What is the preferred drug for cardiac amyloidosis?

Drug Treatment for Cardiac Amyloidosis

The preferred drug treatment for cardiac amyloidosis depends critically on the type: for AL (light chain) cardiac amyloidosis, daratumumab combined with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is the preferred first-line therapy, while for ATTR (transthyretin) cardiac amyloidosis, tafamidis is the FDA-approved standard of care. 1, 2

Critical First Step: Accurate Amyloid Typing

Before initiating any disease-specific therapy, you must accurately determine whether the patient has AL or ATTR amyloidosis, as these require completely different treatments. 3, 4

Diagnostic algorithm:

• Perform comprehensive monoclonal protein screening with serum free light chain assay (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) simultaneously 3
• If monoclonal proteins are absent, proceed with Tc-99m-PYP bone scintigraphy to confirm ATTR cardiac amyloidosis 4
• Mass spectrometry (LC-MS/MS) of tissue biopsy remains the gold standard for amyloid typing with 88% sensitivity and 96% specificity 3, 4

Treatment for AL Cardiac Amyloidosis

First-Line Therapy

Daratumumab-CyBorD (daratumumab with cyclophosphamide, bortezomib, and dexamethasone) is the preferred first-line treatment for most patients with AL cardiac amyloidosis, achieving very good partial response or better in 78.5% of patients compared to 49.2% with CyBorD alone. 1, 3, 4

This regimen recently received FDA approval and represents a paradigm shift from the previous standard of care. 1

Alternative for Transplant-Eligible Patients

For highly selected patients, consider high-dose melphalan followed by autologous stem cell transplantation (HDM/SCT) if they meet strict eligibility criteria: 1, 3

• Age <65 years
• Mayo stage 1-2
• NYHA class <3
• Ejection fraction >40-45%
• eGFR >50 ml/min/1.74 m²
• Systolic blood pressure >90 mmHg

Important caveat: Treatment-related mortality with HDM/SCT is approximately 3% even in experienced centers, but median survival exceeds 15 years in patients achieving complete response. 1 However, Dara-CyBorD may supplant this approach as first-line therapy even for transplant-eligible patients. 1

Critical Monitoring for Cardiotoxicity

All AL amyloidosis therapies carry cardiac toxicity risks that require close monitoring: 1

Daratumumab toxicities:

• Cardiac failure in 12% (grade 3-4 in 6%)
• Cardiac arrhythmia in 8% (grade 3-4 in 2%)
• Atrial fibrillation in 6% (grade 3-4 in 2%) 1

Bortezomib toxicities:

• Grade 3 heart failure in 6.4%

• 10% decrease in LVEF in 23% 1

Cyclophosphamide toxicities:

• Myocarditis, myopericarditis, pericardial effusion including cardiac tamponade
• Supraventricular and ventricular arrhythmias
• Risk increases with high doses, advanced age, and previous cardiac radiation 1

Corticosteroids (dexamethasone) toxicities:

• Peripheral edema, pulmonary edema, fluid overload 1

Close collaboration between hematology and cardiology is mandatory for monitoring cardiotoxicity during disease-directed therapy. 1, 3

Treatment for ATTR Cardiac Amyloidosis

FDA-Approved Therapy

Tafamidis is the FDA-approved treatment for ATTR cardiomyopathy in adults with NYHA Class I-III symptoms to reduce cardiovascular mortality and cardiovascular-related hospitalization. 2, 4

Dosing options: 2

• VYNDAQEL 80 mg (four 20-mg tafamidis meglumine capsules) orally once daily, OR
• VYNDAMAX 61 mg (one 61-mg tafamidis capsule) orally once daily

Evidence of efficacy: Tafamidis demonstrated lower all-cause mortality (29.5% versus 42.9%) and lower cardiovascular-related hospitalization (0.48 versus 0.70 per year) after 30 months compared to placebo. 4

Mechanism: Tafamidis works by stabilizing the TTR tetramer, preventing dissociation into monomers that form amyloid fibrils. 5, 6

Emerging Therapies

Recent data led to approval of acoramidis for ATTR-CA, while patisiran received refusal based on the APOLLO-B trial. 5 Novel CRISPR-Cas9-based drugs (NTLA-2001) and monoclonal antibodies targeting misfolded ATTR (PRX004, NI301A) are under investigation. 5

Supportive Cardiac Management (Both Types)

Heart Failure Management

Judicious diuresis remains the cornerstone of heart failure therapy in cardiac amyloidosis. 1, 4

Critical pitfalls to avoid: 1, 6

• Avoid or use extreme caution with beta-blockers and rate-slowing drugs - these are deleterious in restrictive cardiomyopathy
• Limit use of ACE inhibitors and ARBs - they provide little benefit and are often poorly tolerated due to hypotension
• Avoid digoxin - it binds to amyloid fibrils and increases risk of toxicity 1

Anticoagulation

Anticoagulation is reasonable in patients with cardiac amyloidosis and atrial fibrillation to reduce stroke risk, independent of CHA₂DS₂-VASc score (Class 2a recommendation). 4

The rationale is that intracardiac thrombus risk is high even in sinus rhythm due to atrial mechanical "standstill" from amyloid infiltration. 1 However, weigh this against increased bleeding risk from amyloid angiopathy. 1

Arrhythmia Management

For arrhythmias, amiodarone is the preferred antiarrhythmic agent. 3 Consider pacemaker or defibrillator implantation in patients with high risk of sudden death. 6

Treatment Goals and Response Monitoring

For AL amyloidosis: The goal is to eradicate pathological plasma cells and remove amyloidogenic light chains from circulation. 1, 3

Response assessment timeline: 3, 7

• Hematologic response: 3-6 months
• Organ-specific response: 6-12 months

Regular monitoring should include: 4

• NT-proBNP and troponin levels
• Echocardiography with strain measurements
• Electrocardiogram and Holter monitoring
• NYHA functional class assessment

Common Pitfalls

There are no absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status in AL cardiac amyloidosis - even patients with advanced cardiac involvement should be considered for treatment. 3

Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma alone due to multiple severe organ dysfunctions. 3

Delayed diagnosis remains a major obstacle - maintain high clinical suspicion in patients with unexplained heart failure with preserved ejection fraction, increased left ventricular wall thickness, or red flag symptoms (carpal tunnel syndrome, lumbar canal stenosis, peripheral neuropathy, macroglossia, periorbital purpura). 3, 6