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Review
. 2012 Dec 1;35(12):1127-46.
doi: 10.2165/11633470-000000000-00000.

Individual NSAIDs and Upper Gastrointestinal Complications: A Systematic Review and Meta-Analysis of Observational Studies (The SOS Project)

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Free PMC article
Review

Individual NSAIDs and Upper Gastrointestinal Complications: A Systematic Review and Meta-Analysis of Observational Studies (The SOS Project)

Jordi Castellsague et al. Drug Saf. .
Free PMC article

Abstract

Background: The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community's Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety.

Objective: The aim of this study was to conduct a systematic review and meta-analysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors.

Methods: We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed- and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies.

Results: A total of 2984 articles were identified and 59 were selected for data abstraction. After review of the abstracted information, 28 studies met the meta-analysis inclusion criteria. Pooled RR ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone. RR was less than 2 for aceclofenac, celecoxib (RR 1.45; 95% CI 1.17, 1.81) and ibuprofen (RR 1.84; 95% CI 1.54, 2.20); 2 to less than 4 for rofecoxib (RR 2.32; 95% CI 1.89, 2.86), sulindac (RR 2.89; 95% CI 1.90, 4.42), diclofenac (RR 3.34; 95% CI 2.79, 3.99), meloxicam (RR 3.47; 95% CI 2.19, 5.50), nimesulide (RR 3.83; 95% CI 3.20, 4.60) and ketoprofen (RR 3.92; 95% CI 2.70, 5.69); 4-5 for tenoxicam (RR 4.10; 95% CI 2.16, 7.79), naproxen (RR 4.10; 95% CI 3.22, 5.23), indometacin (RR 4.14; 95% CI 2.91, 5.90) and diflunisal (RR 4.37; 95% CI 1.07, 17.81); and greater than 5 for piroxicam (RR 7.43; 95% CI 5.19, 10.63), ketorolac (RR 11.50; 95% CI 5.56, 23.78) and azapropazone. RRs for the use of high daily doses of NSAIDs versus non-use were 2-3 times higher than those associated with low daily doses.

Conclusions: We confirmed variability in the risk of UGIC among individual NSAIDs as used in clinical practice. Factors influencing findings across studies (e.g. definition and validation of UGIC, exposure assessment, analysis of new vs prevalent users) and the scarce data on the effect of dose and duration of use of NSAIDs and on concurrent use of other medications need to be addressed in future studies, including SOS.

Figures

Fig. 1
Fig. 1
Flow diagram for identification of studies on upper gastrointestinal complications and individual NSAIDs. GI = gastrointestinal.
Table I
Table I
Description of observational studies on the risk of upper gastrointestinal complications associated with the use of individual NSAIDs
Table II
Table II
Exclusions applied in observational studies on the risk of upper gastrointestinal complicationsa
Table III
Table III
Individual and pooled relative risks (95% CIs) of upper gastrointestinal complications associated with the use of individual NSAIDs
Fig. 2
Fig. 2
Pooled relative risks and 95% CIs of upper gastrointestinal complications associated with the use of individual NSAIDs. Vertical bars denote 95% CIs.
Table IV
Table IV
Cut-off values (mg) used to define daily dosea of NSAIDs in observational studies on the risk of upper gastrointestinal complications
Fig. 3
Fig. 3
Pooled relative risks and 95% CIs of upper gastrointestinal complications associated with the daily dose of individual NSAIDs. See table IV for cut-off values used in each study to define high dose and low-medium dose. Vertical bars denote 95% CIs. HD = high dose; LD = low-medium dose.

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