What is Tafamidis (transthyretin stabilizer) used for?

Tafamidis: Indication and Clinical Use

Tafamidis is used to treat transthyretin amyloid cardiomyopathy (ATTR-CM) in patients with NYHA class I to III heart failure symptoms, and it is currently the only therapy proven to reduce cardiovascular mortality and hospitalizations in this disease. 1

Primary Indication: ATTR Cardiac Amyloidosis

Tafamidis is FDA-approved and guideline-recommended for both wild-type (ATTRwt) and hereditary variant (ATTRv) transthyretin cardiac amyloidosis. 1, 2 The 2022 AHA/ACC/HFSA Heart Failure Guidelines provide a Class 1 (strong) recommendation with Level B-R evidence for its use. 1, 3

Mechanism of Action

• Tafamidis functions as a transthyretin tetramer stabilizer by binding to the thyroxine-binding sites of TTR with high affinity (Kd ~2 nM and ~200 nM). 2, 4
• It kinetically stabilizes the TTR tetramer, preventing dissociation into monomers—the rate-limiting step in amyloid fibril formation. 1, 5, 4
• Critically, tafamidis prevents but does not reverse existing amyloid deposition, making early initiation essential for maximum benefit. 1

Proven Clinical Benefits

Mortality and Hospitalization Reduction

The landmark ATTR-ACT trial demonstrated compelling outcomes over 30 months: 1

• All-cause mortality: 29.5% with tafamidis versus 42.9% with placebo (absolute risk reduction of 13.4%)
• Cardiovascular hospitalizations: 0.48 versus 0.70 per year (31% relative reduction)
• Survival curves separate after approximately 18 months, indicating the need for adequate treatment duration to observe benefit. 1, 3

Patient Selection Criteria

Who Should Receive Tafamidis

Appropriate candidates include: 1

• Confirmed ATTR-CM (either wild-type or hereditary variant)
• NYHA functional class I, II, or III heart failure symptoms
• Life expectancy sufficient to benefit from therapy (given 18-month lag to survival benefit)
• eGFR ≥25 mL/min/1.73 m²

Who Should NOT Receive Tafamidis

Contraindications and lack of proven benefit: 1

• NYHA class IV symptoms (no demonstrated benefit)
• Severe aortic stenosis (excluded from trials)
• Severe renal impairment (eGFR <25 mL/min/1.73 m²)
• Non-cardiac disease limiting life expectancy to less than 18-24 months

Timing Considerations

Early initiation is critical. 1, 3 Because tafamidis prevents rather than reverses amyloid deposition, patients treated earlier in their disease course derive greater benefit. The drug stabilizes TTR tetramers in over 90% of patients, but this stabilization only prevents future damage. 6

Dosing and Formulations

Two FDA-approved formulations exist: 1, 2

• Tafamidis meglumine (VYNDAQEL): 80 mg once daily (four 20-mg capsules)
• Tafamidis free acid (VYNDAMAX): 61 mg once daily (one 61-mg capsule)

Both formulations provide equivalent steady-state exposure and are bioequivalent. 2 Food does not significantly affect absorption. 2

Secondary Indication: TTR Familial Amyloid Polyneuropathy

While the primary focus in the U.S. is cardiac amyloidosis, tafamidis is also approved in Europe, Japan, Mexico, and Argentina for TTR familial amyloid polyneuropathy (TTR-FAP). 7, 8 In early-stage Val30Met TTR-FAP patients, tafamidis slows neurologic progression and preserves nutritional status and quality of life. 5, 6, 7

Important Clinical Caveats

Cost-Effectiveness Concerns

The 2022 AHA/ACC/HFSA guidelines explicitly designate tafamidis as "low value" therapy based on cost-effectiveness analysis. 1 At 2020 list prices (~$225,000 annually), the incremental cost-effectiveness ratio exceeds $180,000 per quality-adjusted life year (QALY) gained. 1 The cost would need to decrease by approximately 80% to reach intermediate value thresholds. 1, 3

Diagnostic Algorithm Integration

The ACC/AHA recommends the following approach for suspected ATTR-CM: 1

1. Screen for monoclonal light chains (to exclude AL amyloidosis)
2. If negative, perform technetium pyrophosphate (PYP) cardiac scintigraphy
3. If positive for ATTR-CM, perform TTR gene sequencing to differentiate ATTRwt from ATTRv
4. For ATTRwt or ATTRv with NYHA I-III symptoms, initiate tafamidis

Anticoagulation Consideration

Patients with cardiac amyloidosis and atrial fibrillation should receive anticoagulation regardless of CHA₂DS₂-VASc score (Class 2a recommendation), as intracardiac thrombi occur in approximately one-third of patients, even without diagnosed AF. 1, 3

Thyroid Monitoring

Tafamidis may decrease serum total thyroxine concentrations without changing TSH, due to displacement of thyroxine from TTR binding sites. 2 No clinical hypothyroidism has been observed, but awareness of this laboratory artifact is important. 2

Drug Interactions and Safety

Long-term tafamidis demonstrates excellent tolerability with adverse event rates similar to placebo. 6, 8 No patients in extension studies discontinued due to adverse events. 6 The drug is highly protein-bound (>99%) and primarily undergoes glucuronidation. 2