Evidence-based medicine (EBM) is the integration of the best available evidence with clinical expertise and includes an individual patient’s values, preferences, and unique circumstances. It seeks to provide better, more cost-effective health care for patients. This approach to medical decision-making is a 3-legged stool: 1) best available evidence, 2) clinical expertise, and 3) shared decision-making (SDM) with patients.
Evidence-based medicine prioritizes implementing interventions that affect outcomes that matter, like mortality, morbidity, and quality of life. These outcomes are patient-oriented evidence outcomes, as opposed to disease-oriented evidence outcomes. Examples of disease-oriented evidence include changes in cholesterol or glucose levels, while patient-oriented evidence focuses on matters like heart attacks, strokes, life expectancy, or hospitalizations. In evidence-based medicine, if there was a drug that removed all the amyloid from the brain scan of person with Alzheimer’s but did not affect the outcome or progression of disease, it would be avoided regardless of price or hype.
Patient-oriented evidence is not about laboratory levels; rather, it focuses on data about living longer, living better, staying out of the hospital or nursing home, and functioning better. Evidence-based medicine does not ignore disease-oriented evidence, it just seeks and prioritizes patient-oriented evidence, acknowledging that, at times, only disease-oriented evidence is available, and we use the best available evidence at that moment to guide practice and recommendations.
Patients affect therapeutic decisions. Shared decision-making is important. Drugs or other interventions (e.g., diet, exercise, immunization, and surgery) can only have a chance to work if patients choose to use them. Because they matter, side effects, dosing frequency, cost, and preference all factor into shared decision-making, as well as magnitude of effect (e.g., a 1% vs 10% chance of benefit) and risk versus benefit.
Another thing to consider is, “Does the patient being treated match the people studied?” Take the new Alzheimer’s disease medication lecanemab, as an example. It was tested in people with very mild dementia. People with mild dementia function independently, with occasional forgetfulness, confusion, or lapses in judgement. They may have difficulty finding the right words, forget some recent events, or need help with challenging tasks, like balancing a checkbook. These are the only people with Alzheimer’s for whom lecanemab had some benefit. “Benefit” did not mean the symptoms went away or got better. In this 18-month study, benefit meant getting worse at a slower rate, i.e., their dementia score went from 3.2 to 4.41 on lecanemab, compared to 4.86 on placebo. This indicates patients moved from very mild dementia to mild dementia at a slower rate, taking about 6 months longer to do so.
Lecanemab is an infusion. Compared to placebo, 20% more people had infusion-related reactions, 7% more had small bleeding, and 10% more had edema around amyloid lesions on brain imaging tests. There were no significant differences in deaths, falls, or dizziness.
The drug was not used on people with moderate or severe dementia. In general, no medications have benefitted people at those stages.
We should be wary of therapeutic indication creep, which occurs when a drug is found to be successful for a specific phase of a disease and is then extended (by extrapolation, hope, or desperation), for use for all stages, or even for similar diseases.
Currently, we have disease-oriented evidence for lecanemab on average people with mild dementia who were treated for 18 months. They scored less worse on the clinical dementia rating scale, taking about 6 months longer to move from very mild dementia to mild dementia than those treated with placebo. There were side effects. In addition, the annual cost of lecanemab is about $26,500. The actual cost will likely be closer to triple that when testing, infusion, and monitoring costs are considered. Medicare and Medicaid will probably cover it for the narrow patient types on whom it was tested.
These outcomes are more disease-oriented evidence than patient-oriented evidence. Behavior, represented by such a change in the dementia scale score, is usually not apparent to family members, and we do not know what happens over time as it relates to patient-oriented evidence, such as prolonging independent living or decreasing the rate of progression to severe dementia.
In addition to considering other illness or possible drug interactions (e.g., lecanemab may be an overall risk for those on blood thinners), the shared decision-making part of evidence-based medicine would involve discussions assessing patient values around side effects, risk tolerance, whether 6 months of slowing disease progress is meaningful, whether out-of-pocket costs are “worth it,” and lurking fears or anxieties.
This could be the beginning of good news that translates into patient-oriented evidence for Alzheimer’s. For now, we should specifically consider study findings, proceed cautiously, be optimistic without providing false hope, and see what 36-month data looks like.