What are alternative TTR (transthyretin) stabilizer therapies for cardiac amyloidosis?

Alternative TTR Stabilizer Therapies for Cardiac Amyloidosis

Tafamidis is the only FDA-approved TTR stabilizer therapy for cardiac amyloidosis with proven mortality benefit, but several alternative TTR stabilizer therapies exist for patients who cannot access or tolerate tafamidis. 1

First-Line Therapy

Tafamidis

• FDA-approved indication: Treatment of wild-type or hereditary transthyretin-mediated amyloid cardiomyopathy in adults 2
• Dosing: Either VYNDAQEL 80 mg (4 × 20 mg capsules) or VYNDAMAX 61 mg once daily 2
• Efficacy: Reduces all-cause mortality (29.5% vs 42.9%) and cardiovascular-related hospitalizations (0.48 vs 0.70 per year) in patients with NYHA class I-III symptoms 1
• Mechanism: Binds to the thyroxine-binding site of TTR, preventing TTR tetramer dissociation and subsequent amyloid formation 3
• Economic consideration: Low economic value at 2020 list prices (>$180,000 per QALY gained) 1

Alternative TTR Stabilizers

Diflunisal

• Non-steroidal anti-inflammatory drug (NSAID) that stabilizes TTR tetramers
• Evidence: Limited benefit on surrogate endpoints such as LV mass 1
• Cautions:
  • Renal dysfunction
  • Gastrointestinal bleeding risk
  • Fluid retention (potentially problematic in heart failure)
• Not FDA-approved for ATTR-CM

Epigallocatechin-3-gallate (EGCG)

• Natural polyphenol found in green tea
• Mechanism: Reduces amyloid fibril formation
• Evidence: In a small, non-randomized study, regular green tea consumption was associated with:
  • Decreased wall thickness
  • Improved LV function
  • Improved NYHA functional class 1
• Not FDA-approved for ATTR-CM

Doxycycline plus Tauroursodeoxycholic Acid (TUDCA)

• Mechanism: Targets tissue clearance of amyloid fibrils
• Evidence: Limited benefit on surrogate endpoints such as LV mass 1
• Not FDA-approved for ATTR-CM

TTR Silencers (RNA-targeted therapies)

Patisiran

• Mechanism: siRNA that inhibits hepatic TTR synthesis
• Current approval: Only for ATTRv with polyneuropathy
• Ongoing trials: Evaluating impact on cardiovascular morbidity and mortality 1

Inotersen

• Mechanism: Antisense oligonucleotide that inhibits hepatic TTR synthesis
• Current approval: Only for ATTRv with polyneuropathy
• Ongoing trials: Evaluating impact on cardiovascular morbidity and mortality 1

Treatment Algorithm for ATTR Cardiac Amyloidosis

1. Confirm diagnosis:

   • Bone scintigraphy for patients with high clinical suspicion without evidence of monoclonal light chains 1
   • Genetic testing to differentiate hereditary variant (ATTRv) from wild-type (ATTRwt) 1

2. First-line therapy:

   • Tafamidis for patients with NYHA class I-III symptoms 1

3. If tafamidis is not accessible or tolerated:

   • Consider diflunisal (with careful monitoring of renal function and GI symptoms)
   • Consider EGCG (green tea extract)

4. For ATTRv with polyneuropathy:

   • Consider TTR silencer therapy (patisiran or inotersen) 1

5. Supportive care for all patients:

   • Anticoagulation for patients with atrial fibrillation regardless of CHA₂DS₂-VASc score 1
   • Diuretics for volume management (with caution to avoid overdiuresis) 1
   • Individualize standard heart failure therapies (GDMT may be poorly tolerated) 1

Important Considerations and Pitfalls

• Avoid:

  • Digoxin (binds to amyloid fibrils, risk of toxicity even with normal serum levels) 1
  • Calcium channel blockers (bind to amyloid fibrils, can cause exaggerated hypotension) 1

• Caution with:

  • Beta-blockers (may worsen symptoms as patients rely on heart rate to maintain cardiac output) 1
  • ACEi/ARBs/ARNi (vasodilating effects may exacerbate hypotension, especially with autonomic dysfunction) 1

• Early treatment: Tafamidis prevents but does not reverse amyloid deposition, so early treatment is crucial for maximum benefit 1

• Advanced options: For selected patients with hereditary ATTR, combined heart and liver transplantation may be considered (liver transplantation cures the disease process as TTR is synthesized in the liver) 1