Indirect Comparison Study Hints at Lower ARIA and ICH-Related Mortality Risk in Lecanemab Over Donanemab

A new indirect treatment comparison study showed that lecanemab (Leqembi; Eisai) had significantly lower risks of amyloid-related imaging abnormality (ARIA) outcomes overall and in subgroups of interest compared with donanemab (Kisulna; Eli Lilly). These results, which also showed lower mortality related to ARIA or intracerebral hemorrhage (ICH) in lecanemab, reinforce the importance of understanding comparative real-world safety profiles to better inform treatment decisions for patients with Alzheimer disease (AD).¹

Researchers reported that treatment with lecanemab demonstrated significantly lower risk of any ARIA, ARIA with edema/effusions (ARIA-E) or ARIA with microhemorrhage or superficial siderosis (ARIA-H), compared with donanemab with a risk difference-in-difference of -10.1% (95% CI, -15.3% to -5.0%). Presented at the 2025 Alzheimer’s Association International Conference, held July 27-30, in Toronto, Canada, authors noted that the risk difference-in-difference for ARIA-E (-10.7%; 95% CI, -14.5% to -6.9%) and ARIA-H (-10.1%; 95% CI, -15.0% to -5.2%) were also significantly lower with lecanemab treatment.

The study, presented by Anna Burke, MD, the director of Alzheimer’s and Memory Disorders Division at Barrow Neurological Institute Barrow, comprised an indirect treatment comparison of ARIA outcomes and mortality rates to understand safety differences. For the analysis, researchers used ARIA rates in the FDA-approved labels, FDA review documents, or peer-reviewed publications. The study outcomes included ARIA-E, ARIA-H, ICH at least 1cm, APOE4 status, all-cause death, and additional ARIA outcomes in the overall clinical trial population over 18 months. Investigators utilized Anchored Bucher indirect treatment comparisons to compare rates of ARIA outcomes between lecanemab and donanemab, with placebo as the common comparator.

In the subgroup of APOE4 carriers, risk difference-in-differences were -11.1% for ARIA-E (95% CI, -16.0%, -6.2%), and -14.4% for ARIA-H (95% CI, -20.5% to -8.2%), favoring lecanemab. Notably, lecanemab had also a significantly lower risk of microhemorrhage (-7.5%; 95% CI, -12.1% to -2.9%), and superficial siderosis (-8.8%; 95% CI, -12.0% to -5.6%). Additionally, the incidence of ICH (0.3%; 95% CI, -0.5%, 1.1%) and mortality (-1.0%; 95% CI, -2.4%, 0.5%) were not significantly different between the 2 treatments. Authors noted that lecanemab displayed a significantly lower risk of death with concurrent ARIA or ICH (-0.5%; 95% CI, -0.9%, 0.0%) compared with donanemab.

Following the initial abstract submission to AAIC 2025, Eisai incorporated data from TRAILBLAZER-ALZ 6 (NCT05738486) after the release of the trial’s 18-month findings and the recent update to donanemab’s titration schedule in its label. A network meta-analysis that factored in the revised donanemab dosing from TRAILBLAZER-ALZ 6 supported the results of the Bucher indirect comparison, showing a lower incidence of ARIA in patients treated with lecanemab compared with donanemab.

Lecanemab and donanemab, 2 antiamyloid antibodies, received FDA approval for the treatment of early AD and entered clinical practice in July 2023 and July 2024, respectively. In another study on lecanemab and donanemab presented at AAIC 2025, results revealed that early adopters of the approved antiamyloid therapies were, on average, more socially advantaged compared with the general dementia patient population, despite exhibiting high rates of cardiovascular risk and cardiovascular complication.²

Using data from Epic Cosmos, the retrospective study analyzed 3242 patients who received lecanemab and 160 who received donanemab infusions between July 1, 2023 and November 29, 2024. In the comparator group, researchers included 1,907,655 patients who took oral dementia medications including donepezil, rivastigmine, galantamine, or memantine. Findings from the study showed that patients who received antiamyloid therapy were younger, more likely to be White and non-Hispanic, a man, commercially insured or on Medicare, and less likely to be on Medicaid. Authors also noted that these patients were also more likely to reside in socioeconomically advantaged ZIP codes.

Presented by Jay B. Lusk, MD, MBA, a preventive medicine resident at the University of North Carolina at Chapel Hill, the study reported that the average 10-year atherosclerotic cardiovascular disease (ASCVD) risk score for patients who received antiamyloid therapy was 19.9. Additionally, authors noted that 36.9% of patients had an ASCVD risk score greater than 10 in 12 months, and 84.6% had a systolic blood pressure above 135 mmHg in the year prior to therapy. A total of 1,345 patients (37.5%) had a history of major adverse cardiac and cerebrovascular events (MACCE) before therapy. In 12 months of initiating therapy, 95 patients (2.7%; 95% CI, 2.1–3.2%) had a new MACCE diagnosis, and 58 patients (1.7%; 95% CI, 1.3–2.1%) received a new diagnosis of a cerebrovascular event.