BMJ  2004;329:948 (23 October), doi:10.1136/bmj.38232.680567.EB (published 8 October 2004)

Primary care

The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review

Lee Hooper, lecturer1, Tamara J Brown, research associate2, Rachel A Elliott, clinical senior lecturer3, Katherine Payne, research fellow4, Chris Roberts, senior lecturer in medical statistics5, Deborah Symmons, professor6

1 Cochrane Oral Health Group, University of Manchester and Central Manchester and Manchester Children's University Healthcare Trust, Manchester Dental Education Centre, University Dental Hospital, Manchester M15 6FH, 2 Health Economics Research at Manchester, University of Manchester, 3 School of Pharmacy and Pharmaceutical Sciences, University of Manchester, 4 North West Genetics Knowledge Park, Manchester, 5 Biostatistics Group, School of Epidemiology and Health Sciences, University of Manchester, 6 ARC Epidemiology Unit, University of Manchester

Correspondence to: L Hooper lee.hooper{at}man.ac.uk

Abstract

Objectives To assess the effectiveness of five gastroprotective strategies for people taking non-steroidal anti-inflammatory drugs (NSAIDs)—H2 receptor antagonists plus non-selective (or cyclo-oxygenase-1) NSAIDs; proton pump inhibitors plus non-selective NSAIDs; misoprostol plus non-selective NSAIDs; COX-2 selective NSAIDs; or COX-2 specific NSAIDs—in reducing serious gastrointestinal complications, symptomatic ulcers, serious cardiovascular or renal disease, and deaths, and improving quality of life.

Data sources The Cochrane Library, Medline, Embase, Current Controlled Trials, and System for Information on Grey Literature in Europe (SIGLE) were searched to May 2002. Bibliographies and author contacts were used to identify further studies; non-English articles were included.

Review methods Trial selection, data extraction, and quality assessment were performed independently, in duplicate. Articles were rejected only if the study was not a randomised controlled trial; did not assess a gastroprotective strategy versus placebo; included exclusively children or healthy volunteers; lasted less than 21 days; or did not measure review outcomes. Quality assessment included allocation concealment and baseline similarity.

Random effects meta-analysis, meta-regression and subgrouping were used to pool effects and analyse associations with length of follow up, mean age, and baseline gastrointestinal status. Heterogeneity was examined and sensitivity analyses performed.

Results Of 112 included randomised controlled trials (74 666 participants), five were judged to be at low risk of bias, and 138 deaths and 248 serious gastrointestinal events were reported overall. On comparing gastroprotective strategies versus placebo we found no evidence of effectiveness of H2 receptor antagonists for any primary outcomes (few events reported); proton pump inhibitors may reduce the risk of symptomatic ulcers (relative risk 0.09, 95% confidence interval 0.02 to 0.47); misoprostol reduces the risk of serious gastrointestinal complications (0.57, 0.36 to 0.91) and symptomatic ulcers (0.36, 0.20 to 0.67); COX-2 selectives reduce the risk of symptomatic ulcers (0.41, 0.26 to 0.65) and COX-2 specifics reduce the risk of symptomatic ulcers (0.49, 0.38 to 0.62) and possibly serious gastrointestinal complications (0.55, 0.38 to 0.80). All strategies except COX-2 selectives reduce the risk of endoscopic ulcers (at least 3 mm in diameter).

Conclusions Misoprostol, COX-2 specific and selective NSAIDs, and probably proton pump inhibitors significantly reduce the risk of symptomatic ulcers, and misoprostol and probably COX-2 specifics significantly reduce the risk of serious gastrointestinal complications, but data quality is low. More data on H2 receptor antagonists and proton pump inhibitors are needed, as is better reporting of rare but important outcomes.

Introduction

In 1999, more than 18.5 million courses of non-steroidal anti-inflammatory drugs (NSAIDs) were prescribed in England and Wales1 for musculoskeletal conditions such as rheumatoid arthritis, osteoarthritis, and back pain. NSAIDs cause gastrointestinal side effects, ranging in severity from mild dyspepsia to gastric haemorrhage and perforation, potentially resulting in admission to hospital, surgery, and death. In the United Kingdom they result in 10 000 admissions to hospital and 2000 deaths annually.2

Standard protection against gastrointestinal toxicity induced by NSAIDs has entailed co-prescription of gastroprotective agents such as H2 receptor antagonists, proton pump inhibitors, or prostaglandin analogues (primarily misoprostol), but prescription of COX-2 (cyclo-oxygenase-2) NSAIDs alone is now an alternative. Some older NSAIDs exhibit substantial COX-2 activity (COX-2 selectives, which include etodolac, meloxicam, nabumetone, and nimesulide). Newer COX-2 NSAIDs have been developed for their COX-2 activity (COX-2 specifics include celecoxib and rofecoxib). Guidelines from the National Institute for Clinical Excellence (NICE) say that COX-2 NSAIDs and non-selective (COX-1 or conventional) NSAIDs without gastroprotection are equivalent in reducing pain and improving physical functioning in people with arthritis, and fewer gastrointestinal events are associated with COX-2 NSAIDs.1 Lister3 4 found that several NSAIDs all had equivalent efficacy at equivalent dosage (at population level), therefore all NSAIDs were assumed to be of equal efficacy.

This review aimed to assess effectiveness of five protective strategies—non-selective NSAID plus H2 receptor antagonists; non-selective NSAID plus proton pump inhibitors; non-selective NSAID plus misoprostol; COX-2 selective NSAID only; or COX-2 specific NSAID only—in reducing the incidence of gastrointestinal adverse effects.

Methods

Searching
We searched the Cochrane Library, Medline, Embase, Current Controlled Trials, and System for Information on Grey Literature in Europe (SIGLE) in May 2002.

Selection
We rejected articles only if the reviewers could determine that the article was not a randomised controlled trial; the trial did not address any of the five treatment strategies compared with non-selective NSAIDs alone; the trial included exclusively children or healthy volunteers; the study period was less than 21 days; or none of our outcomes were measured.

Primary outcomes were serious gastrointestinal complications (including haemorrhage, haemorrhagic erosions, recurrent upper gastrointestinal bleeds, perforation, pyloric obstruction, melaena); symptomatic ulcers; serious cardiovascular or renal illness; health related quality of life (not measures of arthritis pain or disability); and mortality.

Secondary outcomes included total gastrointestinal symptoms, endoscopic ulcers, anaemia, occult bleeding, total dropouts, and dropouts owing to gastrointestinal symptoms.

Validity assessment
Quality assessment of randomised controlled trials included information on randomisation procedures, allocation concealment, similarity at baseline, blinding of participants, providers of care and assessors of outcomes, and losses to follow up. We based the summary risk of bias on assessment of allocation concealment and baseline comparability (see table 1).


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  		Table 1 Study characteristics and summary risk of bias of the studies included in the five comparisons

 

Quantitative data synthesis
Where appropriate we used relative risks in random effects meta-analysis. We performed random effects meta-regression to analyse associations between treatment effect and duration of follow up; participants' mean age; baseline gastrointestinal status (quantified as percentage of participants with a history of ulcers or bleeds); and number of initial risk factors for gastrointestinal toxicity. The outcome was symptomatic ulcers.

Results

Table 1 shows characteristics and validity of included studies; table 2 shows results from the meta-analysis; and the figure shows effects on serious gastrointestinal complications (forest plots for the remaining primary outcomes are on bmj.com).


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  		Table 2 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

 


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  		Effects of gastroprotective strategies on serious gastrointestinal complications

 

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 taking H2 receptor antagonists compared with placebo (relative risk 0.55, 95% confidence interval 0.4 to 0.7).

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 nonselectives (0.41, 0.3 to 0.7). 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).

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 {infty} to number needed to treat to benefit 8).

Discussion

Summary
Comparing gastroprotective strategies with placebo, we found no evidence of effectiveness of H2 receptor antagonists for any primary outcomes (few events reported); proton pump inhibitors may reduce the risk of symptomatic ulcers; misoprostol reduces the risk of serious gastrointestinal complications and symptomatic ulcers; COX-2 selectives reduce the risk of symptomatic ulcers; and COX-2 specifics reduce the risk of symptomatic ulcers and possibly serious gastrointestinal complications. All strategies except COX-2 selectives reduce the risk of endoscopic ulcers.

We judged five of 112 included randomised controlled trials (74 666 participants) as having a low risk of bias, and overall 138 deaths and 248 serious gastrointestinal events were reported.

Limitations and strengths of the study
Sparse reporting of our primary outcomes was a weakness of the review. Many publications did not report important outcomes, or they mentioned events in an ad hoc manner. In collecting these few events their real level of occurrence may not have been accurately reflected, which may have led to bias. Some outcomes overlapped—for example, a patient who died from a serious gastrointestinal bleed was recorded in both the "mortality" and the "serious gastrointestinal complications" outcomes. However, an individual was recorded only once within any outcome category.

We hoped to overcome this lack of data partly through contact with study authors, but we received few replies. A common response from contact authors was that the relevant data were held by the sponsoring pharmaceutical company. When additional information arrived it invariably improved the study's quality ratings. Few studies clearly reported allocation concealment or blinding of outcome assessors; some trials are likely to be of higher methodological quality than our analysis indicates. The recent review of celecoxib studies by Deeks et al accessed manufacturer reports (which provide greater detail than published studies) and rated all nine studies highly.5


What is already known on this topic

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to have gastrointestinal side effects

These range from mild dyspepsia to death from gastric haemorrhage and perforation

Gastroprotective agents are commonly co-prescribed with NSAIDs to protect against these side effects

What this study adds

Misoprostol, COX-2 specific and selective NSAIDs, and probably proton pump inhibitors reduce the risk of symptomatic ulcers

Misoprostol and probably COX-2 specific NSAIDs reduce the risk of serious gastrointestinal complications, but the quality of data is low


Few studies listed funding sources that did not include a pharmaceutical company. This may increase bias where few hard outcomes occur or are reported.6 7

The lack of significant results in the meta-regressions does not necessarily imply a lack of a relation between risk of ulcers and study duration, baseline gastrointestinal status, or age in people taking these gastroprotectors. Our use of summary data (rather than data at the level of the patient) weakened our power to see small effects.

The large body of evidence comparing COX-2 NSAIDs with non-selectives is not matched by studies of the other gastroprotectors. Fewer than 2000 people participated in the proton pump inhibitor trials, but more than 25 000 participated in studies of both selective and COX-2 specifics. We may pick up small effects of COX-2 NSAIDs as significant but miss larger effects of other gastroprotectors, because of the relative volumes of data.

Implications for further research
A need exists for rare but important events (such as deaths, cardiovascular events, or serious gastrointestinal bleeds) to be recorded in trials (even where such trials are not powered to analyse the events), published in papers, and so become available for independent meta-analysis. At the very least, named contact authors should have access to these data.

A case is made for more independently funded research into gastroprotective agents. A very large, independent, multicentre trial measuring important outcomes for at least a year and with H2 receptor antagonists, proton pump inhibitors, misoprostol, COX-2 selective, COX-2 specific, and placebo arms would be ideal.

{elps.f1}This is the abridged version of an article that was posted on bmj.com on 8 October 2004: http://bmj.com/cgi/doi/10.1136/bmj.38232.680567.EB

Many thanks to our kind and expert project steering group: Linda Davies (University of Manchester), Andrew Herxheimer (Cochrane Collaboration), Qasim Aziz (Hope Hospital, Salford). Thank you too to those researchers who generously replied to our emails and letters with information and suggestions: Kate Adams (GlaxoSmithKline), John Borrill (Pharmacia), DMChang (Tri-Service General Hospital, Taiwan), Julian Cole (Merck Sharp & Dohme), Cyndy Collis (TAP Pharmaceuticals), Frank Degner (Boehringer Ingelheim), Lisa DeTora (Merck), Jay L Goldstein (University of Illinois at Chicago), Susan Jick (Boston Collaborative Drug Surveillance Program), Ronald Jubb (University of Birmingham), Loren Laine (University of Southern California), Louise Levine (Lilly Research Laboratories), Muhammad Mamdani (University of Toronto), David Neustadt (University of Louisville), Jeffrey B Raskin (University of Miami), Sanford H Roth (Arizona Research and Education) and Sangeeta Sharma (Institute of Human Behaviour and Allied Sciences, Delhi). Our gratitude also extends to Karen Schafheutle (University of Manchester) for German translations, Mary Ingram (University of Manchester) for help in locating papers, Roger Webb (University of Manchester) for initiating the study, and Alaa Rostom (University of Ottawa) for comments and support during the review.

Contributors: See bmj.com

Funding: NHS Executive, UK (NHS HTA project number 01/40/02).

Competing interests: DS has been reimbursed by Pharmacia for attending a conference.

Ethical approval: Not required.

References

  1. National Institute for Clinical Excellence. Guidance on the use of cyclo-oxygenase (COX) II selective inhibitors, celecoxib, rofecoxib, meloxicam, and etodolac for osteoarthritis and rheumatoid arthritis. London, NICE: 2001. (Technology Appraisal Guidance, 27.)
  2. Blower AL, Brooks A, Fenn GC, Hill A, Pearce MY, Morant S, et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997;11: 283-91.[CrossRef][Web of Science][Medline]
  3. Eversmeyer W, Poland M, DeLapp RE, Jensen CP. Safety experience with nabumetone versus diclofenac, naproxen, ibuprofen, and piroxicam in osteoarthritis and rheumatoid arthritis. Am J Med 1993;95: 10S-8S.[CrossRef][Medline]
  4. Lister BJ, Poland M, DeLapp RE. Efficacy of nabumetone versus diclofenac, naproxen, ibuprofen, and piroxicam in osteoarthritis and rheumatoid arthritis. Am J Med 1993;95: 2S-9S.
  5. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. BMJ 2002;325: 619-23.[Abstract/Free Full Text]
  6. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003;326: 1167-73.[Abstract/Free Full Text]
  7. Rochon PA, Gurwitz JH, Simms RW, Fortin PR, Felson DT, Minaker KL, et al. A study of manufacturer-supported trials of nonsteroidal anti-inflammatory drugs in the treatment of arthritis. Arch Intern Med 1994;154: 157-63.[Abstract/Free Full Text]
(Accepted 23 August 2004)


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