The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: syste
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《英国医生杂志》
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@man.ac.uk
Abstract
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 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 of 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. We also assessed the effects of length of follow up, age of participants, baseline gastrointestinal status, number of risk factors, and initial NSAID dose.
Methods
Figure 1 shows the flow of participants through the trial15; table 1 shows characteristics and validity of included studies; table 2 shows results from the meta-analysis; and figures 2, 3, 4 and 5 show forest plots of the primary outcomes.
Fig 1 Flow of studies through the trial
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
Fig 2 Effects of gastroprotective strategies on serious gastrointestinal complications
Fig 3 Effects of gastroprotective strategies on symptomatic ulcers
Fig 4 Effects of gastroprotective strategies on serious cardiovascular or renal illness
Fig 5 Effects of gastroprotective strategies on deaths
We found no evidence of publication bias in any of the five comparisons. The 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.
Discussion
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.)
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.
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.
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.
Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev 2002;(4): CD002296.
Cochrane Reviewers Handbook 4.1 . Oxford, England (www.cochrane.org/cochrane/hbook.htm): Cochrane Collaboration, 2000.
Juni P, Altman DG, Egger M. Assessing the quality of randomised controlled trials. In Egger M, Davey Smith G, Altman DG, eds. Systematic reviews in health care: meta-analysis in context. London: BMJ Publishing Group, 2001: 87-108.
Altman DG. Practical statistics for medical research. London: Chapman & Hall, 1991.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin Trials 1986;7: 177-88.
Sterne JAC, Bradburn MJ, Egger M. Meta-analysis in Stata. In: Egger M, Davey Smith G, Altman DG, eds. Systematic reviews in health care: meta-analysis in context. London: BMJ Publishing Group, 2001: 347-69.
British Medical Association, Royal Pharmaceutical Society of Great Britain. British national formulary. London: BMA, RPS, 2003. (No 45.)
Sterne JAC, Egger M, Davey Smith G. Investigating and dealing with publication and other biases. In: Egger M, Davey Smith G, Altman DG, eds. Systematic reviews in health care: meta-analysis in context. London: BMJ Publishing Group, 2001: 189-208.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315: 629-34.
Begg CB. Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50: 1088-101.
Moher D, Eastwood S, Olkin I, Rennie D, Stroup D. Improving the quality of reports on meta-analyses of randomised controlled trials: the QUOROM statement. Quality of reporting of meta-analyses. Lancet 1999;354: 1896-900.
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.
Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003;326: 1167-73.
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.
Dieppe P, Bartlett C, Davey P, Doyal L, Ebrahim S. Balancing benefits and harms: the example of non-steroidal anti-inflammatory drugs. BMJ 2004;329: 31-4.(Lee Hooper, lecturer1, Ta)
Correspondence to: L Hooper lee.hooper@man.ac.uk
Abstract
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 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 of 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. We also assessed the effects of length of follow up, age of participants, baseline gastrointestinal status, number of risk factors, and initial NSAID dose.
Methods
Figure 1 shows the flow of participants through the trial15; table 1 shows characteristics and validity of included studies; table 2 shows results from the meta-analysis; and figures 2, 3, 4 and 5 show forest plots of the primary outcomes.
Fig 1 Flow of studies through the trial
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
Fig 2 Effects of gastroprotective strategies on serious gastrointestinal complications
Fig 3 Effects of gastroprotective strategies on symptomatic ulcers
Fig 4 Effects of gastroprotective strategies on serious cardiovascular or renal illness
Fig 5 Effects of gastroprotective strategies on deaths
We found no evidence of publication bias in any of the five comparisons. The 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.
Discussion
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.)
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.
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.
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.
Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev 2002;(4): CD002296.
Cochrane Reviewers Handbook 4.1 . Oxford, England (www.cochrane.org/cochrane/hbook.htm): Cochrane Collaboration, 2000.
Juni P, Altman DG, Egger M. Assessing the quality of randomised controlled trials. In Egger M, Davey Smith G, Altman DG, eds. Systematic reviews in health care: meta-analysis in context. London: BMJ Publishing Group, 2001: 87-108.
Altman DG. Practical statistics for medical research. London: Chapman & Hall, 1991.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin Trials 1986;7: 177-88.
Sterne JAC, Bradburn MJ, Egger M. Meta-analysis in Stata. In: Egger M, Davey Smith G, Altman DG, eds. Systematic reviews in health care: meta-analysis in context. London: BMJ Publishing Group, 2001: 347-69.
British Medical Association, Royal Pharmaceutical Society of Great Britain. British national formulary. London: BMA, RPS, 2003. (No 45.)
Sterne JAC, Egger M, Davey Smith G. Investigating and dealing with publication and other biases. In: Egger M, Davey Smith G, Altman DG, eds. Systematic reviews in health care: meta-analysis in context. London: BMJ Publishing Group, 2001: 189-208.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315: 629-34.
Begg CB. Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50: 1088-101.
Moher D, Eastwood S, Olkin I, Rennie D, Stroup D. Improving the quality of reports on meta-analyses of randomised controlled trials: the QUOROM statement. Quality of reporting of meta-analyses. Lancet 1999;354: 1896-900.
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.
Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003;326: 1167-73.
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.
Dieppe P, Bartlett C, Davey P, Doyal L, Ebrahim S. Balancing benefits and harms: the example of non-steroidal anti-inflammatory drugs. BMJ 2004;329: 31-4.(Lee Hooper, lecturer1, Ta)