How do you set realistic expectations about the benefit and risk of lecanemab to patients and caregivers?

Setting Realistic Expectations for Lecanemab: Benefits and Risks

When counseling patients and caregivers about lecanemab, you must clearly communicate that while the drug shows statistically significant slowing of cognitive decline, the clinical benefit is modest—approximately a 27% reduction in decline on rating scales over 18 months—and may not be perceptible to many patients in their daily lives, while carrying substantial risks including brain swelling (13.6%) and bleeding (16% microhemorrhages) that require intensive monitoring. 1, 2

Framework for Benefit Discussion

Quantifying the Cognitive Benefit

• The primary outcome showed a 0.45-point difference on the CDR-SB scale at 18 months, representing a 27% slowing of decline compared to placebo 1
• Translate this into practical terms: patients on lecanemab declined from baseline by 1.21 points versus 1.66 points on placebo—both groups still declined, but lecanemab slowed the rate 1
• The effect size may be smaller than the minimally important clinical difference, meaning many patients and caregivers may not perceive a noticeable difference in daily function 3
• Emphasize that lecanemab does not stop or reverse Alzheimer's disease; it modestly slows progression during the early stages 4

Time Course of Benefits

• Statistically significant differences emerged at 6 months and persisted through 18 months across all endpoints 1
• The medication requires biweekly infusions indefinitely to maintain any potential benefit 5
• There is no evidence yet demonstrating whether benefits extend beyond 18 months or accumulate over longer periods 3

Who Benefits Most

• Both APOE ε4 carriers and non-carriers showed statistically significant treatment effects 1
• However, APOE ε4 homozygotes (15% of trial population) did not show treatment effect on the primary endpoint, though secondary endpoints favored lecanemab 1
• Patients must have confirmed amyloid pathology and be in the mild cognitive impairment or mild dementia stage—not earlier or later stages 6, 4

Framework for Risk Discussion

Amyloid-Related Imaging Abnormalities (ARIA)

ARIA represents the most significant safety concern and must be discussed thoroughly:

• ARIA-E (brain swelling/edema) occurred in 13.6% of patients overall 2
• ARIA-H (microhemorrhages) occurred in 16.0% of patients 2
• Risk is dramatically higher in APOE ε4 carriers: 16.8% for carriers overall and 34.5% for homozygotes 2
• Most ARIA is asymptomatic and detected only on MRI, but symptomatic cases occurred in 11% (brain edema) and 0.5% (intracranial bleeding) 3

Symptomatic ARIA can present as:

• Headache, confusion, dizziness, vision changes, nausea, aphasia, weakness, or seizure 1
• Serious symptoms can occur and ARIA can be fatal—there were 3 deaths due to intracerebral hemorrhage in clinical trials 2
• Symptoms can mimic ischemic stroke, requiring additional testing to differentiate 1

Timing and Monitoring Requirements

• ARIA-E generally occurs within 3-6 months of treatment initiation 2
• Mandatory MRI monitoring before the 5th, 7th, and 14th infusions (approximately weeks 16,24, and 52) 7
• Patients must be able to comply with this intensive monitoring schedule 5

Infusion-Related Reactions

• Infusion reactions occurred in 24.5% of lecanemab patients versus 7% on placebo 2, 8
• Most reactions are mild (flu-like symptoms, nausea, vomiting, blood pressure changes) and occur with the first infusion 1
• Hypersensitivity reactions including angioedema and anaphylaxis have occurred 1

Contraindications and Special Warnings

Anticoagulation represents a critical safety concern:

• Patients requiring anticoagulants or antithrombotic medications should not receive lecanemab until more safety data are available, as these medications substantially increase bleeding risk 4, 3
• Three deaths from intracerebral hemorrhage occurred in trials, including patients on tissue plasminogen activator and anticoagulants 2

Structured Communication Approach

Pre-Treatment Discussion Elements

Use visual formats when possible, as they enhance comprehension without bias 9:

1. Present absolute numbers, not just percentages: "Out of 100 people treated, about 14 will develop brain swelling and 16 will develop small brain bleeds" 2

2. Discuss time to benefit versus time to harm: Benefits emerge gradually over 6-18 months, while ARIA typically occurs within 3-6 months 1, 2

3. Address APOE ε4 status explicitly: Testing should be performed and results discussed, as homozygotes have 34.5% ARIA-E risk and may not benefit on the primary outcome 1, 2

4. Explain monitoring burden: Biweekly infusions, multiple MRIs, potential need for temporary or permanent discontinuation if ARIA develops 7, 5

Balancing Hope with Realism

Frame the discussion around patient-centered goals 9:

• Ask what the patient hopes to achieve: maintaining independence, slowing memory loss, staying engaged with family
• Explain that lecanemab may provide a few additional months of slower decline, but will not restore lost function or prevent eventual progression 4, 3
• Discuss alternative or complementary approaches including cholinesterase inhibitors, lifestyle modifications, and supportive care 9

Ongoing Communication Requirements

Communication between clinicians and patients is a key element of good clinical practice 4:

• Patients and care partners must understand potential benefits, potential harms, and monitoring requirements before starting therapy 4
• Provide written information and encourage questions at multiple visits 9
• Advise patients to carry information that they are being treated with lecanemab in case of emergency 1
• Discuss signs and symptoms of ARIA and instruct patients to report them immediately 1

Special Considerations for Vulnerable Populations

• Culture-specific communication and building trust are foundational for successful use 4
• Consider health literacy and numeracy levels when presenting risk information 9
• Involve caregivers in all discussions, as they often provide more reliable reports than patients due to anosognosia 10
• Assess whether cognitive limitations might interfere with medication management and determine if a caregiver can co-manage therapy 9

Common Pitfalls to Avoid

1. Do not overstate benefits: The 27% reduction in decline is relative, not absolute, and both groups still declined 1, 3

2. Do not minimize ARIA risks: While most cases are asymptomatic, serious and fatal cases have occurred 2

3. Do not proceed without APOE genotyping: This information is critical for informed risk assessment 4, 2

4. Do not treat patients on anticoagulation: The bleeding risk is too high with current evidence 4, 3

5. Do not use lecanemab in patients without objective cognitive impairment: It is indicated only for symptomatic disease (MCI or mild dementia), not for biomarker-positive individuals with normal cognition 6, 7