Although FDA-approved Alzheimer's disease (AD) treatment strategies (cholinesterase inhibitors and memantine) offer proven
benefits, providers recognize unmet needs beyond what is currently available. Consequently there is a significant use of anecdotal
yet unproven combinations for treating AD in practice. Based on the best evidence, combination drug therapy is the standard
of care for treating other medical conditions such as malignancies, human immunodeficiency virus (HIV), and hypertension.
We review recent combination drug therapy studies in AD. To date, the best evidence-based combination strategy is for moderate-to-severe
AD, in which the addition of memantine to stable donepezil therapy was found to benefit cognition, behavior, and function.
In milder stages of AD, the benefit of combination drug therapy has not been demonstrated. This review highlights the urgent
need to systematically test additional rational drug combinations and the need for future trials to enroll adequate sample
sizes and utilize relevant and sensitive outcome measures.
Xiong G, Doraiswamy PM. Combination drug therapy for Alzheimer's disease: What is evidence-based, and what is not? Geriatrics
2005; 60(June):22-26.
Key words: Alzheimer's disease • cholinesterase inhibitor • memantine combination drug therapy • polypharmacy
Cholinesterase inhibitors (ChEIs) including donepezil, rivastigmine, and galantamine, and the N-methyl-D-aspartate (NMDA)
antagonist, memantine, are the only medications currently approved by the U.S. Food and Drug Administration (FDA) for the
treatment of Alzheimer's disease (AD). Other agents, such as vitamins, statins, estrogen, ginkgo biloba, anti-inflammatory
agents, antidepressants, antipsychotics, and mood stabilizers, have been commonly used, off-label, as combination therapies.
Additional needs—such as dealing with progressive cognitive decline, depression, and agitation—are beyond today's monotherapies.
Informal surveys of clinicians indicate that unproven combinations are frequently used in routine practice to treat AD.1
Rational polypharmacy Despite concerns about increased side-effects, higher costs, and possibly lower medication adherence with polypharmacy, healthcare
professionals and family members are desperate for additional treatment options for AD patients.2
Why combination drug therapy? ChEIs cannot be expected to correct every deficit, because acetylcholine deficiency is not the
only problem in AD. Several other pathways have been hypothesized to contribute to the pathogenesis of AD, including excess
oxidative stress, decreased cerebral metabolic rate, and alterations in several neurotransmitter systems—in addition to the
pathologic accumulation of β-amyloid and neurofibrillary tangles.3 Combination drug therapies, which offer the prospect of additive or synergistic benefits, can be used to target multiple
pathologic processes. Other advantages of combination drug therapy include the potential to lower the dose of the more toxic
agent and to target specific, unremitting symptoms not relieved by one agent alone.
In balancing these benefits and risks, it is important to take an evidence-based approach. Combination drug therapies—initial
versus step-wise approaches—can be found in the treatment of other disease states. Initial combination therapy is the standard
of care in the treatment of malignancies and human immunodeficiency virus (HIV). Multiple agents are used to achieve maximum
efficacy by aggressively attacking several targets simultaneously to exploit synergy and to minimize individual toxicity.
For the treatment of hypertension, a step-wise augmentation approach is commonly employed. Yet even this approach is evolving,
as initial fixed-dose combination therapies with two classes of antihypertensive agents have proven to be more effective than
monotherapy alone.4,5
Table Studies of combination therapies in Alzheimers disease
|
Combination therapies in AD Although successfully applied to a variety of disease states, combination strategies in AD have had mixed results to date.
The table summarizes recently published combination drug therapy studies in AD.6-11 There is a paucity of prospective combination drug therapy trials, and of these, only one published prospective randomized
controlled trial (RCT)6 found an incremental benefit for combination drug therapy over monotherapy for AD. The results of several other completed
trials of proprietary compounds (where concomitant cholinergic therapy was allowed) are not yet public and therefore not available
for review.
ChEI and memantine: Memantine, as an add-on therapy for patients with moderate-to-severe AD on stable doses of donepezil, showed significant benefits
on several primary and secondary outcome measures in a 24-week multicenter trial involving 404 patients with moderate-to-severe
AD [Mini-Mental State Examination (MMSE) score of 5 to 14, mean 7.9 3.64].6 The average duration of therapy was 129 weeks in the placebo group and 126 weeks in the combination group. Subjects were
randomized to receive memantine, titrated to 10 mg bid, or placebo, in addition to donepezil. The donepezil-memantine group
performed better than the donepezil-placebo group on cognition (Severe Impairment Battery, SIB), activities of daily living
(AD Cooperative Study-Activities of Daily Living Inventory, ADCS-ADL19), and key secondary endpoints, including Clinician's
Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory (NPI), and the Behavioral
Rating Scale for Geriatric Patients (BGP Care Dependency Subscale). The combination was well tolerated. Despite objectively
measurable benefits, improvements exerpienced by the individual patient remain to be better characterized.
Although this was a well-designed and clearly positive study, it did not address the question of whether adding memantine
to donepezil is better than switching from donepezil to memantine monotherapy. This study showed a 3.4-point reduction on
the SIB between the donepezil-memantine and donepezil-placebo groups (a 3-point reduction on the SIB is approximately equivalent
to a 1-point reduction on the MMSE in severe dementia, the exact significance of this as experienced by the individual patient
is often difficult to detemine). However, in a study of memantine alone for moderate-to-severe AD, Reisberg et al showed that
the memantine group lost an average of 6.1 fewer points on the SIB than placebo group.12 The smaller effect in the combination study suggests that donepezil may also be effective in moderate-to-severe AD because
donepezil could have contributed to the lower benefit observed in the combination study.
The benefit of donepezil in moderate-to-severe AD was also shown in a recent study.13 However, as the populations enrolled in the two studies differ, such indirect comparison warrants caution. Further, since
the study did not include rivastigmine or galantamine, its application to patients on other ChEIs in moderate-to-severe AD
awaits further evidence.
Antioxidant combinations: Another large scale RCT (n = 341), sponsored by the National Institutes of Health (NIH), compared patients with moderate AD
on placebo, vitamin E (alpha-tocopherol), 1,000 IU bid; selegiline, 10 mg/d; and a combination of vitamin E and selegiline,
over 2 years.7 The combination of vitamin E and selegiline was effective but less so than either agent alone. After adjustment for baseline
MMSE, each of the active treatments significantly delayed the time to primary outcome, defined as time to occurence of death,
institutionalization, loss of ability to perform basic ADLs, or severe dementia with Clinical Dementia Rating of 3, by 670
days for vitamin E (p = 0.001), by 655 days for selegiline (p = 0.012), and by 585 days for the combination (p = 0.049) as compared with placebo (440 days).
Despite randomization, there was a trend toward higher baseline MMSE scores in the placebo group and lower baseline MMSE scores
in the vitamin E group. Only after adjusting for baseline MMSE did the primary endpoints demonstrate difference among the
treatment and placebo groups. Secondary outcomes included six additional measures of cognition, behavior, and function (MMSE,
AD Assessment Scale, Blessed Dementia Scale, Equivalent Institutional Service, Dependence Scale, and Behavior Rating Scale
for Dementia). Two of the measures, the Blessed Dementia Scale and the Dependence Scale, showed significant differences between
the treatment groups compared with placebo, but again no difference between monotherapy compared with the combination. The
need to adjust for baseline MMSE despite initial randomization potentially introduced bias and weakened the study's conclusions.
An accompanying editorial also raised a concern about the validity of the composite outcome measure used.14 Therefore, it is difficult to draw definitive conclusions from this study.
The efficacy of the selegiline and vitamin E study raises the question of whether vitamin E or selegiline might be added to
a ChEI. Despite little evidence for its use, the combination of vitamin E with a ChEI has achieved widespread popularity among
clinicians, largely because of the negligible toxicity of vitamin E.
An observational cohort study has reported efficacy of a donepezil and vitamin E combination.10 The authors reviewed 130 charts from 1997-2001 and included 40 patients (MMSE 10 to 24) who were on stable doses of donepezil
(> 5 mg/d) and vitamin E (> 1,000 IU/d) over a 3-year period. This cohort was compared with patients from the Consortium to
Establish a Registry for AD (CERAD) database from 1986-1996. It showed that cumulative MMSE score deterioration on the combination
therapy was 1.43 4.19, 4.05 4.75, and 6.27 5.68, for years 1, 2, and 3, respectively. Average cumulative change in the
CERAD group was 3.36 4.57, 6.515.36, and 9.12 6.01 after 1, 2, and 3 years, respectively. The treatment group performed
significantly better than the CERAD controlled group (which received no treatment). The use of a non-randomized, retrospective
cohort as the control group severely limited the internal validity of this study. Thus, the donepezil and vitamin E combination
is not supported by current evidence; additional prospective trials are needed.
ChEI and estrogen: ChEI and estrogen combination therapies have been studied in two RCTs and several retrospective analyses.8-9 In a post-hoc analysis of a tacrine trial (n=343; MMSE 10 to 26), patients on estrogen replacement therapy prior to study
entry improved on the AD Assessment Scale-Cognitive Scale (ADAS-Cog) and CIBIC more than women not receiving estrogen who
were randomized to either tacrine or placebo.8 The study's conclusions were limited by its retrospective design and possible selection bias (eg, women who were taking estrogen
were younger and better educated).
A rivastigmine and hormone replacement therapy (HRT) combination was studied in a 28-week RCT (n=117) in mild-to-moderate
AD (MMSE 10 to 26). Compared with rivastigmine and placebo, the combination was no better in several measures including ADAS-Cog,
Instrumental Activities of Daily Living Scale (IADL), NPI, and Clinical Global Change Scale (CGC-plus).9 Because each arm had less than 60 patients, under-powering is possible.
The estrogen story exemplifies the need for prospective studies since previous retrospective studies favoring estrogen use
were not confirmed by RCTs. In fact, data from the Women's Health Initiative has shown that HRT (as conjugated equine estrogen)
may contribute to the risk of dementia.15 Therefore, conclusions drawn from observational or retrospective studies may be premature and need to be cautiously interpreted.
Other emerging studies. Because inflammation and atherosclerosis have been postulated as additional mechanisms contributing to AD,3 nonsteroidal anti-inflammatory drugs (NSAIDS) and statins have been investigated as additional treatment options. Epidemiologic
studies showed that NSAIDS appear promising in AD, although with mixed results.16 Several RCTs (6 to 12 months) in mild-to-moderate AD patients comparing cyclooxygenase-2 (COX-2) inhibitors versus placebo
have been completed but not published.
Statin use was examined in a retrospective analysis of three trials with AD patients (n = 1,325) on galantamine, in which
6.9% of the patients were on statins. Patients who were on statins did not show additional cognitive benefits over those not
taking statins, but tended to have more motor side effects.16 Several prospective studies with statins are underway. One pilot study of 64 mild-to-moderate AD patients taking atorvastatin
and concurrent ChEIs reportedly showed promising results by slowing decline on the MMSE and ADAS-Cog.17
Ongoing trials of various other strategies, including vitamins, mifepristone (glucocorticoid antagonist), anti-amyloid agents,
growth factors, antidepressants,18 and antipsychotics have permitted concurrent use of ChEIs and hence are de-facto combination drug therapy studies. The results
of these trials are anticipated.
Future needs Whereas a definitive cure for Alzheimer's disease is unlikely in the near future, it can be predicted that multiple interventions
will be needed. Currently, only combinations of symptom-targeted therapies are feasible in practice because these are the
only agents clinically indicated in patients with AD. ChEIs, memantine, or both will likely become foundation therapies to
which other agents are added. Premature adaptation of results from retrospective studies into clinical practice should be
cautioned. Conclusions from retrospective investigations have not necessarily endured the more rigorous RCT design. Nevertheless,
due to limited resources, it is not feasible to test every possible combination. Thus, rational combinations will need to
be selected based on monotherapy trials, available experimental data, and the drugs' relative safety.
This review did not find any evidence to support definitively the use of initial combination drug therapy in early AD. The
study on the use of memantine in moderate-to-severe AD as an add-on combination to ChEIs is not only a positive study but
also is likely the most judiciously designed study published thus far. Lessons can be learned from this study and from failed
combination drug therapy studies with respect to well-defined a priori clinical outcome measures, statistical power calculation, internal validity, and avoidance of premature conclusions from
post-hoc analyses.
Additionally, use of clinical, neuropsychologic, and imaging outcomes in the future may increase the sensitivity of detecting
combination regimens that are effective in modifying the course of AD.
Given the widespread use of off-label therapies in AD, our review highlights the paucity of published prospective combination
drug therapy trials in AD and the lack of efficacy for most combinations evaluated to date. As our population ages and the
prevalence of AD rises, there is an urgent need for collaborative efforts between government, industry, academia, and patient
groups to address this gap.
Dr. Xiong is chief resident in internal medicine and psychiatry at Duke Univeristy Medical Center, Durham, NC.
Dr. Doraiswamy is director, psychiatry clinical trials, Duke University Medical Center, Durham, NC.
Disclosure: Dr. Xiong has no real or apparent conflict of interest with the subject under discussion. Dr. Doraiswamy has received research
grants and honoraria from Forest, Pfizer, Eisai, Novartis, and Janssen, pharmaceutical companies that market or develop dementia
drugs.
This review is based on a talk given by Dr. Doraiswamy at the 2003 annual meeting of the American Psychiatric Association.
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