Clinical Pearls & Morning Reports

Posted by Carla Rothaus, MD

Published October 25, 2023


Was patisiran beneficial for patients with ATTR amyloidosis in the trial by Maurer et al.?

Current treatment options for transthyretin amyloidosis with cardiomyopathy are limited. Maurer et al. conducted a phase 3, randomized, placebo-controlled trial that assessed the safety and efficacy of patisiran in patients with variant or wild-type transthyretin cardiac amyloidosis. Read the Original Article here.

Clinical Pearls

Q: Do wild-type and variant transthyretin amyloidosis have different clinical phenotypes?

A: Transthyretin amyloidosis, also called ATTR amyloidosis, is a progressive, debilitating, and ultimately fatal disease caused by misfolded transthyretin protein that accumulates as amyloid fibrils in multiple organs, including the heart, nerves, gastrointestinal tract, and musculoskeletal tissues. Patients with inherited TTR gene variants have hereditary, also known as variant, ATTR amyloidosis, which can manifest as cardiomyopathy, polyneuropathy, or a mixture of the two phenotypes. Patients with wild-type ATTR amyloidosis predominantly have cardiomyopathy, although polyneuropathy may coexist.

Q: What is the mechanism of action of patisiran?

A: Patisiran, an RNA interference therapeutic agent with a lipid nanoparticle delivery system, targets the common 3′ untranslated region of TTR messenger RNA in the liver to reduce circulating transthyretin protein levels in both variant and wild-type ATTR amyloidosis. Patisiran has been approved for the treatment of variant ATTR amyloidosis in patients with polyneuropathy.

Morning Report Questions

Q: Was patisiran beneficial for patients with ATTR cardiac amyloidosis in the trial by Maurer et al.?

A: The trial showed that treatment with patisiran was associated with preserved functional capacity, health status, and quality of life, as measured by the 6-minute walk test and the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score (with higher scores indicating better health status) after 12 months of treatment. The magnitude of decline from baseline in the 6-minute walk distance at 12 months was significantly lower in the patisiran group than in the placebo group, with a median change from baseline of -8.15 m (95% confidence interval [CI], -16.42 to 1.50) in the patisiran group and -21.35 m (95% CI, -34.05 to -7.52) in the placebo group; the Hodges-Lehmann estimate of the median difference was 14.69 m (95% CI, 0.69 to 28.69; P = 0.02). The KCCQ-OS score decreased from baseline in the placebo group (least-squares mean change, -3.4 points [95% CI, -5.9 to -0.9]) and increased slightly from baseline in the patisiran group (least-squares mean change, 0.3 points [95% CI, -2.2 to 2.8]), representing a least-squares mean difference of 3.7 points (95% CI, 0.2 to 7.2; P = 0.04).

Q: What were some limitations of the trial?

A: The trial excluded patients who are the most severely affected by ATTR amyloidosis (i.e., patients with both New York Heart Association [NYHA] class III and ATTR amyloidosis stage 3 or with NYHA Class IV heart failure). However, recent studies have shown that the clinical phenotype of patients who receive a diagnosis of ATTR cardiac amyloidosis is changing, which is likely to be related, in part, to an increase in disease awareness and improvements in diagnostic pathways; patients in whom ATTR cardiac amyloidosis has been diagnosed in recent years have had less severe disease and a shorter duration of symptoms before diagnosis. This trial population may be more representative of the current demographic characteristics of patients than the population in previous studies, thus precluding any direct comparison of outcomes. Another limitation, owing to the duration of the trial, is that the 12-month randomized trial period did not provide sufficient power to assess the effect of treatment on end points related to mortality and hospitalization.

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