Treatment of Cardiac Amyloidosis with Heart Failure
For a patient with cardiac amyloidosis and heart failure, immediately determine the amyloid type (AL vs ATTR) through serum and urine light chain testing, as this fundamentally dictates treatment: AL amyloidosis requires urgent hematology-oncology referral for chemotherapy, while ATTR amyloidosis (both wild-type and variant) should receive tafamidis 80 mg daily if NYHA class I-III symptoms are present. 1
Diagnostic Algorithm First
Before initiating treatment, you must differentiate amyloid type: 1
- Check serum and urine for monoclonal light chains (immunofixation electrophoresis) 1
- If monoclonal light chains present: Proceed to hematology-oncology consultation and consider endomyocardial biopsy to confirm AL amyloidosis 1
- If no monoclonal light chains: Perform Tc-99m-PYP bone scintigraphy to confirm ATTR amyloidosis (non-invasive diagnosis possible) 1
- If ATTR confirmed: Perform TTR gene sequencing to differentiate hereditary variant (ATTRv) from wild-type (ATTRwt) 1
Treatment Based on Amyloid Type
AL Amyloidosis (Light Chain)
Immediate hematology-oncology referral is mandatory - cardiologists diagnose but hematologists treat AL amyloidosis. 1, 2
- Treatment consists of proteasome inhibitor-based chemotherapy with daratumumab 2
- Autologous stem cell transplantation when feasible 2
- This is beyond the scope of cardiology management but requires close collaboration between hematology-oncology and cardiology 1, 2
ATTR Amyloidosis (Both Wild-Type and Variant)
Tafamidis is the only FDA-approved disease-modifying therapy proven to reduce cardiovascular mortality and hospitalization. 1, 3, 4
Tafamidis Dosing and Indications
- Dose: Tafamidis 80 mg once daily (four 20-mg capsules) OR tafamidis 61 mg once daily (single capsule formulation) 1, 4
- Indication: NYHA class I-III heart failure symptoms (Class 1 recommendation, Level B-R evidence) 1, 3
- Mechanism: Stabilizes TTR tetramer, preventing dissociation into amyloidogenic monomers 1, 5
Evidence for Tafamidis
The ATTR-ACT trial demonstrated: 1, 3, 6
- 29.5% vs 42.9% all-cause mortality (tafamidis vs placebo) at 30 months 1, 3
- 0.48 vs 0.70 cardiovascular hospitalizations per year 1, 3
- Survival curves separate after 18 months, indicating benefit accumulates over time 1, 3
- Long-term extension data (up to 90 months) shows sustained mortality benefit, particularly in NAC stage I-II patients 6
Patient Selection for Tafamidis
Initiate early in disease course for maximum benefit - tafamidis prevents but does not reverse amyloid deposition. 1, 3
- NYHA class I-III symptoms
- Life expectancy not limited by non-cardiac disease (benefit appears after 18 months)
- eGFR ≥25 mL/min/1.73 m²
Avoid or uncertain benefit: 1, 3
- NYHA class IV symptoms (no observed benefit)
- Severe aortic stenosis
- eGFR <25 mL/min/1.73 m²
Additional ATTR-Specific Therapies
For ATTRv with polyneuropathy (not cardiac-only disease): 1
- TTR silencers (patisiran, inotersen, vutrisiran) are FDA-approved for polyneuropathy, not cardiac disease 1
- Patisiran: 0.3 mg/kg IV every 3 weeks (requires premedication with corticosteroid, acetaminophen, antihistamines) 1
- Inotersen: 284 mg SC weekly (requires weekly platelet monitoring, biweekly renal function monitoring) 1
- All TTR silencers require vitamin A 3,000 IU daily supplementation (TTR transports retinol) 1
Heart Failure Management in Cardiac Amyloidosis
Standard guideline-directed medical therapy (GDMT) for heart failure is often poorly tolerated and must be used cautiously. 1
Medications to Use Cautiously
- ACE inhibitors, ARBs, ARNi: Vasodilation may exacerbate hypotension, especially with amyloid-associated autonomic dysfunction 1
- Beta-blockers: May worsen heart failure symptoms as ATTR-CM patients rely on heart rate to maintain cardiac output 1
- Diuretics: Useful for congestion but use cautiously to avoid overdiuresis and hypotension 1
Medications to AVOID
- Digoxin: Binds to amyloid fibrils, causing toxicity even with normal serum levels 1
- Calcium channel blockers (nifedipine, verapamil): Bind to amyloid fibrils causing exaggerated hypotension and negative inotropy 1
Device Therapy
- ICDs: Benefit unclear in ATTR-CM; case-control studies show uncertain benefit 1
- CRT: Not studied in ATTR-CM with HFrEF 1
- Pacemakers: Consider for symptomatic bradycardia, but factor in life expectancy 1
Anticoagulation for Atrial Fibrillation
Anticoagulate all cardiac amyloidosis patients with atrial fibrillation regardless of CHA₂DS₂-VASc score (Class 2a recommendation). 1, 3
- Warfarin (INR 2-3) or direct oral anticoagulants 1
- Cardiac amyloidosis carries high thromboembolic risk independent of traditional risk scores 1
Genetic Counseling and Family Screening
For ATTRv (hereditary variant): 1
Advanced Therapies
For end-stage disease refractory to medical therapy: 2
- Heart transplantation
- Combined heart-kidney transplantation
- Combined heart-liver transplantation (for ATTRv to eliminate source of mutant TTR) 2
Monitoring on Tafamidis
Regular follow-up should assess: 3
- NT-proBNP and troponin levels
- Echocardiography with strain measurements
- ECG and Holter monitoring
- NYHA functional class
Critical Pitfalls to Avoid
- Delaying light chain testing - This is the first and most critical step to differentiate AL from ATTR 1
- Using standard heart failure medications aggressively - These are often poorly tolerated in restrictive cardiomyopathy 1
- Prescribing digoxin or calcium channel blockers - These bind amyloid fibrils and cause harm 1
- Waiting for advanced symptoms before starting tafamidis - Early initiation provides greater benefit 1, 3, 6
- Forgetting anticoagulation in atrial fibrillation - High stroke risk regardless of CHA₂DS₂-VASc score 1
Cost Consideration
Tafamidis provides low economic value at 2020 list prices (>$180,000 per QALY gained), though this should not preclude use in appropriate candidates given proven mortality benefit. 1, 3