RNA interference therapy in transthyretin amyloid cardiomyopathy: a systematic review and meta-analysis of randomised controlled trials

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and life-threatening disease characterized by the deposition of misfolded transthyretin amyloid fibrils in the heart. This accumulation leads to infiltrative cardiomyopathy, heart failure, and arrhythmias. RNA interference (RNAi) agents, patisiran and vutrisiran, have emerged as treatment options for ATTR-CM by targeting hepatic production of transthyretin. Whether they have a class effect on patient outcomes in ATTR-CM remains unexplored. Purpose We aimed to assess the efficacy and safety of RNAi therapies, patisiran and vutrisiran, in the treatment of ATTR-CM. Methods We systematically searched PubMed, Embase, and Cochrane databases to include randomised placebo-controlled trials of RNAi therapeutics in patients with ATTR-CM. We pooled mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CI) for continuous and binary endpoints, respectively. Results We included three randomised trials comprising 880 patients, of whom 467 (53.1%) were randomised to RNAi. The mean patient age was 71.5 years, and 88.6% were male. As compared with placebo, RNAi agents significantly reduced mean serum transthyretin levels (MD -187.58 mg/dL, 95% CI -201.63, -173.53; p< 0.001; Figure 1A) and modestly improved Kansas City Cardiomyopathy Questionnaire scores (MD 5.94 points; 95% CI 1.07, 10.82; p = 0.02; Figure 1B) and left ventricular global longitudinal strain (MD -0.97%; 95% CI: -1.56, -0.38; p = 0.001; Figure 1C). There was no significant difference between RNAi therapeutics and placebo in terms of all-cause mortality (RR 0.75; 95% CI 0.52, 1.06; p = 0.10; Figure 1D) or cardiac serious adverse events (RR 0.91; 95% CI: 0.66, 1.27; p = 0.58; Figure 1E). Conclusion In this meta-analysis of randomised controlled trials, RNAi therapeutics, patisiran and vutrisiran, significantly reduced serum transthyretin levels and improved quality of life and imaging parameters in ATTR-CM. These findings suggest the potential of these agents to slow disease progression. Further RCTs are warranted to assess the long-term effects of this therapy.