RATIONALE: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed medicines, commonly used to mitigate pain, inflammation, and cardiovascular prevention, among others. Chronic NSAID consumption increases the risk of acute renal failure, stroke, myocardial infarction, and gastrointestinal toxicity, ranging from mild dyspepsia to serious ulcer complications such as bleeding, obstruction, and perforation. Proton pump inhibitors (PPIs) may exert a gastroprotective effect from NSAID gastroduodenal injury by reducing gastric acid secretion.
OBJECTIVES: To assess the effects of proton pump inhibitors on the prevention of dyspepsia and ulcers in people with chronic consumption of non-steroidal anti-inflammatory drugs.
SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid), and two trial registers up to 23 October 2023, as well as reference checking, citation searching, and contact with study authors to identify additional studies.
ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) and cluster-RCTs comparing PPIs taken orally versus placebo, histamine 2-receptor antagonists, misoprostol, or sucralfate in adults and children with chronic consumption of NSAIDs for four weeks or longer.
OUTCOMES: Our outcomes were global symptoms of dyspepsia, incident ulcer, adverse events, ulcer complications, and quality of life.
RISK OF BIAS: We used the Cochrane RoB 2 tool for RCTs and the tool extension for cluster-RCTs.
SYNTHESIS METHODS: We conducted meta-analyses using random-effects models to calculate risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes and mean differences (MD) and 95% CIs for continuous outcomes. Due to statistical heterogeneity, we conducted meta-analyses for all but two outcomes. We summarised the certainty of evidence according to GRADE methods.
INCLUDED STUDIES: We included 12 studies with 8760 participants. All studies were conducted in an outpatient setting in Africa, Asia, Europe, North America, Central America, South America, and Australia. They were published between 1996 and 2014. All studies measured outcomes in the short term (up to 12 months).
SYNTHESIS OF RESULTS: PPI versus placebo PPIs may have little to no effect on global symptoms of dyspepsia assessed as a dichotomous outcome, but the evidence is very uncertain (meta-analysis was not possible due to high and unexplained statistical heterogeneity and point estimates of RR ranged from 0.36 to 1.13; 8 studies; 4944 participants; very low-certainty evidence). PPIs probably result in a slight reduction in global symptoms of dyspepsia assessed as a continuous outcome (MD -0.56, 95% CI -0.74 to -0.38; 2 studies, 1149 participants; moderate-certainty evidence). PPIs probably result in a reduction in incident ulcers compared to placebo (RR 0.29, 95% CI 0.23 to 0.36; 11 studies, 7022 participants; moderate-certainty evidence). PPIs may have few or no adverse events, but the evidence is very uncertain (meta-analysis was not possible due to high and unexplained statistical heterogeneity and point estimates of RR ranged from 0.67 to 6.35; 12 studies, 7530 participants; very low-certainty evidence). PPIs may reduce ulcer complications compared with placebo (RR 0.33, 95% CI 0.10 to 1.07; P = 0.30; I= 18%; 5 studies, 4394 participants; low-certainty evidence). PPIs probably result in a slight increase in quality of life (MD 0.39, 95% CI 0.23 to 0.55; 2 studies, 1149 participants; moderate-certainty evidence). PPI versus histamine 2-receptor antagonists PPIs may increase incident ulcers (RR 2.00, 95% CI 0.21 to 19.44; 1 study, 26 participants; low-certainty evidence). The included study did not report data on global symptoms of dyspepsia, adverse events, ulcer complications, or quality of life. PPI versus misoprostol PPIs may increase incident ulcers (RR 2.32, 95% CI 1.25 to 4.30; 1 study, 402 participants; very low-certainty evidence) and may have fewer adverse events (RR 0.38, 0.25 to 0.57; 1 study, 402 participants; very low-certainty evidence), but the evidence is very uncertain. The included study did not report data on global symptoms of dyspepsia, ulcer complications, or quality of life. No studies compared PPI against sucralfate. Most included studies were at overall high risk of bias or overall some concerns of risk of bias. Imprecision in the effect estimates was also a concern. 2
AUTHORS' CONCLUSIONS: Compared with placebo, PPIs may have no effect on the presence of global symptoms of dyspepsia and probably result in a slight reduction in global symptoms of dyspepsia scales. PPI probably reduces incident ulcers and may have little to no effect on adverse events. PPIs may reduce ulcer complications and probably slightly increase quality of life. Compared with histamine 2-receptor antagonists, PPIs may increase incident ulcers. The evidence for this comparison came from only one study. Compared with misoprostol, PPIs may increase incident ulcers and may reduce adverse events, but the evidence is very uncertain. The evidence for this comparison came from only one study. The certainty of the evidence for most outcomes and comparisons was low or very low, except for global symptoms of dyspepsia measured as a continuous outcome, incident ulcer, and quality of life in the comparison of PPI versus placebo. Further research is needed to assess the effect of PPIs compared to other active treatments such as sucralfate, misoprostol, or histamine 2-receptor antagonists. Well-designed and reported studies focussing on patient-important outcomes and addressing the methodological limitations found in the present included studies would be informative. These could include different baseline ulcer risks, ages, and types of NSAIDs. Long-term follow-up would be beneficial.
FUNDING: This Cochrane review had no dedicated funding.
REGISTRATION: Protocol (2022): doi.org/10.1002/14651858.CD014585.
