On July 6, 2023, lecanemab received full approval from the U.S. Food and Drug Administration for the treatment of mild cognitive impairment or early dementia due to Alzheimer’s disease following the Phase 3 CLARITY-AD study.¹ In a patient population with mild cognitive impairment or early dementia, lecanemab slowed the progression of disability as measured by the Clinical Dementia Rating – Sum of Boxes by 27% over 18 months. Aside from debates about the clinical significance of the drug’s disease-modifying effects, lecanemab shows great promise in people with this devastating and progressive disease and has been widely recognized by the Centers for Medicare and Medicaid Services (CMS). It’s being featured.

Currently, in the early stages of a drug’s rollout, patients are carefully selected to minimize the drug’s potential side effects.Key safety concerns in monoclonal antibody (anti-amyloid mAbs) trials targeting amyloid beta^1,2 There are amyloid-associated imaging abnormalities (ARIA), of which the most concerning is megacerebral hemorrhage. Although most ARIA cases are asymptomatic, megabrain hemorrhages are rare but troubling because they can cause death and disability. Concurrent anticoagulant therapy, cerebral amyloid angiopathy, and apolipoprotein ε4 homozygosity are established risk factors. In CLARITY-AD, lecanemab increased the risk of major bleeding compared with placebo (0.7% vs. 0.2%), and the risk was higher in patients receiving anticoagulants compared with those not (2.4%). vs. 0%).^1,3 There were three deaths related to lecanemab treatment during the open-label phase of CLARITY-AD.³ All of these were caused by massive cerebral hemorrhage. Similarly, in the Phase 3 TRAILBLAZER-ALZ 2 trial, there were three deaths due to severe ARIA with donamab.²

Antithrombotic therapy presents a unique challenge for patients considering anti-amyloid mAbs. In approving lecanemab, the Food and Drug Administration warned against its use in individuals with apolipoprotein epsilon 4 homozygosity, but did not advise on the risks of concomitant anticoagulation therapy.^Four Recommendations for appropriate use by the Alzheimer’s Association Treatment Working Group take a more conservative approach, stating that patients with cerebral amyloid angiopathy and those currently prescribed anticoagulants are at potential risk of bleeding. said that it should not be a candidate for lecanemab because its potential benefits outweigh its potential benefits.³ Although recommendations regarding the combination of anticoagulants and anti-amyloid mAbs may evolve, many lecanemab programs exclude patients on anticoagulants. Although cerebral amyloid angiopathy and apolipoprotein ε4 homozygosity are recognizable fixed risk factors, antithrombotic drug use is quite dynamic.

Ischemic stroke, myocardial infarction, and pulmonary embolism are three common acute clinical conditions that require treatment with thrombolytic and anticoagulant drugs and urgent clinical decisions; It is expected that this will be particularly difficult and require careful management for patients treated with . Advance directive conversations. For example, in acute ischemic stroke, tissue plasminogen activator should be administered as soon as possible within 4.5 hours of symptom onset. In ST-segment elevation myocardial infarction, the standard treatment is intravenous heparin during percutaneous coronary intervention followed by dual antiplatelet therapy with a door-to-balloon time of less than 90 minutes. In acute pulmonary embolism, low molecular weight heparin should be administered as soon as possible. In severe cases, systemic tissue plasminogen activator or catheter-based thrombolytic therapy are appropriate life-saving interventions. Lecanemab is administered intravenously every two weeks and has a half-life of 5 to 7 days. Currently, no reversal agents exist for lecanemab. In these clinical scenarios, the risk of major cerebral hemorrhage from antithrombotic drugs must be quickly weighed against the risk of untreated stroke, myocardial infarction, or pulmonary embolism, which can be impossibly difficult. It’s a challenge. Given the uncertainties and potential for harm, current appropriate use recommendations are against treating patients receiving lecanemab for ischemic stroke with thrombolytics. .³ This uncertainty and potential for harm was highlighted in a case report^Five:A patient not on anticoagulants but homozygous for apolipoprotein ε4 develops multifocal intraparenchymal hemorrhage after receiving a tissue plasminogen activator for acute ischemic stroke. did. Because of the challenges of the emergency situation, patients may be clinically unstable and unable to fully participate in clinical decision-making, so prior to initiating lecanemab, a very difficult advance directive conversation is required. The need is emphasized.

During advance treatment planning, patients and physicians should discuss emergency situations and determine what treatments will achieve their goals if these clinical scenarios occur. Optimism bias, the tendency to underestimate the likelihood of negative events and the perception that such events are a remote possibility, makes these conversations sensitive. Nevertheless, it is much better to make these decisions in the clinic rather than in an emergency situation. Advance treatment planning can be shared with all clinicians treating the patient, allowing for timely and appropriate treatment decisions.

Advance care planning should also consider non-emergency situations, such as a possible new diagnosis of atrial fibrillation. In such scenarios, the need for anticoagulant therapy for stroke prevention should be anticipated and discussed. Newly diagnosed AF among anti-amyloid mAb users, given that 10-12% of Medicare beneficiaries initially diagnosed with AF have a pre-existing diagnosis of Alzheimer’s disease or dementia. expected to occur frequently.⁶ Nearly all patients treated with anti-amyloid monoclonal antibodies who develop new-onset atrial fibrillation are at high risk for cardioembolic stroke and should be considered for long-term anticoagulation. Without anticoagulation, the annual risk of stroke is 5% to 7%, and such strokes result in a mortality rate of 25% within 30 days and a third of survivors. 2 resulting in severe disability. For some patients, slowing the progression of Alzheimer’s disease with lecanemab may seem more important than preventing strokes caused by atrial fibrillation. But such decisions are never obvious. First, lecanemab slows the progression of Alzheimer’s disease by 24% to 37%;¹ The rate of patient decline varies markedly, and tools to accurately predict an individual’s rate of progression are lacking. Second, CLARITY-AD excluded patients with a history of stroke in the year before enrollment, and the benefit of lecanemab in patients with a recent history of stroke is unknown. Third, atrial fibrillation without anticoagulation carries a reasonable risk of causing acute ischemic stroke, the treatment of which requires tissue plasminogen activator. Percutaneous left atrial appendage occlusion should not be considered as an alternative to anticoagulant therapy for which lecanemab is indicated. The device requires a minimum of 45 days of anticoagulation (longer if there is a device leak or thrombosis), followed by two types of antiplatelet therapy for up to 6 months and 325 mg daily for life. Aspirin should be given. The decision to discontinue lecanemab is necessary, but it will be difficult news for patients and their families.

At this time, decisions regarding the use of lecanemab must be based on limited safety data. There is a need to generate data on the risk of cerebral hemorrhage in lecanemab and future anti-amyloid monoclonal antibody users with comorbidity or high risk of cardiovascular disease. As anti-amyloid mAbs are used in routine clinical practice, their safety needs to be actively monitored using empirical data on the risk and severity of cerebral hemorrhage and identification of factors associated with severe ARIA. there is. CMS requirements for prescriber participation in eligible registries allow for the accumulation of clinical data, but to be fully useful, registries must include information on blood pressure management, comorbidities, concomitant medication use, biomarkers, and brain imaging. Must include patient-level data, including: ALZ-NET is one such registry and has been approved by CMS for evidence development registry coverage for recaneumab coverage.

Lecanemab is an important therapeutic advance for people with mild cognitive impairment or early dementia associated with Alzheimer’s disease. The risk of megacerebral hemorrhage is further increased by antithrombotic drugs, making it difficult for older adults who often develop acute and chronic cardiovascular disease. To address this challenge, we need to create interdisciplinary treatment teams for Alzheimer’s disease, develop shared decision-making models for proactive care planning, and generate the empirical data needed to guide treatment decisions. This is an urgent matter.

Corresponding author: Darae Ko, MD, MSc, Hinda and Arthur Marcus Institute for Aging Research, 1200 Center St, Boston, MA 02131 (daraeko@hsl.harvard.edu).

Published online: March 15, 2024. doi:10.1001/jama.2024.2991

Conflict of interest disclosure: In addition to the submitted research, Dr. Coe reported receiving grants (K23HL151903) from Boston Scientific and the National Heart, Lung, and Blood Institute. Consulting fees from Windrose Consulting Group. Lecture fees from Academic CME during research implementation. Dr. Pascual-Leone reported being supported in part by grants from the National Institutes of Health (R01AG076708, R01AG059089, R03AG072233, P01 AG031720) and the Bright Focus Foundation. He serves as a paid member of the scientific advisory boards of Neuroelectrics, Magstim, Tetraneuron, Skin2Neuron, and he serves on the scientific advisory boards of MedRhythms. TI Solutions and he co-founded Linus Health. He serves as Linus Health’s chief medical officer. We also have several published and pending applications on real-time integration of transcranial magnetic stimulation with electroencephalography and magnetic resonance imaging, applications of non-invasive brain stimulation in various neurological diseases, and digital biomarkers for cognitive and digital assessment. Listed as inventor on patent. For early diagnosis of dementia other than the submitted work. Dr. Shah reported receiving grant funding (K76AG074919) from the National Institute on Aging outside of the submitted research. No other disclosures were reported.

Disclaimer: Neuroelectrics, Magstim, Tetraneuron, Skin2Neuron, MedRhythms, TI Solutions, and Linus Health did not contribute to the submitted research.