The results of the AD2000 study of donepezil (Aricept) in Alzheimer's—published in the June 26 Lancet—made a big splash in the media pond. While confirming previous findings of modest benefits on certain tests, the study authors challenge claims that the drug has valuable effects on "real-life" measures of disability, and they charge that is not cost-effective.
The use of cholinesterase inhibitors (ChEIs) has exploded in just a few years, producing golden eggs for several pharmaceutical companies. Detractors have noted that the benefits are far from outstanding. In particular, there is no strong clinical trial evidence to suggest that patients should stay on the drugs for more than a year or two, though many apparently do (see ARF Live Discussion on ChEIs). While many short-term studies indicate beneficial effects on neuropsychological tests and activities of daily living scales, there has been little study of whether the drugs provide benefits over the long term, especially in terms of overall disability and the need for institutionalization.
The publicly funded AD2000 study, conducted by the Clinical Trials Unit of the University of Birmingham in England, was created to fill this void, and also to address concerns that the research to date has mainly been industry-funded, with design biases toward showing benefits. AD2000 was intended to assess donepezil in a "real-clinic" situation, in contrast to industry trials, whose inclusion and exclusion criteria tend to exclude the majority of dementia patients. Originally slated to enroll 3,000 patients for a single phase of 60 weeks, the study ended up with only 566. The study was redesigned to follow all these patients through a series of phases.
The blame for the low turnout can be laid on a variety of forces, argue the authors, including the rapid speed with which ChEIs became available to patients at large. Once this occurred, it became difficult to recruit patients for a trial in which they might be receiving a placebo. This lower number of subjects means the study lost statistical power to make conclusive assessments about its primary outcomes of institutionalization and progression of disability, writes Lon Schneider of the University of Southern California in Los Angeles in an editorial accompanying the study.
Even into the trial, these same forces exerted a strong influence—the high attrition rate is partly due to patients opting for open-label treatment with ChEIs. Of the 486 patients entering the 48-week Phase 1, only 293 completed that phase; 111 patients completed Phase 2; and 20 patients completed phase 3. However, other factors such as death and institutionalization also contributed to the drop in subjects.
Despite the attrition rate, the study did not lose power for the secondary endpoints; these include changes in specific tests scores such as MMSE or the Bristol activities of daily living score (BADLS). Indeed, AD2000 confirmed and extended previous results, showing that in the donepezil subjects cognition averaged 0.8 MMSE points better, and functionality measured at 1.0 BADLS points better, and that this benefit was maintained over the first two years of the trial.
In terms of the primary endpoints, the AD2000 researchers report no differences between the drug and placebo groups in terms of institutionalization—42 percent vs. 44 percent at three years (p=0.4). Similarly, they report no differences in disability progression between donepezil and placebo groups—58 percent versus 59 percent at three years (p=0.4). The researchers also report finding no differences between donepezil and placebo in terms of behavioural and psychological symptoms, caregiver psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths, or between 5 mg and 10 mg donepezil.
Despite the lack of power for primary endpoints, both the authors and commentator Schneider feel that the results deserve notice. The study results, writes Schneider, "…undermine an assumption that improvements in cognition and ADL scores generalize to maintenance of function, cost savings, or delay in institutionalization. … Results are incompatible with many drug-company-sponsored observational studies and advertisements claiming remarkable effects for cholinesterase inhibitors. For example, claims that donepezil stabilises cognitive decline, or delays nursing-home placement by 2-5 years now can be seen as implausible in the light of AD2000."
The authors argue that "AD2000 found no evidence that costs of caring for patients with Alzheimer's disease in the community are reduced by donepezil. Indeed, our findings suggest that these drugs would increase [British National Health Service] cost per patient—mostly hospital care—by around 40 percent without any offsetting through reductions in service use."
Some previous economic models have suggested that ChEI-related improvement on tests such as the MMSE will lead to cost reductions, but the authors argue that the studies these models were built upon "clearly overestimate benefit because of selection bias." The only study that, in the opinion of the authors, was properly set up to assess economic endpoints failed to find a benefit from donepezil (Wimo et al., 2003).
But wouldn't the small, but significant, MMSE and BADLS improvements with donepezil over the two-year study mean that patients experienced an increased quality of life? Without question, it is a difficult thing to assess, but the authors note that the U.S. FDA's guidelines on a worthwhile clinical response would require at least a 1.4 MMSE point difference, and many clinicians believe that the minimum clinical benchmark is a 3.0 point difference on the MMSE, both figures outside the confidence intervals for these data.
The authors make another argument against the interpretation of previous clinical trials of ChEIs. "The significantly worse cognitive and functional decline seen among retrieved dropouts in AD2000 compared to those who continued treatment confirms that differential dropout, particularly if analyses do not include retrieved dropouts, exaggerates efficacy," the authors write, noting that differential dropout was not discussed in previous clinical trial reports.
What about separating responders from non-responders early on and sparing expenses and pointless side effects for the non-responders? The potential for this appears to be low. "Reliable discrimination between responders and non-responders—on the basis of changes on simple scale outcome measures of cognition, functionality, and behavioural and psychological symptoms—is not possible," argue authors.
Ultimately, it is those who pay for the drugs—whether public or private—who will make the decisions about their availability. In the popular press, medical statistician Robert Gray, director of the University of Birmingham Clinical Trials Unit and spokesman for the study, has argued that in England the money spent on cholinesterase inhibitors would be better spent on doctors and nurses and better social support for patients and their caregivers.—Hakon Heimer