Risks of Macrohemorrhage in Patients Receiving Donanemab

Definition and Screening

Macrohemorrhages in the context of anti-amyloid antibody therapy are defined as intraparenchymal hemorrhages >10mm in diameter, which are detectable on MRI, according to the American College of Radiology 1, 3
These hemorrhages are part of the spectrum of Amyloid-Related Imaging Abnormalities with hemorrhage (ARIA-H) that can occur with anti-amyloid monoclonal antibody therapies, as reported by the American College of Radiology 2
Pre-treatment screening with MRI is mandatory within 12 months of initiating donanemab therapy to detect exclusionary findings, including existing macrohemorrhages, as recommended by the American College of Radiology 1, 3

Pre-existing cerebrovascular pathology, particularly history of prior macrohemorrhages >10mm in diameter, presence of 4 or more microhemorrhages <10mm in diameter, superficial siderosis, and cerebral amyloid angiopathy (CAA), increase the risk of macrohemorrhage with donanemab, according to the American College of Radiology 1, 2, 3
APOE ε4 carrier status, especially homozygotes, is a patient-specific risk factor for macrohemorrhage with donanemab, as reported by Praxis Medical Insights 4

In clinical trials, ARIA-H (including microhemorrhages and macrohemorrhages) had an incidence ranging from 15% to 20%, according to the American College of Radiology 1, 2
Specifically for donanemab, ARIA-E (edema) was detected in up to 26.7% of patients in the TRAILBLAZER-ALZ phase 2 and 3 trials, as reported by the American College of Radiology 1, 2

MRI monitoring is essential for early detection of ARIA-H, including macrohemorrhages, and must include specific sequences such as DWI, T2 FLAIR, and T2* GRE or SWI, as recommended by the American College of Radiology 1, 2, 3
3T MRI units provide greater sensitivity for detection of hemorrhagic abnormalities, according to the American College of Radiology 1, 3

Patients with pre-existing macrohemorrhages >10mm should be excluded from donanemab therapy, as recommended by the American College of Radiology 1, 3
Management of ARIA-H depends on clinical symptoms and MRI grading severity, and may require temporary suspension or permanent cessation of treatment, according to the American College of Radiology 2

Thorough pre-treatment screening to exclude high-risk patients is essential, as recommended by the American College of Radiology 1, 3
Consider APOE ε4 testing before treatment to assess ARIA risk, as reported by Praxis Medical Insights 4
Blood pressure control is important for preventing macrohemorrhage, as reported by the Stroke journal 5

Benefit-risk assessment should consider that clinical benefit may be reduced in certain patient populations, as reported by Praxis Medical Insights 4
The presence of lobar macrohemorrhages may suggest underlying cerebral amyloid angiopathy, which increases the risk of recurrent hemorrhage, according to the Stroke journal 5, 6