Treatment of Cardiac Transthyretin Amyloidosis: An Update

Michele Emdin; Alberto Aimo; Claudio Rapezzi; Marianna Fontana; Federico Perfetto; Petar M. Seferović; Andrea Barison; Vincenzo Castiglione; Giuseppe Vergaro; Alberto Giannoni; Claudio Passino; Giampaolo Merlini


Eur Heart J. 2019;40(45):3699-3706. 

In This Article

Inhibition of the Synthesis of Mutated Transthyretin

Liver Transplantation and Combined Liver–Heart Transplantation

Orthotopic liver transplantation was first proposed in 1990 as a potentially curative treatment of ATTRv-related polyneuropathy.[15] Liver transplantation removes the source of mutated TTR molecules and prolongs survival, with a 20-year survival rate of 55.3%.[16] Higher body mass index, younger age (<50 years), shorter disease duration, and V30M vs. non-V30M mutations have been identified as independent predictors of better survival.[16] Nonetheless, tissue accumulation of TTR can continue after liver transplantation, likely because TTR amyloid fibres promote subsequent deposition of TTRwt. This was demonstrated in an autopsy study, in which patients not undergoing liver transplantation showed 60% variant TTR and 40% TTRwt in the heart, while the variant to TTRwt ratio was 25% to 75% after liver transplantation.[17] Furthermore, patients with the V30M mutation undergoing liver transplantation showed increasing interventricular septal thickness at serial echocardiographic monitoring, denoting ongoing deposition of TTRwt in the transplanted heart.[18]

Combined heart and liver transplantation is feasible in younger patients with ATTRv cardiomyopathy, and small patient series suggest that it is associated with better prognosis than cardiac transplantation alone.[19] On the other hand, it is currently unclear if liver transplantation is needed in the V122I mutation (i.e. the commonest TTR mutation causing cardiomyopathy).[4] Limited organ availability, exclusion of older patients and of those with advanced systemic disease, and risks related to surgery and life-long immunosuppression represent further problems of liver or combined transplantation. Liver transplantation is not an option for patients with ATTRwt.[19]

Inhibition of TTR Gene Expression

Patisiran is a small interfering RNA blocking the expression of both variant and wt TTR.[20] It is encapsulated in lipid nanoparticles targeting the liver and administered through intravenous infusion.[20,21] A phase 2 study on 29 patients with ATTRv and polyneuropathy showed that two doses of patisiran 0.3 mg/kg every 3 weeks reduced mean serum TTR levels by about 80%.[21] This potent TTR knockdown was observed for both ATTRwt and ATTRv (V30M), and in patients receiving TTR tetramer stabilizers.[21] In the APOLLO phase 3 trial enrolling 225 patients with ATTRv and polyneuropathy, those on patisiran (0.3 mg/kg once every 3 weeks for 18 months) experienced a significant improvement in neurological status. Severe adverse events had a similar incidence in the patisiran and placebo arms (28% vs. 36%); common adverse events occurring more frequently with patisiran included peripheral oedema, infusion-related reactions, and vision problems.[13] These results led to the approval of patisiran for the treatment of adults with ATTRv-related polyneuropathy both in the USA and in the European Union, although patisiran has been approved in Europe only for the treatment of mild-to-moderate disease (Stage 1–2).

In the APOLLO trial, patients with echocardiographic evidence of cardiac involvement (n = 126, 56% of the total population) in the patisiran group displayed significantly lower decrease in cardiac output and increase in LV end-diastolic volume. Additionally, these patients experienced significant reduction in mean LV wall thickness, relative wall thickness, LV mass, and N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP) compared with baseline.[13,22] These findings suggest that patisiran slows down LV functional deterioration, but also promotes favourable myocardial remodelling, an effect that was not demonstrated for inotersen and is still under investigation for tafamidis.

Another siRNA, revusiran, was investigated in a phase 3 trial (ENDEAVOUR), designed to assess 6-min walking distance and serum TTR levels in 200 patients with ATTRv cardiomyopathy. Patients were randomized 2:1 to revusiran or placebo, with revusiran administered subcutaneously at 500 mg daily for 5 days, then weekly for 18 months.[23] The study was discontinued because of 'an imbalance in mortality observed between patients treated with revusiran and placebo'.[23]

The antisense oligonucleotides inotersen inhibits the production of both variant and wt TTR.[24] A single centre, open-label study evaluated 15 patients with cardiac ATTR (8 ATTRv, 7 ATTRwt), receiving weekly subcutaneous injections of inotersen (300 mg) for 12 months. Peak reduction in TTR concentration varied from 39% to 91% (mean 72%). Patients showed a stabilization of disease as measured by LV wall thickness, LV mass, 6-min walking distance, and global systolic strain. The treatment was well tolerated, with no changes in renal function, low rates of thrombocytopenia, or injection site reactions.[24] In the multicentre, randomized, double-blind, placebo-controlled, phase 3 NEURO-TTR trial, patients with ATTRv and polyneuropathy (n = 172) were randomized to inotersen (300 mg weekly) or placebo. After 66 weeks, inotersen was well tolerated and slowed the decline in neurology scores.[14] Following these results, inotersen has received FDA approval for patients with ATTRv-related polyneuropathy. In the NEURO-TTR trial, cardiomyopathy was present in 63% of patients, but the study was not powered to measure the effects of inotersen on cardiac disease.[14]