What is the recommended treatment for Transthyretin (TTR) Amyloid Cardiomyopathy?

Treatment of Transthyretin Amyloid Cardiomyopathy

Tafamidis is the first-line treatment for patients with wild-type or variant transthyretin amyloid cardiomyopathy (ATTR-CM) with NYHA class I to III symptoms to reduce cardiovascular mortality and hospitalizations. 1

Diagnosis and Classification

Before initiating treatment, accurate diagnosis and classification of ATTR-CM is essential:

1. Screening for amyloidosis:

   • Serum and urine immunofixation electrophoresis
   • Serum free light chain assay 1

2. Confirming ATTR-CM:

   • Bone scintigraphy in patients without evidence of monoclonal light chains 1
   • TTR gene sequencing to differentiate hereditary variant (ATTRv) from wild-type (ATTRwt) ATTR-CM 1

First-Line Treatment

Tafamidis

• Dosing: Either VYNDAQEL 80 mg (four 20-mg tafamidis meglumine capsules) or VYNDAMAX 61 mg (one 61-mg tafamidis capsule) orally once daily 2
• Efficacy:
  • Reduces all-cause mortality (HR 0.70,95% CI 0.51-0.96) 3
  • Reduces cardiovascular-related hospitalizations (RR 0.68,95% CI 0.56-0.81) 3
  • Slows decline in functional capacity (6-minute walk test) and quality of life 3
• Benefits across subgroups:
  • Effective regardless of baseline LVEF (both <50% and ≥50%) 4
  • Benefits both variant and wild-type ATTR-CM 5
  • Most effective when started early in the disease course 5

Dose Considerations

• Long-term data supports tafamidis 80 mg as the optimal dose 6
• While the 20-mg dose showed benefit in clinical trials, the 80-mg dose demonstrated superior long-term survival benefit (HR 0.700,95% CI 0.501-0.979, p=0.0374) 6
• Economic considerations: At 2020 list prices, tafamidis provides low economic value (>$180,000 per QALY gained) 1

Management of Complications

Atrial Fibrillation

• Anticoagulation is recommended for all patients with cardiac amyloidosis and AF regardless of CHA₂DS₂-VASc score 1, 7
• This recommendation is stronger than for the general population due to higher stroke risk in ATTR-CM

Heart Failure Management

• Standard heart failure medications may be poorly tolerated in ATTR-CM 1
• Cautions:
  • ARNi, ACEi, and ARBs may exacerbate hypotension, especially with amyloid-associated autonomic dysfunction
  • Beta-blockers may worsen symptoms as patients with ATTR-CM rely on heart rate response to maintain cardiac output
  • Diuretics should be used cautiously to avoid overdiuresis and hypotension 1

Neuropathic Symptoms (if present)

• For neuropathic pain: Pregabalin, gabapentin, or duloxetine 1
• For orthostatic hypotension: Midodrine, droxidopa, or pyridostigmine 1

Additional Treatment Options

For ATTRv with Polyneuropathy

• TTR silencers:
  • Patisiran: 0.3 mg/kg IV every 3 weeks 1
  • Inotersen: 284 mg SC once weekly 1
  • Vutrisiran: 25 mg SC every 3 months 1
  • Note: These are currently only approved for ATTRv with polyneuropathy, not specifically for cardiac manifestations

Medications to Avoid

• Digoxin: Binds to amyloid fibrils, increasing risk of toxicity 1
• Calcium channel blockers: Can cause exaggerated hypotension and negative inotropic effects 1

Advanced Therapies

For end-stage disease:

• Heart transplantation may be considered for selected patients with advanced heart failure 7
• Combined heart and liver transplantation may be considered for selected patients with hereditary ATTR-CM 1, 7

Monitoring and Follow-up

• Regular assessment of:
  • NYHA functional class
  • NT-proBNP levels
  • Echocardiographic parameters
  • Symptoms of disease progression

Clinical Pearls

• Early diagnosis and treatment initiation is critical for better outcomes 5
• The benefits of tafamidis persist long-term, with continued survival advantage for those started on treatment early 5
• Patients with NYHA class I-II symptoms derive greater benefit from tafamidis than those with more advanced disease 1
• Regular reassessment of thrombotic and bleeding risks is essential in patients on anticoagulation 7