR, stabilizing the tetramer and preventing dissociation into amyloidogenic monomers 1
  • Dosing: Available as tafamidis meglumine 20mg or tafamidis 61mg (bioequivalent formulations) 2
  • Efficacy: 30% reduction in all-cause mortality and 32% reduction in cardiovascular hospitalizations over 30 months 3
  • Long-term data: Continued survival benefit with early treatment (HR 0.59) with median follow-up of 58.5 months 4
  • Most effective when started early in disease course 1, 3

Alternative TTR Stabilizers

• Acoramidis (Attruby): Recently FDA-approved

  • Near-complete TTR stabilizer (~96%)
  • Reduced all-cause mortality by up to 42% and cardiovascular hospitalizations by ~50% over 30-42 months 1

• Diflunisal: Non-steroidal anti-inflammatory drug

  • Not FDA-approved for this indication but has demonstrated effectiveness in slowing disease progression in ATTRv polyneuropathy 1
  • Consider in patients who cannot access or afford tafamidis

TTR Silencers

Currently FDA-approved for ATTRv polyneuropathy but not specifically for cardiac amyloidosis:

• Patisiran: Small interfering RNA

  • Dosing: 0.3 mg/kg IV every 3 weeks (maximum 30 mg) 1
  • Reduces TTR production

• Inotersen: Antisense oligonucleotide

  • Dosing: 284 mg SC once weekly 1
  • Requires vitamin A supplementation (3,000 IU daily)
  • Monitoring needed for thrombocytopenia and glomerulonephritis

• Vutrisiran: Small interfering RNA (similar to patisiran)

  • Dosing: 25 mg SC every 3 months 1
  • Requires vitamin A supplementation (3,000 IU daily)

Organ Transplantation

• Combined cardiac and liver transplantation: For hereditary (ATTRv) amyloidosis
  • 5-year survival rate of 50-80% in selected patients 5
  • Liver transplantation cures the amyloidosis disease process since TTR is synthesized in the liver 5

Supportive Therapies for Symptom Management

Heart Failure Management

• Diuretics: Mainstay therapy for fluid overload

  • Use with caution to avoid hypotension 1
  • Loop diuretics (furosemide, torsemide, bumetanide) are primary treatment for symptomatic relief 3

• Medications to use with caution or avoid:

  • Beta-blockers: May be useful to increase diastolic filling time and control heart rate in atrial fibrillation, but use with caution 5
  • Calcium channel blockers: Should not be administered as they bind to amyloid fibrils causing exaggerated hypotension 5
  • Digoxin: Should be avoided as it binds to amyloid fibrils, predisposing to toxicity even with normal serum levels 5

Anticoagulation

• Warfarin or direct thrombin inhibitors: Indicated for patients with atrial fibrillation or history of embolic stroke/TIA 5
• Consider anticoagulation regardless of CHA₂DS₂-VASc score in patients with atrial fibrillation 1

Experimental/Adjunctive Therapies

• Epigallocatechin-3-gallate (EGCG): Found in green tea

  • May reduce amyloid fibril formation
  • Small non-randomized study showed decreased wall thickness and improved LV function 5, 1

• Doxycycline plus TUDCA: Limited benefit on surrogate endpoints like LV mass 1

Treatment Algorithm

1. Confirm diagnosis through tissue biopsy or technetium-99m pyrophosphate scan and genetic testing
2. Assess disease type: ATTRwt vs ATTRv
3. Initiate TTR stabilizer therapy:
   • First-line: Tafamidis (preferred) or Acoramidis
   • Alternative: Diflunisal if tafamidis not available
4. Consider TTR silencers for patients with ATTRv polyneuropathy
5. Manage heart failure symptoms with careful diuresis
6. Evaluate for anticoagulation if atrial fibrillation present
7. Consider transplantation in selected patients with hereditary ATTR

Important Considerations

• Early diagnosis and treatment are crucial for better outcomes 1
• Patients treated with tafamidis early have significantly better long-term survival than those who start treatment later 4
• Standard heart failure medications may be poorly tolerated due to hypotension risk 1
• Regular monitoring of cardiac biomarkers and assessment for disease progression is essential

Remember that without treatment, heart failure due to ATTR amyloidosis is associated with a median survival of approximately 5 years 3, making early diagnosis and prompt initiation of disease-modifying therapy critical.