Effect of Acoramidis on Recurrent and Cumulative Cardiovascular Outcomes in ATTR-CM
Ahmad MasriDaniel P. JudgeFrederick L. RubergJulian D. GillmoreJustin L. GrodinLaura ObiciMatthew J. MaurerSteen Hvitfeldt PoulsenPeter van der MeerRichard K. ChengSarah CuddyAmrut V. AmbardekarKuangnan XiongXiaofan CaoGillian MurtaghSuresh SiddhantiAdam CastañoJean‐François TambyJonathan C. FoxKevin AlexanderRonald Witteles
Key result
Acoramidis cuts CV death or recurrent CV hospitalization ~49% vs. placebo through 30 months.
- HR 0.51
- 95% CI 0.43-0.62
- P<0.0001
- n=611
Why the study?
Does acoramidis reduce the cumulative incidence of cardiovascular mortality or recurrent cardiovascular hospitalizations in patients with transthyretin amyloid cardiomyopathy?
Key Points
- To assess the efficacy of acoramidis on the cumulative incidence and recurrent burden of cardiovascular outcomes in transthyretin amyloid cardiomyopathy.
- Conducted a post hoc exploratory recurrent-event analysis of the phase 3 ATTRibute-CM trial and its open-label extension in a modified intention-to-treat population (acoramidis, n = 409; placebo, n = 202).
- Estimated mean cumulative events and between-group differences for centrally adjudicated cardiovascular-related mortality and recurrent cardiovascular hospitalizations using a modified Andersen-Gill model through month 30 and month 42.
- Acoramidis significantly reduced the cumulative risk of cardiovascular-related mortality or recurrent cardiovascular-related hospitalization through month 30 versus placebo (HR: 0.51; 95% CI: 0.43–0.62; P < 0.0001), avoiding 53 events per 100 treated participants (95% CI: 29–79).
- Annualized frequency of recurrent cardiovascular-related hospitalizations was significantly reduced through month 30 (relative risk ratio: 0.50; 95% CI: 0.35–0.69; P < 0.0001).
- Continuous acoramidis reduced cardiovascular-related mortality at month 42 compared to placebo-to-acoramidis transition (HR: 0.55; 95% CI: 0.39–0.79; P = 0.0011).
Study Design
Type
RCT (n=611)
Structured PICO
Does acoramidis reduce the cumulative incidence of cardiovascular mortality or recurrent cardiovascular hospitalizations in patients with transthyretin amyloid cardiomyopathy?
P
Population
611 participants with transthyretin amyloid cardiomyopathy (ATTR-CM) followed for up to 42 months.
I
Intervention
Acoramidis (oral therapy)
C
Comparator
Placebo (followed by placebo-to-acoramidis in the open-label extension)
O
Outcome
Cumulative incidence of centrally adjudicated CV-related mortality (CVM) or recurrent CV-related hospitalization (CVH) through month 30composite
Main Result
Hazard Ratio: 0.51 (95% CI 0.43–0.62)
p-value: p=< 0.0001
Limitations
- Post hoc exploratory analysis
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Acoramidis demonstrated early and sustained clinical efficacy on the totality of cumulative cardiovascular outcomes, where accrued events start to numerically diverge within the first month of treatment. As a practicing cardiologist, these findings are incredibly meaningful because it draws attention to the time-sensitive nature of transthyretin amyloidosis diagnosis and treatment initiation, where a safe and effective treatment such as acoramidis can potentially have an early effect on reducing patients' risk of cardiovascular hospitalizations and events.”
“The time-sensitive nature of transthyretin cardiomyopathy is something that has been on many people's minds, but I think this is the first piece of evidence that should push us forward. And then even once you establish the diagnosis, a lot of the time it ends up being that the patients have to then come back for therapy and treatment discussions, and that again adds more time.”
“With outcomes such as cardiovascular mortality and recurrent cardiovascular hospitalization, these are very tangible, hard clinical outcomes that we have to care about.”
Implication
Acoramidis significantly reduces the cumulative burden of cardiovascular mortality and recurrent hospitalizations in patients with ATTR-CM, with benefits emerging as early as 1 month.
Abstract
BACKGROUND: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive disease with a significant burden of recurrent cardiovascular (CV) events. Acoramidis, an approved oral therapy for ATTR-CM, achieves early, near-complete (≥90%) TTR stabilization. In the phase 3 ATTRibute-CM (Efficacy and Safety of Acoramidis in Participants with Transthyretin Amyloid Cardiomyopathy) study, acoramidis significantly reduced the composite of all-cause mortality or first CV-related hospitalization (CVH), with an effect observed at month 3. Its efficacy on the burden of cumulative CV outcome events has not been reported. OBJECTIVES: This study was a post hoc exploratory recurrent-event analysis of the efficacy of acoramidis on the cumulative incidence of CV outcomes from ATTRibute-CM and its open-label extension. METHODS: Cumulative incidences of centrally adjudicated CV-related mortality (CVM) or recurrent CVH (first and, if applicable, subsequent CVH), recurrent CVH alone (month 30), and CVM (month 42) were measured in the modified intention-to-treat population (acoramidis, n = 409; placebo, n = 202). Mean cumulative events by treatment, and the difference between treatment groups were estimated by using a modified Andersen-Gill model. RESULTS: Acoramidis significantly reduced the cumulative risk of CVM or recurrent CVH through month 30 vs placebo (HR: 0.51; 95% CI: 0.43-0.62; P < 0.0001). A notable proportion of CV outcome events (19% of CVM or recurrent CVH events, 22% of CVH) occurred within the first 6 months. Numerically fewer cumulative events were observed with acoramidis compared with placebo at month 1, and the difference increased progressively, resulting at month 30 in 53 events avoided per 100 treated participants (95% CI: 29-79). At month 42, CVM was reduced with continuous acoramidis vs placebo-to-acoramidis (HR: 0.55; 95% CI: 0.39-0.79; P = 0.0011). The annualized frequency of recurrent CVH was significantly decreased through month 30 (relative risk ratio: 0.50; 95% CI: 0.35-0.69; P < 0.0001). CONCLUSIONS: Acoramidis significantly reduced the cumulative burden of CV outcomes in ATTR-CM over 30 months. Numerically fewer events were observed with acoramidis vs placebo by month 1, and the difference increased progressively over time, resulting in 53 events avoided per 100 treated patients at month 30. Almost one-fourth of the cumulative CV events occurred within the first 6 months. These exploratory findings suggest that cumulative event burden may occur early, highlighting the importance of timely evaluation, diagnosis and treatment in ATTR-CM.
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Cite This Study
Masri et al. (2025) conducted an RCT in Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) (n=611). Acoramidis vs. Placebo was evaluated on Cumulative risk of cardiovascular-related mortality (CVM) or recurrent cardiovascular hospitalization (CVH) through month 30 (HR 0.51, 95% CI 0.43-0.62, p=< 0.0001). Acoramidis significantly reduced the cumulative risk of cardiovascular mortality or recurrent cardiovascular hospitalization through 30 months compared with placebo (HR 0.51; 95% CI 0.43-0.62; P<0.0001).