Meta-Analysis of Nonsteroidal Antiinflammatory Drug Use and Risk of Dementia

Anton J. M. de Craen , Jacobijn Gussekloo, Bram Vrijsen and Rudi G. J. Westendorp

From the Section of Gerontology and Geriatrics, Department of General Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.

Received for publication March 23, 2004; accepted for publication August 11, 2004.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The authors performed a systematic review to summarize the epidemiologic evidence on the association between use of nonsteroidal antiinflammatory drugs (NSAIDs) and the risk of dementia. A total of 25 case-control and cohort studies that reported an odds ratio/relative risk were included. Study-specific log relative risks were weighted by the inverse of their variances to obtain pooled relative risks and 95% confidence intervals. The authors divided the reports into studies with prevalent dementia cases, studies with incident dementia cases, and studies where cognitive decline was used as the clinical endpoint. The pooled relative risks of the three groups of studies were 0.51 (95% confidence interval (CI): 0.37, 0.70), 0.79 (95% CI: 0.68, 0.92), and 1.23 (95% CI: 0.70, 2.31), respectively. Within these subgroups, heterogeneity was present only in the studies with prevalent cases (p = 0.001). Because the benefit of NSAIDs in preventing dementia or cognitive impairment was 50% in studies with prevalent dementia cases, declined to 20% in studies with incident dementia cases, and was absent in studies where cognitive decline was used as the endpoint, the authors conclude that most of the reported beneficial effects of NSAIDs may result from various forms of bias: recall bias, prescription bias, and publication bias.

Alzheimer disease; anti-inflammatory agents, non-steroidal; dementia; meta-analysis


Abbreviations: CI, confidence interval; NSAID(s), nonsteroidal antiinflammatory drug(s).


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Many observational studies have investigated the association between use of nonsteroidal antiinflammatory drugs (NSAIDs) and risk of Alzheimer’s disease, dementia, and cognitive decline (130). Studies differed greatly in design, population, and exposure. Many found an inverse association while others found no association. More recently, the results of a number of secondary prevention studies have been reported. Most of them showed no beneficial effect of use of NSAIDs on cognitive function (3133). Results of primary prevention trials are not available. Hence, whether NSAIDs truly have a favorable effect in preventing dementia remains controversial (34). We performed a systematic review of the literature to summarize the epidemiologic evidence on the association between use of NSAIDs and the risk of dementia and to identify possible sources of heterogeneity between studies.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Systematic search
We started by using a widely quoted 1996 review on NSAIDs and risk of Alzheimer’s disease (35) in two ways: 1) we evaluated the articles that were included in that review and 2) we used the Science Citation Index to identify studies that cited that review. Next, we searched the MEDLINE database using the search term "NSAID" combined with "Alzheimer’s disease," "dementia," or "cognitive decline," limited to studies in humans. We did not apply any language restriction. Titles and abstracts of both search strategies were independently examined for eligibility by two of us (A. J. M. C. and J. G.). In case of doubt, the full article was retrieved and eligibility was discussed. Both original articles and reviews were retrieved. This whole process was repeated for references from identified studies and reviews.

Eligibility criteria and data collection
Studies were eligible for inclusion if they satisfied the following three criteria: 1) case-control or cohort study in humans, 2) exposure defined as use of NSAID, and 3) cases defined as Alzheimer’s disease, dementia, or cognitive impairment.

Data were independently extracted from each study by two reviewers (A. J. M. C. and J. G.) using preprinted forms. We recorded study design, characteristics of exposure, definitions of cases and controls, prevalent or incident case ascertainment, total number of cases in the exposed group and total number of cases in the unexposed group, the measure of association (odds ratio, relative risk, or hazard ratio), the magnitude of the association with its corresponding 95 percent confidence interval, and the variables adjusted for in the analysis. When separate results were reported within one study for both Alzheimer’s disease and dementia, the results for dementia were recorded. When varying levels of NSAID use were reported, we took the results for the largest group of NSAID users.

Statistical analysis
Results of cohort studies were typically expressed as relative risk or hazard ratio, while results of case-control studies were usually expressed as odds ratio. A hazard ratio is the ratio of instantaneous probability of the outcome event (Alzheimer’s disease, dementia, or cognitive decline) in the exposed group compared with that in the nonexposed group and can be considered a relative risk. Because dementia is a rare event (<5 percent), odds ratios from case-control studies are also good estimates for the relative risk. For simplicity, we refer to relative risk for all three types of measures of association. The logarithm of the relative risk with its corresponding standard error, taken directly from the studies or calculated from the reported 95 percent confidence interval, provided the data points for the meta-analysis. We used the DerSimonian and Laird (36) random effects model to compute pooled relative risks and to assess statistical heterogeneity. We did not exclude outliers simply on the basis of the statistical test, because heterogeneity is expected in a meta-analysis of epidemiologic studies, but we searched for the sources (i.e., methodological or biologic). Subgroup and sensitivity analyses were carried out when appropriate. We evaluated publication bias by means of visual inspection of funnel plots and formal statistical testing (37). In a funnel plot, the relative risk of the study is displayed against the weight of the study, which is the inverse of the square of the standard error. Funnel plots generally show a peak. This is the point where the studies with smaller standard errors are found and usually represents the point of the approximate true effect. Formal statistical assessment of funnel plot asymmetry was done with linear regression analysis, where the log odds ratio divided by its standard error was regressed against the inverse of the standard error (37). Reported p values are from the intercept of the regression analysis, which provides a measure of asymmetry. Case-control studies with incident dementia cases and cohort studies were classified as studies with incident cases. Studies where cognition was the main outcome of interest among users and nonusers of NSAIDs were classified as studies with cognitive decline cases.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Searching the Science Citation Index yielded 402 publications referring to the review of McGeer et al. (35), and the MEDLINE search yielded 337 publications. After retrieval of potential articles and subsequent discussion, we found 30 studies meeting our eligibility criteria (130). Four studies (14) were excluded because a relative risk could not be extracted from the report (one study did not report on the association (1), two studies found no association (2, 3), and one study compared the cognitive function of patients who had Alzheimer’s disease and were taking NSAIDs with that of patients who had Alzheimer’s disease and were not taking NSAIDs (4)), and one study (5) was excluded because it was based on the same data as another publication. Descriptive details of the remaining 25 studies included in our meta-analysis are presented in table 1. Eleven studies used prevalent cases (616), 10 studies used incident cases (1726), and four studies used cognitive decline as clinical outcome (2730). Both the definition and length of exposure of use of NSAIDs varied among studies.


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TABLE 1. Description of studies on the use of nonsteroidal antiinflammatory drugs and risk of dementia
 
Table 2 presents the individual relative risks of all 25 retrieved studies. We divided the reports into studies with prevalent cases, studies with incident cases, and studies with cognitive decline as the endpoint. The funnel plot (figure 1) shows the relative risks of the 25 studies plotted against their weights. A relative risk smaller than one indicates that use of NSAIDs is beneficial. The pooled relative risks of these three groups of studies were 0.51 (95 percent confidence interval (CI): 0.37, 0.70) for studies with prevalent dementia cases, 0.79 (95 percent CI: 0.68, 0.92) for studies with incident dementia cases, and 1.23 (95 percent CI: 0.70, 2.31) for studies with cognitive decline as the endpoint. Within these subgroups, heterogeneity was present in the studies with prevalent cases (p = 0.001) but not in the studies with incident cases (p = 0.60). Statistical testing for heterogeneity of studies where cognitive decline was used as the endpoint gave a p value of 0.08. Within the three subgroups, there was an indication for the presence of publication bias in the studies with prevalent cases (p = 0.04), whereas there was no indication in the studies with incident cases (p = 0.96) or in the studies where cognitive decline was used as the endpoint (p = 0.38).


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TABLE 2. Summary results of studies on the use of nonsteroidal antiinflammatory drugs and risk of dementia
 


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FIGURE 1. Funnel plot of relative risks of 25 studies of use of nonsteroidal antiinflammatory drugs and risk of dementia. "Weight" is the study weight calculated from the inverse of the square of the standard error of the log relative risk.

 
Furthermore, we analyzed the case-control studies with incident dementia cases and cohort studies separately. The case-control studies with incident dementia cases gave a pooled relative risk of 0.77 (95 percent CI: 0.61, 0.96), while the cohort studies gave a pooled relative risk estimate of 0.79 (95 percent CI: 0.61, 1.01).

Finally, the results of the randomized clinical trials that evaluated the efficacy of an NSAID against placebo are presented in table 3. All trials included patients with Alzheimer’s disease or patients with probable Alzheimer’s disease. None of the trials showed a statistically significant reduction in cognitive decline.


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TABLE 3. Summary results of placebo controlled trials of the use of nonsteroidal antiinflammatory drugs in Alzheimer’s disease
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The results of our study indicate that the benefit of NSAIDs in preventing dementia and cognitive impairment was 50 percent in studies with prevalent dementia cases, declined to 20 percent in studies with incident dementia cases, and was absent in studies where cognitive decline was used as the endpoint.

There are at least three forms of bias that could explain why the benefit from NSAIDs was larger in studies with prevalent cases than in studies with incident cases: recall bias, prescription bias, and publication bias. First, subjects from studies with prevalent cases have impaired memory at the time of study, which makes data collection between cases and controls likely to be different, resulting in recall bias. Second, prescription bias occurs more frequently in studies with prevalent cases because demented patients have a reduced perception of pain (38, 39), possibly leading to a reduced use of NSAIDs. Moreover, because of the adverse effects of NSAIDs, physicians might be less inclined to prescribe NSAIDs to demented subjects. Hence, in the studies with prevalent cases, the reduced intake of NSAIDs might be more the consequence of the dementia than the cause. Third, it is apparent from the funnel plot that the studies with prevalent cases are more heterogeneous and more skewed to the left than the follow-up studies, resulting in larger pooled estimates of benefit of NSAID use in these studies.

We found no difference in relative risk between the case-control studies with incident dementia cases and cohort studies, although the potential for recall bias in case-control studies is theoretically higher. However, a total number of 10 studies to investigate the presence of recall bias is rather small. Therefore, the interpretation of the absence of a significant difference between the two types of design with incident dementia cases should be interpreted with caution.

There were 10 studies with incident cases of dementia. Within these 10 studies, there were four case-control studies with incident dementia cases and six cohort studies. Both types of study gave a similar pooled estimate of relative risk. If recall bias was a major form of bias, the relative risk of the case-control studies should have been smaller. However, because of the wide confidence intervals around both estimates (because of the small number of studies), it is difficult to ascertain whether the studies truly had equal estimates.

There was a significant association between NSAID use and studies with incident cases of dementia, while there was no significant association in studies where cognitive decline was used as the outcome. Prescription bias might also be the cause of this difference. Incident subjects with cognitive decline will be relatively free from cognitive dysfunction at baseline, while incident cases with dementia are in a relatively later stage of the disease. In the earlier stages of the disease, prescription bias might not be present. To explore whether prescription bias is the cause of the observed association between NSAID use and Alzheimer’s disease or whether there is a true beneficial effect, we decided upon randomized clinical trials whose patients were without early signs of Alzheimer’s disease (40).

If the period between NSAID use and disease onset is relatively short, then it is difficult to differentiate between cause and effect. With a short period between exposure and outcome, reduced intake of NSAIDs among subjects with dementia could also be the consequence of the disease. Four studies (14, 16, 20, 26) tried to avoid this bias by evaluating the use of acetaminophen, to control for differing patterns of drug use between demented and nondemented subjects. Many authors argued that, because the demented and nondemented subjects did not differ in their acetaminophen use but did vary in their NSAID use, NSAIDs must be associated with better cognitive function. We think, however, that, in demented patients who might report less pain than nondemented subjects, NSAIDs are the first drugs to be prescribed less frequently. This means that studies with prevalent cases are more likely to suffer from prescription bias than studies with incident cases.

Because Alzheimer’s disease, the most common dementia, has an insidious onset, it is also important to know what the different studies used as the index date. All studies with prevalent cases took the date of diagnosis of dementia, while three studies with incident dementia cases took the date of first symptoms of disease (17, 21, 24), and seven studies with incident dementia cases used the date of diagnosis of dementia. The three studies where the date of onset of symptoms was used had similar relative risk estimates as the seven studies where the date of diagnosis was used.

Some publications used in this meta-analysis originate from one cohort. For example, the Canadian Study of Health and Aging and the Rotterdam Study both contributed two publications. However, in both cases, one publication addressed the association in the prevalent dementia cases and the other publication addressed the association in the incident dementia cases. Hence, we decided to include both articles in our analyses. Moreover, the study named Established Populations for Epidemiologic Studies of the Elderly consists of four cohorts. In our analyses, we used estimates reported from the separate cohorts. The study reported by Saag et al. (27) uses data from the Iowa cohort, while Hanlon et al. (28) use data from the Duke cohort. The study reported by Rozzini et al. (5) uses data from the East Boston, Massachusetts, New Haven, Connecticut, and Iowa cohorts. In discussing their results, Rozzini et al. indicate that the study by Saag et al. is "substantially different in measure of cognitive functioning and analytical approach, ... making comparability between that study and our study problematic" (5, p. 1029). Including the study by Rozzini et al. in our analyses would have overweighted the data of the Iowa cohort in the Established Populations for Epidemiologic Studies of the Elderly. We could have chosen to include the study reported by Rozzini et al. in our analyses instead of the study by Saag et al. This would have resulted in a lower pooled relative risk. However, including the study reported by Rozzini et al. instead of the study by Saag et al. does not affect our interpretation of the data.

The five studies that used cognitive decline as the endpoint all used different cognitive measures. Hence, we cannot exclude that NSAIDs might have a beneficial effect on a specific cognitive domain. However, on average, the effect of use of NSAIDs on cognitive decline is null, which is consistent with the finding that most randomized trials so far have shown: no beneficial effect on the course of dementia as measured with the cognitive subscale of the Alzheimer’s Disease Assessment Scale. Moreover, the two studies that were excluded from our meta-analysis (2, 3) because a relative risk could not be extracted both showed no association between use of NSAID and cognitive decline.

A recent meta-analysis of NSAIDs and risk of dementia concluded, "NSAIDs offer some protection against the development of Alzheimer’s disease" (41, p. 128). This conclusion was based mainly on the observation that short-term users (<1 month) had far less risk reduction than long-term users (>24 months) (relative risk = 0.95 vs. 0.27, respectively). These authors did not address possible confounding factors (42), nor did they explain the discrepancy between the studies with prevalent cases and the studies with incident cases. Again, the discrepancy in risk reduction between short-term and long-term users can well be explained by recall bias and prescription bias. By including studies with cognitive decline as the endpoint and thereby creating more distance between exposure and effect, we now demonstrate that bias and confounding are more likely explanations for the observed association.

Traditional teaching holds Alzheimer’s disease and vascular dementia as two separate clinical entities that can be differentiated by careful clinical and necropsy evaluation. Several recent observations, however, suggest that the situation might be different. Vascular risk factors also contribute to Alzheimer’s disease (43) and, conversely, ß-amyloid depositions are also frequently found in subjects with vascular dementia (44). Hence, it is likely that Alzheimer’s disease and vascular dementia are two extreme expressions of one disease entity, dementia (45). A prominent feature of both disease entities is progressive cognitive decline. Hence, combining and comparing the various endpoints in one analysis gives a good indication for the possible benefits of NSAIDs in the various stages of the disease.

Until now, most randomized clinical trials have found no beneficial effect of NSAIDs in preventing cognitive decline (3133). There might be three explanations for these negative studies. First, there is no protective effect of NSAIDs. Second, most of these studies were carried out in subjects with early signs of cognitive impairment. Administration of antiinflammatory drugs at that point in the disease process might simply be too late. Third, it has recently been demonstrated that various NSAIDs have differential propensities on the inflammatory response and deposition of ß-amyloid (46). This finding calls for identification of the critical pathways in the inflammatory response and the corresponding drugs that are capable of interfering in that pathway.

In conclusion, the benefit of NSAIDs in preventing dementia or cognitive impairment was 50 percent in studies with prevalent dementia cases, declined to 20 percent in studies with incident dementia cases, and was absent in studies where cognitive decline was used as the endpoint. This indicates that most of the beneficial effects of NSAIDs from observational studies are likely to be the result of recall bias, prescription bias, and publication bias. Before further large and costly trials are designed to assess the potential protective effects of NSAIDS, the specific critical pathways in the inflammatory process in dementia amendable to drug intervention should be identified.


    NOTES
 
Correspondence to Dr. A. J. M. de Craen, Section of Gerontology and Geriatrics, C2-R, Leiden University Medical Center, P.O. Box 9600, Leiden 2300 RC, the Netherlands (e-mail: craen{at}lumc.nl). Back


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 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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