Prognostic value of outpatient worsening HF in ATTR-CM and effect of patisiran

In a post-hoc analysis of APOLLO-B among patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), outpatient worsening HF was associated with increased risks of disease progression, CV events, and mortality. Patisiran reduced the risk of outpatient worsening HF compared with placebo.

This summary is based on the publication of Fontana M, Maurer MS, Gillmore JD, et al. - Worsening of Heart Failure in Outpatients With Transthyretin Amyloidosis and Cardiomyopathy in the APOLLO-B Trial. J Am Coll Cardiol. 2025 Feb 25;85(7):744-752. doi: 10.1016/j.jacc.2024.10.097.

Introduction and methods

Background

Transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease characterized by the deposition of amyloid fibrils, which consist of misfolded transthyretin aggregates, in the myocardium. Early prognostic markers can help to identify patients with increased risk of worsening HF who may need treatment modification. Initiation or intensification of loop diuretic therapy in the outpatient setting is a predictor of adverse outcomes, not only in patients with HF [1-4], but also in those with ATTR-CM [5-7].

Treatment with patisiran, an RNA interference therapeutic agent that inhibits the production of TTR in the liver, resulted in preserved functional capacity, health status, and quality of life compared with placebo in ATTR-CM patients, as shown by the APOLLO-B (A Study to Evaluate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy) trial [8].

Aim of the study

In a post-hoc analysis of APOLLO-B trial, the authors examined the clinical and prognostic significance of outpatient worsening HF in ATTR-CM patients, the potential value of the inclusion of outpatient worsening HF in an expanded composite endpoint, and the impact of patisiran on this and other outcomes.

Methods

The APOLLO-B trial was an international, double-blind, placebo-controlled, phase 3 RCT in which 360 patients with variant or wild-type ATTR-CM and HF were randomized to intravenous patisiran 0.3 mg/kg (maximum dose: 30 mg) or placebo once every 3 weeks for 12 months. Thereafter, patients were eligible to be enrolled in the open-label extension (OLE) period, during which they received patisiran 0.3 mg/kg every 3 weeks for up to 3 years (n=334; 93%). Treatment with tafamidis at baseline was permitted (used by up to 30% of the patients).

Outpatient worsening HF was defined as initiation of or a sustained increase (duration ≥7 days) in the daily dose of oral loop diuretics. Recurrent outpatient worsening HF was defined as oral diuretic intensification that occurred ≥7 days after the prior oral diuretic initiation or intensification. During the double-blind and OLE periods (24 months in total), 157 patient (43.7%) had ≥1 outpatient worsening HF event and 47 (13.1%) died.

Outcomes

The associations of outpatient worsening HF with the following endpoints were assessed: a composite outcome of all-cause mortality or CV events (i.e., CV hospitalizations and urgent HF visits), all-cause mortality, CV events, and changes from baseline to 12 months in 6-minute walk distance (6MWD), KCCQ – Overall Summary Score (OSS), NT-proBNP levels, NYHA functional class, and ATTR disease stage as defined by the National Amyloidosis Centre (NAC) in the UK.

In addition, the effects of patisiran on outpatient worsening HF, the composite outcome of all-cause mortality or CV events, and a composite outcome of all-cause mortality, CV events, or outpatient worsening HF over 24 months were investigated.

Main results

Associations between outpatient worsening HF and clinical outcomes

• During 24-month follow-up, outpatient worsening HF was associated with increased risks of all-cause mortality or CV events (HR: 2.21; 95%CI: 1.58–3.08), all-cause mortality (HR: 2.18; 95%CI: 1.28–3.69), and CV events (HR: 2.18; 95%CI: 1.53–3.09).
• Patients with outpatient worsening HF events during the 12-month double-blind period showed greater decreases from baseline compared with those with no outpatient worsening HF events in mean ± SEM 6MWD ( −43.05 ± 6.36 m vs. −2.73 ± 4.87 m; P<0.001) and mean ± SEM KCCQ-OSS (−3.74 ± 1.49 vs. 0.37 ± 1.26; P=0.036) and a greater increase from baseline in mean ± SEM NT-proBNP levels (1,230.0 ± 203.5 ng/L vs. 345.4 ± 72.7 ng/L; P<0.001).
• Outpatient worsening HF was also associated with greater worsening of NAC stage (P=0.006) and NYHA functional class (P=0.007) at 12 months.

Treatment effect of patisiran on outpatient worsening HF

• In a time-to-first-event analysis, initial randomization to patisiran was associated with a reduced risk of outpatient worsening HF over 24 months compared with initial assignment to placebo (HR: 0.70; 95%CI: 0.51–0.96).
• Recurrent event analysis showed the HR for patisiran versus placebo treatment for the composite outcome of all-cause mortality or CV events over 24 months was 0.82 (95%CI: 0.57–1.18). When outpatient worsening HF was added to this endpoint, the total number of patients with an event increased from 141 to 215 (52% increase) and the HR was 0.78 (95%CI: 0.60–1.02).

Conclusion

In this post-hoc analysis of the APOLLO-B trial, 44% of the patients ATTR-CM experienced outpatient worsening HF (i.e., initiation or intensification of oral loop diuretics) over 24 months. Outpatient worsening HF was associated with disease progression and increased risks of all-cause mortality and CV events. Continuous treatment with patisiran for 24 months reduced the risk of outpatient worsening HF compared with 12-month placebo treatment followed by open-label patisiran treatment for 12 months. The authors state that “addition of outpatient worsening HF to a composite endpoint of all-cause mortality [or] CV events led to an increase in the number of clinically meaningful events, supporting the consideration of an expanded endpoint in future trials in ATTR-CM.”

Find this article online at J Am Coll Cardiol.

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