What are the treatment options for cardiac amyloidosis?

Treatment of Cardiac Amyloidosis

The treatment of cardiac amyloidosis depends critically on the amyloid type: for AL (light-chain) amyloidosis, daratumumab-CyBorD is the preferred first-line therapy, while for ATTR (transthyretin) amyloidosis, tafamidis is the FDA-approved disease-modifying treatment. 1, 2

Step 1: Confirm Amyloid Type Before Treatment

Accurate typing of the amyloid protein is mandatory before initiating any disease-specific therapy, as AL and ATTR amyloidosis require completely different treatments. 1

• Perform comprehensive monoclonal protein screening with serum free light chain assay (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) to exclude AL amyloidosis 1, 3
• If monoclonal proteins are absent, proceed with Tc-99m-PYP nuclear scintigraphy to confirm ATTR cardiac amyloidosis 3
• Mass spectrometry (LC-MS/MS) of tissue biopsy is the gold standard for amyloid typing, with 88% sensitivity and 96% specificity 1
• For confirmed ATTR amyloidosis, perform TTR gene sequencing to distinguish hereditary from wild-type forms 1, 4

Common pitfall: Do not rely on SPEP/UPEP alone to exclude AL amyloidosis, as these tests have lower sensitivity than immunofixation methods 1, 3

Step 2: Disease-Specific Treatment for AL Cardiac Amyloidosis

First-Line Therapy

Daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is the preferred first-line treatment for AL cardiac amyloidosis, achieving very good partial response or better in 78.5% of patients compared to 49.2% with CyBorD alone. 1, 3

• The goal is to eradicate the pathological plasma cell clone and remove amyloidogenic light chains from circulation 1
• Treatment should be initiated promptly, as cardiac involvement is the primary driver of mortality in AL amyloidosis 3
• Close collaboration between hematology and cardiology is mandatory to monitor for cardiac decompensation during therapy 1, 3

Alternative Option: Autologous Stem Cell Transplantation

High-dose melphalan followed by autologous stem cell transplantation (HDM/SCT) should be considered for carefully selected patients who are transplant-eligible. 1, 3

• Eligibility criteria include age <60-65 years, adequate cardiac function (typically NT-proBNP <5000 ng/L), good performance status, and limited organ involvement 3
• Treatment-related mortality is approximately 3% in experienced centers 3, 5
• Daratumumab-CyBorD may supplant HDM/SCT as first-line therapy even in eligible patients based on recent evidence 1

Monitoring Cardiac Toxicity

Monitor closely for cardiac decompensation, including heart failure exacerbation, atrial arrhythmias, and thromboembolism during plasma cell-directed therapy. 1, 3

• Daratumumab carries risks of cardiac failure (12%), cardiac arrhythmias (8%), and atrial fibrillation (6%) 3
• Proteasome inhibitors (bortezomib, carfilzomib) can cause Grade 3 heart failure and decreased LVEF 3
• There are no absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status in AL cardiac amyloidosis 1, 3

Critical caveat: Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma alone due to multiorgan dysfunction 1, 3

Step 3: Disease-Specific Treatment for ATTR Cardiac Amyloidosis

FDA-Approved Therapy

Tafamidis (VYNDAQEL/VYNDAMAX) is indicated for treatment of ATTR cardiomyopathy in adults with NYHA Class I-III symptoms to reduce cardiovascular mortality and cardiovascular-related hospitalization. 2

• Tafamidis demonstrated significantly lower all-cause mortality (29.5% vs 42.9%) and reduced cardiovascular hospitalizations (0.48 vs 0.70 per year) compared to placebo after 30 months 4, 2
• This applies to both wild-type and hereditary ATTR cardiac amyloidosis 2
• Dosing: tafamidis meglumine 80 mg daily or tafamidis 61 mg daily 2
• Both doses showed similar efficacy in reducing mortality and hospitalizations 2

Additional Considerations for Hereditary ATTR

For hereditary ATTR with polyneuropathy, RNA-interfering drugs such as patisiran should be considered. 6

• These agents target TTR gene silencing to prevent TTR formation 7, 6
• Liver transplantation may be considered in select cases of hereditary ATTR to eliminate the source of mutant TTR production 8

Step 4: Supportive Cardiac Management (All Types)

Heart Failure Management

Judicious diuresis remains the cornerstone of heart failure therapy in cardiac amyloidosis, but standard heart failure medications must be used with extreme caution or avoided. 1, 4

• Diuretics: Use carefully to achieve euvolemia without causing hypotension from underfilling of a stiff ventricle 1
• ACE inhibitors/ARBs: Should be used with caution and probably avoided due to high risk of hypotension in restrictive physiology 1, 4
• Beta-blockers: Use cautiously if at all, as cardiac output is heart rate-dependent in severe restrictive physiology; probably should be avoided in AL amyloidosis 1
• Digoxin: Avoid, as it binds to amyloid fibrils and can cause toxicity even at normal serum levels 1
• Calcium channel blockers: Avoid, as they bind to amyloid fibrils causing exaggerated hypotension and negative inotropy 1

Key principle: The stiff, restrictive heart in cardiac amyloidosis does not tolerate standard neurohormonal blockade well 1

Anticoagulation Strategy

Anticoagulation is reasonable in patients with cardiac amyloidosis and atrial fibrillation to reduce stroke risk, independent of CHA₂DS₂-VASc score. 4

• Risk of intracardiac thrombus is high even in sinus rhythm due to atrial mechanical "standstill" from amyloid infiltration 1
• Anticoagulation is indicated in patients with atrial fibrillation, history of embolic stroke/TIA, or demonstrable intracardiac thrombus 1
• Weigh benefits against increased bleeding risk from potential amyloid angiopathy 1

Arrhythmia and Conduction Management

Pacemaker implantation is frequently required for conduction abnormalities in cardiac amyloidosis. 9

• Beta-blockers may be used cautiously to control heart rate in atrial fibrillation and increase diastolic filling time, but avoid if cardiac output is low 1, 4
• Monitor closely for bradyarrhythmias and high-grade AV block requiring permanent pacing 9

Step 5: Advanced Interventions for End-Stage Disease

Heart Transplantation Considerations

Heart transplantation is generally not recommended for AL cardiac amyloidosis due to high risk of recurrence in the transplanted heart, with 5-year survival of only 20-30%. 4

• Survival may improve to 35-55% at 5 years if heart transplantation is followed by bone marrow transplantation 4
• For hereditary ATTR, combined heart-liver transplantation may be considered to eliminate the source of mutant TTR 8
• Heart or heart-kidney transplantation may be considered for select patients with wild-type ATTR or hereditary ATTR without significant extracardiac involvement 7

Step 6: Response Monitoring

For AL Amyloidosis

Assess both hematologic response (absence of amyloidogenic light chains) and organ-specific cardiac response. 3, 4

• Monitor serum free light chains, NT-proBNP, and troponin levels regularly 4
• Hematologic response typically occurs within 3-6 months 5
• Cardiac organ response may take 6-12 months 5
• Perform serial echocardiography with strain imaging to assess for regression of amyloid infiltration 4

For ATTR Amyloidosis

Monitor functional status, biomarkers, and imaging parameters to assess disease stabilization. 4

• Track NYHA functional class, 6-minute walk test distance, and Kansas City Cardiomyopathy Questionnaire scores 2
• Serial NT-proBNP and troponin measurements 4
• Echocardiography with strain analysis and cardiac MRI when available 4

Important note: Recent studies demonstrate that timely treatment can lead to regression of myocardial amyloid infiltration on cardiac imaging in both AL and ATTR amyloidosis 10