The FDA's approval of lecanemab in 2023 marked a significant advancement in Alzheimer's treatment. However, a new opinion paper and expert recommendations emphasize the need for caution when considering lecanemab for patients with cardiovascular disease (CVD) or risk factors due to increased cerebral bleeding risks.
In the CLARITY-AD trial, lecanemab demonstrated a 27% reduction in cognitive decline at 18 months compared to placebo in patients with mild cognitive impairment or early dementia due to Alzheimer's disease. The trial also met key secondary endpoints, including reductions in amyloid burden. Infusion-related reactions were observed in 26.4% of patients in the lecanemab group, and amyloid-related imaging abnormalities with edema or effusions (ARIA-E) occurred in 12.6% of lecanemab recipients.
Increased Hemorrhage Risk
Published in JAMA in March 2024, Ko et al. highlighted the need for caution when using lecanemab in patients with CVD or risk factors. The risk of macrohemorrhage was 0.7% with lecanemab versus 0.2% with placebo, with a further increase in patients receiving anticoagulant therapy.
"While there is no firm guidance, it does seem prudent for the time being to avoid lecanemab in patients who need to be on anticoagulant therapy," stated Dr. Deepak L. Bhatt, director of Mount Sinai Fuster Heart Hospital.
Subsequent findings from the open-label extension of the CLARITY-AD trial revealed three treatment-related deaths due to cerebral macrohemorrhages. One patient had CVD and was receiving anticoagulant therapy, and another died after receiving tissue plasminogen activator for acute stroke.
Expert Opinions and Recommendations
Dr. Mitch S. V. Elkind, chief clinical science officer of the American Heart Association, explained, "While reducing harmful amyloid in the brain, these monoclonal antibodies may secondarily contribute to inflammation and weakening of brain blood vessels, increasing the risk of brain swelling and hemorrhage, which can be disabling or even fatal."
Given that older adult patients for whom lecanemab is indicated often have conditions like atrial fibrillation, myocardial infarction, ischemic stroke, and pulmonary embolism, which are treated with antithrombotic therapy, the risk of cerebral bleeding is increased for those already receiving lecanemab.
"Current recommendations are based on limited data, and more research is needed. However, some work groups of experts primarily involved in the care of patients with Alzheimer disease have recommended that patients who require anticoagulants not be prescribed lecanemab due to the increased risk of bleeding," Dr. Elkind noted.
Additional Risk Factors and Monitoring
Besides anticoagulant use, other risk factors for intracerebral bleeding include apolipoprotein E ε4 (APOE4) gene carrier status, especially APOE4 homozygosity, and cerebral amyloid angiopathy-related inflammation/amyloid beta-related angiitis (CAA-ri/ABRA).
The authors of the Appropriate Use Recommendations (AUR) for lecanemab recommend APOE genotyping of all lecanemab candidates prior to treatment initiation to guide risk discussions. They also advise clinicians to obtain magnetic resonance imaging (MRI) on all patients before starting lecanemab.
Following treatment initiation, MRIs should be obtained prior to the 5th, 7th, and 14th infusions, and before the 26th infusion in higher-risk patients, to assess for microhemorrhages, macrohemorrhages, brain swelling, and superficial siderosis. The risk of bleeding with lecanemab is highest soon after treatment initiation.
"Imaging evidence of numerous new microhemorrhages or even a single large hemorrhage should lead to cessation of lecanemab therapy," Dr. Elkind advised. "Patients should also be monitored for symptoms such as headache, confusion, or focal neurological changes, which could also be a sign of brain hemorrhage."
The Need for More Research
"There is ongoing registry-based research that will provide useful information about how lecanemab performs in patients in the real world, including in patients with known cardiovascular disease," Dr. Bhatt said. "Ideally, there would also be more randomized clinical trials investigating the use of lecanemab in patients with significant cardiovascular disease."
Further research is needed to determine the mechanisms by which anti-amyloid therapies can weaken blood vessels and cause edema bleeding and to develop antidotes to these side effects. More data are also needed on the magnitude of risks of ARIA in real-world populations, risk factors for bleeding, and optimal mitigation strategies.
