What is the management approach for cardiac amyloidosis?

Management of Cardiac Amyloidosis

The management of cardiac amyloidosis requires disease-specific therapy targeting the underlying amyloid type, along with supportive heart failure treatment and management of extracardiac manifestations. 1

Diagnosis and Classification

Before initiating treatment, accurate typing of cardiac amyloidosis is essential:

1. Initial Screening:

   • Serum and urine immunofixation electrophoresis
   • Serum free light chain assay 1

2. If no monoclonal light chains detected:

   • Bone scintigraphy (Tc-99m-PYP) to confirm ATTR cardiac amyloidosis 1
   • Genetic testing with TTR gene sequencing to differentiate hereditary variant (ATTRv) from wild-type (ATTRwt) 1

Disease-Specific Therapy

ATTR Cardiomyopathy (ATTR-CM)

1. First-line therapy:

   • Tafamidis (80 mg VYNDAQEL or 61 mg VYNDAMAX orally once daily) - the only FDA-approved therapy shown to reduce cardiovascular mortality and hospitalizations in ATTR-CM 1, 2
   • Note: Despite high cost (>$180,000 per QALY gained), tafamidis provides significant clinical benefit 1

2. Alternative TTR stabilizers:

   • Diflunisal - for patients who cannot use tafamidis, though not FDA-approved for this indication and should be avoided in patients with significant kidney impairment (eGFR <45 mL/min/1.73 m²) or volume overload 1
   • Acoramidis (Attruby) - a novel TTR stabilizer recently approved 3

3. TTR silencers (for ATTRv with polyneuropathy):

   • Patisiran (0.3 mg/kg IV every 3 weeks)
   • Inotersen (284 mg SC weekly)
   • Vutrisiran (25 mg SC every 3 months) 1, 3
   • All require vitamin A supplementation (3,000 IU daily) 1

AL Cardiomyopathy (AL-CM)

1. First-line therapy:

   • Daratumumab + CyBorD (cyclophosphamide, bortezomib, dexamethasone) 3, 4
   • Bortezomib-based regimens with dexamethasone and an alkylating agent 3

2. For eligible patients:

   • High-dose melphalan + autologous stem cell transplantation (HDM/SCT) - generally contraindicated in patients with EF <40% 3, 5

3. For advanced cardiac involvement (NT-proBNP >8,500 pg/mL):

   • Single-agent daratumumab with minimal dexamethasone 3

Supportive Heart Failure Management

1. Volume management:

   • Diuretics are the mainstay of treatment 1, 5
   • Loop diuretics (torsemide or bumetanide may be more effective than furosemide when intestinal wall edema is present)
   • Consider adding thiazide diuretics (e.g., metolazone) for resistant cases
   • Intravenous albumin infusions may help when serum albumin <1.5-2 g/dL 1

2. Blood pressure management:

   • ACE inhibitors/ARBs may be used for anti-proteinuric effects if blood pressure permits 1
   • Caution with traditional heart failure medications as they may be poorly tolerated

3. Arrhythmia management:

   • Anticoagulation for atrial fibrillation regardless of CHA₂DS₂-VASc score 1, 3
   • Low-dose beta-blockers or amiodarone for rhythm control 5

Management of Extracardiac Manifestations

Neuropathy

1. Disease-directed therapy for ATTRv polyneuropathy:

   • TTR silencers (patisiran, inotersen, vutrisiran) 1

2. Symptomatic management of neuropathic pain:

   • Pregabalin (75 mg twice daily, titrate up to 300-600 mg/day)
   • Gabapentin
   • Duloxetine
   • Use tricyclic antidepressants cautiously due to risk of worsening orthostatic hypotension 1

Autonomic Dysfunction

1. Orthostatic hypotension:
   • Increased salt/fluid intake
   • Salt tablets
   • Fludrocortisone
   • Midodrine
   • Droxidopa
   • Pyridostigmine (may be better tolerated in patients with cardiac involvement) 1
   • Compression stockings and abdominal binders 1

Kidney Involvement

1. Supportive management:
   • Dietary sodium restriction
   • Careful diuretic use
   • ACE inhibitors/ARBs if blood pressure allows
   • Monitor for cardiorenal syndrome 1

Advanced Therapies for End-Stage Disease

1. Heart transplantation:

   • Consider for selected patients with advanced/stage D heart failure 1, 4
   • Contraindications include significant extracardiac manifestations (neuropathy, malnutrition) and uncontrolled disease (AL amyloidosis) 1

2. Combined organ transplantation:

   • Heart-liver transplantation for selected patients with hereditary ATTR 3, 4
   • Heart transplantation followed by bone marrow transplantation for selected AL amyloidosis patients 3

3. Mechanical circulatory support:

   • Generally poorly tolerated due to small LV cavity and biventricular involvement 1

Monitoring and Follow-up

• Regular assessment every 6-12 months including:
  • Cardiac biomarkers (troponin, NT-proBNP)
  • Echocardiography
  • Functional status assessment
  • For AL amyloidosis: serum free light chains
  • For patients on TTR silencers: specific monitoring requirements (e.g., weekly platelet counts for inotersen) 1, 3

Common Pitfalls and Caveats

1. Medication sensitivities:

   • Patients with cardiac amyloidosis often have exaggerated responses to vasodilators and negative inotropes
   • Standard heart failure medications may be poorly tolerated

2. Monitoring challenges:

   • Amyloid deposits persist in tissue even after successful treatment
   • Kidney function may not improve despite successful hematologic response in AL amyloidosis 1

3. Treatment timing:

   • Early diagnosis and treatment is critical for better outcomes 3
   • Advanced disease may limit eligibility for certain therapies

4. Drug-specific monitoring:

   • Patisiran: Premedicate with corticosteroids, acetaminophen, and antihistamines
   • Inotersen: Monitor platelet counts weekly and renal function biweekly 1