Impact of Heart Failure Severity on Vutrisiran Efficacy in Transthyretin Amyloidosis With Cardiomyopathy.

Summary

In this exploratory subgroup analysis of the HELIOS-B randomized trial (n=654), vutrisiran reduced all-cause mortality and recurrent cardiovascular events across NYHA I–III, NT-proBNP tertiles, and early disease stages, with the greatest benefit in earlier, less severe ATTR-CM. Effects were consistent in patients not on tafamidis.

Key Findings

• Across NYHA I/II/III, hazard ratios for the composite of ACM and recurrent CV events favored vutrisiran (e.g., HR 0.54 in NYHA I; 0.77 in NYHA II; 0.68 in NYHA III).
• Benefit was most pronounced in earlier disease (e.g., NAC stage 1 HR 0.49) and lower NT-proBNP tertiles (e.g., <1,368 ng/L HR 0.52).
• Similar benefits were observed in patients not receiving tafamidis at baseline, supporting monotherapy efficacy.

Clinical Implications

Consider initiating vutrisiran earlier in the disease course of ATTR-CM to maximize clinical benefit; patients across NYHA I–III may derive benefit, with the largest effect in earlier stages. This may influence sequencing with tafamidis and monitoring strategies (e.g., NT-proBNP).

Limitations

• Exploratory subgroup analysis with limited power in smaller strata; some confidence intervals cross unity
• Excluded NYHA IV and some very advanced cases (NYHA III with NAC stage 3), limiting generalizability to the sickest patients

Future Directions

Head-to-head and sequencing studies versus tafamidis; pragmatic trials targeting early-stage ATTR-CM; biomarker-guided therapy and real-world effectiveness in NYHA III–IV and NAC stage 3.