1. In this randomized controlled trial, patisiran demonstrated a reduction in functional capacity decline transthyretin amyloidosis (ATTR amyloidosis) with a cardiac component as compared to placebo.
2. Compared to placebo, patisiran demonstrated a higher rate of infusion-related reactions, arthralgias, and muscle spasms.
Evidence Rating Level: 1 (Excellent)
Study Rundown: ATTR amyloidosis is a serious condition caused by the accumulation of abnormally folded amyloid fibrils in key organ systems, leading to dysfunction. Wild-type ATTR amyloidosis commonly affects the heart, leading to severe functional decline, reduced heart function, and progressive heart failure. Patisiran is an RNA interference therapeutic agent that functions to reduce the level of transthyretin protein available in the circulation, with promising data on its effects thus far. However, the clinical efficacy and safety of patisiran for patients with wild-type ATTR amyloidosis is currently unclear. As such, this study was a multi-site, double-blind, randomized trial comparing patisiran against a placebo amongst adult participants with ATTR cardiac-involving amyloidosis. Results of the analysis found that patisiran was more effective at preventing functional decline and improving quality of life at 12 months compared to placebo. However, it was associated with a higher rate of infusion-related reactions, arthralgias, and muscle spasms compared to placebo. Limitations in the study design prevent generalization to patients with advanced cardiac disease. Overall, the results of the trial are promising and demonstrate that patisiran may be an effective therapy for patients with cardiac-involving wild-type ATTR amyloidosis when compared to placebo.
In-Depth [randomized controlled trial]: This was an international, multicentre, double-blind, randomized, placebo-controlled trial investigating the effect of patisiran, compared to placebo on preserved functional capacity amongst patients with ATTR cardiac amyloidosis. The primary outcome of interest was a change in the distance participants were able to walk on a six-minute walk test one year after the trial started. Additional outcomes included scores on the Kansas City Cardiomyopathy Questionnaire – Overall Summary (KCCQ-OS) as well as composite death, rate of cardiovascular events, and hospitalizations. Adult patients between the ages of 18 to 85 with wild-type ATTR cardiac amyloidosis, evidence of cardiac involvement on echocardiography, a history of heart failure, and an end-diastolic interventricular septal wall thickness of greater than 12mm were included in the trial. Key exclusion criteria included an NYHA classification of three or four, non-cardiac involving ATTR amyloidosis, and an eGFR of less than 45mL per minute per 1.73m2. After applying the inclusion and exclusion criteria, participants were assigned in a 1:1 ratio to receive 0.3mg/kg of patisiran (n=181), or placebo (n=178). Results of the primary analysis found that the patisiran group resulted in a smaller six-minute walk distance decline at one year compared to the placebo group (p=0.02). Further, the KCCQ-OS score within the patisiran group increased at one year, compared to the KCCQ-OS score in the placebo group, which decreased (p=0.04). Concerning adverse events, the rates of infusion-related reactions, arthralgias, and muscle spasms occurred at a higher rate within the patisiran group compared to the placebo. This trial provided evidence that patisiran can significantly improve functional capacity for patients with wild-type ATTR cardiac amyloidosis.
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