effects of rofecoxib or naproxen vs placebo on ad

8/9/2019 Effects of Rofecoxib or Naproxen vs Placebo on AD

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Paul s. Aisen; Kimberly A. Shafer;

Michael Grundman et al

Effects of Rofecoxib or Naproxen

Vs Placebo on Alzheimers Diseaseprogression


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3/20

Definition

Alzheimer's Disease (AD): is the leading

cause of senile dementia, it usually starts in

the 40s or 50s; first symptoms are impairedmemory which is followed by impaired

thought and speech and finally complete

helplessness.(WordNet 2.0)


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Context

There are laboratory evidence that

inflammatory mechanisms contribute to

neuronal injury in Alzheimer disease (AD);along with epidemiological evidence

suggesting that nonsteroidal anti-

inflammatory drugs (NSAIDs) mayfavorably influence the course of the

disease.


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Purpose

To determine whether treatment with a

selective cyclooxygenase (COX) -2

inhibitor(rofecoxib) or a traditional

nonselective NSAID (naproxen (Aleve) slows

cognitive decline in patients with mild-to-

moderate AD.


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The Study

Where: George Town University Medical Center,

Washington DC(?)

When: between 2000 and 2003. Published in 2003 Sample:Of 474 screened, 351 participated: 51y.o or more,

with mild to moderate AD

Intervention: Rofecoxib 25 mg daily or naproxen 220 mg

twice daily or placebo for 1 year with 2 months of

washout.

Funding: grants from the National Institute on Aging and

the General Clinical Research Center Program of the

National Center for research Resources; BayerConsumer,

Inc provided Naproxen and matching placebo


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The Sample


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Methodology: study design

Multi-centers (40 centers)

Randomized Controlled Trial (RCT)-

Phase II. (p. 88-90 Research Techniques for the Health Sciences. 4th ED)

Pretest-posttest control group design.(p.87)

3 groups parallel design (here 2 groups

received the drugs instead of only 1) (p.90)

Double-blind (p.82)


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Methodology:Outcome

Measures (Instruments)Alzheimers Disease Assessment Scale-Cognitive (ADAS-Cog) subscale

Clinical Dementia Rating sum-of-boxes(CDR-SOB)

Alzheimers Disease Cooperative Studyactivities of daily living (ADCS-ADL) scale

Neuropsychiatric Inventory (NPI)

Quality of Life-AD (QOL-AD)


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Methodology: Statistical

AnalysisPrimary Analysis (comparison of the change

in ADAS-Cog score)

ANCOVA (Intent to treat basis): analyzesdifferences of the experimental groups on

the dependent variable only after initial

differences on the pretest measures aretaken into account.(p.77, Research Techniques for the Health Sciences. 4th ED)


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Methodology: Statistical

Analysis (cont.)Secondary Analysis (change in ADAS-Cog scores)

Last Observation Carried Forward (dropout)

Analysis of completers only (those who completedthe week 52 visit)

Longitudinal regression analysis (pair-wisecomparison of the naproxen vs. placebo and

rofecoxib vs. placebo)Cox Proportional hazards Model (survival

analysis)


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Results


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Adverse events results


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Results

Test scores among the three groups were not

statistically different, but the trend in the rofecoxib

group was toward greater cognitive decline (mean

change in ADAS-Cog scores were -5.7, -5.8, and

-7.7 for placebo, naproxen, and rofecoxib groups,

respectively). In contrast, ADCS-ADL scores

indicated some benefit from use of rofecoxib, but the

authors suggest that this may be related to an

analgesic effect-patients feeling better and being more active-

rather than a direct effect on AD.


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Results

The primary outcome measure (ADAS-Cog

score) showed no difference between the

placebo and treatment groups with either ofthe NSAIDs.

The secondary outcomes showed no

evidence of a treatment effect.


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Conclusion

The results show that neither naproxen nor

rofecoxib slow cognitive decline in people

with mild to moderate Alzheimers disease.

At 1 year, there were no significant

differences in either cognitive decline or any

of the secondary outcome measures among

Groups.


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Discussion

Objective was clearly stated and matched

the study.

The sample size and selection

The methodology used

Results: external and internal validity

The research can be replicated

The topic of the study is an important one


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Discussion (cont.)

The choice of testing 2 different NSAIDs

for the study design was appropriate

because no consensus exists to date onwhich type of NSAID might work best

against AD inflammation or lesions while

causing the fewest adverse effects.


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Discussion (cont.)

Few data suggest that NSAIDs may be effective in

slowing the progression of AD in patients who

already have the disease. This study was based on

only 1 pilot trial conducted in 1993 that showed a

beneficial effect of indomethacin (NSAID) for slowing the

progression of AD in patients.

the previous epidemiologic data supported a role for

NSAIDs in prevention of AD and not in treatment.Thus, it is not necessarily surprising that no benefit

was observed in this patient trial.


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Discussion (cont.)

There were some interesting results in the Adverse

Events section with the report of new cases of

hypertension in the active groups as Rofecoxib underthe brand name Vioxx was removed from the market

due to an association with increased cardiovascular

events.

This study is an important contribution to the

collective effort to evaluate therapeutic strategies to

treat or prevent AD.

effects of rofecoxib or naproxen vs placebo on ad

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