What is the treatment protocol for cardiac amyloidosis?

Treatment Protocol for Cardiac Amyloidosis

The treatment of cardiac amyloidosis must be tailored to the specific type of amyloid protein involved, with AL amyloidosis requiring plasma cell-directed therapy and ATTR amyloidosis benefiting from TTR stabilizers. 1

Diagnosis and Classification

Before initiating treatment, proper diagnosis and classification are essential:

• Definitive diagnosis requires histological confirmation through biopsy (abdominal fat pad, gingiva, rectum, bone marrow, or affected organs) with Congo red staining showing apple-green birefringence under polarized microscopy 1
• Identify the type of amyloidosis through immunohistochemistry, as this determines treatment strategy and prognosis 1
• If TTR amyloid is detected, DNA mutational analysis should be performed to differentiate between senile (wild-type) and hereditary amyloidosis 1
• Non-invasive imaging such as echocardiography and cardiac MRI can support diagnosis in patients with systemic amyloidosis 1

Treatment by Amyloid Type

AL (Light Chain) Amyloidosis

• First-line therapy: Bortezomib-based regimens in combination with dexamethasone and an alkylating agent 1

  • Common regimens include cyclophosphamide-bortezomib-dexamethasone (CyBorD) or bortezomib-melphalan-dexamethasone 1
  • For patients with advanced cardiac involvement (NT-proBNP >8,500 pg/mL), consider daratumumab with minimal dexamethasone to reduce cardiotoxicity 1

• For eligible patients: High-dose melphalan followed by autologous stem cell transplantation 1

  • Note: Patients with significant cardiac involvement have higher morbidity and mortality with this approach 1
  • Median survival is 6.4 years in patients without cardiac involvement versus 1.6 years in those with cardiac involvement 1

• For patients ineligible for stem cell transplantation: Alternative chemotherapy regimens 1

  • Melphalan and dexamethasone
  • Cyclophosphamide, thalidomide, and dexamethasone
  • Continuous oral melphalan

• For relapsed/refractory disease: 1

  • Daratumumab (if not used in first-line)
  • Immunomodulatory-based regimens (lenalidomide, pomalidomide, thalidomide)
  • Ixazomib (oral proteasome inhibitor)
  • Venetoclax for patients with t(11;14) cytogenetic alteration

ATTR (Transthyretin) Amyloidosis

• FDA-approved therapy: Tafamidis (VYNDAQEL 80 mg or VYNDAMAX 61 mg orally once daily) 2

  • Indicated for both wild-type and hereditary ATTR cardiomyopathy
  • Reduces cardiovascular mortality and cardiovascular-related hospitalization 2

• For hereditary ATTR amyloidosis: Consider combined cardiac and liver transplantation 1

  • Liver transplantation can cure the amyloidosis process since TTR protein is synthesized in the liver 1
  • 5-year survival rate of 50% to 80% 1

• Emerging therapies: 1

  • TTR gene silencers (patisiran, inotersen)
  • TTR stabilizers (diflunisal)
  • Epigallocatechin-3-gallate (found in green tea) may reduce amyloid fibril formation

Supportive Heart Failure Management

• Diuretics: Main supportive therapy for heart failure symptoms and congestion 1

  • Use cautiously to avoid hypotension from underfilling of a stiff heart 1

• Anticoagulation: 1

  • Warfarin (target INR 2-3) or direct thrombin inhibitors are strongly indicated for patients with:
    • Atrial fibrillation
    • History of embolic stroke/transient ischemic attack
  • Consider anticoagulation even in sinus rhythm due to high risk of intracardiac thrombus formation

• Device therapy: Consider for cardiac rhythm abnormalities with consideration of life expectancy 1

Medications to Avoid or Use with Caution

• Avoid digoxin: Binds to amyloid fibrils causing toxicity even with normal serum levels 1

• Avoid calcium channel antagonists (nifedipine, verapamil): Bind to amyloid fibrils causing exaggerated hypotension and negative inotropy 1

• Use with caution or avoid:

  • ACE inhibitors/ARBs: May cause hypotension 1
  • β-blockers: Use cautiously if at all when cardiac output is low; probably avoid in AL amyloidosis 1

Monitoring Response to Treatment

• For AL amyloidosis: 1

  • Hematologic response: Monitor serum free light chains (typically within 3-6 months of treatment)
  • Organ response: Assess NT-proBNP, troponin, echocardiography (typically 6-12 months after hematologic response)

• Response criteria for AL amyloidosis: 1

  • Complete hematologic response: Absence of amyloidogenic light chains
  • Cardiac response: Decrease in NT-proBNP by >30% and <300 ng/L (if baseline NT-proBNP >650 ng/L)

Advanced Interventions for End-Stage Disease

• Cardiac transplantation: 1
  • Generally not recommended for AL amyloidosis due to high risk of recurrence (5-year survival only 20-30%)
  • May be considered for ATTR amyloidosis with better outcomes
  • For AL amyloidosis, cardiac transplantation followed by bone marrow transplantation may improve survival (5-year survival rate of 35-55%)

Common Pitfalls to Avoid

• Delayed diagnosis: Early recognition is critical for improved outcomes 3
• Inappropriate heart failure management: Standard heart failure treatments may be poorly tolerated 1
• Missing the amyloid type: Treatment is fundamentally different between AL and ATTR types 4
• Overlooking multisystem involvement: Assess all potentially affected organs to guide treatment 1