A total of 2984 articles on NSAIDs and GI complications were identified. Of these, 2974 articles were identified in the PubMed search and ten additional articles were identified through the references of relevant studies (figure 1). The review of titles and abstracts of these studies led to select 59 articles for full data abstraction. After review of the abstracted information, 28 studies on the use of individual NSAIDs and the risk of UGIC met the inclusion criteria and were included in the meta-analysis.[7,11–35] The remaining 31 articles were excluded for the following reasons: the reference group was other than non-use of NSAIDs in nine studies;[36–44] the outcome was overall upper and lower GI complications in three studies;[45–47] the outcome was uncomplicated upper GI events in two studies;[48,49] the study population was restricted to users of specific drugs or to patients with specific diseases in three studies;[50–52] the study population and the study period overlapped in four studies;[53–56] and the study design did not meet the inclusion criteria in ten studies (i.e. different type of study or measures of association and exposure assessment).[57–66]
Selected characteristics of the 28 studies included in the meta-analysis are summarized in table I; 3 studies were cohort studies,[20,24,26] 10 were nested case-control studies,[7,11,17–19,23,25,33,35,67] and 15 were case-control studies.[12–16,21,22,27–32,34,68] Twelve studies, all case-control studies, were field studies collecting individual information by standardized questionnaires. The 16 remaining studies used information recorded in healthcare databases.
Cases were defined as hospitalization or referral to a specialist for upper GI bleeding in 13 studies,[12,15,16,19–22,27–30,33,34] and for bleeding and/or perforation in 15 other studies; four studies also included cases of uncomplicated peptic ulcer.[14,17,33,68] The site of complication was defined as gastric and/or duodenal in all studies, and two included oesophageal complications.[12,32] Most studies, both field and database studies, required information from endoscopy or other diagnostic procedures to confirm UGIC. Six studies conducted in healthcare databases did not conduct any validation of the cases identified.[14,17–20,68] Sixteen studies reported aggregate results for patients with and without a history of UGIC,[7,12–14,16,20–23,28,31–34,67,68] and 12 provided results for patients without a history of UGIC;[11,15,17–19,24–27,29,30,35] the remaining study was a case-crossover study. Most studies excluded subjects with a history of a known cause of UGIC, including the use of gastrotoxic medications and life-threatening diseases (table II). Four studies did not have any exclusion criteria.[20,22,28,34] Among the 14 case-control studies, seven included hospital controls;[12,13,16,21,29–31] five included both hospital and community controls;[22,27,28,32,34] one included community controls; and two were case-crossover studies.[14,68] All case-control studies were matched on age, sex (except one study), hospital or geographic area, and index date. Three of the case-control studies with hospital and community controls estimated separate results for each set of controls;[22,28,34] as results between the two sets were similar, we included in the meta-analysis results reported using hospital controls. In cohort studies, current use of NSAIDs was defined as the time covered by each prescription,[20,24] and one study extended the coverage by 15 days. Most case-control studies defined current use of NSAIDs as any use ending at the index date or within 7 days before the index date. A few case-control studies considered current use as that ending up to 30 days[11,13,17,19,28,35] or 90 days before the index date. Two cohort studies focused on new users of NSAIDs,[20,26] and one nested case-control study provided results for both new users and all users (incident and prevalent) of NSAIDs. In addition to age and sex, the most frequent confounders considered were a history of peptic ulcer (21 studies),[7,11,15–31,35,67] smoking (13 studies),[7,11,15,18,20,21,23,27–32] alcohol use (9 studies),[7,15,19,21,27,28,30–32] use of proton-pump inhibitors and anti-ulcer medications (11 studies),[16–23,30,67,68] and concurrent use of medications increasing the risk of UGIC (16 studies).[7,11,15,16,19–21,23,27,29–31,33,35,67,68] The quality of the studies measured with the NOS was, in general, very good: for the selection component, 12 studies had the maximum score of 4[7,11,15,22–25,32,33,35,67,68] and 13 studies had the next highest score of 3;[13,14,16–19,21,26,28,29,30,32,34] for comparability, 24 studies had the maximum score of 2;[7,11,14–19,21–33,35,67,68] and for the exposure/outcome component, 14 studies had the maximum score of 3[7,11,13,17–19,23–26,33,35,67,68] and 10 studies had the next highest score of 2.[12,14,16,20,21,28–30,32,34]
The studies included in the meta-analysis allowed us to estimate pooled RRs for the current use of 16 different NSAIDs (table III and figure 2). Forest plots for each individual NSAID are available in the SDC. Using random-effects models, pooled RRs ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone. Pooled RR was less than 2 for aceclofenac, celecoxib and ibuprofen; between 2 and less than 4 for rofecoxib, sulindac, diclofenac, meloxicam, nimesulide and ketoprofen; between 4 and less than 5 for tenoxicam, naproxen, indometacin and diflunisal; and greater than 5 for piroxicam, ketorolac and azapropazone. Pooled RRs from studies providing results for patients without a history of UGIC were similar to those from the overall analysis except for naproxen (more than 10% change), 3.10 (95% CI 2.45, 3.91) and diclofenac, 3.76 (95% CI 2.71, 5.21). Data in patients with a history of peptic ulcer disease were available only for celecoxib (two studies) and rofecoxib (one study).[67,68] The pooled RR for celecoxib in this population was 1.50 (95% CI 1.16, 1.94).
Pooled RRs from case-control studies were higher than those from cohort studies for all NSAIDs except ibuprofen, ketorolac and sulindac. In general, pooled RRs from fixed-effects models were slightly lower than those from random-effects models. In general, there was significant heterogeneity between studies, which decreased in the subsequent subgroup analysis exploring methodological and clinical diversity.
Pooled RRs for the effect of daily dose were estimated for eight different NSAIDs. Cut-off values used in each study to define the daily dose of each NSAID are presented in table IV. Variations in cut-off values were, in general, small except for those used for ibuprofen (200 mg) and naproxen (220 mg) in one study, and for ibuprofen (≪2400 mg) in another study. RRs for the use of high daily doses of NSAIDs were approximately 2- to 3-fold greater than RRs for low-medium doses (figure 3). The pooled RR for high daily dose of ibuprofen was similar to that for high daily dose of diclofenac. Exclusion of results from the studies with different cut-off values for ibuprofen[14,33] and naproxen did not substantially change the pooled results for these individual NSAIDs. For ibuprofen, RRs were 2.15 (95% CI 1.66, 2.79) for low-medium dose and 4.22 (95% CI 1.76, 10.12) for high dose. For naproxen, the RR for low-medium daily dose was 3.62 (95% CI 2.62, 4.99) [the excluded study did not provide data on high dose].
A total of 12 studies provided results specifically for upper GI bleeding for eight different NSAIDs; ten of these studies were case-control field studies. Pooled RRs were higher than those from all UGIC (bleeding, perforation and/or obstruction). Pooled RRs were 1.09 (95% CI 0.77, 1.53) for celecoxib; 1.43 (95% CI 0.65, 3.15) for aceclofenac; 1.88 (95% CI 1.00, 3.51) for ibuprofen; 2.25 (95% CI 1.56, 3.25) for rofecoxib; 4.20 (95% CI 3.03, 5.83) for diclofenac; 5.64 (95% CI 3.60, 8.83) for indometacin; 5.72 (95% CI 3.83, 8.53) for naproxen; and 13.36 (95% CI 9.62, 18.54) for piroxicam.
Pooled RRs from studies conducted from the year 2000 onward[7,15–18,21,67,68] were slightly higher than those from studies conducted before the year 2000 for ibuprofen, 2.13 (95% CI 1.66, 2.73) versus 1.50 (95% CI 1.12, 2.01); ketoprofen, 4.28 (95% CI 2.36, 7.76) versus 3.70 (95% CI 2.27, 6.05); and nimesulide, 3.89 (95% CI 3.18, 4.74) versus 3.50 (95% CI 2.03, 6.03); but lower for diclofenac, 3.08 (95% CI 2.47, 3.84) versus 3.63 (95% CI 2.81, 4.70).
Only one study provided information on the effect modification of gastroprotective agents. In that study, RRs for all individual NSAIDs were lower among patients receiving ulcer-healing drugs than among those not receiving them.