shows the flow of participants through the trial15
; shows characteristics and validity of included studies; shows results from the meta-analysis; and figures , , and show forest plots of the primary outcomes.
Flow of studies through the trial
Results of a meta-analysis for the five gastroprotective strategies on primary and secondary health outcomes. Values are numbers of events (relative risks, with 95% confidence intervals) unless otherwise indicated
Effects of gastroprotective strategies on serious gastrointestinal complications
Effects of gastroprotective strategies on symptomatic ulcers
Effects of gastroprotective strategies on serious cardiovascular or renal illness
Effects of gastroprotective strategies on deaths
We found no evidence of publication bias in any of the five comparisons. The κ coefficient for agreement on allocation concealment was 0.36 (95% confidence interval 0.18 to 0.53), observed agreement 91.3%. Extra data from authors on outcomes and study design arrived for eight included studies.
H2 receptor antagonists plus non-selective NSAID versus placebo plus non-selective NSAID
Fifteen randomised controlled trials (including 2621 participants) studied this comparison; we assessed risk of bias as low in none of them.
Only one serious gastrointestinal event, one symptomatic ulcer, one death, and four serious cardiovascular events were reported, with no data on health related quality of life measures. Data were insufficient to draw conclusions on effect of H2 receptor antagonists compared with placebo on any primary outcomes. More data related to endoscopic ulcers, which were significantly reduced in participants on H2 receptor antagonists compared with placebo (relative risk 0.55, 95% confidence interval 0.4 to 0.7). Subgrouping was not possible owing to paucity of primary outcomes.
Proton pump inhibitors plus non-selective NSAID versus placebo plus non-selective NSAID
Six randomised controlled trials (1358 participants) compared proton pump inhibitors with placebo; we assessed one as having a low risk of bias.
Few studies reported this review's primary outcomes. It was not possible to assess the effect of proton pump inhibitors compared with placebo on serious gastrointestinal complications, serious cardiovascular or renal illness, quality of life, or death. The apparently significant reduction of symptomatic ulcers in patients taking proton pump inhibitors (0.09, 0.0 to 0.5) compared with placebo was lost on sensitivity analysis. Endoscopic ulcers seemed significantly reduced in participants taking proton pump inhibitors compared with placebo; this finding was stable to sensitivity analysis (0.37, 0.3 to 0.5).
Misoprostol plus non-selective NSAID versus placebo plus non-selective NSAID
Twenty three randomised controlled trials compared misoprostol with placebo (16 945 participants); we assessed one as having a low risk of bias.
Misoprostol significantly reduced serious gastrointestinal complications (0.57, 0.4 to 0.9), symptomatic ulcers (0.36, 0.2 to 0.7), and endoscopic ulcers (0.33, 0.3 to 0.4); all findings were stable to sensitivity analysis, with no apparent heterogeneity. No significant effects of misoprostol on serious cardiovascular or renal illness, deaths, anaemia or occult bleeding occurred, but few events had been recorded.
COX-2 selective NSAID versus non-selective NSAID
Fifty one randomised controlled trials compared COX-2 selective NSAIDs with non-selective NSAIDs (28 178 participants); we assessed the risk of bias as low in none of them.
Symptomatic ulcers were less likely in patients taking COX-2 selectives than in patients taking non-selectives (0.41, 0.3 to 0.7, result robust to sensitivity analysis, without apparent heterogeneity). Fewer than 50 events were reported for other primary outcomes, none reached significance. Few endoscopic ulcers occurred, with no significant differences from non-selectives.
COX-2 specific NSAID versus non-selective NSAID
Seventeen randomised controlled trials compared COX-2 specific NSAIDs with non-selective NSAIDs (25 564 participants). We assessed summary risk of bias as low in three studies.
Serious gastrointestinal complications (0.55, 0.4 to 0.8) and symptomatic ulcers (0.49, 0.4 to 0.6) seemed significantly reduced in participants randomised to COX-2 specifics compared with non-selectives (symptomatic ulcers, but not serious gastrointestinal complications, were robust to sensitivity analysis, both without apparent heterogeneity). Serious cardiovascular or renal illness and total deaths were not significantly different, and data were insufficient to draw conclusions regarding quality of life. Endoscopic ulcers were significantly less common in patients taking COX-2 specifics (0.25, 0.2 to 0.3, results stable to sensitivity analysis).
Associations between treatment effects and potential effect modifiers
Meta-regression found no significant relations between relative risk of symptomatic ulcers (for COX-2 selectives and specifics) or endoscopic ulcers (for H2 receptor antagonists, proton pump inhibitors, misoprostol) and duration of follow up, mean age, or baseline gastrointestinal status. The exception was between endoscopic ulcers and study duration for misoprostol, showing reduced protection from endoscopic ulcers in longer trials. Subgrouping trials by mean age (over 65 years or not) did not show any clear pattern in reductions of absolute risk for serious gastrointestinal events, symptomatic ulcers, or endoscopic ulcers, but data were sparse (not shown).
Numbers needed to treat to prevent one symptomatic ulcer
For misoprostol we could not calculate the number needed to treat to prevent one additional symptomatic ulcer for groups of people with normal gastrointestinal tracts, some erosions, or submucosal haemorrhages (but no frank ulcers) on endoscopy. It was infinite for H2 receptor antagonists and COX-2 specifics (risk differences zero), 14 (8 to 100) for proton pump inhibitors, and 17 (number needed to treat to harm 100 to ∞ to number needed to treat to benefit 8) for COX-2 selectives.