What is the optimal treatment approach for patients with amyloidosis and Heart Failure with Reduced Ejection Fraction (HFrEF)?

Optimal Treatment Approach for Amyloidosis and HFrEF

For patients with cardiac amyloidosis and HFrEF, treatment should be tailored to the specific type of amyloidosis, with tafamidis as first-line therapy for transthyretin amyloidosis (ATTR-CM) and specialized hematology-oncology treatment for light chain amyloidosis, while standard HFrEF therapies should be used cautiously with close monitoring for hypotension.

Diagnosis and Classification

Before initiating treatment, proper diagnosis and classification of amyloidosis is crucial:

1. Screening for amyloidosis type:

   • Check for monoclonal light chains with serum and urine immunofixation electrophoresis and serum free light chains 1
   • If negative for light chains, perform bone scintigraphy (Tc-99m-PYP) to confirm transthyretin cardiac amyloidosis 1
   • For confirmed transthyretin amyloidosis, perform TTR gene sequencing to differentiate hereditary variant from wild-type 1

2. Red flags for cardiac amyloidosis:

   • Left ventricular wall thickness ≥14 mm with fatigue, dyspnea, or edema
   • Discordance between wall thickness on echocardiogram and QRS voltage on ECG
   • History of carpal tunnel syndrome, spinal stenosis, or autonomic/sensory polyneuropathy 1
   • Recent data shows that ATTR-CA can present with various HF phenotypes, including HFrEF (21.6%), HFmrEF (17.8%), and HFpEF (60.6%) 2

Treatment Approach by Amyloidosis Type

Transthyretin Amyloidosis (ATTR-CM)

1. First-line therapy:

   • Tafamidis is indicated for wild-type or hereditary ATTR-CM to reduce cardiovascular mortality and hospitalization (Class I, Level B-R) 1, 3
   • Specifically approved for adults with ATTR-CM to reduce cardiovascular mortality and cardiovascular-related hospitalization 3

2. Anticoagulation:

   • Anticoagulation is reasonable in patients with cardiac amyloidosis and atrial fibrillation regardless of CHA₂DS₂-VASc score (Class IIa, Level C-LD) 1

Light Chain Amyloidosis (AL)

1. First-line therapy:

   • Refer to hematology-oncology for specialized treatment 1
   • Traditional treatments include alkylator-based chemotherapy or high-dose melphalan followed by autologous stem cell transplantation (ASCT) 4
   • Novel agents including proteasome inhibitors, immunomodulators, and monoclonal antibodies may be considered 4

2. Advanced cases:

   • Consider orthotopic heart transplantation (OHT) followed by ASCT in selected cases 4

HFrEF Management in Amyloidosis

Standard HFrEF therapies should be used cautiously in amyloidosis patients due to increased sensitivity to hypotension:

1. First-line medications (use with caution):

   • SGLT2 inhibitors (dapagliflozin, empagliflozin): Start early as they have minimal impact on blood pressure and can be used with eGFR >20 ml/min/1.73m² 1, 5
   • Mineralocorticoid Receptor Antagonists (MRAs) (spironolactone, eplerenone): Have minimal impact on blood pressure; monitor potassium and renal function 1, 5

2. Second-line medications (use with extreme caution):

   • Beta-blockers: Consider if heart rate >70 bpm; prefer selective β₁ receptor blockers in patients with low blood pressure 5
   • ACE inhibitors/ARBs/ARNIs: Use at lower doses with careful titration; monitor for hypotension 1

3. Volume management:

   • Diuretics: Adjust according to volume status; avoid overdiuresis which may worsen hypotension 5

4. Special considerations:

   • Ivabradine: Consider for patients in sinus rhythm who cannot tolerate beta-blockers or have HR >70 bpm despite maximum tolerated beta-blocker dose 5
   • Digoxin: May be used for rate control in patients with atrial fibrillation who cannot tolerate beta-blockers 5

Medication Titration Strategy

1. Start low, go slow:

   • Begin with lower doses than typical HFrEF patients
   • Up-titrate one drug at a time using small increments every 2-4 weeks 5
   • Monitor blood pressure closely; asymptomatic low BP should not be a reason for GDMT reduction 1

2. Prioritization of therapies:

   • Start with medications that have the least effect on blood pressure (SGLT2 inhibitors, MRAs) 1, 5
   • Add other agents cautiously based on hemodynamic tolerance

3. Hypotension management:

   • If systolic BP <80 mmHg or symptomatic hypotension occurs, consider reduction or cessation of one or more medications 1
   • When discontinuation is needed, start with the least tolerated medication 1

Contraindications and Monitoring

1. Avoid:

   • NSAIDs and COX-2 inhibitors (risk of worsening heart failure) 5
   • Thiazolidinediones (glitazones) 5
   • Combining ARB with ACE inhibitor and MRA (risk of renal dysfunction and hyperkalemia) 5
   • Diltiazem/verapamil in HFrEF patients 5

2. Monitoring:

   • Regular assessment of volume status and symptoms 5
   • Daily weight monitoring with action plan for weight gain >2 kg in 3 days 5
   • Monitor renal function and electrolytes, especially with RAAS inhibitors 5

Advanced Therapies

1. Device therapy:

   • Consider cardiac resynchronization therapy (CRT) for patients with QRS duration ≥150 msec and LBBB morphology 5
   • Consider implantable cardioverter-defibrillator (ICD) for patients with LVEF ≤35% despite ≥3 months of optimal medical therapy (with expected survival >1 year) 5

2. Transplantation:

   • For ATTR-CM: Consider orthotopic liver transplantation (OLT) in selected cases 4
   • For AL amyloidosis: Consider combined heart transplantation and subsequent stem cell transplantation in selected cases 4

By following this approach, clinicians can optimize treatment for patients with amyloidosis and HFrEF while minimizing adverse effects and improving outcomes.