gastro-duodenal technology ulcers associated with the use

Gastro-duodenal Ulcers Associated with the Use of Non-steroidal Anti-inflammatory Drugs: A Systematic Review of Preventive Pharmacological Interventions

Technology Report

Issue 38 September 2003

Cite as: Rostom A, Dubé C, Jolicoeur E, Boucher M, Joyce J. Gastro-duodenal ulcers associated with the use of non-steroidal anti-inflammatory drugs: a systematic review of preventive pharmacological interventions. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 2003. Technology report no 38. Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CCOHTA. CCOHTA is a non-profit organization funded by the federal, provincial and territorial governments. Legal Deposit - 2003 National Library of Canada ISBN: 1-894620-92-5 (print) ISBN: 1-894620-93-3 (electronic version) Publications Mail Agreement Number: 40026386

Publications can be requested from:

CCOHTA 600-865 Carling Avenue

Ottawa, Ontario, Canada K1S 5S8 Tel. (613) 226-2553 Fax. (613) 226-5392

Email: [email protected]

or download from CCOHTA’s web site: http://www.ccohta.ca

Canadian Coordinating Office for Health Technology Assessment

Gastro-duodenal Ulcers Associated with the Use of

Non-steroidal Anti-inflammatory Drugs: A Systematic Review of Preventive

Pharmacological Interventions

Alaa Rostom MD MSc FRCPC1 Catherine Dubé MD MSc FRCPC1

Emilie Jolicoeur MD1 Michel Boucher BPharm MSc2

Janet Joyce MLS2

September 2003

________________________ 1 University of Ottawa, Ottawa, Ontario 2 Canadian Coordinating Office for Health Technology Assessment, Ottawa, Ontario

i

Reviewers These individuals kindly provided comments on this report. External Reviewers Isabelle Chabot, PhD Manager, Health Economics and Outcomes Research Merck Frosst Canada & Co. Kirkland, Quebec

Betsy Miller, BScPharm MSc Executive Director Patient Access and Outcomes Research Pharmacia Canada Inc. Mississauga, Ontario

John M. Fardy, MD MSc FRCPC Associate Professor of Medicine (Gastroenterology) Memorial University of Newfoundland St. John's, Newfoundland and Labrador

Andreas Maetzel, MD MSc PhD Scientist, Assistant Professor Division of Clinical Decision Making University Health Network University of Toronto Toronto, Ontario

Gail Huxley, Scientific Development Manager National Medicine Boehringer Ingelheim (Canada) Ltd. Burlington, Ontario

Alan B.R. Thomson, MD PhD FRCPC FACP FACG Professor of Medicine University of Alberta Edmonton, Alberta

John K. Marshall, MD MSc FRCPC Assistant Professor Division of Gastroenterology McMaster University Hamilton, Ontario

Angie Wong, BScPharm MSc Manager, Outcomes Research Pharmacia Canada Inc. Mississauga, Ontario

This report was also reviewed by Pfizer Canada Inc., Kirkland, Quebec. CCOHTA Scientific Advisory Panel Reviewers Kenneth Marshall, MD Professor of Family Medicine (retired) University of Western Ontario London, Ontario

George Wells, PhD Director, Department of Epidemiology and Community Medicine University of Ottawa Ottawa, Ontario

This report is a review of existing public literature, studies, materials and other information and documentation (collectively the “source documentation”) which are available to CCOHTA. The accuracy of the contents of the source documentation on which this report is based is not warranted, assured or represented in any way by CCOHTA and CCOHTA does not assume responsibility for the quality, propriety, inaccuracies or reasonableness of any statements, information or conclusions contained in the source documentation. CCOHTA takes sole responsibility for the final form and content of this report. The statements and conclusions in this report are those of CCOHTA and not of its Panel members or reviewers.

ii

Authorship

Alaa Rostom, the principal investigator, participated in all aspects of the project and was responsible for the primary writing of the report. Catherine Dubé participated in the design of the project, selection of relevant studies and analysis of the data. She also critically reviewed all drafts of the report. Emilie Jolicoeur participated in the selection of included studies and in data abstraction and assisted in analysis and interpretation of the results. She also critically reviewed all drafts of the report. Michel Boucher participated in the design of the project, selection of relevant studies and writing of the initial draft and all report revisions. He also coordinated the external review process. Janet Joyce was responsible for designing and conducting the literature search, writing the search methods, preparing the search strategies appendix and compiling the bibliography. Conflict of Interest Dr. John K. Marshall declared that he has received speaker’s fees from Merck Frosst Canada & Co.

REPORT IN BRIEF September 2003 Drugs to Prevent Gastro-duodenal Ulcers Associated with the Use of NSAIDs

Technology Name • Non-steroidal anti-inflammatory drugs (NSAIDs) • Gastroprotective agents: misoprostol, histamine type-2

receptor antagonists (H2RAs), proton pump inhibitors (PPIs) • Cyclooxygenase (COX)-2 selective NSAIDs:

celecoxib, rofecoxib, meloxicam. Disease/Condition Traditional NSAIDs, which are used to treat painful arthritic and inflammatory disorders, can produce gastro-intestinal (GI) adverse effects. The incidence of serious complications is low, but it is an important clinical issue because of the widespread use of these medications. Technology Description Gastroprotective agents can help protect the stomach when an NSAID is used. COX is an enzyme. Type 1 COX (COX-1) is involved in protecting the stomach lining, while the second type (COX-2) may be important in promoting the pain of arthritic diseases. Traditional NSAIDs inhibit the effects of COX-1 and COX-2. NSAIDs that selectively inhibit COX-2 theoretically should have little effect on the GI tract. The Issue The efficacy and safety profiles of available gastro-protective agents should be compared when they are used to protect against NSAID-induced GI damage. The GI safety profiles of COX-2 selective NSAIDs should be compared with those of traditional non-selective NSAIDs. Assessment Objectives 1. To assess how well gastroprotective agents protect

against the upper GI damage caused by traditional non-selective NSAIDs.

2. To compare the upper GI damage caused by COX-2 selective NSAIDs with that caused by traditional non-selective NSAIDs.

3. To compare the upper GI damage caused by COX-2 selective NSAIDs with that caused by placebo.

Method For the first objective, a Cochrane Collaboration meta-analysis was updated. For the other objectives, a literature search was used to identify studies that assessed the GI safety of the newer COX-2 selective NSAIDs. Conclusions Gastroprotective agents • Misoprostol, PPIs and double doses of H2RAs are

effective at reducing the risk of endoscopically identified NSAID-induced ulcers.

• Standard doses of H2RAs are ineffective at reducing the risk of endoscopically identified NSAID-induced ulcers.

• Misoprostol is the only agent that has been shown to reduce the risk of NSAID-induced clinically important ulcer complications. Its use, however, is associated with significant adverse effects, particularly at higher doses.

COX-2 selective NSAIDs • COX-2 selective NSAIDs are associated with a lower

risk of endoscopically identified ulcers and of clinically important ulcer complications when compared with traditional non-selective NSAIDs in general.

• COX-2 selective NSAIDs were found to be safer than naproxen and ibuprofen (high dose), but no significant difference was found between the COX-2 selective NSAIDs reviewed and diclofenac.

• Preliminary results indicate that the reduced GI complication rate due to celecoxib may be lost when it is administered with acetylsalicylic acid (ASA). This has not been tested for rofecoxib.

• Meloxicam does not seem to be safer than traditional non-selective NSAIDs.

• It is unclear whether the co-administration of a COX-2 selective NSAID and a gastroprotective agent significantly improves safety over the use of a COX-2 selective NSAID alone or the use of a traditional non-selective NSAID with gastroprotection.

This summary is based on a comprehensive health technology assessment report available from CCOHTA’s web site (www.ccohta.ca): Rostom A, Dubé C, Jolicoeur E, Boucher M, Joyce J. Gastroduodenal ulcers associated with the use of non-steroidal anti-inflammatory drugs: a systematic review of preventive pharmacological interventions.

Canadian Coordinating Office For Health Technology Assessment (CCOHTA) 600-865 Carling Avenue, Ottawa, ON, Canada K1S 5S8 Tel: 613-226-2553 Fax: 613-226-5392 www.ccohta.ca

CCOHTA is an independent, non-profit health research agency funded by the federal, provincial and territorial governments.

iv

EXECUTIVE SUMMARY Background Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat arthritic and inflammatory syndromes and acute and chronic pain. These agents, however, are associated with gastro-intestinal (GI) complications such as perforation or hemorrhage, with an occurrence of about 2% per year in average risk patients and as high as 10% per year in high risk patients. Although the former rate is low, it is important because of the common use of these medications. Several pharmacological strategies have been developed to reduce the risk of NSAID-induced GI complications. One approach is the use of concurrent prophylactic gastroprotective agents such as misoprostol, histamine type-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs). Alternatively, newer cyclooxygenase-isoform type 2 (COX-2) selective NSAIDs have been developed in an attempt to offer greater GI safety. Objectives Our objectives in this systematic review are to: 1. assess the effectiveness of common pharmacological interventions used for the prevention of

the upper GI toxicity that is associated with non-selective NSAIDs 2. compare the upper GI toxicity of COX-2 selective NSAIDs with that of non-selective

NSAIDs, with or without the concomitant use of gastroprotective agents 3. assess the upper GI toxicity of the COX-2 selective NSAIDs available in Canada by

comparing them with placebo. Methods A literature search was used to identify randomized controlled trials (RCTs) of prophylactic agents used to prevent upper GI toxicity and RCTs that assessed the GI safety of the newer COX-2 selective NSAIDs [celecoxib (Celebrex™), meloxicam (Mobicox™), rofecoxib (Vioxx®)]. Study selection and data extraction were performed in duplicate by independent reviewers. Data were analyzed using RevMan 4.1 in accordance with accepted meta-analysis techniques.

Results The results of this meta-analysis show that misoprostol, PPIs, and double doses of H2RAs are effective at reducing the risk of endoscopically identified NSAID-induced gastric and duodenal ulcers. Standard doses of H2RAs, however, are ineffective at reducing the risk of NSAID-induced gastric ulcers. Misoprostol is the only prophylactic agent that has been evaluated in a trial assessing clinical ulcers as opposed to endoscopic ulcers. It has been shown that misoprostol reduces the risk of NSAID-related ulcer complications, but its use is associated with significant adverse effects, particularly at higher doses.

Compared with most non-selective NSAIDs, COX-2 selective NSAIDs are associated with significantly fewer endoscopically identified ulcers and clinically important ulcer complications and with fewer treatment withdrawals due to GI symptoms. An exception is the comparator NSAID diclofenac. When diclofenac is compared with the COX-2 selective NSAIDs studied, no

v

statistically significant differences are observed for any of these endpoints. In one study, the use of rofecoxib is associated with more cardiovascular events when compared with naproxen. Another study shows that the use of acetylsalicylic acid (ASA) may diminish the benefit of celecoxib when compared with non-selective NSAIDs. High-quality studies fail to show any significant benefit from meloxicam as compared with the non-selective NSAIDs piroxicam and diclofenac with respect to clinically important ulcer complications. Inclusion of data from six meloxicam efficacy studies, however, reveal a statistically significant relative risk reduction of 52% compared with non-selective NSAIDs, but this inclusion does not show any benefit of meloxicam over diclofenac. Last, the benefit from the growing clinical use of COX-2 selective NSAIDs with added prophylaxis remains untested. Conclusions Gastroprotective agents • Misoprostol, PPIs, and double doses of H2RAs are effective at reducing the risk of

endoscopically identified gastric and duodenal NSAID-induced ulcers. • Standard doses of H2RAs are ineffective at reducing the risk of endoscopically identified

NSAID-induced gastric ulcers. • Misoprostol is the only prophylactic agent that has been evaluated in a true clinical outcome

trial. It reduces the risk of NSAID-related ulcer complications, but its use is associated with significant adverse effects, particularly at higher doses.

• PPIs are effective at healing NSAID-induced ulcers even when patients continue the use of NSAIDs. Misoprostol, however, may be more effective than PPIs at reducing the risk of NSAID-induced gastric ulcers.

COX-2 selective NSAIDs • With regards to GI toxicity, COX-2 selective NSAIDs are safer than naproxen and high-dose

ibuprofen and are better tolerated than non-selective NSAIDs in general. No significant difference between the COX-2 selective NSAIDs considered and diclofenac was found, suggesting that COX-2 selective NSAIDs may not be a different “class” of agents. Instead, they may be part of a continuum of agents that includes the “standard NSAIDs” but with differing GI toxicities. A superior GI safety profile over one non-selective NSAID does not imply that a given COX-2 selective NSAID is safer than all non-selective NSAIDs.

• Since COX-2 selective NSAIDs have little anti-platelet effect, the co-administration of ASA is inevitable in patients with an indication for low-dose ASA. This raises preliminary concerns that will need to be confirmed in ongoing studies. These concerns are based on the apparent absence of benefit of celecoxib over non-selective NSAIDs when ASA is co-administered with celecoxib in the CLASS study, and on the absence of data regarding the co-administration of rofecoxib and ASA, since patients requiring ASA are excluded from the VIGOR trial.

• The benefit of the growing clinical use of COX-2 selective NSAIDs with added prophylaxis remains untested.

vi

TABLE OF CONTENTS EXECUTIVE SUMMARY .......................................................................................................... iv ABBREVIATIONS.................................................................................................................... viii 1 INTRODUCTION................................................................................................................ 1

1.1 Background..................................................................................................................... 1 1.2 Technology Overview..................................................................................................... 2

2 OBJECTIVES ...................................................................................................................... 3 3 METHODS ........................................................................................................................... 3

3.1 Literature Search............................................................................................................. 3 3.2 Data Retrieval and Quality Assessment.......................................................................... 4

3.2.1 Selection of relevant studies ................................................................................ 4 3.2.2 Quality assessment............................................................................................... 4

3.3 Study Inclusion Criteria .................................................................................................. 4 3.3.1 Types of participants............................................................................................ 4 3.3.2 Types of interventions.......................................................................................... 4 3.3.3 Types of studies ................................................................................................... 5 3.3.4 Outcome measures ............................................................................................... 6

3.4 Statistical Analysis.......................................................................................................... 6 3.5 Heterogeneity.................................................................................................................. 7 3.6 Publication Bias .............................................................................................................. 7 3.7 Subgroup Analyses ......................................................................................................... 7 3.8 Sensitivity Analyses........................................................................................................ 8

4 RESULTS ............................................................................................................................. 9

4.1 Study Selection ............................................................................................................... 9 4.2 Prophylactic Gastroprotective Therapy ........................................................................ 14

4.2.1 Misoprostol ........................................................................................................ 14 4.2.2 H2RAs ................................................................................................................ 15 4.2.3 PPIs .................................................................................................................... 16 4.2.4 Head-to-head comparisons................................................................................. 17

4.3 COX-2 Selective NSAIDs ............................................................................................ 18 4.3.1 COX-2 selective NSAIDs versus non-selective NSAIDS................................. 22

5 DISCUSSION ..................................................................................................................... 39

5.1 Prophylactic Gastroprotective Therapy ........................................................................ 39 5.1.1 Misoprostol ........................................................................................................ 39 5.1.2 H2RAs ................................................................................................................ 39 5.1.3 PPIs .................................................................................................................... 39

5.2 COX-2 Selective NSAIDs ............................................................................................ 40

vii

6 CONCLUSIONS ................................................................................................................ 46 6.1 Gastroprotective Agents................................................................................................ 46 6.2 COX-2 Selective NSAIDs ............................................................................................ 46

7 REFERENCES................................................................................................................... 47 Appendix 1: Literature Search Strategy........................................................................................ 57 Appendix 2: Data Extraction Form............................................................................................... 66 Appendix 3: Outcomes ................................................................................................................. 67 Appendix 4: Jadad Scale............................................................................................................... 68

viii

ABBREVIATIONS AMI acute myocardial infarction ARR absolute risk reduction ASA acetylsalicylic acid CI confidence interval COX cyclooxygenase FDA Federal Drug Administration GI gastro-intestinal H2RA histamine-2 receptor antagonist NDA new drug application (FDA) NNH number needed to harm NNT number needed to treat NS not significant NSAID non-steroidal anti-inflammatory drug OA osteoarthritis PPI proton pump inhibitor POB perforation, obstruction, bleeding PUB perforation, ulcer, bleeding, or symptomatic ulcer RA rheumatoid arthritis RCT randomized controlled trial RR relative risk RRR relative risk reduction SAE serious adverse event

1

1 INTRODUCTION 1.1 Background Non-steroidal anti-inflammatory drugs (NSAIDs) are agents used in the management of patients with arthritic and inflammatory conditions.1 Their established efficacy makes NSAIDs among the most frequently used medications. The estimated world market is over $6 billion annually.2 In Canada, these widely prescribed agents generate several million dollars in sales every year (Table 1).

Table 1: Estimated number of prescriptions and associated sales for NSAIDs dispensed in Canadian retail pharmacies

Type of NSAIDs 1999

Prescriptions (sales)

2000 Prescriptions

(sales)

2001 Prescriptions

(sales) Non-selective 7,960,831

($241 million) 6,145,700

($179 million) 5,404,140

($153 million) COX-2 selective 1,906,580

($101 million) 6,282,132

($364 million) 7,724,157

($467 million) Total 9,867,411

($342 million) 12,427,832

($543 million) 13,128,297

($620 million) Source: Canadian Compuscript, IMS Health

Table 1 shows that the number of prescriptions for NSAIDs has been increasing over the last three years. This increase is driven by the new selective cyclooxygenase type 2 (COX-2) selective NSAIDs, suggesting prescribers and patients are not only replacing existing non-selective therapy with more selective agents, but also increasing their use of NSAIDs in general. NSAIDs are linked to gastro-intestinal (GI) toxicities.1,3-13 Their use is commonly associated with symptoms such as nausea and dyspepsia, which correlate poorly with serious adverse GI events.13,14 Endoscopic ulcers occur in as many as 40% of chronic NSAID users,3 but as many as 85% of these ulcers may never become clinically important.13,15 Serious NSAID-induced complications such as hemorrhage, perforation or death occur collectively with an incidence of about 2% per year in average risk NSAID users, and up to 10% per year in high risk patients.13 Because of the large numbers of individuals involved, however, the use of these drugs is linked to over 70,000 hospitalizations and over 7,000 deaths annually in the United States.5 The use of prophylactic therapy to prevent NSAID-induced GI complications is considerable, given the large number of patients taking these drugs. Routine use of prophylactic therapy is recommended for patients with risk factors for peptic ulcer disease such as previous peptic ulcers, age over 60 years, concomitant use of corticosteroids, prior discontinuation of NSAIDs for GI side effects, high daily dose of NSAIDs and significant disability.9

2

1.2 Technology Overview It is hypothesized that two mechanisms may be responsible for NSAID-induced gastric damage: an irritant effect and a systemic effect mediated by COX inhibition, leading to reduced prostaglandin synthesis. At least three isoforms of COX have been identified. Two are of clinical significance for this report.16 COX-1 is usually expressed (constituative) in gastric mucosa and in other organs. Its inhibition may impair the gastric mucosa’s ability to protect itself. COX-2, an inducible isoform, may be expressed in the presence and involved in the promotion of inflammation.17 This co-enzyme may also be involved in neoplastic conditions.18 Inhibition of COX-2 is believed to be responsible for the anti-inflammatory and analgesic effects of NSAIDs.17 The unsatisfactory therapeutic profile of classic NSAIDs prompted the development of three strategies in an effort to curtail their adverse effects:

1. the substitution of less toxic agents such as acetaminophen, when possible 2. the use of prophylactic gastroprotective agents, such as misoprostol, histamine2-receptors

antagonists (H2RAs) or proton pump inhibitors (PPIs), with non-selective NSAIDs 3. the use of newly developed, more selective COX-2 NSAIDs. Each gastroprotective agent or class of agents has a different mechanism of action. Misoprostol (Cytotec®) is a synthetic prostaglandin E1 analogue with antisecretory and cytoprotective properties. H2RAs (cimetidine, famotidine, nizatidine, ranitidine) reduce the secretion of gastric acid by competitively and selectively inhibiting the action of histamine on H2 receptors of the parietal cells. PPIs (lansoprazole, omeprazole, pantoprazole) are specific inhibitors of gastric secretion; they act by irreversibly binding to K+-H+-ATPase (an enzyme that transports acid across the parietal cell).17

The use of COX-2 selective NSAIDs is an alternative to the combined use of prophylactic gastroprotective therapy and non-selective NSAIDs.17 When this review was undertaken in 2002, there were three agents marketed as COX-2 selective NSAIDs in Canada: celecoxib (CelebrexTM), meloxicam (MobicoxTM) and rofecoxib (Vioxx®).

3

2 OBJECTIVES

The objectives of this systematic review are to: 1. assess the effectiveness of misoprostol, H2RAs and PPIs for the prevention of upper GI

toxicity associated with non-selective NSAIDs 2. compare the upper GI toxicity of COX-2 selective NSAIDs with that of non-selective

NSAIDs with or without the concomitant use of gastroprotective agents 3. assess the upper GI toxicity of the COX-2 selective NSAIDs available in Canada by

comparing them with placebo. 3 METHODS A systematic review of randomized controlled trials (RCTs) was conducted to meet the three objectives. The first objective was addressed by updating the Cochrane Collaboration systematic review published in 2000 by Rostom et al.19,20 For the other two objectives, the review was expanded to include trials that compare the new COX-2 selective NSAIDs to non-selective NSAIDs. 3.1 Literature Search A Dialog® OneSearch® on MEDLINE®, ToxFile, EMBASE®, BIOSIS Previews®, Pharmaceutical News Index (PNI)® and Current Contents Search® for published and scientific meeting literature was performed. The Cochrane Library was searched separately. The search was done in accordance with published recommendations. 21,22 No language restrictions were applied. In addition to the searches that were done for the original Cochrane review,20 the literature search was updated to cover January 2000 to September 2002 (Appendix 1). We also sought literature to assess the GI safety of the three COX-2 selective NSAIDS available in Canada (Appendix 1). We searched the web sites of the International Network of Agencies for Health Technology Assessment (INAHTA), specialized databases [e.g. University of York National Health Service (NHS) Centre for Reviews and Dissemination (CRD)] and Conference Papers Index. Internet searching (e.g. using GoogleTM), was done to identify health technology assessment reports, meeting abstracts and grey literature. Registries were searched for ongoing trials. Content experts were asked to provide additional studies and information regarding ongoing trials. Since the assessment of the GI safety of the three COX-2 selective NSAIDs available in Canada was not an update but an original review, manufacturers of these drug were contacted for relevant information.

4

3.2 Data Retrieval and Quality Assessment

3.2.1 Selection of relevant studies The reference lists of all potentially relevant articles, including reviews, meta-analyses, consensus statements and conference proceedings, were reviewed to identify potentially relevant trials. The output of the electronic search was screened to ensure that relevant articles were captured (MB, AR). The abstracts of the identified articles were assessed for potential inclusion in the review by two independent reviewers (AR, CD). The full articles were retrieved in duplicate. Two independent reviewers assessed the potentially relevant trials, selected the RCTs and extracted the relevant data (AR, EJ). For each included RCT, data were collected regarding the trial design, patient characteristics, intervention drugs, dosages, NSAIDs used and outcomes, using an extraction form (Appendix 2 and 3). Differences were resolved by referring to the RCTs and establishing consensus. Any remaining differences were resolved with the help of an independent gastroenterology or statistics expert. It was necessary to obtain data for two unpublished RCTs and to supplement the data for several published trials from the FDA web site and by contacting the FDA. Included RCTs were classified as being primary or secondary prophylaxis trials and by period of outcome.

3.2.2 Quality assessment All RCTs were scored for quality by two independent reviewers (AR, EJ) using a modification of the scale developed by Jadad et al23 (Appendix 4). For each study, the adequacy of randomization and blinding and the completeness of follow-up were determined. The quality of allocation concealment was also assessed.24 Differences were resolved by consensus. 3.3 Study Inclusion Criteria 3.3.1 Types of participants Included participants met three conditions: they had osteoarthritis (OA), rheumatoid arthritis (RA) or other arthritic conditions; they were older than 18 years; and they required chronic (four weeks or longer) use of an NSAID. If patients younger than age 18 were enrolled, the trial was included if >75% of the participants were over age 18.

3.3.2 Types of interventions

• Objective 1: The pharmaceutical agents considered included misoprostol, H2RAs or PPIs

used for the prevention of NSAID-induced upper GI toxicity. For this review, standard-dose H2RA was defined as the equivalent of ranitidine 150 mg twice daily, while double-dose H2RA was defined as the equivalent of ranitidine 300 mg twice daily. Misoprostol daily dosages were classified as low (400 µg), medium (600 µg) or high (800 µg).

5

• Objectives 2 and 3: The pharmaceutical agents considered included the COX-2 selective NSAIDs available in Canada: celecoxib (CelebrexTM), meloxicam (MobicoxTM) and rofecoxib (Vioxx®). For this review, low-dose COX-2 selective NSAIDs was defined as celecoxib 200 mg bid or less, rofecoxib 25 mg daily or less and meloxicam 7.5 mg daily. High-dose COX-2 was defined as celecoxib 400 mg bid, rofecoxib 50 mg daily and meloxicam 15 mg daily.

• Definition of COX-2 selective NSAIDs: Variability exists in the literature regarding the

criteria by which an NSAID is classified as COX-2 selective and the techniques used to make this determination. The most accepted technique involves determination of the COX-2 IC50 to COX-1 IC50 ratio (a ratio of the concentrations of the drug that result in 50% blockage of the COX-2 and COX-1 isoenzymes) through a whole blood assay. A value below 1 indicates greater affinity for COX-2 inhibition than COX-1 inhibition: the lower the value, the greater the COX-2 selectivity. A ratio below 1, however, does not guarantee COX-2 selectivity in clinical practice since other factors are at play. These include COX-2 selectivity at the gastric mucosa and the effect of clinical dosages of the drug on its COX-2 selectivity (i.e. an agent may be COX-2 selective only at subtherapeutic doses). Also, reported COX-2 to COX-1 IC50 ratios for the available COX-2 selective NSAIDs differ.25-30

3.3.3 Types of studies Only RCTs were included. All trials had to meet the following criteria: • the duration of NSAID exposure was four weeks or longer (chronic NSAID exposure) • the proportion of patients with endoscopic ulcers or clinical GI events could be determined • endoscopic ulcers were defined as being at least 3 mm in diameter or could be distinguished

from erosions based on the authors’ descriptions (it was noted whether endoscopy was performed based on symptoms or as part of a protocol).

Objective 1: RCTs of misoprostol, H2RAs or PPIs were considered eligible for inclusion if these drugs were assessed for their ability to prevent NSAID-induced upper GI toxicity and the intervention was compared to placebo or to another agent thought to be effective in this clinical setting. Objective 2: RCTs of COX-2 selective NSAIDs (celecoxib, rofecoxib, meloxicam) were considered eligible for inclusion if: (a) for COX-2 selective versus non-selective NSAIDs, the trial assessed the drugs’ upper GI

toxicity, compared to non-selective NSAID therapy without concurrent use of gastroprotective agents

b) for COX-2 selective versus non-selective NSAIDs with prophylaxis, the trial assessed the drugs’ upper GI toxicity compared to non-selective NSAID therapy with concurrent use of gastroprotective agents.

Objective 3: RCTs of COX-2 selective NSAIDs were considered eligible for inclusion if the study assessed the drugs’ upper GI toxicity compared to placebo.

6

“Primary” prophylaxis studies included patients who did not have an ulcer as determined during screening endoscopy. Studies were considered “secondary” prophylaxis trials if the enrolled patients had NSAID-induced ulcers that were healed in a preceding study. Short-term studies (<4 weeks) on healthy volunteers were not considered, since the clinical importance of acute NSAID-induced erosions and submucosal hemorrhages is thought to be minimal.

3.3.4 Outcome measures There are several measurable endpoints used to assess upper GI toxicity in NSAID clinical trials. Each endpoint is analyzed separately. The primary outcomes are: • endoscopic ulcer: a commonly used surrogate outcome that may lead to more serious

clinically important adverse events; defined as a mucosal defect at least 3 mm in diameter or distinguished from erosions based on the authors’ descriptions

• clinical GI events: clinically important adverse events such as upper GI hemorrhage, perforation, pyloric obstruction and death

• GI symptoms: dyspepsia, nausea, abdominal pain or diarrhea • other measures of toxicity or lack of efficacy • overall treatment withdrawals • treatment withdrawals due to specific symptoms • symptoms not causing treatment withdrawals. 3.4 Statistical Analysis In prior work, outcome data are expressed as a proportion for all endpoints. Review Manager (RevMan) version 4.1 was used to analyze the dichotomous (binary) data obtained. Endoscopic, clinical and symptom-based outcomes were analyzed separately. The results in this review are expressed as the relative risk (RR) of the outcome obtained with the intervention as compared with outcomes obtained with placebo or comparators, using a fixed effect model. Initial explanations for any heterogeneity are based on study differences or groupings and adjusted appropriately. A random-effects model was used to combine heterogeneous trials only if it was clinically and statistically appropriate. The results were expressed as RRs rather than the standard odds ratios since the concept of risk would be simpler than odds. The absolute risk reduction (ARR) and the number needed to treat (NNT) were calculated for appropriate clinical endpoints to help frame the magnitude of the treatment effects. When clinically and statistically appropriate, differences between groups in stratified analyses were formally tested for significance using techniques described by Deeks and Altman.31 A qualitative systematic review was conducted for endpoints and trials that could not be appropriately combined.

7

For objective 2b, it was decided a priori that if no trials could be found that compared the GI toxicity of COX-2 selective NSAIDs to that of non-selective NSAIDs with prophylaxis, attempts would be made at indirect comparison if the trials were similar in: • design • patient population (including OA, RA, age, co-morbidities); • comparator drugs, i.e. non-selective NSAIDs • study endpoints: endoscopic ulcers, clinical GI events (hemorrhage, perforation, pyloric

obstruction or death), symptoms (nausea, vomiting, dyspepsia, abdominal pain or diarrhea).

If indirect comparisons are made, they are explained in the report.

3.5 Heterogeneity

Heterogeneity is tested using a chi-square test with N-1 degrees of freedom, where N equals the number of trials contributing data. A p value of less than 0.10 is considered to be evidence of statistical heterogeneity.32 L’Abbé plots and standard forest plots are used to depict the observed heterogeneity graphically.33 Galbraith plots show the COX-2 selective NSAID study endpoints of clinical ulcer complications and endoscopic gastric ulcers. These also present the precision of each included trial.34 Attempts are made to explain any heterogeneity through the exploration of clinical and statistical factors related to the observation. All graphs are produced in Microsoft Excel 2000.

3.6 Publication Bias

The existence of publication bias was explored through the use of the inverted funnel plot using data on the primary outcome of endoscopic gastric ulcers and clinical ulcer complications.

3.7 Subgroup Analyses

Subgroup analyses are based on dose, duration of therapy and primary versus secondary prophylaxis trials. Analyses by dosages are important for misoprostol where higher doses are associated with more side effects, for H2RAs where standard doses may be ineffective at reducing NSAID ulcer risk and for newer COX-2 selective NSAIDs where selectivity for the COX-2 isoenzyme may be diminished at higher doses. The subgroup analyses are also stratified by intervention (COX-2 selective NSAIDs) and by comparator non-selective NSAIDs.

8

3.8 Sensitivity Analyses

We did sensitivity analyses to test the robustness of the results. The variables considered were: • the mean quality score as a cutoff to define high- and low-quality trials • the definition of endoscopic ulcer size (>3 mm versus >5 mm) (this analysis was to be

assessed at the outset but these data are only available in a subset of the COX-2 selective NSAID trials, so the usefulness is limited; overall, data for ulcers >3 mm are used)

• type of NSAID used, COX-2 selective NSAID individually and through cross-tabulations.

9

4 RESULTS 4.1 Study Selection We identified 898 abstracts in the initial search strategy. Two reviewers (AR, MB) independently assessed these abstracts and deemed 241 to be potentially relevant. For these, the full publication was obtained and independently evaluated for inclusion (AR, CD). In total, 42 RCTs fulfilled the inclusion criteria. The data of included trials were extracted in duplicate using a standard extraction sheet (AR, EJ). AR and EJ also independently rated the quality of each included RCT. Five trials considered prophylaxis against the GI toxicity of non-selective NSAIDS, whereas 37 focused on COX-2 selective NSAIDs (Figure 1). Table 2a describes the five new non-selective NSAID prophylaxis trials. Table 2b describes the 22 ulcer complication trials (including the eight meloxicam efficacy trials). These are further divided into endoscopic ulcer trials (Table 2c: seven trials) and clinical ulcer complications trials (Table 2d: seven trials and eight meloxicam efficacy trials). Side effects from efficacy trials are detailed in another table (Table 2e: 15 trials). A few trials that consider more than one intervention could be used in several analyses.

10

Figure 1: Selection of RCTs

* NSAID prophylaxis refers to trials of GI event prophylaxis in non-selective NSAID users. ** There were seven primary clinical ulcer complication trials, but eight meloxicam efficacy trials allowed the extraction of perforation, ulcer, bleeding (PUB) data.

Initial search strategy 898 abstracts

Fulfilled inclusion criteria 42 RCTs

COX-2 selective NSAIDs 37 trials

Endoscopic ulcer 7 trials

Potentially relevant trials 241 abstracts

Ulcer complications** 7+8 meloxicam efficacy trials

NSAID prophylaxis* 5 new trials

Side effects from efficacy trials 23 (includes 8 meloxicam

efficacy trials)

PPI 3 trials

Misoprostol 2 trials

11

Table 2a: Characteristics of new GI event prophylaxis RCTs in non-selective NSAID users added since original Cochrane Collaboration meta-analysis

Comparisons Trials

Intervention Comparator Dose Number of

Patients Mean age

(years) Arthritis

Type Primary versus

Secondary Prophylaxis*

Follow-up Quality Score

Graham35 2002 Misoprostol and NSAIDs

Lansoprazole and placebo

Misoprostol 800 ug/day, lansoprazole

15 and 30 mg/day

537 60 Various Secondary 12 weeks 4

Chan 200136 Misoprostol and naproxen

Nabumetone Misoprostol 400 ug/day, naproxen

500 to 1,000 mg/day, nabumetone

1,000 to 1,500 mg/day

90 75 (median

age reported)

Various Secondary 24 weeks 4

Chan 200237,38 Celecoxib Diclofenac and omeprazole

Celecoxib 400 mg/day, diclofenac 150 mg/day, omeprazole 20 mg/day

287 63 Various Secondary 6 months 5

Bianchi Porro 200039

Pantoprazole and NSAIDs**

Placebo Pantoprazole 40 mg/day 84 58 OA and RA*

Primary 12 weeks 4

* Primary prophylaxis=trial in patients without previous ulcer, secondary prophylaxis=trial in patients who had recent ulcer that was healed, OA=osteoarthritis, RA=rheumatoid arthritis **NSAIDs in this trial = diclofenac, ketoprofen, indomathecin

11

12

12

Table 2b: COX-2 selective NSAID RCTs characteristics

Comparisons Endpoint

Trial

Intervention Comparator Celecoxib Celecoxib NSAID

Number of Patients

Mean Age (Years)

Arthritis Type

Follow-up

Quality Score

Goldstein 200140 200 mg bid Naproxen 500 mg bid 537 57 OA and RA 4, 8, 12 weeks 5 Emery 199941 200 mg bid Diclofenac 75 mg bid 655 55 RA 24 weeks 5 Simon 199942 100 mg bid

200 mg bid 400 mg bid

Naproxen 500 mg bid Placebo

1,149 54 RA 2, 6, 12 weeks 5

FDA study 02143 50 mg bid 100 mg bid 200 mg bid


1,108 N/A OA 2, 6, 12 weeks 2

FDA study 07143 200 mg bid Diclofenac 75 mg bid Ibuprofen 800 mg tid

1,097 N/A OA and RA 4, 8, 12 weeks 2

Rofecoxib Rofecoxib Laine 199944 25 mg/day

50 mg/day

Ibuprofen 800 mg tid 742 62

OA 6 weeks, 3, 6 months

5

End

osco

pic

Ulc

er

Hawkey 200045 25 mg/day 50 mg/day

Ibuprofen 800 mg tid 775 62 OA 6 weeks, 3, 6 months

5

Celecoxib Celecoxib NSAID Silverstein 200046 (CLASS)

400 mg bid Diclofenac 75 mg bid Ibuprofen 800 mg tid

8,059 60 OA and RA 4, 13, 26 weeks

(1 year FDA)

5

Goldstein 200047 (combined analysis study)*

25 mg bid to 400 mg bid 7 dose steps

Naproxen 500 mg bid Diclofenac 75 mg bid Ibuprofen 800 mg tid

11,008

59 OA and RA 2 to 24 weeks 3

SUCCESS-148-53 Abstract# 100 mg bid 200 mg bid

Naproxen 500 mg bid 13,274 62 OA 6, 12 weeks 2

Rofecoxib Rofecoxib Bombardier 2000 (VIGOR)54

50 mg/day Naproxen 500 mg bid 8,076 58 RA 6 weeks, 4, 8,12 months

5

Clin

ical

Ulc

er C

ompl

icat

ions

Langman 199955 (combined analysis study)

25 mg/day 50 mg/day

Ibuprofen 800 mg tid Diclofenac 50 mg tid Nabumetone 1,500 mg

5,435

63 OA 6 weeks, 4, 6, 12, 24

months

3

13

Table 2b (continued): COX-2 selective NSAID RCTs characteristics

Meloxicam Meloxicam Dequeker 1998 (SELECT)56 7.5 mg/day Piroxicam 8,656 61 OA 4 weeks 4 Hawkey 1998 (MELISSA)57 7.5 mg/day Diclofenac

100 mg/day 9,323 62 OA 4 weeks 4

Yocum58 2000& 3.75 to 15 mg Diclofenac 100 mg/day

774 62 OA 12 weeks 3

Goei59 1997& 15 mg Diclofenac 100 mg/day

258 71 OA 6 weeks 3

Hosie60 1997& 15 mg Piroxicam 20 mg 455 67 OA 6 months 3 Hosie61 1996& 7.5 mg Diclofenac

100 mg/day 335 64 OA 6 months 3

Lindén62 1996& 15 mg Piroxicam 20 mg 260 67 OA 6 weeks 3 Wojtulewski63 1996& 7.5 mg Naproxen 750 mg 379 N/A RA 6 months 3 Distel 199664,65 (combined analysis study)

7.5 to 15 mg Piroxicam 20 mg/day Naproxen 1,000 mg/day Diclofenac 100 mg/day

6,129 59 OA and RA Up to 1 year 3

Lemmel66 1997& 7.5 to 15 mg Placebo 468 54 RA 3 weeks 3

Clin

ical

Ulc

er C

ompl

icat

ions

Lund67 1998& 7.5 to 30 mg Placebo 513 68 OA 3 weeks 3 *Combined analysis means inclusion of all initial pre-CLASS FDA-New drug application (NDA) studies. #SUCCESS-1 trial includes the Canadian study (Haraoui et al) and the world study (which likely includes the Canadian study). &These meloxicam studies are efficacy trials. Because their GI data are poor quality, the score assigned was 3 even though they may be rated higher if considered for efficacy.

13

14

4.2 Prophylactic Gastroprotective Therapy

The NSAID prophylaxis trials found for this review are used to update the Cochrane Collaboration meta-analysis by Rostom et al.19,20 This review is updated with five RCTs, which do not change the results of the original review. The characteristics of these trials are listed in Table 2a. 4.2.1 Misoprostol

Misoprostol is the only prophylactic agent that has been shown to reduce the occurrence of clinically important ulcer complications.13 a) Endoscopic ulcer trials In total, 22 trials assessed the effect of misoprostol on the prevention of NSAID-induced endoscopically confirmed ulcers.13,35,36,68-86 Eleven trials with 3,687 patients compared the incidence of endoscopic ulcers with misoprostol to that with placebo after at least three months of NSAID exposure.35,36,68,69,75-78,81,83,86 The cumulative incidence of endoscopic gastric and duodenal ulcers with placebo were 15% and 6% respectively. Misoprostol significantly reduced the RR of gastric and duodenal ulcers by 74% (RR=0.26; 95% confidence interval (CI): 0.17 to 0.39 random effects) and 53% (RR=0.47; 95% CI: 0.33 to 0.69 random effects). These RRs corresponded to 12% and 3% ARRs for gastric and duodenal ulcers respectively. The heterogeneity in these estimates was due to inclusion of all misoprostol doses in the analyses. Analysis of the trials stratified by dose eliminated the heterogeneity. Subgroup analyses: dose of misoprostol All the studied doses of misoprostol were associated with a significantly reduced risk of endoscopic ulcers. A dose-response relationship was demonstrated for endoscopic gastric ulcers. There were six trials where 2,461 patients used misoprostol 400 µg daily,36,69,76,78,81,86 one where 928 patients used 600 µg daily81 and seven where 2,423 patients used 800 µg daily.35,68,75-77,81,83 Misoprostol 800 µg daily was associated with the lowest risk (RR=0.17; 95% CI: 0.11 to 0.24) of endoscopic gastric ulcers when compared with placebo, whereas misoprostol 400 µg daily was associated with a RR of 0.42 (95% CI: 0.28 to 0.67 random effects model for heterogeneity). The heterogeneity in the 400 µg/day group was the result of the addition of the Chan study.36 This trial compared naproxen with low-dose misoprostol to nabumetone alone. In this trial, the risk of ulcers was inexplicably greater in the misoprostol group, but this result was based on the differences between the safety of the comparator NSAIDs rather than the prophylactic agent. In a sensitivity analysis, removal of the Chan study eliminated the heterogeneity without significantly altering the results, giving low-dose misoprostol prophylaxis a RR of 0.39 (95% CI: 0.3 to 0.51). This difference between high- and low-dose misoprostol reached statistical significance (p=0.0055). The intermediate misoprostol dose (600 µg daily) was not significantly different from either the low or high dose. Also, the pooled relative risk reduction (RRR) of 78% (ARR=4.7%, RR=0.22; 95% CI: 0.09 to 0.49) for prevention of duodenal ulcers with misoprostol 800 µg daily was not significantly superior to those of the lower daily dosages.

15

Subgroup analysis: short-term duration of NSAID exposure Eight trials, with 2,206 patients, assessed the rates of endoscopic ulcers with misoprostol compared to placebo at 1 to 1.5 months70-72,74,75,79,80,84 Pooled results from these trials revealed an 83% RRR of gastric ulcers with misoprostol (RR=0.17; 95% CI: 0.09 to 0.31) and a 72% RRR of duodenal ulcers (RR=0.28; 95% CI: 0.14 to 0.56). One trial compared misoprostol to a newer cytoprotective agent, dosmafate, for NSAID prophylaxis and found no statistically significant difference in ulcer rates between the two.73 b) Clinical ulcer complications Only one RCT, the MUCOSA trial, evaluated the efficacy of misoprostol prophylaxis against clinically important NSAID-induced ulcer complications. In this trial of 8,843 patients studied over six months, the incidence of clinical ulcer complications was about 1.5% per year.13 Misoprostol 800 µg/day was associated with a statistically significant 40% risk reduction (odds ratio=0.598; 95% CI: 0.364 to 0.982) of combined clinical ulcer complications (p=0.049), representing a risk difference of 0.38% (from 0.95% to 0.57%). In our analysis, the MUCOSA results represented a 51% RRR in clinical ulcer complications (RR=0.49; 95% CI: 0.29 to 0.88). Adverse effects Misoprostol was associated with a small but statistically significant 1.6-fold excess risk of treatment withdrawals due to drug-induced adverse events and a statistically significant excess risk of treatment withdrawals due to nausea (RR=1.30; 95% CI: 1.08 to 1.55), diarrhea (RR=2.40; 95% CI: 2.05 to 2.81) and abdominal pain (RR=1.36; 95% CI: 1.20 to 1.55). In this trial, 732 of 4,404 patients on misoprostol experienced diarrhea or abdominal pain, compared with 399 of 4,439 on placebo for a RR of 1.82 associated with misoprostol (p<0.001). Overall, 27% of patients on misoprosol experienced one or more side effects.13 When analyzed by dose, only misoprostol 800 µg led to a statistically significant excess risk of treatment withdrawals due to diarrhea (RR=2.45; 95% CI: 2.09 to 2.88) and abdominal pain (RR=1.38; 95% CI: 1.17 to 1.63). The risk of diarrhea with misoprostol 800 µg/day (RR=3.25; 95% CI: 2.60 to 4.06) was significantly higher than that with 400 µg/day (RR=1.81; 95% CI: 1.52 to 2.16, p=0.0012).19,20 Analyses by quality Both high- and low-quality misoprostol trials demonstrated a statistically significant reduction in endoscopic ulcers.

4.2.2 H2RAs

a) Endoscopic ulcer trials Seven trials with 1,188 patients assessed the effect of standard-dose H2RAs on the prevention of endoscopic NSAID ulcers at one month.87-93 Five trials with 1,005 patients assessed these outcomes at three months or longer.87,91,94-96 Standard-dose H2RAs were effective at reducing the risk of duodenal ulcers (RR=0.24; 95% CI: 0.10 to 0.57 and RR=0.36; 95% CI: 0.18 to 0.74 at one and three or more months respectively), but not the risk of gastric ulcers [not significant (NS)].19,20 One trial without a placebo comparator was excluded in the pooled estimate.94 The

16

failure to reduce the risk of gastric ulcers is problematic since up to 80% of NSAID ulcers are gastric. Three RCTs with 298 patients assessed the efficacy of double-dose H2RA for the prevention of NSAID-induced upper GI toxicity.87,97,98 When compared with placebo, double-dose H2RAs were associated with a statistically significant reduction in the risk of duodenal (RR= 0.26; 95% CI: 0.11 to 0.65) and gastric ulcers (RR=0.44; 95% CI: 0.26 to 0.74). This 56% RRR in gastric ulcers corresponded to a 12% absolute risk difference (range 23.1% to 11.3%). Analysis of the secondary prophylaxis trials alone yielded similar results. b) Clinical ulcer complications We did not find any H2RA trials that assessed clinical ulcer complications. Symptoms H2RAs, in standard or double doses, were unassociated with an excess risk of total withdrawals, treatment withdrawals due to side effects or treatment withdrawals due to symptoms, when compared to placebo. Symptoms of abdominal pain were, however, significantly reduced with high-dose H2RAs when compared with placebo (RR=0.57; 95% CI: 0.33 to 0.98). Analyses by quality In contrast to high-quality trials, low-quality trials failed to demonstrate that standard-dose H2RAs prevented endoscopic duodenal ulcers. No significant differences were observed for treatment withdrawals and symptoms when trials of different quality were compared.

4.2.3 PPIs

Eight RCTs with 2,181 patients assessed the effect of PPIs on the prevention of NSAID- induced upper GI toxicity.35,38,78,99-103 Three trials compared omeprazole to placebo.78,102,103 Of the two trials that compared a PPI to placebo and to misoprostol, one studied lansoprazole35 and the other studied omeprazole in prophylaxis.78 Chan compared the combination of omeprazole and diclofenac to celecoxib, 37,38 while Jensen compared omeprazole to misoprostol.100 Another study compared pantoprazole to placebo,99 while the last compared omeprazole to ranitidine 150 mg.101

a) PPIs compared to placebo PPIs significantly reduced the risk of both endoscopic duodenal (RR=0.19; 95% CI: 0.09 to 0.37) and gastric ulcers (RR=0.40; 95% CI: 0.32 to 0.51) compared with placebo. The results were similar in both primary and secondary prophylaxis trials.

b) Clinical ulcer complications No PPI trials that assessed clinical ulcer complications were found.

17

Symptoms The omeprazole trials used the same composite endpoints to define successful treatment.78,101-103 In these trials, omeprazole significantly reduced “dyspeptic symptoms” as defined by the authors. Side effects were not different from those observed with placebo.

4.2.4 Head-to-head comparisons a) Misoprostol versus H2RAs Two trials, with 600 patients in total, compared misoprostol to ranitidine 150 mg twice daily.81,85 Misoprostol seemed to be superior to standard-dose ranitidine for the prevention of NSAID-induced gastric ulcers (RR= 0.12; 95% CI: 0.03 to 0.51), but not for duodenal ulcers (RR= 1.00; 95% CI: 0.14 to 7.14). b) PPIs versus ranitidine In a study of 425 patients, Yeomans et al. compared omeprazole 20 mg daily to ranitidine 150 mg twice daily in prophylaxis for patients on NSAIDs.101 In this study, omeprazole was superior to standard-dose ranitidine for the prevention of gastric (RR= 0.32; 95% CI: 0.17 to 0.62) and duodenal ulcers (RR=0.11; 95% CI: 0.01 to 0.89). c) PPIs versus misoprostol Two secondary prophylaxis trials with a total of 838 patients35,78compared a PPI to misoprostol. Hawkey et al.78 compared low-dose misoprostol (400 µg) daily to omeprazole 20 mg daily, while Graham35compared high-dose misoprostol (800 µg) to lansoprazole 15 or 30 mg daily. PPIs were found to be significantly superior to misoprostol for the prevention of duodenal (RR=0.29; 95% CI: 0.15 to 0.56), but not gastric ulcers. The Hawkey trial78 showed a non-significant trend towards greater benefit with misoprostol over omeprazole for the prevention of gastric ulcers, while the Graham study35 showed that misoprostol is superior to lansoprazole for the prevention of gastric ulcers. Our pooled results mirrored these findings, but statistical heterogeneity occurred. The use of a random-effects model failed to demonstrate a statistically significant benefit of misoprostol over PPIs for gastric-ulcer prevention (RR=0.59; 95% CI: 0.27 to 1.25). Jensen et al.100 presented an abstract of a prospective, randomized parallel-group trial comparing omeprazole (20 mg bid) to misoprostol (200 µg qid) in high-risk patients who required the continued use of NSAIDs or ASA. In this trial, patients had a documented severe GI hemorrhage while on NSAIDs. Treatment failures were defined as ulcer bleeding, severe adverse effects or symptomatic ulcers. Although the sample size of 46 patients was small, the authors found fewer treatment failures with omeprazole than with misoprostol (4.4% versus 30.4%, p=0.02). If only ulcer bleeding or symptomatic ulcers were considered, however, a statistical difference was not seen (RR=0.25; 95% CI: 0.03 to 2.07). d) Symptoms In the two head-to-head comparisons of omeprazole and misoprostol,35,78omeprazole was associated with significantly fewer treatment withdrawals overall (RR=0.64; 95% CI: 0.45 to 0.91) and significantly fewer treatment withdrawals due to side effects (RR=0.48; 95% CI: 0.29 to 0.78). There were no significant differences between low-dose H2RAs and PPIs in treatment withdrawals due to side effects (RR= 1.90; 95% CI: 0.77 to 4.67) or symptoms of abdominal

18

pain or diarrhea.101 When compared with H2RAs used for less than two months, misoprostol caused significantly more treatment withdrawals due to abdominal pain (RR=3.00; 95% CI: 1.11 to 8.14) and nausea (RR=3.67; 95% CI: 1.03 to 13.00) as well as more symptoms of dyspepsia (RR=1.59; 95% CI: 1.01 to 2.49) and diarrhea (RR= 2.03; 95% CI: 1.38 to 2.99).82,85

4.3 COX-2 Selective NSAIDs

This review identified 37 trials describing the GI toxicity of COX-2 selective NSAIDs. Seven trials considered endoscopic ulcers as endpoints (Table 2c)40-45and seven publications presented the results of studies that used clinical ulcer complications as endpoints (Table 2d).46,47,52,54-57 The remaining were either safety or tolerability studies or examined the clinical efficacy of COX-2 selective NSAIDs compared to non-selective NSAIDS, but allowed for extraction of GI tolerability data (Table 2e).58-63,66,67,104-118

19

Table 2c: Characteristics of included trials (endoscopic ulcers)


Trial Intervention Comparator

Celecoxib Celecoxib NSAID

Number of Patients

Mean Age (Years)

Arthritis Type

Follow-up

Quality Score

Goldstein 200140 200 mg bid Naproxen 500 mg bid 537 57 OA and RA

4, 8, 12 weeks 5

Emery 199941 200 mg bid Diclofenac 75 mg bid 655 55 RA 24 weeks 5 Simon 199942 100 mg bid

200 mg bid 400 mg bid


1,149 54 RA 2, 6, 12 weeks 5

FDA study 02143 50 mg bid 100 mg bid 200 mg bid


1,108 N/A OA 2, 6, 12 weeks 2*

FDA study 07143 200 mg bid Diclofenac 75 mg bid Ibuprofen 800 mg tid

1,097 N/A OA and RA

4, 8, 12 weeks 2*

Rofecoxib Rofecoxib Laine 199944 25 mg/day

50 mg/day

Ibuprofen 800 mg tid 742 62

OA 6 weeks, 3,6 months

5

End

osco

pic

Ulc

er

Hawkey 200045 25 mg/day 50 mg/day

Ibuprofen 800 mg tid 775 62 OA 6 weeks, 3,6 months

5

*Quality score for FDA studies 21 and 71 is likely better than assigned, but only summary data from FDA were available. N/A=not available.

19

20

Table 2d: Characteristics of included trials (clinical ulcer complications)




Number of Patients

Mean Age (Years)

Arthritis Type

Follow-up

Quality Score

Silverstein 200046 (CLASS)

400 mg bid Diclofenac 75 mg bid Ibuprofen 800 mg tid

8,059 60 OA and RA

4, 13, 26 weeks

(1 year FDA)

5

Goldstein 200047 (Combined analysis study)*

25 mg bid to 400 mg bid 7 dose steps

Naproxen 500 mg bid Diclofenac 75 mg bid Ibuprofen 800 mg tid

11,008

59 OA and RA

2 to 24 weeks 3

SUCCESS-148-53 Abstract# 100 mg bid 200 mg bid

Naproxen 500 mg bid 13,274 62 OA 6, 12 weeks 2

Rofecoxib Rofecoxib Bombardier 2000 (VIGOR)54 50 mg/day Naproxen 500 mg bid 8,076 58 RA 6 weeks, 4, 8,

12 months 5

Langman 199955 (Combined analysis study)

25 mg/day 50 mg/day

Ibuprofen 800 mg tid Diclofenac 50 mg tid Nabumetone 1,500 mg

5,435

63 OA 6 weeks, 4, 6, 12, 24 months

3

Meloxicam Meloxicam Dequeker 1998 (SELECT)56 7.5 mg/day Piroxicam 8,656 61 OA 4 weeks 4 Hawkey 1998 (MELISSA)57 7.5 mg/day Diclofenac 100 mg/day 9,323 62 OA 4 weeks 4 Yocum58 2000& 3.75 to 15 mg Diclofenac 100 mg/day 774 62 OA 12 weeks 3

Goei59 1997& 15 mg Diclofenac 100 mg/day 258 71 OA 6 weeks 3 Hosie60 1997& 15 mg Piroxicam 20 mg 455 67 OA 6 months 3 Hosie61 1996& 7.5 mg Diclofenac 100 mg/day 335 64 OA 6 months 3 Lindén62 1996& 15 mg Piroxicam 20 mg 260 67 OA 6 weeks 3 Wojtulewski63 1996& 7.5 mg Naproxen 750 mg 379 N/A RA 6 months 3 Distel 199664,65 (combined analysis study)

7.5 to 15 mg Piroxicam 20 mg/day Naproxen 1,000 mg/day Diclofenac 100 mg/day

6,129 59 OA and RA

Up to 1 year 3

Lemmel66 1997& 7.5 to 15 mg Placebo 468 54 RA 3 weeks 3

Clin

ical

Ulc

er C

ompl

icat

ions

Lund67 1998& 7.5 to 30 mg Placebo 513 68 OA 3 weeks 3 *Combined analysis means inclusion of all initial pre-CLASS FDA new drug application (NDA) studies. #SUCCESS-1 trial includes the Canadian study (Haraoui et al), and the world study (which likely includes the Canadian study). &These meloxicam studies are efficacy trials. Because their GI data quality is poor, the score assigned was 3 event though they may be rated higher if considered for efficacy.

20

21

Table 2e: Characteristics of included trials (safety, tolerability or clinical efficacy)




Number of Patients

Mean Age (Years)

Arthritis Type

Follow-up

Quality Score

McKenna 2001116 100 mg bid Diclofenac Placebo

600 62 OA 2, 6 weeks 3

Bensen 1999105 50 mg bid 100 mg bid 200 mg bid

Naproxen Placebo

1,003 62 OA 2, 6, 12 weeks 5

Williams 2000104 200 mg/day Placebo 686 63 OA 2, 6 weeks 4 Rofecoxib Rofecoxib Truitt 2001107 12.5 to 25 mg Nabumetone

Placebo 341 83 OA 1, 2, 4, 6

weeks 5

Day 2000108 12.5 to 25 mg Ibuprofen 809 64 OA 2, 4, 6 weeks 5 Cannon 2000109 12.5 to 25 mg Diclofenac 784 64 OA Up to 1 year 5 Saag 1998112 12.5 to 25 mg Ibuprofen

Placebo 736 61 OA 2, 4, 6 weeks 5

Saag 2000113 12.5 to 25 mg Diclofenac 693 62 OA Up to 1 year 5 Acevedo 2001106 12.5 mg/day Arthrotec® (diclofenac

50 mg/misoprostol 200 µg) 483 62 OA 2, 4, 6 weeks 5

Geba 2001117 25 mg/day Naproxen 5,597 63 OA 3, 6, 9, 12 weeks

2

Ehrich 1999110 25 to 125 mg Placebo 219 64 OA 1, 2, 4, 6 weeks

5

Schnitzer 1999111 5 to 50 mg Placebo 658 55 RA 2, 4, 8 weeks 3 Celecoxib and rofecoxib Whelton 2001115 Celecoxib

200 mg/day Rofecoxib 25 mg/day

None 811 74 OA 1, 2, 6 weeks 5

Geba 2002114 Celecoxib 200 mg/day Rofecoxib 12.5 to 25 mg

Acetaminophen 382 63 OA 2, 4, 6 weeks 5

Tol

erab

ility

McKenna 2001118 Celecoxib 200 mg/day Rofecoxib 25 mg/day

Placebo 182 62 OA 3, 6 weeks 5

21

22

4.3.1 COX-2 selective NSAIDs versus non-selective NSAIDS a) Endoscopic ulcer trials Seven trials with a total of 4,678 patients assessed the proportion of patients who developed endoscopic ulcers while taking a COX-2 selective NSAID compared to those taking a non-selective NSAID.40-45 Of the five trials that assessed celecoxib,40,43 two remain unpublished and were obtained from the FDA web site (FDA studies 21 and 71).43 Two studies assessed rofecoxib.44,45 A search of the FDA rofecoxib new drug application (NDA) documentation did not reveal any other endoscopic ulcer trials. The included endoscopic ulcer trials are similar in design and involve similar patient populations. To confirm the similarity of patient populations, we summarized the proportions of ulcers in the non-selective NSAID arms of these trials. This also allowed for indirect comparisons of the risk reductions seen with COX-2 selective NSAIDs with those seen in the NSAID prophylaxis trials. Among the endoscopic COX-2 selective NSAID trials, the proportions of gastric and duodenal ulcers in patients who were taking non-selective NSAIDs were 18.9% and 5.6% respectively. The proportion of gastroduodenal ulcers overall in the non-selective NSAID arms was 24.2%. The results for celecoxib trials were similar to the overall results. Among the rofecoxib trials, however, 39.1%, 5.6% and 46.3% of patients in the non-selective NSAID arms developed endoscopic gastric, duodenal and combined gastroduodenal ulcers respectively. In the NSAID prophylaxis studies, gastric ulcers occurred in the non-selective NSAID arms (without prophylaxis) in a range of 12% to 20% for all interventions. In secondary prophylaxis trials, 40% of patients on non-selective NSAIDs alone developed gastric ulcers as opposed to 10% to 14% in primary prophylaxis trials. Duodenal ulcers occurred in 6% of those taking non-selective NSAIDs. Thus, there was consistency between the proportions of endoscopic ulcers in the control groups of the original NSAID prophylaxis studies and those of the COX-2 selective NSAID studies. Reduction in gastric ulcers Five trials with a total of 2,123 patients compared the safety of low-dose COX-2 selective NSAIDs to a comparator non-selective NSAID over three to six months interval for endoscopic gastric ulcers.40-42,44,45 The use of a COX-2 selective NSAID in this setting was associated with an 84% RRR in gastric ulcers (RR=0.16; 95% CI: 0.12 to 0.22). Three studies, with a total of 981 patients, compared the proportions of gastric ulcers with high-dose COX-2 selective NSAIDs to non-selective NSAIDS.42,44,45 High-dose COX-2 selective NSAIDs were associated with a 77% RRR in gastric ulcers (RR=0.23; 95% CI: 0.16 to 0.32). When low- and high-dose COX-2 selective NSAID trials were considered together (2,613 patients), there was an 82% RRR in gastric ulcers (RR=0.18; 95% CI: 0.14 to 0.23). These RRRs represented a 22% ARR in gastric ulcers with COX-2 selective NSAIDs compared with non-selective NSAIDs (Table 3).

23

Table 3: Endoscopic ulcers associated with COX-2 selective versus non-selective NSAIDs

Outcome COX-2 Dose

Number of Trials

Number of Patients RR 95% CI ARR Hetero-

geneity Gastric 5 2,123 0.16* 0.12 to

0.22 22% No

Gastric with FDA studies 21 and 71 7 4,187 0.22* 0.14 to

0.34 15% Yes

Duodenal 5 2,123 0.38* 0.25 to 0.60 4% No

Duodenal with FDA studies 21 and 71

7 4,187 0.29* 0.20 to 0.43 4% No

Gastro-duodenal 5 2,123 0.22* 0.17 to 0.27 26% No

Gastro-duodenal with FDA studies 21 and 71

Low

7 4,187 0.26* 0.21 to 0.31 18% No

Gastric 3 981 0.23* 0.16 to 0.32 24% No

Duodenal 3 981 0.43* 0.22 to 0.84 3% No

Gastro-duodenal

High

3 981 0.28* 0.22 to 0.37 29% No

Gastric 5 2,613 0.18* 0.14 to 0.23 22% No

Gastric with FDA studies 21 and 71 7 4,677 0.24* 0.17 to

0.36 15% Yes

Duodenal 5 2,613 0.40* 0.27 to 0.60 4% No

Duodenal with FDA studies 21 and 71

7 4,677 0.29d 0.17 to 0.49 4% Yes

Gastro-duodenal 5 2,613 0.24* 0.20 to 0.29 26% No

Gastro-duodenal with FDA studies 21 and 71

Low and high

7 4,677 0.27* 0.23 to 0.32 19% No

*denotes statistical significance FDA studies did not contribute to the high-dose outcome.

Duodenal ulcers The same five trials also compared the proportions of duodenal ulcers that occurred with the use of low-dose COX-2 selective NSAIDs to those that occurred with the use of non-selective NSAIDs.40-42,44,45 Low-dose COX-2 selective NSAIDs were associated with a 62% RRR in duodenal ulcers (RR=0.38; 95% CI: 0.25 to 0.60). In the same three trials,42,44,45 high-dose COX-2 selective NSAIDs were associated with a 57% RRR in duodenal ulcers compared with non-selective NSAIDs (RR=0.43; 95% CI: 0.22 to 0.84). There was a 60% RRR in duodenal ulcers compared with non-

24

selective NSAIDs when both low- and high-dose studies were considered (RR=0.40; 95% CI: 0.27 to 0.60). This represented a 4% ARR between COX-2 selective NSAIDs and non-selective NSAIDs (Table 3). Overall, COX-2 selective NSAIDs were more effective at reducing the risk of gastric ulcers than the risk of duodenal ulcers (RR=0.18 versus 0.40). The difference reached statistical significance (p<0.001). This effect was consistent when celecoxib and rofecoxib were analyzed separately. Gastro-duodenal ulcers Five trials with a total of 2,613 patients showed a 76% RRR in combined gastro-duodenal ulcers with COX-2 selective NSAIDs versus non-selective NSAIDs (RR=0.24; 95% CI: 0.20 to 0.29).40-42,44,45 This represented a 26% ARR, which was driven by the effect of COX-2 selective NSAIDs on gastric ulcers. For this analysis, low- and high-dose trials were considered together. The results for the separate low- and high-dose analyses were similar (Table 3). The results from the two unpublished celecoxib studies (FDA 21 and 71) were excluded.43 These trials tended to have a weaker effect than the others and introduced heterogeneity in the three subgroup analyses (low-dose gastric ulcer, combined-dose gastric and duodenal ulcer) (Table 3). Galbraith analysis of these endpoints suggested that this heterogeneity was mainly due to FDA study 7133,34(Figure 2).

Figure 2: Galbraith plot for endoscopic gastro-duodenal ulcers (all trials)

In Figure 2 (Galbraith plot), the labelled diamonds represent individual trials. Small trials with the least precise results occur towards the left, while the largest trials with the most precise results occur towards the right. The solid black line represents the overall RR for the presented trials. In the absence of statistical heterogeneity, approximately 95% of trials would be expected to lie between the dotted lines. Those trials in this area but approaching the dotted lines must be considered as possible sources of heterogeneity. In this example, FDA study 71 lies outside the area of expected homogeneity.

25

Unfortunately, it was impossible to obtain details about FDA study 71 to help explain its discrepant results since it was unpublished. This trial compared celecoxib to ibupropfen and to diclofenac. Heterogeneity existed regardless of whether the comparator NSAIDs were considered together or individually. When these subgroups were analyzed using a random effects model, however, inclusion of these trials did not alter the overall results significantly. There was no evidence of statistical heterogeneity for the endpoint of gastro-duodenal ulcers with combined low- and high-dose COX-2 selective NSAIDs. Inclusion of these two trials lowered the RRR from 76% to 73% (RR=0.27; 95% CI: 0.23 to 0.32), corresponding to an ARR of 19% (Table 3).

Gastro-duodenal ulcers: analyses by COX-2 selective NSAIDs Five trials with a total of 3,590 patients compared celecoxib to non-selective NSAIDs, showing a 72% RRR in total gastro-duodenal ulcers (RR=0.28; 95% CI: 0.23 to 0.35).40-43Two trials with a total of 1,087 patients compared rofecoxib to non-selective NSAIDs. In this case, a 75% RRR was seen with rofecoxib (RR=0.25; 95% CI: 0.20 to 0.32)44,45 (Table 4). This result is not statistically different from that seen with celecoxib. The results were similar if FDA studies 21 and 71 were removed from the analysis (Table 5).

Table 4: Endoscopic ulcers stratified by COX-2 selective NSAID (including FDA studies 21 and 71)

Outcome COX-2

Selective NSAID

Number of Trials


geneity

Celecoxib 5 3,590 0.28* 0.23 to 0.35 14% No

Rofecoxib 2 1,087 0.25* 0.20 to 0.32 35% No

Endoscopic gastro-duodenal ulcer Total 7 4,677 0.27* 0.23 to

0.32 19% No

*denotes statistical significance

Table 5: Endoscopic ulcers: stratified by COX-2 selective NSAID (excluding FDA studies 21 and 71)

Outcome COX-2

Selective NSAID

Number of Trials


geneity

Celecoxib 3 1,526 0.22* 0.16 to 0.30 20% No

Rofecoxib 2 1,087 0.25* 0.20 to 0.32 35% No

Endoscopic gastro-duodenal ulcer Total 5 2,614 0.24* 0.20 to

0.28 27% No


26

Gastro-duodenal ulcers: analysis by comparator NSAIDs Three trials (including FDA study 21)43 compared celecoxib to naproxen and showed a 77% RRR in endoscopic ulcers in favour of celecoxib (RR=0.23; 95% CI: 0.17 to 0.30).40,42,43 Likewise, three trials [two rofecoxib44,45 and one celecoxib (FDA study 71)43] showed a 73% RRR with COX-2 selective NSAIDs compared with ibuprofen (RR=0.27; 95% CI: 0.22 to 0.33) (Table 6). Celecoxib was not statistically different from diclofenac (RR=0.45; 95% CI: 0.15 to 1.29) when two trials including FDA study 7141,43 were combined (Table 6). No trial compared rofecoxib to diclofenac.

Table 6: Endoscopic ulcers associated with COX-2 selective NSAID stratified by comparator non-selective NSAIDs (including FDA studies 21 and 71)

Outcome Comparator NSAID

Number of Trials


geneity Naproxen 3 2,063 0.23* 0.17 to

0.30 18% No

Ibuprofen 3 1,797 0.27* 0.22 to 0.33 27% No

Endoscopic gastro-duodenal ulcer Diclofenac 2 1,182 0.45 0.15 to

1.29 6% Yes

*denotes statistical significance FDA study 71 compared celecoxib to ibuprofen and diclofenac. In this trial, there was no significant RRR between celecoxib and diclofenac for gastric ulcers, but there was a significant 66% RRR when it was compared with ibuprofen (RR=0.34; 95% CI: 0.23 to 0.51).43 This was the only trial to compare a COX-2 selective NSAID to more than one non-selective NSAID. Gastro-duodenal ulcers: COX-2 selective NSAIDs versus placebo Four trials (including FDA study 21)43 with a total of 2,576 patients compared low- and high-dose COX-2 selective NSAIDs to placebo.42-45 With the same analyses described for COX-2 selective NSAIDs versus non-selective NSAIDS, no significant differences were found between COX-2 selective NSAIDs and placebo. For example, the RR for combined gastro-duodenal ulcers with combined low- and high-dose COX-2 selective NSAIDs versus placebo was a non-significant 1.09 (95% CI: 0.74 to 1.60). Removal of FDA study 21 did not significantly alter the results. FDA study 71 did not have a placebo arm.

b) Clinical Ulcer complications COX-2 selective NSAIDs versus non-selective NSAIDs Seven trials with a total of 61,282 patients assessed the safety of COX-2 selective NSAIDs using the clinically important endpoint of ulcer complications: perforation, obstruction and bleeding (POB).46,47,50,54-57 Three of these trials used celecoxib,46,47,52 two used rofecoxib54,55and two used meloxicam.56,57 Two of these trials were combined analyses of the early efficacy and the endoscopic trials,47,55and one was available only as an abstract.52 Two important trials in this group were the CLASS46 and VIGOR54 trials.

27

Overall, COX-2 selective NSAIDs are associated with a 61% RRR in clinically important GI outcomes compared with non-selective NSAIDs (RR=0.39; 95% CI: 0.27 to 0.56). This corresponds to a 0.21% ARR. The same analysis with the CLASS study46 12-month data obtained from the FDA web site drops the RRR to 55% (RR= 0.45; 95% CI: 0.32 to 0.63).43 The difference between the RRs obtained from these two analyses is not statistically significant (Table 7).

Table 7: Ulcer complications (POB) stratified by COX-2 selective NSAIDs

Outcome COX-2

Selective NSAID

Number of Trials


geneity

Celecoxib (6 months) 3 30,306 0.23* 0.07 to

0.78 0.21% Yes

Celecoxib (12 months) 3 30,306 0.260 0.06 to

1.16 0.17% Yes

Rofecoxib 2 12,997 0.42* 0.24 to 0.73 0.39% No

Meloxicam 2 17,979 0.500 0.22 to 1.17 0.088% No

Combined (6 months) 7 61,282 0.39* 0.27 to

0.56 0.21% No

Clinical ulcer (POB)


0.63 0.19% No

*denotes statistical significance The same seven trials combined the clinically important GI outcomes with a “symptomatic ulcer” endpoint to make a composite endpoint of ulcer complications and symptomatic ulcers (PUB).46,47,52,54-

57Using this endpoint, COX-2 selective NSAIDs were associated with a 53% RRR in PUBs compared to non-selective NSAIDs (RR=0.47; 95% CI: 0.38 to 0.57) (Table 8).

Table 8: Ulcer complications and symptomatic ulcers (PUB) stratified by COX-2 selective NSAIDs

Outcome COX-2

Selective NSAID

Number of Trials

Number of Patients RR 95% CI RD Hetero-

geneity Celecoxib (6 months) 3 30,306 0.41* 0.21 to

0.78 0.44% Yes

Celecoxib (12 months) 3 30,306 0.43* 0.21 to

0.88 0.70% Yes

Rofecoxib 2 12,997 0.47* 0.36 to 0.63 1.30% No

Meloxicam 2 17,979 0.530 0.26 to 1.05 0.12% No


0.57 0.51% No

Clinical ulcer

and symptomatic ulcer (PUB)


0.60 0.51% No


28

The same analysis with the CLASS trial46 12-month data did not significantly alter the results (RR= 0.49; 95% CI: 0.41 to 0.60)43 (Table 8). For these analyses, the meloxicam efficacy trials, which did not seek to address ulcer complications, were excluded. Analyses stratified by COX-2 selective NSAIDs Three trials with 30,306 patients compared celecoxib to NSAIDs.46,47,52 Significant heterogeneity existed in this analysis, most likely due to differing NSAID comparators. Using a random effects model, celecoxib was associated with a 77% RRR over non-selective NSAIDs (RR=0.23; 95% CI: 0.07 to 0.78) (Table 7). Two trials compared rofecoxib to NSAIDs.54,55 In this analysis, no heterogeneity existed and rofecoxib was associated with a 58% RRR in ulcer complications (RR=0.42; 95% CI: 0.24 to 0.73) (Table 7). Two high-quality trials compared meloxicam to a non-selective NSAID using methods similar to those in the CLASS and VIGOR trials.56,57 Individually, the Hawkey et al.57and Dequeker et al.56 trials failed to show a statistically significant benefit of meloxicam over diclofenac or piroxicam for either POBs or PUBs. Combining the two trials failed to show a statistical benefit of meloxicam over comparator NSAIDs for these endpoints [RR=0.50; 95% CI: 0.22 to 1.17 for POBs (Table 7), RR=0.53; 95% CI: 0.26 to 1.05 for PUBs (Table 8)]. We identified an additional eight meloxicam clinical efficacy trials with a total of 3,468 patients. These also considered GI adverse effects in their safety analyses.58-63,66,67Two of these trials compared meloxicam to placebo,66,67 leaving six trials (2,300 patients) that compared meloxicam to non-selective NSAIDs.58-63 One of these six was not used in the RR analysis since no PUBs occurred in any of the groups.58 Its data, however, were used in the ARR calculation. From an efficacy perspective, these trials were of good quality, but the reporting of clinical ulcer complications was poor, the criteria by which ulcer complications were adjudicated were not given or poorly described and all but one62 had no ulcer complications in at least one group resulting in empty cell analyses.31 Consequently, we did the combined analysis of the meloxicam trials separately. Inclusion of these trials allowed the RRR of 52% in PUBs with meloxicam to reach statistical significance (RR=0.48; 95% CI: 0.26 to 0.88). Their inclusion in the overall PUB analysis (63,582 patients), however, did not change the outcome (RR=0.47; 95% CI: 0.38 to 0.57) (Table 8). Sensitivity analyses of POB and PUB: combined analysis studies Combined analyses studies existed for each COX-2 selective NSAID being considered.47,55,65 These studies pooled the GI safety data presumably from all unpublished and published trials that the respective companies have on file. Thus, these studies combined data from short and longer term trials, early efficacy and safety trials and endoscopic endpoint trials. The combination of these varying types of data was a potential source of bias. Furthermore, assessing the quality of these studies was subjective since they were neither RCTs nor true meta-analyses. Based on our analysis, the study by Goldstein et al.47demonstrates a large 90% RRR of clinical ulcer complications (RR=0.10; 95% CI: 0.02 to 0.45). No other clinical study approaches this magnitude in RRR except the unpublished 12-week SUCCESS-1 trial. Furthermore, the risk reduction seen in clinical events in the Goldstein et al.47 study is greater than or similar to the reductions in endoscopic ulcers seen with this agent. This goes against the pattern observed for all the prophylaxis trials and the other COX-2 selective NSAID trials. It suggests that there is a fundamental difference in this

29

combined analysis study. In an otherwise similar combined analysis study, Langman et al.55 demonstrate results that fall in line with those of high-quality RCTs (Figure 3).

Figure 3: Galbraith plot of COX-2 selective NSAIDs versus non-selective NSAIDs trials

assessing ulcer complications and symptomatic ulcers (PUB)

The Goldstein et al.47 study falls well outside the limits for homogeneity suggesting that this study differs significantly from the others. The VIGOR trial has the greatest precision of the trials included in this analysis.

Removal of these combined studies, however, does not significantly alter the results for either POB or PUB endpoints, using either the six- or 12-month CLASS data (Tables 9 and 10) (POB RR=0.44; 95% CI: 0.30 to 0.65, PUB RR=0.51; 95% CI: 0.40 to 0.63 with six-month CLASS data). Furthermore, removal of the unpublished SUCCESS-1 trial does not alter the overall results (POB RR=0.48; 95% CI: 0.32 to 0.72, PUB RR=0.51; 95% CI: 0.40 to 0.64 with six-month CLASS data).

30

Table 9: Clinical ulcer (POB) in sensitivity analysis

Outcome CLASS Study Combined Study Number of Trials

Number of Patients RR 95% CI ARR Heterogeneity

Combined 7 61,282 0.39* 0.27 to 0.56 0.21% No

Remove meloxicam 5 43,303 0.37* 0.25 to 0.55 0.18% No

Remove meta-analysesa 5 47,217 0.44* 0.30 to

0.65 0.16% No 6-month data

As above minus SUCCESS-1 4 34,023 0.48* 0.32 to

0.72 0.13% No

Combined 7 61,282 0.45* 0.32 to 0.63 0.19% No

Remove meloxicam 5 43,303 0.35* 0.17 to 0.71 0.16% Yes

Remove meta-analysesa 5 47,217 0.51* 0.35 to

0.73 0.14% No

Clinical ulcer (POB)

12-month data


0.81 0.11% No

*denotes statistical significance a Meta-analyses=Goldstein et al. (2000) and Langman et al. (1999) combined analysis studies. POB data was unavailable for meloxicam efficacy trials, PUB data presented in Table 10.

30

31

Table 10: Clinical ulcer plus symptomatic ulcer (PUB) in sensitivity analysis

Outcome CLASS Study Combined Study

Number of Trials

Number of Patients RR 95% CI RD Heterogeneity

Combined 7 61,282 0.47* 0.38 to 0.57 0.58% No

As above with all meloxicama 13 63,582 0.47* 0.38 to

0.57 0.51% No

Remove meloxicam 5 43,303 0.46* 0.38 to

0.57 0.47% No

Remove meta-analysesb 5 47,217 0.51* 0.40 to

0.63 0.37% No

6-month data


0.64 0.33% No

Combined 7 61,282 0.49* 0.41 to 0.60 0.58% No

As above with all meloxicama 13 63,582 0.49* 0.40 to

0.59 0.51% No

Remove meloxicam 5 43,303 0.47* 0.33 to

0.67 0.47% Yes

Remove meta-analysesb 5 47,217 0.53* 0.43 to

0.66 0.37% No

Clinical ulcer and symptomatic

ulcer (PUB)

12-month data


0.68 0.33% No

*denotes statistical significance aAll meloxicam trials include primary efficacy trials that reported on clinical ulcer events and symptoms. bMeta-analyses=Goldstein et al. (2000) and Langman et al. (1999) combined analysis studies.

31

32

As it may be argued that meloxicam did not have the same degree of COX-2 selectivity as the others, we performed several sensitivity analyses, with or without the meloxicam trials. Removal of the trials did not significantly change the overall results for either POBs or PUBs, using either the six- or 12-month CLASS trial data (Tables 9 and 10). We identified two combined analysis studies of unpublished meloxicam randomized and non-randomized trials presumably held in company files.64,65 Although there were differences in their numbers, these trials represented duplicate publications. It is unclear how many (if any) of the trials included in this combined analysis were subsequently published and thus were included in our analysis. From Table 2d, the combined analysis by Distel et al.64,65 included 6,129 patients, 4,080 of whom were in RCTs. Over half of those included in RCTs were in trials with a duration of less than one month and thus, would have been excluded in our meta-analysis. For comparison, the eight meloxicam efficacy trials that we identified involved 3,468 patients, but two of these trials were comparisons of meloxicam to placebo. Thus, PUB data were extractable from six trials with a total of 2,300 patients. Consequently, we could not combine the Distel et al.64,65data reliably (Figure 4). In a sensitivity analysis based on this duplicate publication however, meloxicam was associated with an 86% RRR in PUBs, compared with combined non-selective NSAIDs (piroxicam, naproxen and diclofenac) (RR=0.14; 95% CI: 0.05 to 0.41).65 This degree of risk reduction, as detailed for the Goldstein et al. study,47 was inconsistent with all previous data. The 63% RRR with meloxicam (RR=0.37; 95% CI: 0.11 to 1.27) was non-significant if the data from the six published trials that compared meloxicam to non-selective NSAIDs were used.

33

Figure 4: L’Abbé plot of GI event rates: meloxicam versus non-selective NSAIDs (all trials)

COX-2 selective NSAIDs compared to specific non-selective NSAIDs The Goldstein et al. combined analysis study included multiple trials with naproxen but outcomes related to naproxen or other NSAIDs could not be determined regarding POBs.47 We did obtain the NSAID data of the Goldstein et al. study from the FDA web site for the PUB endpoint (FDA study 62).43 Similarly, the Langman et al. combined analysis included two trials (protocols 34 and 35) on the efficacy and safety of rofecoxib, compared to 150 mg of diclofenac/ day, for OA of the knee (590 out of 5,435 patients were exposed to diclofenac).55 The data in this subset of the Langman et al. combined analysis were available from FDA document NDA 21-042.119 These two trials showed significantly more treatment withdrawals due to lack of efficacy with rofecoxib than with diclofenac.119 Again, COX-2 selective NSAIDs seemed to be superior to naproxen and ibuprofen, but as in the endoscopic trials, were not statistically superior to diclofenac among three trials individually or when the trials were combined (RR=0.73; 95% CI: 0.46 to 1.14).46,55,57 The results were similar when the six- or 12-month CLASS data were used. One single higher quality trial compared meloxicam to piroxicam for PUBs56 (Tables 11 and 12).

34

Table 11: Ulcer complication plus symptomatic ulcer (PUB) stratified by comparator non-selective NSAID using CLASS published six-month data

Outcome

COX-2 Selective NSAID Versus

Number of Trials


geneity

Piroxicam 1 8,656 0.44 0.18 to 1.07 0.21% -

Naproxen 1 8,076 0.46* 0.34 to 0.63 1.7% -

Piroxicam and naproxen 2 16,732 0.46* 0.34 to

0.62 0.96% No

Ibuprofen 2 10,187 0.56* 0.36 to 0.86 0.55% No

Clinical ulcer and

symptomatic ulcer (PUB)

Diclofenac 3 19,242 0.73 0.46 to 1.14 0.10% No

*denotes statistical significance The meloxicam efficacy trials were excluded in this analysis.

Table 12: Ulcer complication plus symptomatic ulcer (PUB) stratified by comparator non-selective NSAID using CLASS 12-month data

Outcome


Number of Trials

Number of Patients RR 95% CI RD Hetero-

geneity

Piroxicam 1 8,656 0.44 0.18 to 1.07 0.21% -

Naproxen 1 8,076 0.46* 0.34 to 0.63 1.7% -

Piroxicam and

naproxen 2 16,732 0.46* 0.34 to

0.62 0.96% No

Ibuprofen 2 10,187 0.61* 0.42 to 0.91 0.57% No

Clinical ulcer and


Diclofenac 3 19,242 0.78 0.52 to 1.18 0.097% No

*denotes statistical significance Rofecoxib has not been directly compared to diclofenac in a high-quality clinical ulcer complication trial such as VIGOR. The data for rofecoxib versus diclofenac are derived from a subset of the Langman et al study,55 so a high-quality trial may show a different result.

35

Nonetheless, from a GI perspective, available data suggest that COX-2 selective NSAIDs are not significantly safer than diclofenac.

In a separate sensitivity analysis, we performed the same analysis with the addition of the meloxicam efficacy trials (Table 13). The overall results stayed the same. Meloxicam was not superior to piroxicam. The combined COX-2 selective NSAID trials showed a statistically significant benefit over naproxen and ibuprofen. But in a combined analysis of six trials with a total of 19,835 patients, COX-2 selective NSAIDs were not statistically different from diclofenac (RR=0.70; 95% CI: 0.45 to 1.09).

Table 13: Ulcer complication plus symptomatic ulcer (PUB) stratified by comparator non-

selective NSAID and including all meloxicam efficacy trials

Outcome


Number of Trials


geneity

Piroxicam 3 9,367 0.48 0.22 to 1.07 0.21% No

Naproxen 2 8,455 0.45* 0.33 to 0.61 1.7% No

Piroxicam and

naproxen 5 17,822 0.46* 0.34 to

0.61 0.96% No

Ibuprofen 2 10,187 0.56* 0.36 to 0.86 0.55% No

Clinical ulcer and


Diclofenac 6 19,835 0.70 0.45 to 1.09 0.10% No

*denotes statistical significance c) Head to head comparisons: non-selective NSAID and PPI versus celecoxib Recently, Chan et al.37 compared a strategy of a non-selective NSAID with a gastroprotective agent versus celecoxib alone in high risk arthritic patients who had suffered a recent GI hemorrhage on NSAIDs. Ulcer healing was confirmed by endoscopy in 290 subjects who were then randomized to receive celecoxib 400 mg/day alone or diclofenac 150 mg/day with omeprazole 20 mg/day. After six months of follow-up, 24 serious GI events had occurred. Sixteen cases of recurrent ulcer bleeding occurred (seven with celecoxib and nine with diclofenac plus omeprazole). All but one was due to recurrent bleeding from the identified gastric ulcer site. The six-month probability of recurrent bleeding was 4.9% and 6.4% for the celecoxib and diclofenac-omeprazole groups respectively (not statistically significant). Of the 260 patients who were not taking ASA, the six-month probability of recurrent bleeding was 4.5% and 5.6% for the celecoxib and diclofenac-omeprazole groups respectively (not statistically significant). The authors concluded that the two strategies for recurrent ulcer prevention were equivalent. The annual incidences of NSAID-related ulcer bleeding in this trial of nearly 10 per 100 person-years were high. In the MUCOSA study, high risk patients taking non-selective NSAIDs without prophylaxis had a 9% six-month incidence of ulcer complications.

36

d) Symptoms and treatment withdrawals Treatment withdrawals due to GI side effects: COX-2 selective NSAIDs versus non-selective NSAIDs Twenty-two trials with 44,840 patients compared low- or high-dose COX-2 selective NSAIDs to non-selective NSAIDs for treatment withdrawals due to all side effects. Overall, COX-2 selective NSAIDs were associated with a significantly lower risk of treatment withdrawals [RR: 0.81 (95% CI: 0.73 to 0.90)]. The previous NSAID Cochrane Collaboration meta-analysis, however, identified treatment withdrawals due to GI symptoms as the most reliably reported endpoint. Fifteen trials (12 low-dose, two high-dose and one low- and high-dose) with a total of 49,706 patients assessed this endpoint.40-42,46,48,49,53,54,56,60,61,63,105,109,113,117 Data extracted from the SUCCESS-1 trial came from several abstracts. Low-dose COX-2 selective NSAIDs were associated with a 29% RRR in treatment withdrawals due to GI side effects when compared with non-selective NSAIDs (RR=0.71; 95% CI: 0.65 to 0.77). Among the three trials that used high- dose COX-2 selective NSAIDs, the RRR was 22% (RR=0.78; 95% CI: 0.69 to 0.87).42,46,54 Overall, low- or high-dose COX-2 selective NSAIDs reduced the RR of treatment withdrawals due to GI side effects by 27% (RR=0.73; 95% CI: 0.69 to 0.79). This result was driven by the low-dose trials. These RRRs corresponded to a 2% ARR (Table 14). Treatment withdrawals due to GI side effects: COX-2 selective NSAIDs versus placebo Thirteen trials with 6,311 patients compared low-dose COX-2 selective NSAIDs to placebo for treatment withdrawals due to side effects overall. In this analysis, no statistically significant difference was seen in the number of treatment withdrawals due to side effects, although there was a trend towards an increase with COX-2 selective NSAIDs compared with placebo (Table 14) (RR=1.13; 95% CI: 0.91 to 1.40).42,44,45,66,67,104,105,107,108,110,111,113,116Among eight trials (4,478 patients) using low- or high-dose COX-2 selective NSAIDs, there was a slight but not statistically significant increased risk of treatment withdrawals due to GI side effects when compared to placebo (Table 14) (RR=1.35; 95% CI: 0.83 to 2.20).42,58,66,104,105,111,113,116High-dose COX-2 selective NSAIDs, however, significantly increased the RR of treatment withdrawals due to side effects, when compared with placebo among six trials (1,863 patients) (Table 14) (RR=1.62; 95% CI: 1.16 to 2.25)42,44,45,67,110,111Two trials42,111compared high-dose COX-2 selective NSAIDs to placebo for treatment withdrawals due to GI side effects. Treatment withdrawals occurred in one trial.42 No significant difference was observed (RR=3.71; 95% CI: 0.78 to 17.66). Symptoms As reported in the NSAID prophylaxis Cochrane Collaboration review,19 the reporting of drug-related symptoms and side effects was often associated with heterogeneity. This was partly due to the fact that there was overlap in clinicians’ definitions of dyspepsia, heart burn, indigestion and abdominal pain.

37

Table 14: Treatment withdrawals due to GI side effects and symptoms

Endpoint Outcome

COX-2 Selective NSAIDs Versus

COX-2 Dose Number of Trials

Number of

Patients RR 95% CI ARR Heterogeneity

Side effects L and H 22 44,840 0.81* 0.73 to 0.90 2% Yes

GI side effects L 13 33,444 0.71* 0.65 to 0.77 2% No

GI side effects H 3 16,487 0.78* 0.67 to 0.86 2% No

GI side effects

NSAID

L and H 15 49,706 0.73* 0.69 to 0.79 2% No

Side effects L 13 6,311 1.130 0.91 to 1.40 1% No

Side effects H 6 1,863 1.62* 1.16 to 2.25 3% No

Drops-outs

GI side effects

Placebo

L and H 8 4,478 1.350 0.83 to 2.20 1% No

Side effects L and H 17 34,578 0.950 0.90 to 1.0 3% Yes

GI side effects L 14 36,564 0.75* 0.72 to 0.78 5% No

GI side effects H 2 8,411 0.85* 0.80 to 0.90 5% No

Dyspepsia L 10 35,214 0.75* 0.64 to 0.88 2% Yes

Dyspepsia H 2 8,411 0.89* 0.81 to 0.99 2% No Abdominal

pain L 11 35,567 0.63* 0.52 to 0.76 2% Yes

Abdominal pain H 3 8,756 0.75* 0.67 to 0.85 3% No

Symptoms

Nausea

NSAID

L and H 120 43,490 0.74* 0.68 to 0.81 1% No

*denotes statistical significance L=low, H=high

37

38

Among 14 trials with 36,564 patients40-42,48,49,53,56-60,62,63,105,116 low-dose COX-2 selective NSAIDS were associated with a 25% RRR in overall GI side effects, compared with non-selective NSAIDs (RR=0.75; 95% CI: 0.72 to 0.78). Only two trials42,46 assessed this outcome with high-dose COX-2 selective NSAIDs (RR=0.85; 95% CI: 0.80 to 0.90). COX-2 selective NSAIDs also demonstrated a 26% RRR in nausea, compared with non-selective NSAIDs, in 12 trials (43,490 patients) (RR= 0.74; 95% CI: 0.68 to 0.81).40,41,46,48,51,53,56,57,59,107-109,113,116 The SUCCESS-1 trial results were extracted from several abstracts (Table 14).

39

5 DISCUSSION 5.1 Prophylactic Gastroprotective Therapy

The systematic review of prophylactic agents for the prevention of NSAID-induced upper GI toxicity was accomplished by updating the 2000 Cochrane Collaboration meta-analysis by Rostom et al.19,20 In our update, five new trials were found. The robustness of the original meta-analysis was improved, but the conclusions stayed the same. 5.1.1 Misoprostol For patients taking NSAIDs, misoprostol remains the only prophylactic agent that has been shown to reduce the occurrence of clinically important ulcer complications such as bleeding, perforation or hemorrhage. Misoprostol reduces the risk of these events by 51% [OR=0.487; (95% CI: 0.268; 0.886)], which represents a 0.38% ARR. Approximately 260 patients would have to be treated with misoprostol to prevent one clinically important GI event. This NNT would drop as higher risk patients are considered. Unfortunately, misoprostol is associated with a significant rate of side effects, such as abdominal pain and diarrhea, which are also dose-dependent. Thus, at the doses shown to be effective at reducing clinically important events, misoprostol is associated with the highest rates of side effects. This limits its clinical usefulness. 5.1.2 H2RAs H2RAs are ineffective at reducing the incidence of endoscopic gastric ulcers. Double-dose H2RAs, however, at doses equivalent to ranitidine 300 mg twice a day are effective at reducing the occurrence of both endoscopic gastric and duodenal ulcers. The added cost and the inconvenience of taking double doses make this medication less attractive as a standard prophylactic agent. 5.1.3 PPIs PPIs, at standard once-daily dosing, were effective at reducing the incidence of endoscopic gastric and duodenal ulcers, reduced NSAID-induced dyspeptic symptoms and were well tolerated. In the combined analysis of two head-to-head trials of misoprostol versus PPIs, however, there was no statistically significant difference between them for the prevention of NSAID-induced gastric ulcers. The RCT by Graham et al.35 found that misoprostol was more effective than PPIs for gastric ulcer prevention. Likewise, Graham et al. re-analyzed the data from the original OMNIUM78 and ASTRONAUT101 trials and found that these trials may have overestimated the effect of PPIs at reducing NSAID-induced gastric ulcers. In this re-analysis, misoprostol 400 µg/day was more effective than omeprazole 20 mg/day at reducing gastric ulcers (8.2% versus 16.6% for misoprostol and omeprazole respectively, p<0.05) and PPIs were no better than misoprostol at preventing gastric ulcers in Helicobacter pylori (H. pylori) positive

40

subjects. PPIs were more effective, however, at reducing duodenal ulcers than gastric ulcers as our meta-analysis has shown.120 It was difficult to comment on the relative efficacy of the prophylactic agents since the trials involving head-to-head comparisons often used doses of the comparator drug that are less effective. For example, misoprostol and omeprazole were compared to standard-dose ranitidine, and omeprazole was compared to misoprostol 400 µg/day. With this limitation, misoprostol was found to be superior to standard-dose H2RAs at reducing endoscopic gastric ulcers. Omeprazole was superior to standard-dose ranitidine at reducing the risk of both endoscopic gastric and duodenal ulcers. Misoprostol, however, may be more effective than the PPIs for the prevention of NSAID-induced gastric ulcers.

5.2 COX-2 Selective NSAIDs

The results of this meta-analysis show that COX-2 selective NSAIDs are associated with reductions in endoscopic gastric, duodenal and gastro-duodenal ulcers when compared with non-selective NSAIDs. The benefit of COX-2 selective NSAIDs is greater for gastric ulcers than for duodenal ulcers. The proportions of patients with ulcers in the non-selective NSAID arms of the COX-2 endoscopic trials are similar to those seen in the prophylaxis trials. For all the interventions included in our review, duodenal ulcers occur in 6% of patients taking non-selective NSAIDs. The occurrence of gastric ulcers, however, varies from as high as 40% in secondary prophylaxis trials to 10% to 14% in the primary prophylaxis trials. Since these trials are all similar in design and in patient populations, it is reasonable to descriptively compare risk reductions among the agents used for prophylaxis and the COX-2 selective NSAIDs with respect to endoscopic ulcers. COX-2 selective NSAIDs are more effective at reducing the risk of gastric ulcers than that of duodenal ulcers. This statistically significant effect is also seen with misoprostol overall and in a similar trend with low-dose misoprostol. In contrast, double-dose H2RAs and PPIs show non-significant trends toward greater reductions in the risk of duodenal ulcers rather than gastric ulcers. The difference between the RR of duodenal (RR=0.19) and gastric ulcers (RR=0.40) for PPIs nearly reaches statistical significance (p=0.068). High-dose misoprostol is equally effective at reducing the risk of gastric (RR=0.17) and duodenal ulcers (RR=0.21). This similarity between the COX-2 effect and that seen with misoprostol has biological plausibility and adds weight to the COX-2 hypothesis, i.e. COX-2 selective agents do not deplete gastric prostaglandins as much as non-selective NSAIDs, while misoprostol replenishes gastric prostoglandins when used with non-selective NSAIDs. These data are strengthened by the results in the trials of Hawkey et al.78 and Graham et al.,35 which suggest that misoprostol may be more effective than PPIs at reducing the risk of NSAID-induced gastric ulcers. These, however, are exploratory analyses. We found one trial that directly compared a COX-2 selective NSAID to a strategy involving the use of a non-selective NSAID (diclofenac) with a prophylactic agent (omeprazole).37 This trial, conducted in a Hong Kong population negative for H. pylori, demonstrated equivalence of the

41

two strategies. Both strategies, however, had a high (5%) ulcer complication rate at six months. For comparison, in the MUCOSA trial, high risk subjects (those having four risk factors) taking a non-selective NSAID alone had a 9% six-month complication rate. Whether this finding was related to the Chan et al. study population or the trial design was unclear, but it suggested that neither strategy would be attractive. Furthermore, this trial was designed to establish equivalence, and a sample size of 290 patients may be too small to demonstrate this. The results should be confirmed in a North American or European population. In support of the Chan et al. trial, our meta-analysis suggests that both strategies are effective at reducing the risk of endoscopic ulcerations among patients requiring the chronic use of anti-inflammatory drugs. The risk reductions in endoscopic ulcers seem similar in a strategy of non-selective NSAIDs with gastroprototective prophylaxis as in a strategy of COX-2 selective NSAIDs alone. This statement, however, is based on indirect comparisons, given the similarity of control-group ulcer rates across all interventions. There is a potential for bias, however, since factors such as comparator NSAIDs and dosages could not be considered simultaneously, given the small number of trials in our meta-analysis. COX-2 selective NSAIDs are associated with an overall 61% RRR in clinically important ulcer complications (POBs) and an overall 53% RRR in combined clinical and symptomatic ulcers (PUBs). In these analyses, all COX-2 selective NSAIDs and all comparator NSAIDs are considered together. Overall, the use of COX-2 selective NSAIDs in our combined analyses is associated with a 0.21% ARR when compared to non-selective NSAIDs. Thus, 476 average risk NSAID users (NNT) would have to be treated with a COX-2 selective NSAID rather than a non-selective NSAID to prevent one POB. We performed sensitivity analyses on ulcer complication results to ensure that they were robust. Removal of the lower quality combined analysis studies and the unpublished SUCCESS-1 trial (which tended to show greater RRRs than the higher quality RCTs) lowered the RRR from 61% for POBs to 52% (RR=0.48; 95% CI: 0.32 to 0.72). This difference was not statistically significant. For PUBs, the RRR fell from 53% to 51% (RR=0.49; 95% CI: 0.41 to 0.60). This difference was also not statistically significant. Considering a risk difference analysis, the drop from 0.21% to 0.13% for POBs means that 770 average risk NSAID users (NNT) would have to be treated with a COX-2 selective NSAID to prevent one POB, if only the higher quality trials are considered. For PUBs, the NNT would rise from 188 to 270 if only higher quality trials are considered. The results of the SUCCESS-1 trial should clarify where in the presented range the overall risk reductions with COX-2 selective NSAIDs will fall. From our analysis, the RRRs for POB lie in the range of 50% to 60%, while the RRR for PUBs is approximately 50%. There are no head-to-head comparisons of the COX-2 selective NSAIDs. Based on our stratified analyses, however, rofecoxib is superior to naproxen for POBs and PUBs,54 whereas for POBs, celecoxib fails to show a statistically significant benefit over diclofenac and ibuprofen combined or diclofenac alone.46 Meloxicam does not show statistically significant benefits over either piroxicam or diclofenac in the high-quality individual trials or when these are combined (95% CI: 0.22 to 1.17). This finding may reflect the lower COX-2 selectivity of meloxicam. Inclusion

42

of the data from the meloxicam efficacy trials, however, allows meloxicam’s 52% RRR in PUBs to reach statistical significance (CI: 0.26 to 0.88). The importance of this difference should raise alarm, considering that the two high-quality trials (17,979 patients) fail to show a statistically significant benefit for POBs or PUBs, but the addition of data from six efficacy trials (2,300 patients) allows the analysis to reach statistical significance. First, all but one of the efficacy trials have no events in one or more groups. Second, although these trials are of good quality from the efficacy perspective, they are poor from the perspective of reporting on clinical ulcer complications. The 11% increase in the number of patients achieved through the inclusion of these trials may have sufficiently raised the power of the analysis to show a statistically significant benefit of meloxicam over certain non-selective NSAIDs. The clinical ulcer complication analyses with the Galbraith plots and L’Abbé plots for heterogeneity (Figures 3 and 4), revealed an apparent problem with the Goldstein et al. and Distel et al. combined analyses studies.47,65 These studies showed risk reductions in clinical ulcers greater than those seen in the endoscopic trials and were out of step with the higher quality RCTs (Figure 3). With endoscopic ulcers trials, the risk reductions achieved through the use of prophylaxis were high (70% to 90%) depending on whether gastric or duodenal ulcers were considered. This pattern was seen in the endoscopic COX-2 selective NSAID analyses, where risk reductions of 70% to 80% were seen. The risk reductions in clinically important events in average risk patients, however, were consistently lower. In the COX-2 selective NSAID trials, the risk reductions for the combined analyses ranged from about 50% to 60% depending on the analysis. Likewise, the MUCOSA trial demonstrated a 51% RRR in a similarly defined POBs analysis. Thus, it was difficult to put into perspective the Goldstein et al. and Distel et al. study results. In the three combined analysis studies that we identified,47,55,65 various types of trials were combined, including the early safety and tolerability trials, the clinical efficacy trials that reported GI adverse events and the endoscopic trials. The combination of such varying data could introduce bias into these analyses. For example, the reporting of clinical ulcer complications may have been unreliable or inconsistent in the early efficacy trials. Also, when one endpoint in the combined analysis studies was the “symptomatic ulcer,” how could trials in which endoscopy was a scheduled portion of the protocol be reliably combined? Stratified analysis of the COX-2 selective NSAID trials by the comparator NSAID revealed that COX-2 selective NSAIDs were superior to naproxen and ibuprofen but not to diclofenac. Among three trials that compared COX-2 selective NSAIDs to diclofenac (19,499 patients), the COX-2 selective NSAIDs were not significantly better than diclofenac for PUBs. The results were robust to sensitivity analysis with the CLASS six- and 12-month data and to analysis by individual COX-2 selective NSAID. The PUB data for rofecoxib versus diclofenac, however, were derived from a group of 590 patients included in the Langman et al. combined analysis study. Nonetheless, these data suggested that COX-2 selective NSAIDs were safer than more toxic non-selective NSAIDs, but may be no different than less toxic non-selective NSAIDs such as diclofenac. These data may also explain why the CLASS study failed to meet its primary

43

endpoint, while the VIGOR study using the more toxic comparator NSAID naproxen showed a statistical superiority of rofecoxib over naproxen for both PUBs and POBs. In population studies and other reports, ibuprofen is the safest non-selective NSAID with regards to GI toxicity and is often used as the gold standard comparator. In our analyses, however, when compared to COX-2 selective NSAIDs, diclofenac is the safest comparator. This finding is confirmed in a meta-analysis by Henry et al.121 As in previous reports, ibuprofen is found to be the safest non-selective NSAID and based on the mean rank method, diclofenac is the second safest. The authors find that ibuprofen’s apparent safety is due mainly to the use of low doses in clinical practice and in over-the-counter use. In higher doses, ibuprofen is associated with toxicity similar to that of other NSAIDs. In our meta-analysis, ibuprofen is used in a high dose of 2.4 g/day in the trials where it is a comparator. Diclofenac has a greater COX-2 selectivity than ibuprofen and one close to that of celecoxib,25 which may explain the results of the CLASS trial. The CLASS trial compared celecoxib to ibuprofen and to diclofenac.46 This trial did not show a statistically significant benefit of celecoxib over the combined non-selective NSAID groups for its primary outcome of ulcer complications (POB), though it showed a benefit if the composite PUB endpoint was used. In subgroup analyses, celecoxib was superior to combined NSAIDs in patients not taking ASA but not for those on celecoxib and ASA. The risk of ulcer complications in patients taking celecoxib and ASA was nearly four times that of those who were not taking ASA. There would be no advantage for a patient needing ASA to take celecoxib rather than diclofenac. Paradoxically, patients taking ibuprofen and low-dose ASA suffered fewer ulcer complications than patients taking either celecoxib or diclofenac and low-dose ASA, though one must be cautious in putting weight on this small post hoc analysis.122,123 These data were a contrast to the suggestions, based on the initial endoscopic trials, that it may be safer to take ASA with celecoxib than with non-selective NSAIDs.122,123 The CLASS trial also presented problems that lie beyond this review’s scope. According to the original FDA submission, the stepwise analysis of the CLASS data depended on a statistically significant difference between celecoxib and the combined non-selective NSAID groups for POBs. If this analysis failed, then no further analyses would be undertaken. In the published CLASS trial, the POB endpoint failed to reach statistical significance yet multiple subgroup analyses were performed. Furthermore, according to several documents on the FDA web site, multiple letters to the editors of journals124,125 and an article in the Washington Post,126 the CLASS trial lasted 12 months rather than the published six months. The celecoxib sponsors argued that the statistical technique of data imputation was required because more subjects dropped out of the non-selective NSAID arms than those with celecoxib. Thus, patients who continued on celecoxib remained at risk for GI events, while the disproportionate number of those on non-selective NSAIDs who had dropped out could not suffer a significant GI event. The FDA reviewers refuted these arguments.122,123 Recently, Deeks et al. undertook a systematic review of RCTs comparing celecoxib to another NSAID. They concluded that celecoxib was as effective as other NSAIDs in the management of OA and RA and that its use was associated with a significant improvement in GI safety and tolerability.127 The safety findings in the Deeks et al. were also criticized because it used CLASS’s six-month results, as opposed to the 12-month data compiled by the FDA.128-130 For this reason, we chose to ignore these findings in our review. In this review, sensitivity analyses were done on the six-month and the 12-month CLASS data, with

44

the results not affecting the overall combined analysis. Overall, a statistically significant benefit of COX-2 selective NSAIDs over combined non-selective NSAIDs remained. The VIGOR trial was a well conducted RCT of rofecoxib versus the relatively GI-toxic non-selective NSAID naproxen in RA patients not taking ASA. The results showed a statistical superiority of rofecoxib over naproxen for both POBs and PUBs. This finding was recently reflected in the Canadian prescribing information for Vioxx® [Important safety information for patients taking Vioxx® (rofecoxib)].131 Unfortunately, a safety issue was identified in the VIGOR trial. The FDA web site revealed that subjects in the rofecoxib arm were at higher risk of cardiovascular complications than those taking naproxen. This difference may be interpreted as a positive effect of naproxen, a detrimental effect of rofecoxib, a combination of the two effects, or a chance occurrence. Naproxen was not tested as an antiplatelet drug in cardiovascular prevention trials.132 The Canadian prescribing information of Vioxx® was recently revised to include cardiovascular data from the VIGOR study [Important safety information for patients taking Vioxx® (rofecoxib)].131 Also, the safety of the co-administration of ASA and rofecoxib remains unknown, since ASA users were excluded from the VIGOR trial. If the results were similar to those seen in the CLASS trial, then reduced safety would be expected when rofecoxib is used with ASA, particularly if it is compared with a less toxic NSAID such as diclofenac. Large trials are being conducted to assess the cardiovascular risk associated with COX-2 selective NSAIDs. A recent observational study by Mamdani et al. compared the rates of acute myocardial infarction (AMI) among elderly patients dispensed celecoxib, rofecoxib, naproxen and other non-selective NSAIDs. The findings suggested that there was no increase in the short-term risk of AMI in COX-2 selective NSAID users relative to the non-NSAID-using population, when COX-2 selective NSAIDs were used in usual doses.133 In the CLASS and VIGOR trials, the dosages of the COX-2 selective NSAIDs used were two to four times higher than the recommended dosages for treatment of RA and OA. In another observational study, Mamdani et al. compared the rates of upper GI hemorrage in elderly patients given COX-2 selective NSAIDs and non-selective NSAIDs. They reported that the risk of these events with celecoxib and rofecoxib was significantly lower than that with non-selective NSAIDs, but the risk with rofecoxib was significantly higher than that with celecoxib.134 Whether the improved GI safety of COX-2 selective NSAIDs will lead to an overall therapeutic advantage for these agents, compared with non-selective NSAIDs, has been questioned. In a recent review by Wright, an assessment of all serious adverse events (SAEs) (death, admission to hospital, life-threatening event or event leading to serious disability) reported in the CLASS and VIGOR trials was conducted.135 The incidence of SAEs was significantly higher with COX-2 selective NSAIDs than non-selective NSAIDs, leading to a number needed to harm (NNH) of 78 over nine months. According to the author, this increase could be partially caused by the increased thrombotic and cardiac adverse events. Disclosure of all safety and efficacy data was recommended to assess the role of COX-2 selective NSAIDs in the long-term treatment of patients with arthritis.135

45

Given that the COX-2 selective NSAIDs included in this review differ from each other in COX-2 selectivity, and that the comparator NSAIDs have been shown to have differing propensities for GI toxicity, how would an agent such as diclofenac or ibuprofen fare in a CLASS or VIGOR trial compared to more toxic NSAIDs such as naproxen or piroxicam? Based on our meta-analysis and the results of the CLASS trial, diclofenac, for example, would lead to a significant risk reduction in PUBs or POBs when compared with more toxic non-selective NSAIDs. Are these new COX-2 selective NSAIDs a different “class” of agents or are they part of a continuum that includes the "standard NSAIDs" but with differing GI toxicities? The data from this meta-analysis show that the available COX-2 selective NSAIDs have a safer GI profile than other NSAIDs and are better tolerated overall. It has been shown that celecoxib (particulary if it is administered with ASA) and meloxicam (with higher quality and efficacy trials) do not differ from diclofenac. Rofecoxib does not seem to be safer than diclofenac. Although the Langman et al. combined analysis includes two trials (protocols 34 and 35) of the safety and efficacy of rofecoxib compared to 150 mg of diclofenac/day for OA of the knee (590 of 5,435 patients used diclofenac),55 data had to be obtained from an FDA document NDA-21-042.119 These data cannot be extrapolated to suggest that COX-2 selective NSAIDs are safer than all non-selective NSAIDs, even though a given COX-2 selective NSAID was shown to be safer than a specific non-selective NSAID. Finally, our review did not address any economic aspects of the use of gastroprotective therapy to prevent NSAID-induced GI complications, as this was done in a previous evaluation by CCOHTA.136,137

46

6 CONCLUSIONS 6.1 Gastroprotective Agents • Misoprostol, PPIs and double doses of H2RAs are effective at reducing the risk of

endoscopically identified gastric and duodenal NSAID-induced ulcers. • Standard doses of H2RAs are ineffective at reducing the risk of endoscopically identified

NSAID-induced gastric ulcers. • Misoprostol is the only prophylactic agent that has been evaluated in a clinical outcome trial.

It reduces the risk of NSAID-related ulcer complications, but its use is associated with significant adverse effects, particularly at higher doses.

• PPIs are also effective at healing NSAID-induced ulcers even when patients continue to use NSAIDs. Misoprostol, however, may be more effective than PPIs at reducing the risk of NSAID-induced gastric ulcers.

6.2 COX-2 Selective NSAIDs • With regards to GI toxicity, COX-2 selective NSAIDs are safer than naproxen and high-dose

ibuprofen and are better tolerated than non-selective NSAIDs. No significant difference between the COX-2 selective NSAIDs considered and diclofenac was found, suggesting that COX-2 selective NSAIDs may not be a different “class” of agents but may be part of a continuum of agents that includes the “standard NSAIDs” but with differing GI toxicities. A superior GI safety profile over one non-selective NSAID does not imply that a given COX-2 selective NSAID is safer than all non-selective NSAIDs.

• Since COX-2 selective NSAIDs have little anti-platelet effect, the co-administration of ASA is inevitable in patients with an indication for low-dose ASA. This raises preliminary concerns that will need to be confirmed in ongoing studies. These concerns are based on the apparent absence of any benefit of celecoxib over non-selective NSAIDs when ASA is co-administered with celecoxib in the CLASS study and on the absence of data regarding the co-administration of rofecoxib and ASA, since patients requiring ASA are excluded from the VIGOR trial.

• The benefit of the growing clinical use of COX-2 selective NSAIDs with added prophylaxis remains untested.

47

7 REFERENCES

1. Fries JF, Miller SR, Spitz PW, Williams CA, Hubert HB, Bloch DA. Identification of patients at risk for gastropathy associated with NSAID use. J Rheumatol Suppl 1990;20:12-9.

2. Wallace JL. Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years. Gastroenterology 1997;112(3):1000-16.

3. Stalnikowicz R, Rachmilewitz D. NSAID-induced gastroduodenal damage: Is prevention needed? A review and metaanalysis. J Clin Gastroenterol 1993;17(3):238-43.

4. Smalley WE, Griffin MR, Fought RL, Ray WA. Excess costs from gastrointestinal disease associated with nonsteroidal anti-inflammatory drugs. J Gen Intern Med 1996;11(8):461-9.

5. Fries JF. NSAID gastropathy: the second most deadly rheumatic disease? Epidemiology and risk appraisal. J Rheumatol Suppl 1991;28:6-10.

6. Griffin MR, Ray WA, Schaffner W. Nonsteroidal anti-inflammatory drug use and death from peptic ulcer in elderly persons. Ann Intern Med 1988;109(5):359-63.

7. Bollini P, Garcia-Rodriguez LA, Perez-Gutthann S, Walker AM. The impact of research quality and study design on epidemiologic estimates of the effect of nonsteroidal anti-inflammatory drugs on upper gastrointestinal tract disease. Arch Intern Med 1992;152(6):1289-95.

8. McMahon AD, Evans JM, White G, Murray FE, McGilchrist MM, McDevitt DG, et al. A cohort study (with re-sampled comparator groups) to measure the association between new NSAID prescribing and upper gastrointestinal hemorrhage and perforation. J Clin Epidemiol 1997;50(3):351-6.

9. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med 1991;115(10):787-96.

10. Langman MJ, Weil J, Wainwright P, Lawson DH, Rawlins MD, Logan RF, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994;343(8905):1075-8.

11. MacDonald TM, Morant SV, Robinson GC, Shield MJ, McGilchrist MM, Murray FE, et al. Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study. BMJ 1997;315(7119):1333-7.

12. Armstrong CP, Blower AL. Non-steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. Gut 1987;28(5):527-32.

13. Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123(4):241-9.

14. Larkai EN, Smith JI, Lidsky MD. Gastroduodenal mucosa and dyspeptic symptoms in arthritic patients during chronic non-steroidal anti-inflammatory drug use. Am J Gastroenterol 1987;82(11):1153-8.

15. Maetzel A, Ferraz MB, Bombardier C. The cost-effectiveness of misoprostol in preventing serious gastrointestinal events associated with the use of nonsteroidal antiinflammatory drugs. Arthritis Rheum 1998;41(1):16-25.

48

16. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A 2002;99(21):13926-31.

17. Kradjan WA. Gastrointestinal disorders. In: Koda-Kimble AM, Young LY, Kradjan WA, Guglielmo BJ, editors. Applied therapeutics. 7th ed. Philadelphia: Lippincott Williams and Wilkins; 2001. p.25:1-25:28.

18. Dang CT, Shapiro CL, Hudis CA. Potential role of selective COX-2 inhibitors in cancer management. Oncology (Huntingt) 2002;16(5 Suppl 4):30-6.

19. Rostom A, Wells G, Tugwell P, Welch V, Dube C, McGowan J. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev 2000;(4):CD002296.

20. Rostom A, Wells G, Tugwell P, Welch V, Dube C, McGowan J. The prevention of chronic NSAID induced upper gastrointestinal toxicity: a Cochrane collaboration metaanalysis of randomized controlled trials. J Rheumatol 2000;27(9):2203-14.

21. Haynes RB, Wilczynski N, McKibbon KA, Walker CJ, Sinclair JC. Developing optimal search strategies for detecting clinically sound studies in MEDLINE. J Am Med Inform Assoc 1994;1(6):447-58. Available: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=116228&action=stream&blobtype=pdf.

22. Hunt DL, McKibbon KA. Locating and appraising systematic reviews. Ann Intern Med 1997;126(7):532-8.

23. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17(1):1-12.

24. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408-12.

25. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345(6):433-42.

26. Vane JR, Warner TD. Nomenclature for COX-2 inhibitors. Lancet 2000;356(9239):1373-4.

27. Brooks P, Emery P, Evans JF, Fenner H, Hawkey CJ, Patrono C, et al. Interpreting the clinical significance of the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2. Rheumatology 1999;38(8):779-88.

28. Panara MR, Renda G, Sciulli MG, Santini G, Di Giamberardino M, Rotondo MT, et al. Dose-dependent inhibition of platelet cyclooxygenase-1 and monocyte cyclooxygenase-2 by meloxicam in healthy subjects. J Pharmacol Exp Ther 1999;290(1):276-80.

29. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med 1998;104(5):413-21.

30. Patrignani P, Panara MR, Sciulli MG, Santini G, Renda G, Patrono C. Differential inhibition of human prostaglandin endoperoxide synthase-1 and -2 by nonsteroidal anti-inflammatory drugs. J Physiol Pharmacol 1997;48(4):623-31.

31. Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Davey Smith G, Altman DG, editors. Systematic reviews in health care: meta-analysis in context. 2nd ed. London: BMJ Publishing Group; 2001. p.285-312.

32. Petitti DB. Approaches to heterogeneity in meta-analysis. Stat Med 2001;20(23):3625-33.

49

33. L'Abbé KA, Detsky AS, O'Rourke K. Meta-analysis in clinical research. Ann Intern Med 1987;107(2):224-33.

34. Thompson SG. Why and how sources of heterogeneity should be investigated. In: Egger M, Smith GD, Altman DG, editors. Systematic reviews in health care: meta-analysis in context. 2nd ed. London: BMJ Publishing Group; 2001. p.157-75.

35. Graham DY, Agrawal NM, Campbell DR, Haber MM, Collis C, Lukasik NL, et al. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo-controlled study of misoprostol vs lansoprazole. Arch Intern Med 2002;162(2):169-75.

36. Chan FK, Sung JJ, Ching JY, Wu JC, Lee YT, Leung WK, et al. Randomized trial of low-dose misoprostol and naproxen vs. nabumetone to prevent recurrent upper gastrointestinal haemorrhage in users of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 2001;15(1):19-24.

37. Chan FK, Hung LC, Suen BY, Wu JC, Lee KC, Leung VK, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;347(26):2104-10.

38. Chan FKL, Leung WK, Suen BY, Lee YT, Wu JCY, Hui Y, et al. A double-blinded randomized comparison of celecoxib versus omeprazole and diclofenac for secondary prevention of ulcer bleeding in chronic NSAID users [abstract]. 102nd Annual Meeting of the American Gastroenterological Association; 2001; Atlanta.

39. Bianchi Porro G, Lazzaroni M, Imbesi V, Montrone F, Santagada T. Efficacy of pantoprazole in the prevention of peptic ulcers, induced by non-steroidal anti-inflammatory drugs: a prospective, placebo-controlled, double-blind, parallel-group study. Dig Liver Dis 2000;32(3):201-8.

40. Goldstein JL, Correa P, Zhao WW, Burr AM, Hubbard RC, Verburg KM, et al. Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2 inhibitor, compared to naproxen in patients with arthritis. Am J Gastroenterol 2001;96(4):1019-27.

41. Emery P, Zeidler H, Kvien TK, Guslandi M, Naudin R, Stead H, et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet 1999;354(9196):2106-11.

42. Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999;282(20):1921-8.

43. Center for Drug Evaluation and Research, U.S.Food and Drug Administration. Arthritis Drugs Advisory Committee Meeting 12/1/1998: Celebrex. Rockville (MD): The Center; 2001 Mar 8. Available: http://www.fda.gov/cder/foi/adcomm/98/celebrex.htm.

44. Laine L, Harper S, Simon T, Bath R, Johanson J, Schwartz H, et al. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Gastroenterology 1999;117(4):776-83.

45. Hawkey C, Laine L, Simon T, Beaulieu A, Maldonado-Cocco J, Acevedo E, et al. Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2000;43(2):370-7.

46. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA 2000;284(10):1247-55.

50

47. Goldstein JL, Silverstein FE, Agrawal NM, Hubbard RC, Kaiser J, Maurath CJ, et al. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol 2000;95(7):1681-90.

48. Haraoui B, Petrella R, Fort J, Bello A, Syrotuik J, De Carolis E. SUCCESS-1 trial: celecoxib demonstrates similar efficacy and significantly improved tolerability to the conventional NSAID, naproxen, in patients with osteoarthritis (OA) treated in Canada [presentation]. The College of Family Physicians of Canada; Family Medicine Forum; 2001 Feb 25; Vancouver. Available: www.cfpc.ca/cme/fmf/fmfreg2001/_pdf/2001fmfbook.pdf (accessed 2002 Apr).

49. Singh G, Fort JG, Triadafilotoulos G, Bello A. SUCCESS-1: a global osteoarthritis (OA) trial in 13,274 randomized patients. Celecoxib provides similar efficacy to diclofenac and naproxen while providing significantly improved UGI safety [abstract]. Annual Meeting of the American College of Rheumatology; 2001; San Francisco.

50. Singh G, Goldstein J, Bensen W, Agrawal N, Eisen G, Fort J, et al. SUCCESS-1 in osteoarthritis (OA) trial: celecoxib significantly reduces risk of serious upper GI complications compared to NSAIDs while providing similar efficacy in 13,274 randomized patients [abstract]. Annual European Congress of Rheumatology; 2001 Jun 13; Prague. Abstract no OP0053. Available: http://www.eular.org/eular2001/AbstractsOnline.cfm.

51. Singh G, Fort JG, Triadafilopoulos G, Bello A, Boots S. Benefits of using celecoxib in patients on low dose aspirin (ASA): data from SUCCESS 1, a 12-week, multinational trial with 13,274 patients with osteoarthritis [poster]. 65th Annual Scientific Meeting of the American College of Rheumatology; 2001 Nov 11; San Francisco. Poster no 1032. Available: http://www.abstracts-on-line.com/abstracts/ACR/search/results.asp?Num=0%2E7146677.

52. Singh G, Goldstein J, Bensen W, Agrawal N, Eisen G, Fort J, et al. SUCCESS–1 in Osteoarthritis (OA) Trial: celecoxib significantly reduces the risk of serious upper GI complications compared to NSAIDs while providing similar efficacy in 13,274 randomized patients [abstract] Abstr Perspect 2001;5(1). Available: http://www.hopkins-arthritis.som.jhmi.edu/edu/eular2001/oa-treatments-cox2.html.

53. Goldstein JL, Agrawal N, Eisen G, Stenson W, Bello AE, Fort JG, et al. Significantly improved upper gastrointestinal (UGI) tolerability with celecoxib, a COX-2 specific inhibitor, compared with conventional NSAIDS. The Success-1 trial [abstract] Abstr Perspect 2001;5(1).

54. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343(21):1520-8.

55. Langman MJ, Jensen DM, Watson DJ, Harper SE, Zhao PL, Quan H, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282(20):1929-33.

56. Dequeker J, Hawkey C, Kahan A, Steinbrück K, Alegre C, Baumelou E, et al. Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: results of the Safety and Efficacy Large-scale Evaluation of COX-inhibiting Therapies (SELECT) trial in osteoarthritis. Br J Rheumatol 1998;37(9):946-51.

57. Hawkey C, Kahan A, Steinbruck K, Alegre C, Baumelou E, Begaud B, et al. Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. Br J Rheumatol 1998;37(9):937-45.

58. Yocum D, Fleischmann R, Dalgin P, Caldwell J, Hall D, Roszko P, et al. Safety and efficacy of meloxicam in the treatment of osteoarthritis: a 12-week, double-blind, multiple-dose, placebo-controlled trial. Arch Intern Med 2000;160(19):2947-54.

51

59. Goei Thè HS, Lund B, Distel MR, Bluhmki E. A double-blind, randomized trial to compare meloxicam 15 mg with diclofenac 100 mg in the treatment of osteoarthritis of the knee. Osteoarthritis Cartilage 1997;5(4):283-8.

60. Hosie J, Distel M, Bluhmki E. Efficacy and tolerability of meloxicam versus piroxicam in patients with osteoarthritis of the hip or knee. A six-month double-blind study. Clin Drug Invest 1997;13(4):175-84.

61. Hosie J, Distel M, Bluhmki E. Meloxicam in osteoarthritis: a 6-month, double-blind comparison with diclofenac sodium. Br J Rheumatol 1996;35 Suppl 1:39-43.

62. Lindén B, Distel M, Bluhmki E. A double-blind study to compare the efficacy and safety of meloxicam 15 mg with piroxicam 20 mg in patients with osteoarthritis of the hip. Br J Rheumatol 1996;35 Suppl 1:35-8.

63. Wojtulewski JA, Schattenkirchner M, Barceló P, Le Loët X, Bevis PJR, Bluhmki E, et al. A six-month double-blind trial to compare the efficacy and safety of meloxicam 7.5 mg daily and naproxen 750 mg daily in patients with rheumatoid arthritis. Br J Rheumatol 1996;35 Suppl 1:22-8.

64. Distel M, Mueller C, Bluhmki E. Global analysis of gastrointestinal safety of a new NSAID, meloxicam. Inflammopharmacology 1996;4(1):71-81.

65. Distel M, Mueller C, Bluhmki E, Fries J. Safety of meloxicam: a global analysis of clinical trials. Br J Rheumatol 1996;35 Suppl 1:68-77.

66. Lemmel EM, Bolten W, Burgos-Vargas R, Platt P, Nissilä M, Sahlberg D, et al. Efficacy and safety of meloxicam in patients with rheumatoid arthritis. J Rheumatol 1997;24(2):282-90.

67. Lund B, Distel M, Bluhmki E. A double-blind, randomized, placebo-controlled study of efficacy and tolerance of meloxicam treatment in patients with osteoarthritis of the knee. Scand J Rheumatol 1998;27(1):32-7.

68. Agrawal NM, Roth S, Graham DY, White RH, Germain B, Brown JA, et al. Misoprostol compared with sucralfate in the prevention of nonsteroidal anti-inflammatory drug-induced gastric ulcer. A randomized, controlled trial. Ann Intern Med 1991;115(3):195-200.

69. Agrawal NM, Van Kerckhove HE, Erhardt LJ, Geis GS. Misoprostol coadministered with diclofenac for prevention of gastroduodenal ulcers. A one-year study. Dig Dis Sci 1995;40(5):1125-31.

70. Bocanegra TS, Weaver AL, Tindall EA, Sikes DH, Ball JA, Wallemark CB, et al. Diclofenac/misoprostol compared with diclofenac in the treatment of osteoarthritis of the knee or hip: a randomized, placebo controlled trial. J Rheumatol 1998;25(8):1602-11.

71. Bolten W, Gomes JA, Stead H, Geis GS. The gastroduodenal safety and efficacy of the fixed combination of diclofenac and misoprostol in the treatment of osteoarthritis. Br J Rheumatol 1992;31(11):753-8.

72. Chandrasekaran AN, Sambandam PR, Lal HM, Ramakrishnan S, Porkodi R, Krishnamurthy V, et al. Double blind, placebo controlled trial on the cytoprotective effect of misoprostol in subjects with rheumatoid arthritis, osteoarthritis and seronegative spondarthropathy on NSAIDs. J Assoc Physicians India 1991;39(12):919-21.

73. Cohen de Lara A, Gompel H, Baranes C, Bornstein U, Brajer S, Cambray S, et al. Two comparative studies of dosmalfate vs. misoprostol in the prevention of NSAID-induced gastric ulcers in rheumatic patients. Drugs Today 2000;36 Suppl A:73-8.

74. Delmas PD, Lambert R, Capron MH. [Misoprostol in the prevention of gastric erosions caused by nonsteroidal anti-inflammatory agents]. Rev Rhum Ed Fr 1994;61(2):126-31.

52

75. Elliott SL, Yeomans ND, Buchanan RR, Smallwood RA. Efficacy of 12 months' misoprostol as prophylaxis against NSAID-induced gastric ulcers. A placebo-controlled trial. Scand J Rheumatol 1994;23(4):171-6.

76. Graham DY, Agrawal NM, Roth SH. Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial. Lancet 1988;2(8623):1277-80.

77. Graham DY, White RH, Moreland LW, Schubert TT, Katz R, Jaszewski R, et al. Duodenal and gastric ulcer prevention with misoprostol in arthritis patients taking NSAIDs. Misoprostol Study Group. Ann Intern Med 1993;119(4):257-62.

78. Hawkey CJ, Karrasch JA, Szczepanski L, Walker DG, Barkun A, Swannell AJ, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med 1998;338(11):727-34.

79. Henriksson K, Uribe A, Sandstedt B, Nord CE. Helicobacter pylori infection, ABO blood group, and effect of misoprostol on gastroduodenal mucosa in NSAID-treated patients with rheumatoid arthritis. Dig Dis Sci 1993;38(9):1688-96.

80. Melo Gomes JA, Roth SH, Zeeh J, Bruyn GA, Woods EM, Geis GS. Double-blind comparison of efficacy and gastroduodenal safety of diclofenac/misoprostol, piroxicam, and naproxen in the treatment of osteoarthritis. Ann Rheum Dis 1993;52(12):881-5.

81. Raskin JB, White RH, Jackson JE, Weaver AL, Tindall EA, Lies RB, et al. Misoprostol dosage in the prevention of nonsteroidal anti-inflammatory drug-induced gastric and duodenal ulcers: a comparison of three regimens. Ann Intern Med 1995;123(5):344-50.

82. Raskin JB, White RH, Jaszewski R, Korsten MA, Schubert TT, Fort JG. Misoprostol and ranitidine in the prevention of NSAID-induced ulcers: a prospective, double-blind, multicenter study. Am J Gastroenterol 1996;91(2):223-7.

83. Roth SH, Tindall EA, Jain AK, McMahon FG, April PA, Bockow BI, et al. A controlled study comparing the effects of nabumetone, ibuprofen, and ibuprofen plus misoprostol on the upper gastrointestinal tract mucosa. Arch Intern Med 1993;153(22):2565-71.

84. Saggioro A, Alvisi V, Blasi A, Dobrilla G, Fioravanti A, Marcolongo R, et al. Misoprostol prevents NSAID-induced gastroduodenal lesions in patients with osteoarthritis and rheumatoid arthritis [published erratum appears in Ital J Gastroenterol 1991;23(5):273]. Ital J Gastroenterol 1991;23(3):119-23.

85. Valentini M, Cannizzaro R, Poletti M, Bortolussi R, Fracasso A, Testa V, et al. Nonsteroidal antiinflammatory drugs for cancer pain: comparison between misoprostol and ranitidine in prevention of upper gastrointestinal damage. J Clin Oncol 1995;13(10):2637-42.

86. Verdickt W, Moran C, Hantzschel H, Fraga AM, Stead H, Geis GS. A double-blind comparison of the gastroduodenal safety and efficacy of diclofenac and a fixed dose combination of diclofenac and misoprostol in the treatment of rheumatoid arthritis. Scand J Rheumatol 1992;21(2):85-91.

87. Taha AS, Hudson N, Hawkey CJ, Swannell AJ, Trye PN, Cottrell J, et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N Engl J Med 1996;334(22):1435-9.

88. Van Groenendael JH, Markusse HM, Dijkmans BA, Breedveld FC. The effect of ranitidine on NSAID related dyspeptic symptoms with and without peptic ulcer disease of patients with rheumatoid arthritis and osteoarthritis. Clin Rheumatol 1996;15(5):450-6.

53

89. Berkowitz JM, Rogenes PR, Sharp JT, Warner CW. Ranitidine protects against gastroduodenal mucosal damage associated with chronic aspirin therapy. Arch Intern Med 1987;147(12):2137-9.

90. Bianchi Porro G, Pace F, Caruso I. Why are non-steroidal anti-inflammatory drugs important in peptic ulceration? Aliment Pharmacol Ther 1987;1 Suppl:547S.

91. Ehsanullah RS, Page MC, Tildesley G, Wood JR. Prevention of gastroduodenal damage induced by non-steroidal anti-inflammatory drugs: controlled trial of ranitidine. BMJ 1988;297(6655):1017-21.

92. Robinson M, Mills RJ, Euler AR. Ranitidine prevents duodenal ulcers associated with non-steroidal anti-inflammatory drug therapy. Aliment Pharmacol Ther 1991;5(2):143-50.

93. Robinson MG, Griffin JW, Bowers J, Kogan FJ, Kogut DG, Lanza FL, et al. Effect of ranitidine on gastroduodenal mucosal damage induced by nonsteroidal antiinflammatory drugs. Dig Dis Sci 1989;34(3):424-8.

94. Simon B, Muller P. Nizatidine in therapy and prevention of non-steroidal anti-inflammatory drug-induced gastroduodenal ulcer in rheumatic patients. Scand J Gastroenterol Suppl 1994;206:25-8.

95. Levine LR, Cloud ML, Enas NH. Nizatidine prevents peptic ulceration in high-risk patients taking nonsteroidal anti-inflammatory drugs. Arch Intern Med 1993;153(21):2449-54.

96. Swift GL, Heneghan M, Williams GT, Williams BD, O'Sullivan MM, Rhodes J. Effect of ranitidine on gastroduodenal mucosal damage in patients on long-term non-steroidal anti-inflammatory drugs. Digestion 1989;44(2):86-94.

97. Hudson N, Taha AS, Russell RI, Trye P, Cottrell J, Mann SG, et al. Famotidine for healing and maintenance in nonsteroidal anti-inflammatory drug-associated gastroduodenal ulceration. Gastroenterology 1997;112(6):1817-22.

98. ten Wolde S, Dijkmans BA, Janssen M, Hermans J, Lamers CB. High-dose ranitidine for the prevention of recurrent peptic ulcer disease in rheumatoid arthritis patients taking NSAIDs. Aliment Pharmacol Ther 1996;10(3):347-51.

99. Bianchi Porro G., Lazzaroni M, Imbesi V, Montrone F, Santagada T. Efficacy of pantoprazole in the prevention of peptic ulcers, induced by non-steroidal anti-inflammatory drugs: a prospective, placebo-controlled, double-blind, parallel-group study. Dig Liver Dis 2000;32(3):201-8.

100. Jensen DM, Ho S, Hamamah S, Frankl H, Faigel D, DeMarco D, et al. A randomized study of omeprazole compared to misoprostol for prevention of recurrent ulcers and ulcer hemorrhage in high risk patients ingesting aspirin or NSAIDs [abstract]. Gastroenterology 2000;118(4 Suppl 2 Pt 1):AGA A892.

101. Yeomans ND, Tulassay Z, Juhasz L, Racz I, Howard J, van Rensburg CJ, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1998;338(11):719-26.

102. Ekstrom P, Carling L, Wetterhus S, Wingren PE, Anker-Hansen O, Lundegardh G, et al. Prevention of peptic ulcer and dyspeptic symptoms with omeprazole in patients receiving continuous non-steroidal anti-inflammatory drug therapy. A Nordic multicentre study. Scand J Gastroenterol 1996;31(8):753-8.

103. Cullen D, Bardhan KD, Eisner M, Kogut DG, Peacock RA, Thomson JM, et al. Primary gastroduodenal prophylaxis with omeprazole for non-steroidal anti-inflammatory drug users. Aliment Pharmacol Ther 1998;12(2):135-40.

54

104. Williams G, Ettlinger RE, Ruderman EM, Hubbard RC, Lonien ME, Yu SS, et al. Treatment of osteoarthritis with a once-daily dosing regimen of celecoxib: a randomized, controlled trial. J Clin Rheumatol 2000;6(2):65-74.

105. Bensen WG, Fiechtner JJ, McMillen JI, Zhao WW, Yu SS, Woods EM, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc 1999;74(11):1095-105.

106. Acevedo E, Castañeda O, Ugaz M, Beaulieu AD, Pons-Estel B, Caeiro F, et al. Tolerability profiles of rofecoxib (Vioxx) and Arthrotec. A comparison of six weeks treatment in patients with osteoarthritis. Scand J Rheumatol 2001;30(1):19-24.

107. Truitt KE, Sperling RS, Ettinger WH, Jr., Greenwald M, DeTora L, Zeng Q, et al. A multicenter, randomized, controlled trial to evaluate the safety profile, tolerability, and efficacy of rofecoxib in advanced elderly patients with osteoarthritis. Aging Clin Experiment Res 2001;13(2):112-21.

108. Day R, Morrison B, Luza A, Castaneda O, Strusberg A, Nahir M, et al. A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. Arch Intern Med 2000;160(12):1781-7.

109. Cannon GW, Caldwell JR, Holt P, McLean B, Seidenberg B, Bolognese J, et al. Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one-year, randomized, clinical trial in patients with osteoarthritis of the knee and hip. Arthritis Rheum 2000;43(5):978-87.

110. Ehrich EW, Schnitzer TJ, McIlwain H, Levy R, Wolfe F, Weisman M, et al. Effect of specific COX-2 inhibition in osteoarthritis of the knee: a 6 week double blind, placebo controlled pilot study of rofecoxib. J Rheumatol 1999;26(11):2438-47.

111. Schnitzer TJ, Truitt K, Fleischmann R, Dalgin P, Block J, Zeng Q, et al. The safety profile, tolerability, and effective dose range of rofecoxib in the treatment of rheumatoid arthritis. Clin Ther 1999;21(10):1688-702.

112. Saag K, Fisher C, McKay J, Ehrich E, Zhao PL, Bolognese J, et al. MK-0966, a specific COX-2 inhibitor has clinical efficacy comparable to ibuprofen in the treatment of knee and hip osteoarthritis (OS) in a 6-week controlled clinical trial [abstract]. Arthritis Rheum 1998;41 (Suppl 9):S196.

113. Saag K, van der HD, Fisher C, Samara A, DeTora L, Bolognese J, et al. Rofecoxib, a new cyclooxygenase 2 inhibitor, shows sustained efficacy, comparable with other nonsteroidal anti-inflammatory drugs: a 6-week and a 1-year trial in patients with osteoarthritis. Arch Fam Med 2000;9(10):1124-34.

114. Geba GP, Weaver AL, Polis AB, Dixon ME, Schnitzer TJ, VACT Group. Efficacy of rofecoxib, celecoxib, and acetaminophen in osteoarthritis of the knee: a randomized trial. JAMA 2002;287(1):64-71. Available: http://www.eular.org/eular2001/AbstractsOnline.cfm.

115. Whelton A, Fort JG, Puma JA, Normandin D, Bello AE, Verburg KM. Cyclooxygenase-2--specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther 2001;8(2):85-95.

116. McKenna F, Borenstein D, Wendt H, Wallemark C, Lefkowith JB, Geis GS. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol 2001;30(1):11-8.

117. Geba GP, Lisse JR, Perlman M, Polis AB, Dixon ME, Skalky CS, et al. Gastrointestinal tolerability in primary care patients treated with naproxen or rofecoxib for osteoarthritis (OA): the Advantage Trial [abstract]. European Congress of Rheumatology; 2001 Jun 13; Prague. Abstract no SAT0096. Available: http://www.eular.org/eular2001/AbstractsOnline.cfm.

55

118. McKenna F, Weaver A, Fiechtner JJ, Bello AE, Fort JG. COX-2 specific inhibitors in the management of osteoarthritis of the knee: a placebo-controlled, randomized, double-blind study. J Clin Rheumatol 2001;7(3):151-9.

119. Li Q. NDA 21-042: Statistical review of rofecoxib for the treatment of signs and symptoms of osteoarthritis, relief of pain, treatment of primary dysmenorrhea, and improvement of gastrointestinal safety, December 1998-April 1999. In: Approval package: Vioxx (Rofecoxib) Tablets, Merck Research Laboratories Application No.: 021042 and 021052, Approval Date 5/20/99. Rockville (MD): Center for Drugs and Evaluation, U.S. Food and Drug Administration; 1999. Available: http://www.fda.gov/cder/foi/nda/99/021042_52_vioxx_statr_P1.pdf.

120. Graham DY. Critical effect of Helicobacter pylori infection on the effectiveness of omeprazole for prevention of gastric or duodenal ulcers among chronic NSAID users. Helicobacter 2002;7(1):1-8.

121. Henry D, Lim LL, García Rodriguez LA, Perez Gutthann S, Carson JL, Griffin M, et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 1996;312(7046):1563-6.

122. Goldkind L. Medical Officer's Gastroenterology Advisory Committee Briefing Document. Division of Anti-Inflammatory, Analgesis and Opthalmologic Drug Products HFD-500, FDA; 2000. NDA 20-998/S-009 .

123. Witter J. Medical Officer Review. In: Application no 20-998/S9Celebrex (Celecoxib) Capsules,Company:G.D. Searle L.L.C, Approval Date: 6/7/2002 [Supplemental NDA]: Center for Drug Evaluation and Research, FDA; 2000. Available: http://www.fda.gov/cder/foi/nda/2002/20-998S009_Celebrex_medr_P1.pdf.

124. Hrachovec JB, Mora M. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib [letter]. JAMA 2001;286(19):2398.

125. Wright JM, Perry TL, Bassett KL, Chambers GK. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib [letter]. JAMA 2001;286(19):2398-9.

126. Okie S. Missing data on celebrex full study altered picture of drug. Washington Post 2001 May 8;A11 (accessed 2001 Dec 8).

127. 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(7365):619-23.

128. Metcalfe S, Dougherty S, McNee W. Systematic review of celecoxib for osteoarthritis and rheumatoid arthritis. Celecoxib's relative gastrointestinal safety is overstated [letter]. BMJ 2003;326(7384):334-5.

129. Jüni P, Sterchi R, Dieppe P. Systematic review of celecoxib for osteoarthritis and rheumatoid arthritis. Problems compromise review's validity [letter]. BMJ 2003;326(7384):334.

130. Deeks JJ, Smith LA, Bradley MD. Systematic review of celecoxib for osteoarthritis and rheumatoid arthritis [authors' reply]. BMJ 2003;326(7384):335-6.

131. Health Canada approves changes to VIOXX (rofecoxib) label to reflect GI data from landmark study. Doctor's Guide 2002. Available: http://www.docguide.com/news/content.nsf/news/8525697700573E1885256C1C0056D64E?OpenDocument&id=771FA23DD21488AF852568E4004FB996&c=Rheumatoid%20Arthritis&count=10.

132. Cardiovascular adverse effects of coxibs. Prescrire Int 2003;11(62):181-2.

56

133. Mamdani M, Rochon P, Juurlink DN, Anderson GM, Kopp A, Naglie G, et al. Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med 2003;163(4):481-6.

134. Mamdani M, Rochon PA, Juurlink DN, Kopp A, Anderson GM, Naglie G, et al. Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ 2002;325(7365):624.

135. Wright JM. The double-edged sword of COX-2 selective NSAIDs. CMAJ 2002;167(10):1131-7. Available: http://www.cmaj.ca/cgi/content/full/167/10/1131.

136. Maetzel A, Krahn M, Naglie G. The cost-effectiveness of celecoxib and rofecoxib in patients with osteoarthritis or rheumatoid arthritis. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 2001. Technology report no 23. Available: http://www.ccohta.ca/entry_e.html.

137. Maetzel A, Krahn MD, Naglie G. Economic assessment: celecoxib and rofecoxib for patients with osteoarthritis or rheumatoid arthritis. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 2002. Technology overview no 6. Available: http://www.ccohta.ca/entry_e.html.

57

Appendix 1: Literature Search Strategy Search Legend

In Dialog®

De = descriptor, ie. Medical Subject Heading (a controlled, thesaurus term) Ti = title (i.e. word has to occur in title field of the bibliographic record) Ab = abstract (ie word has to occur in abstract field of bibliographic record) ! = explode; picks up narrower terms as well, i.e. terms which are conceptually

subsets of a broader term. For instance, gastritis! also retrieves gastritis, atrophic and astritis, hypertrophic

() = words must be adjacent ? = truncation symbol

DATABASES LIMITS KEY WORDS AND STRATEGY

Dialog® OneSearch®

MEDLINE® (File 155, 1966-2002/Apr W4); ToxFile(File 156, 1966-2002/Feb W4))

2000-2002 for the update of the Cochrane Review; 1990-2002 for the COX-2/GI safety review Search done May 3, 2002

1. gastritis! 2. (gastritis OR gastropathy)/ti,ab 3. gastrointestinal hemorrhage! 4. gi(w2)hemorrhage?/ti,ab 5. gi(w2)haemorrhage?/ti,ab 6. gastrointestinal(w2)hemorrhage?/ti,ab 7. gastrointestinal(w2)haemorrhage?/ti,ab 8. gi(w2)bleed?/ti,ab 9. gastrointestinal(w2)bleed?/ti,ab 10. ulcer(w2)hemorrhage?/ti,ab 11. ulcer(w2)haemorrhage?/ti,ab 12. peptic ulcer perforation/de 13. ulcer(w2)perforation?/ti,ab 14. gi(w2)perforation?/ti,ab 15. gastrointestinal(w2)perforation?/ti,ab 16. mucosa?(w2)injur?/ti,ab 17. peptic ulcer! 18. peptic(w2)ulcer?/ti,ab 19. stomach(w2)ulcer?/ti,ab 20. duodenal(w2)ulcer?/ti,ab 21. gastroduodenal(w2)ulcer?/ti,ab 22. gastric(w2)ulcer?/ti,ab 23. pyloric stenosis/de 24. pyloric(w)stenos?s/ti,ab 25. Set 1:Set 24 26. anti-inflammatory agents, non-steroidal/de 27. non()steroidal()antiflammator?ti,ab 28. nonsteroidal()antiflammator?/ti,ab

58


29. nsaid?/ti,ab 30. meclofenamic acid/de 31. meclofenamic()acid/ti,ab OR rn= 644-62-2 32. sulindac/de OR rn=38194-50-2 OR

sulindac/ti,ab 33. tolmetin/de OR tolmetin/ti,ab OR rn=26171-

23-3 34. naproxen/de OR naproxen/ti,ab OR

rn=22204-53-1 35. phenylbutazone! OR rn = 50-33-9 OR

phenylbutazone/ti,ab 36. rn=129-20-4 OR rn=30748-29-9 OR 57-96-5

OR (oxyphenbutazone OR prenazone OR sulfinpyrazone)/ti,ab

37. ketoprofen/de OR ketoprofen/ti,ab OR rn = 22071-15-4

38. indomethacin! OR indomethacin/ti,ab OR rn=53-86-1

39. ketorolac/de OR ketorolac/ti,ab OR rn=66635-83-4

40. ibuprofen/de OR ibuprofen/ti,ab OR rn=15687-27-1

41. curcumin/de OR curcumin./ti,ab OR rn=458-37-7

42. flurbiprofen/de OR flurbiprofen/ti,ab OR rn=5104-49-4 43. diclofenac/de OR diclofenac/ti,ab OR

rn=15307-86-5 44. clofazimine/de OR clofazimine/ti,ab OR

rn=2030-63-9 45. aspirin/de OR [acetylsalicylic()acid OR

aspirin]/ti,ab OR rn=50-78-2 46. antipyrine/de OR antipytrine/tia,b OR rn=60-

80-0 47. aminopyrine! OR (aminopyrine OR

dipyrone)/ti,ab OR rn=58- 15-1 OR rn= 68-89-3 OR dipyrone/de 48. oxaprozin/ti,ab OR rn=21256-18-8 49. diflunisal/de OR diflunisal/ti,ab OR

rn=22494-42-4 50. choline()magnesium()salicylate?/ti,ab OR

rn=64425-90-7 51. choline()salicylate?/ti,ab OR rn=2016-36-6

59


52. floctafenine/ti,ab OR rn=23779-99-9 53. piroxicam/de OR piroxicam/ti,ab OR

rn=36322-90-4 54. tenoxicam/ti,ab OR rn=59804-37-4 55. nabumetone/ti,ab OR rn=42924-53-8 56. tiaprofenic()acid?/ti,ab OR rn=33005-95-7 57. fenoprofen/de OR fenoprofen/ti,ab OR

rn=31879-05-7 58. mefenamic acid/de OR mefenamic()acid?/ti,ab

or rn= 61-68-7 59. etodolac/de OR etodolac/ti,ab OR rn=41340-

25-4 60. Set 26:Set 59 61. anti-ulcer agents/de 62. sucralfate/de OR sucralfate/ti,ab OR

rn=54182-58-0 63. Set 61:Set 62 64. prostaglandin antagonists/de 65. prostaglandin()antagonist?/ti,ab 66. misoprostol/de OR misoprostol/ti,ab OR

rn=59122-46-2 67. Set 64:Set 66 68. proton pumps!(l)ai 69. proton()pump?()inhibit?/ti,ab OR PPI?/ti,ab 70. omeprazole/de OR omeprazole/ti,ab OR

rn=73590-58-6 71. pantoprazole/ti,ab OR rn=102625-70-7 72. lansoprazole/tia,b OR rn=103577-45-3 73. timoprazole?/ti,ab OR 57237-97-5 74. rabeprazole /ti,ab OR rn=117976-89-3 75. esomeprazole/ti,ab OR Nexium/ti,.ab 76. Set 68:Set 75 77. histamine H2 antagonists/de 78. histamine()H2()antagonist?/ti,ab OR H2RA/ti,ab OR

[histamine()H2()receptor()antagonist? OR histamine()type()2()receptor()antagonist?]/ti,

ab 79. cimetidine/de OR cimetidine/ti,ab OR rn=

51481-61-9 80. famotidine/de OR famotidine/ti,ab OR rn=

76824-35-6 81 nizatidine/de OR nizatidine/.ti,ab OR 82. ranitidine/de OR ranitidine/ti,ab OR

60


rn=66357-35-5 83. Set 77:Set 82 84. Set 25 AND Set 60 85. Set 84 AND (Set 63 OR Set 67 OR Set 76 OR Set 83) 86. dt= (clinical trial OR clinical trial, phase i OR

clinical trial, phase ii OR clinical trial, phase iii OR clinical trial, phase iv OR meta-analysis OR controlled clinical trial OR randomized controlled trial OR multicenter study OR review)

87. clinical trials! 88. (comparative study OR double-blind method

OR random allocation)/de 89. (random? OR controlled trial? OR controlled

clinical trial? OR clinical trial? OR double blind?)/ti,ab

90. (multicent? trial? OR multi cent? trial? OR meta analy? OR metaanaly? OR meta-analysis)/ti,ab

91. (research integration OR research overview? OR quantitative review? OR quantitative overview? OR methodologic review?

OR methodologic overview?)/ti,ab 92. (systematic overview? OR systematic review?

OR integrative research OR quantitative synthesis OR comparative stud? OR

prospective stud? OR retrospective stud? OR single blind? OR triple blind? OR treble blind? OR dummy OR sham OR rct?)/ti,ab

93. Set 86:Set 92 94. Set 85 AND Set 93 95. Set 94/2000:2002 96. Set 95 from 155 97. Set 95 from 156 98. Set 94/1990:2002 99. Set 98 from 155 100. S98 from 156 101. [cyclo()oxygenase()2()inhibit? OR cyclooxygenase()2()inhibit? OR cox()2()inhibit?]/ti,ab 102. [celecoxib OR celebrex]/ti,ab OR rn= 169590-42-5

61


103. [rofecoxib OR vioxx]/ti,ab OR rn=162011- 90-7 104. (meloxicam OR mobic OR movalis OR mobec OR movicox OR parocin OR uticox OR mobicox)/ti,ab OR rn=71125-38-7 105. etodolac/de OR etodolac/ti,ab OR rn=41340- 25-4 106. Set 101:Set 105 107. Set 25 AND Set 106 AND Set 93 108. Set 107/1990:2002 109. Set 108 from 155 110. Set 109 from 156

EMBASE® (File 73, 1974-2002/Apr W4)

111. ulcer perforation/de 112. stomach mucosa injury/de 113. pylorus stenosis! 114. Set 111:Set 113 115. Set 1: 11 116. Set 13:16 117. Set 18:22 118. Set 114:Set 117 119. Set 17 OR Set 24 OR Set 118 120. nonsteroid antiinflammatory agent! 121. Set 120 OR Set 60 122. Set 119 AND Set 121 123. antiulcer agent! OR Set 62 OR gastrointestinal mucosa protective agent! 124. prostaglandin receptor blocking agent! 125. stomach secretion inhibitor! 126. Set 123: Set 125 127. Set 69:Set 75 128. Set 65 OR Set 127 OR Set 83 OR Set 126 129. Set 122 AND Set 128 130. (comparative study OR randomized controlled trial OR prospective study OR retrospective study OR meta analysis OR clinical trial OR multicenter study OR phase 1 clinical trial OR phase 2 clinical trial OR phase 3 clinical trial OR phase 4 clinical trial OR prospective study OR retrospective study OR double blind procedure OR conference paper! OR longitudinal study /de 131. Set 129 AND (Set 130 OR Set 89 OR Set 90 OR Set 91 OR Set 92) 132. Set 131/2000:2001

62


133. Set 132 from Set 73 134. Set 131/1990:2002 135. cyclooxgenase 2 inhibitor! OR Set 106 136. Set 119 AND Set 135 AND (Set 130 OR Set 89 OR Set 90 OR Set 91 OR Set 92) 137. Set 136/1990:2002 138. Set 137 from 73

BIOSIS Previews® (File 5, 1969-2002/Apr W4)

139. gastritis/de 140. gastrointestinal hemorrhage/de 141. gastrointestinal bleeding/de 142. gastric mucosal injury/de 143. gastric ulcer/de 144. gastroduodenal ulcer/de 145. duodenal ulcer/de 146. peptic ulcer/de 147. Set 139:Set 146 148. Set 4:Set 11 149. Set 13:16 150. Set 18:Set 22 151. Set 2 OR Set 24 OR Set 147 OR Set 148 OR Set 149 OR Set 150 152. non-steroidal anti-inflammatory drugs/de 153. nonsteroidal anti-inflammatory drugs/de 154. Set 27:Set 59 155 acetylsalicylic acid/de 156. Set 152:Set 155 157. Set 151 AND Set 156 158. antiulcer-drug/de 159. Set 158 OR sucralfate/de OR sucralfate/ti,ab OR rn=54182-58-0 160. Set 158:Set 159 161. Set 65 OR Set 66 162. proton pump inhibitors/de 163. Set 69 OR pantoprazole/de OR lansoprazole/de 164. Set 70:Set 75 165. Set 162 OR Set 163 OR S164 166. histamine H2-receptor antagonist-drug/de 167. Set 78:Set 82 168. Set 166:Set 167 169. Set 160 OR Set 161 OR Set 165 OR Set 168 170. Set 157 AND Set 169 171. (clinical trial OR randomized trial OR prospective study OR randomized controlled

63


trial OR multicenter study OR randomized clinical trial)/de 172. Set 171 OR Set 89 OR Set 90 OR Set 91 OR Set 92 173. Set 170 AND Set 172 174. Set 173/2000:2002 175. Set 174 from 5 176. Set 151 AND Set 106 AND Set 172 177. Set 176/1990:2002 178. Set 177 from 5

Pharmaceutical News Index (PNI®)(File 42, 1974-2002,Apr W4) Current Contents Search® (File 440, 1990-2002, May W3)

179. Set 4:Set 11 180. Set 13:Set 16 181. Set 18:Set 22 182. Set 2 OR Set 179 OR Set 180 OR Set 181 OR Set 24 183. Set 27:Set 29 184. [meclofenamic()acid OR acetylsalicylic()acid OR choline()magnesium()salicylate? OR choline()salicylate? OR tiaprofenic()acid? OR mefenamic()acid?]/ti,ab 185. (sulindac OR tolmetin OR naproxen OR phenylbutazon OR oxyphenbutazone OR prenazone OR sulfinpyrazone OR ketoprofen OR indomethacin OR ketorolac OR ibuprofen OR curcumin OR flurbiprofen OR diclofenac OR clofazimine OR aspirin OR antipytrine OR aminopyrine OR dipyrone OR oxaprozin OR diflunisal OR floctafenine OR piroxicam OR tenoxicam OR nabumetone OR fenoprofen)/ti,ab 186. Set 183:Set 185 187. Set 182 AND Set 186 188. [anti()ulcer()drug? OR antiulcer()drug? OR sucralfate]/ti,ab 189. [prostaglandin()antagonist? OR misoprostol]/ti,ab 190. [proton()pump?()inhibit? OR PPI? OR omeprazole OR pantoprazole OR lansoprazole OR timoprazole OR rabeprazole OR esomeprazole OR Nexium]/ti,.ab 191. [histamine()H2()antagonist? OR H2RA OR

64


histamine()H2()receptor()antagonist? OR histamine()type()2()receptor()antagonist?]/ ti,ab 192. [cimetidine OR famotidine OR nizatidine]/ti,ab 193. Set 188:Set 192 194. Set 187 AND Set 193 AND (Set 89 OR Set 90 OR Set 91 OR Set 92) 195. Set 194/2000:2002 196. Set 195 from 42 197. Set 195 from 440 198. Set 195 from 173 199. [cyclo()oxygenase()2()inhibit? OR cyclooxygenase()2()inhibit? OR cox()2()inhibit?]/ti,ab 200. (celecoxib OR celebrex OR rofecoxib OR vioxx OR meloxicam OR mobic OR movalis OR mobec OR movicox OR parocin OR uticox OR mobicox OR etodolac)/ti,ab 201. Set 199:Set 200 202. Set 182 AND Set 201 AND (Set 89 OR Set 90 OR Set 91 OR Set 92) 203. Set 202/1990:2002 204. Set 203 from 42 205. Set 203 from 440 206. Set 203/from 173

207. Set 96 OR Set 97 OR Set 133 OR Set 175 OR Set 196 OR Set 197 OR Set 198 208. Reduce duplicates Set 207 209. type s208/4/all from 155,156,73,5,42,440,173 = CochraneUpdate 210. Set 109 OR Set 110 OR Set 138 OR Set 178 OR Set 204 OR Set 205 OR Set 206 211. Type S210/4/all from 155,156,73,5,42,440,173= Cox-2/GI safety

Cochrane Library on CD-ROM (Cochrane Collaboration and Update Software); Conference Papers Index, CCOHTA HTA Checklist; Google™

Dialog® OneSearch® Search Using the strategy above which was devised to

65


on MEDLINE® (File 155), ToxFile(File 156), EMBASE® (File 73), BIOSIS Previews® (File 5), Pharmaceutical News Index (PNI®)(File 42),Currrent Contents Search® (File 440)

performed May 3, 2002

update the original Cochrane search, an additional search on gastroprotective agents under investigation, was performed. These were bioprazol, rebamipide, polaprezinc, nocloprost, lafutidine, dosmalfate, and osutidine. Titles and abstracts of articles were searched, registry numbers, and earlier names, such as FRG 8813, F 3616, T 593

Dialog® Adis Clinical Trials Insight (File 173), Biobase (File 71), Biosis Previews®(File 5), SciSearch®(File 34), Pharmaceutical News Index (File 42), Inside Conferences (File 65), EMBASE (File 72), Pascal (File 144), MEDLINE®(File 154), F-D-C Reports (File 187), Current Contents (File 440). PubMed was also searched.

Search performed April 7, 2003

Re: COX-2/GI safety, an additional search was conducted during the course of the review to identify whether the results of the SUCCESS-1 trial had been published in full.

66

Appendix 2: Data Extraction Form Author: Title: Journal: Treatment groups: 1.

2. 3. 4.

Blinding: single double triple Study:

endoscopic clinical randomized controlled baseline endoscopy Duration of study: Duration of NSAID: Inclusions: Primary or secondary prophylaxis or both Chronic NSAID use Outpatients OA or RA or both Study ≥ 3 weeks yes no Exclusions: PUD Esophageal ulcers or esophagitis Pyloric obstruction Other: Dose: Recommended or high or both (circle)

Group Type, dose

Number Male to female ratio

Prior GI event

Steroid NSAID HP Erosion

67

Appendix 3: Outcomes

Follow-up time

Endoscopic ulcers

Adverse side effect

Drop-outs total

Drop-outs 2° SFX

68

Appendix 4: Jadad Scale Quality Assessment of RCTs Score 1. Was the study described as randomized? yes no Was the method of randomization described? yes no If the method of randomization was explained, was it appropriate?

yes

no

Randomization score: /2 2. Was the study described as double-blind?

yes

no

Was the method of double-blinding described? yes no If the method of blinding was explained, was it appropriate?

yes

no

Double-blind score: /2 3. Was there a description of withdrawals and treatment withdrawals?

yes

no

/1

Total score: /5 Scoring of the Jadad scale: A) Give a score of 1 point for each “yes” and 0 points for each “no.” There are no in-between marks. B) Give 1 additional point if: For question 1, the method to generate the sequence of randomization was described and it was appropriate (table of random numbers, computer generated, coin tossing)

and / or On question 2, the method of double-blinding was described and it was appropriate (identical placebo, active placebo, dummy) Deduct 1 point if: For question 1, the method to generate the sequence of randomization was described and it was inappropriate (patients were allocated alternately or according to date of birth or hospital number)

and / or For question 2, the study was described as double-blind, but the method of blinding was inappropriate (e.g. comparison of tablet versus injection with no double dummy). Other Quality Assessment Item Was the adequacy of allocation concealment described? Adequate / inadequate / unclear

gastro-duodenal technology ulcers associated with the use

Documents