Vutrisiran in ATTR cardiomyopathy: starting early kept a 37% mortality advantage at four years

Design

Open-label extension of a randomised, placebo-controlled trial (HELIOS-B)

Population

466 patients with transthyretin amyloid cardiomyopathy who completed the double-blind phase

Primary outcome

All-cause mortality and cardiovascular events through month 48

Effect

Continuous vs delayed vutrisiran: all-cause death HR 0.63 (0.46 to 0.84)

This is the open-label extension of HELIOS-B. Of 654 patients with transthyretin amyloid cardiomyopathy randomised to vutrisiran or placebo, 466 entered the extension, where everyone received vutrisiran 25 mg every three months. Outcomes were followed to month 48.

Compared with those who switched from placebo, patients on vutrisiran throughout had a lower risk of first cardiovascular event or death (hazard ratio 0.63, 95% CI 0.51 to 0.79) and of all-cause death (0.63, 0.46 to 0.84). Quality of life, functional class, NT-proBNP and troponin all favoured the continuous group, and no new safety signals appeared.

The extension cannot recover the randomised comparison, because patients who survived to enter it were selected. But the persistent gap suggests the time lost on placebo was not made up later. The message for practice is about diagnosis: ATTR cardiomyopathy is still found late, and the case for looking earlier has grown. Access to RNA silencers in India is limited and costly.

• Consider ATTR amyloid in heart failure with preserved ejection fraction and a thick-walled ventricle.
• Look for red flags: carpal tunnel syndrome, spinal stenosis, low-voltage ECG with thick walls, unexplained troponin.
• Use bone scintigraphy with exclusion of a light-chain disorder to diagnose without biopsy.
• Refer early; outcomes favoured patients treated from the start.

Why it matters

The cost of a missed diagnosis in ATTR cardiomyopathy appears not to be recovered once treatment finally starts.

Don't overread it

An open-label extension in trial survivors; it supports, but does not replace, the original randomised result.

The statistics, in plain English

A hazard ratio of 0.63 means a 37% lower rate of death at any point. Because the extension compares patients who were randomised earlier but then all received the drug, the difference reflects the delay in starting rather than the drug versus nothing. Survivor selection into the extension weakens this compared with the original randomised result.

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