The review concluded that the use of proton-pump inhibitor or histamine₂ receptor antagonists may be associated with an increased risk of hospital-acquired or community-acquired pneumonia. Given the absence of high-quality evidence for an effect, the authors' conclusions should be treated with caution.

To evaluate the association between acid-suppressive drugs and risk of pneumonia.

MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to August 2009. Search terms were reported. The search was restricted to English language articles for observational studies. Bibliographies of relevant articles were handsearched.

Randomised controlled trials (RCTS), case-control or cohort studies that investigated the association between acid-suppressive drug use and the risk of pneumonia were eligible for inclusion. Studies had to report results for proton-pump inhibitors and histamine₂ receptor antagonists separately to be eligible for inclusion. Results of eligible trials had to be reported as adjusted odds ratios (ORs), relative risks (RRs) or number of events, with corresponding 95% confidence intervals (CI). RCTs that compared acid suppressing drugs with placebo or sucralfate were eligible for inclusion.

The included RCTs compared various acid-suppressing drugs including cimetidine, ranitidine, nizatidine, famotidine or histamine₂ receptor antagonists. Patients were selected from surgical units, trauma centres, medical, surgical, neurosurgical, paediatric or coronary intensive care units; some patients were severely injured or had intracerebral haemorrhage. For RCTs, the outcomes reported were the incidence of hospital acquired pneumonia.

The included observational studies evaluated the association between proton-pump inhibitors or histamine₂ receptor antagonists and the risk of hospital or community acquired pneumonia. The study period for observational studies ranged from one to 15 years.

Studies were conducted in the UK, USA, Canada, Australia, Netherlands, Denmark, Austria, Switzerland, Germany, Turkey, Czech Republic and India. Included studies were published from 1985 to 2009.

Two reviewers independently selected the studies for review with disagreements resolved by discussion or consultation with other reviewers.

The quality of RCTs was assessed using the Jadad scale for items on randomisation, blinding and withdrawals/dropouts, with a maximum score of 5 points. High quality was defined as a score of 4 or 5 points.

The quality of observational studies was assessed using the Newcastle-Ottowa Scale for items on participants, comparability of groups and the ascertainment of outcomes of interest, with a maximum score of 9. High quality was defined as a score of 9.

It was not clear how many reviewers performed the quality assessment.

The number of participants in each group with pneumonia were extracted. For observational studies these were used to calculate odds ratios (OR) with 95% confidence intervals (CI). For RCTs, the number of events was used to calculate relative risks (RR) with 95% confidence intervals.

The authors did not state how the data extraction was performed.

For observational studies, pooled odds ratios with 95% confidence intervals were calculated using a random-effects model. For RCTs, summary relative risks with 95%confidence intervals were calculated using random-effects models. Heterogeneity was assessed using Ι².

Subgroup analyses were carried out for observational studies according to methodological quality, study design, population, type of pneumonia, dosage and duration of exposure. Subgroup analyses were conducted for RCTs on methodological quality and type of comparator.

Thirty-one studies were included for review (1,969,526 participants). The studies included 23 RCTs (4,168 participants), one case control (72 participants), one population-based case-control (41,818 participants), three nested case-control (1,186,729 participants) and three cohort studies (736,739 participants).

Eight RCTs were rated as high quality and four observational studies were rated as high quality. The authors stated that participants from some RCTs were excluded from the meta-analysis (details were reported in an appendix).

RCTs: The use of acid-suppressing drugs was associated with an increased risk of hospital-acquired pneumonia (RR 1.22 95% CI 1.01 to 1.48; 23 RCTs; 3,640 participants). There was evidence of moderate heterogeneity (Ι²=30.6%). Subgroup analyses revealed a significant increase in risk of hospital acquired pneumonia with histamine₂ receptor antagonists when sucralfate was used as a comparator (RR 1.33 95% CI 1.04 to 1.69) with low heterogeneity (Ι²=24.7%). Subgroup analysis revealed that in high quality RCTs, there was no association between increased risk of pneumonia with use of acid-suppressing drugs (RR 0.96, 95% CI: 0.65 to 1.43). There was evidence of moderate heterogeneity (Ι² =47%).

Observational studies: Proton-pump inhibitors (adjusted OR 1.27 95% CI 1.11 to 1.46; eight studies; 1,929,104 participants) and histamine₂ receptor antagonists (adjusted OR 1.22 95% CI 1.09 to 1.36; six studies; 453,380 participants) use were associated with increased risk of acquiring pneumonia. There was evidence of substantial heterogeneity for proton-pump inhibitors (Ι²=90.5%) but none for histamine₂ receptor antagonist (Ι²=0%). Subgroup analyses found that there was a significant association between use of acid-suppressing drugs and risk of pneumonia for both low-quality (adjusted OR 1.15 95% CI 1.00 to 1.32) and high-quality studies (adjusted OR 1.29 95% CI: 1.17 to 1.42). There was evidence of substantial heterogeneity for low-quality studies (Ι²=82.1%) but none for high quality studies (Ι²=0%). The results of other subgroup analyses were reported.

The use of proton-pump inhibitor or histamine₂ receptor antagonists may be associated with an increased risk of hospital-acquired or community-acquired pneumonia.

The review addressed a clear question with well-defined inclusion criteria. Three relevant databases were searched. As there appeared to be no attempts to search for unpublished data, publication bias could not be ruled out. The search was restricted to English articles for observational studies, which may have introduced language bias. However, the authors reported that a subsequent search for articles in any language did not identify any further eligible observational studies, so it was unlikely that any were missed. The authors did not report whether language restrictions were applied in the search for RCTs, which made it difficult to assess the risk of language bias in this search. Appropriate steps were taken in the study selection to minimised reviewer error and bias, but it was unclear whether similar steps were taken in the other review processes.

The quality of included studies was assessed using appropriate measures; subgroup analyses were performed according to study quality. Most included RCTs were of weaker methodological design. Appropriate methods were used to combine studies. The authors reported that they excluded some patients from analyses, but it was not possible to access information on why these patients had been excluded, so it was not possible to rule out bias from this process. Heterogeneity was high for some outcomes, which suggested that it may not have been appropriate to combine the studies in these cases. The effect sizes for observational studies were low and subgroup analyses of high quality RCTs found no effect.

Given the absence of high quality evidence for an effect, the authors' conclusions should be treated with caution.

Practice: The authors stated that clinicians should use caution in prescribing acid-suppressing drugs to at risk patients. Clinicians should ensure that they use the optimal effective dose.

Research: The authors did not state any implications for research.

Basic Science Research Programme of the National Research Foundation of Korea.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.