Transthyretin Silencing Therapies and the Cardiology Clinic: Selection, Cost and the Diagnostic Bottleneck Upstream

Abstract

HELIOS-B, a 654-patient randomised trial of the RNA-silencing agent vutrisiran in transthyretin amyloid cardiomyopathy,
found a 28% reduction in the composite risk of death and recurrent cardiovascular events (hazard ratio 0.72) and a 36%
reduction in all-cause mortality (hazard ratio 0.64), with a low and similar rate of treatment discontinuation for adverse
events in both arms. This is a genuinely strong trial result for a disease that previously had little to offer beyond symptomatic
management. Two practical problems sit upstream and downstream of that result, however. Upstream, a real-world analysis
found a median delay of 494 days between a heart failure diagnosis and the correct diagnosis of transthyretin amyloid
cardiomyopathy -- longer still, 840 days, when measured from a patient's first loop-diuretic prescription -- with 64% of
patients waiting at least six months, a pattern attributed to diagnostic anchoring on more common heart failure causes;
annual diagnoses have quadrupled since 2016 without that delay shortening. Downstream, the treatment itself carries a list
price of approximately $450,000 per year, against an independent cost-effectiveness assessment that would place a fair price
for this drug class between $13,600 and $39,000 per year. This review sets out the trial evidence for gene-silencing therapy,
the diagnostic bottleneck that determines how many patients ever reach that therapy in time to benefit, and the pricing gap
that determines how many health systems can afford to give it to them.