Alternative TTR Stabilizers for Cardiac Amyloidosis
Diflunisal is the primary alternative TTR stabilizer to tafamidis for cardiac amyloidosis, while patisiran, inotersen, and vutrisiran are effective TTR silencer options for patients with ATTRv polyneuropathy. 1
Current First-Line Treatment
Tafamidis is currently the only FDA-approved therapy with proven efficacy to improve cardiovascular outcomes in ATTR-CM. It works by binding to the thyroxin-binding site of TTR, stabilizing the tetramer and slowing dissociation into monomers, which is the rate-limiting step in the amyloidogenic process 2. In the ATTR-ACT trial, tafamidis demonstrated significant reduction in all-cause mortality (29.5% versus 42.9%) and cardiovascular-related hospitalization (0.48 versus 0.70 per year) after 30 months 3.
Alternative TTR Stabilizers
Diflunisal
- A non-steroidal anti-inflammatory drug that functions as a TTR stabilizer
- Has demonstrated effectiveness in slowing disease progression in ATTRv polyneuropathy, though not FDA-approved for this indication 3
- Can be considered as the primary alternative to tafamidis for patients requiring TTR stabilization 1
- Caution: May have renal and gastrointestinal side effects that require monitoring
Epigallocatechin-3-gallate (EGCG)
- A polyphenol found in green tea that has shown limited benefit on surrogate endpoints such as LV mass 3
- Has been shown to reduce amyloid fibril formation in some studies 1
- Not FDA-approved for ATTR-CM
Doxycycline plus TUDCA (tauroursodeoxycholic acid)
- Has shown limited benefit on surrogate endpoints such as LV mass 3
- Impact on cardiovascular morbidity and mortality has not been assessed 3
- Not FDA-approved for ATTR-CM
TTR Silencers (for ATTRv with polyneuropathy)
While not specifically approved for cardiac amyloidosis, the following medications are FDA-approved for ATTRv with polyneuropathy and may be considered in patients with mixed phenotypes:
Patisiran
- Small interfering RNA that reduces TTR production
- Dosing: 0.3 mg/kg IV every 3 weeks (maximum 30 mg) 3
- Requires premedication with dexamethasone, acetaminophen, diphenhydramine, and famotidine 3
- Requires vitamin A supplementation (3,000 IU daily) 3
Inotersen
- Antisense oligonucleotide that reduces TTR production
- Dosing: 284 mg SC once weekly 3
- Requires vitamin A supplementation (3,000 IU daily) 3
- Important monitoring: Weekly platelet count and biweekly serum creatinine, eGFR, and urine protein-creatinine ratio due to risk of thrombocytopenia and glomerulonephritis 3
Vutrisiran
- Small interfering RNA similar to patisiran but with less frequent dosing
- Dosing: 25 mg SC every 3 months 3
- Requires vitamin A supplementation (3,000 IU daily) 3
Treatment Selection Considerations
When selecting an alternative to tafamidis, consider:
Type of amyloidosis:
Patient factors:
- Renal function (caution with diflunisal in renal impairment)
- Platelet count (monitor closely with inotersen)
- Ability to receive IV infusions (patisiran) vs. self-administered injections (inotersen, vutrisiran)
Disease stage:
- Early intervention is crucial for better outcomes
- Tafamidis shows greater benefit when administered early in the disease course 3
Important Caveats
- There is currently no evidence that TTR stabilizers or silencers benefit polyneuropathy associated with ATTRwt amyloidosis 3
- For patients with cardiac amyloidosis and atrial fibrillation, anticoagulation is reasonable regardless of CHA₂DS₂-VASc score 3
- Standard heart failure medications (beta-blockers, ACE inhibitors, ARBs) may be poorly tolerated in ATTR-CM patients due to hypotension risk 3
- Long-term follow-up data from the ATTR-ACT extension study shows continued benefit of early tafamidis treatment, highlighting the importance of early diagnosis and treatment 4
While tafamidis remains the only FDA-approved therapy specifically for ATTR-CM, these alternative options may be considered based on individual patient characteristics, disease type, and clinical presentation.