Cardiac Amyloidosis Treatment

Abstract

Cardiac amyloidosis (CA) is a restrictive cardiomyopathy with a traditionally poor prognosis. Until recently, CA treatment options were limited and consisted predominantly of managing symptoms and disease-related complications. However, the last decade has seen significant advances in disease-modifying therapies, increased awareness of CA, and improved diagnostic methods resulting in earlier diagnoses. In this review, we provide an overview of current and experimental treatments for the predominant types of CA: transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain (AL)-mediated CA (AL-CA). The mainstay of AL-CA treatment is proteasome inhibitor-based chemotherapy with daratumumab and, when feasible, autologous stem cell transplantation. For ATTR-CA, the stabilizer tafamidis is the only US Food and Drug Administration (FDA)-approved treatment. However, promising novel therapies on the horizon target various points in the ATTR-CA amyloidogenic cascade. These include transthyretin gene (TTR) silencing agents to prevent TTR formation, TTR tetramer stabilization and inhibition of oligomer aggregation to prevent fibril formation, anti-TTR fiber antibodies, and amyloid degradation. For end-stage CA, advanced interventions may need to be considered, including heart, heart-kidney, and, for hereditary ATTR-CA, heart-liver transplantation. Despite the evolution of treatment options, CA management remains complex due to patient frailty and therapeutic side effects or intolerance with advanced cardiac disease. This is particularly relevant for those with AL-CA, when active teamwork between the hematologist-oncologist and the cardiologist is critical for treatment success. Often, referral to an expert center is necessary for timely diagnosis, initiation of treatment, and participation in clinical trials.

Keywords: amyloidosis treatment; autologous stem cell transplantation; cardiac amyloidosis; daratumumab; inotersen; light chain amyloidosis; monoclonal light chains; patisiran; tafamidis; transthyretin amyloidosis.

Figure 1

Targets of treatment along the light chain and transthyretin amyloidogenic pathway. Reproduced with permission from @John Wiley & Sons Ltd on behalf of European Society of Cardiology, Adam et al. AL: amyloid light chain; TTR: transthyretin; siRNA: small interfering ribonucleic acid; ASO: antisense oligonucleotide; TUDCA: tauroursodeoxycholic acid

Figure 2

Primary and secondary outcomes of the ATTR-ACT (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy) Study investigation of pooled tafamidis (80 mg and 20 mg daily dosing) versus placebo. Panel A demonstrates the superiority of pooled tafamidis compared with placebo for the primary analysis using the Finkelstein-Schoenfeld method to hierarchically assess all-cause mortality and cardiovascular-related hospitalization. Panel B shows the Kaplan Meier survival curves demonstrating a reduction in all-cause mortality for pooled tafamidis compared to placebo, with curves diverting at 18-month follow-up (secondary outcome). Panel C shows the frequency of cardiovascular-related hospitalizations (secondary outcome). Reproduced with permission from the @Massachusetts Medical Society, Maurer et al.