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Joo MK, Park CH, Kim JS, Park JM, Ahn JY, Lee BE, Lee JH, Yang HJ, Cho YK, Bang CS, Kim BJ, Jung HK, Kim BW, Lee YC. Clinical Guidelines for Drug-Related Peptic Ulcer, 2020 Revised Edition. Gut Liver 2021; 14:707-726. [PMID: 33191311 PMCID: PMC7667931 DOI: 10.5009/gnl20246] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 08/31/2020] [Accepted: 09/04/2020] [Indexed: 02/06/2023] Open
Abstract
Korean guidelines for nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcer were previously developed in 2009 with the collaboration of the Korean College of Helicobacter and Upper Gastrointestinal Research and Korean Society of Gastroenterology. However, the previous guidelines were based mainly upon a review of the relevant literature and expert opinion. Therefore, the guidelines need to be revised. We organized a guideline Development Committee for drug-related peptic ulcer under the auspices of the Korean College of Helicobacter and Upper Gastrointestinal Research in 2017 and developed nine statements, including four for NSAIDs, three for aspirin and other antiplatelet agents, and two for anticoagulants through a de novo process founded on evidence-based medicine that included a literature search and a meta-analysis, A consensus was reached through the application of the modified Delphi method. The primary target of these guidelines is adult patients undergoing long-term treatment with NSAIDs, aspirin or other antiplatelet agents and anticoagulants. The revised guidelines reflect the expert consensus and is intended to assist clinicians in the management and prevention of drug-induced peptic ulcer and associated conditions.
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Affiliation(s)
- Moon Kyung Joo
- Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Chan Hyuk Park
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Joon Sung Kim
- Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae Myung Park
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Yong Ahn
- Department of Gastroenterology, Asan Medical Center, Asan Digestive Disease Research Institute, University of Ulsan College of Medicine, Seoul, Korea
| | - Bong Eun Lee
- Departments of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
| | - Jeong Hoon Lee
- Department of Gastroenterology, Asan Medical Center, Asan Digestive Disease Research Institute, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyo-Joon Yang
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yu Kyung Cho
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chang Seok Bang
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Beom Jin Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Hye-Kyung Jung
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
| | - Byung-Wook Kim
- Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yong Chan Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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Joo MK, Park CH, Kim JS, Park JM, Ahn JY, Lee BE, Lee JH, Yang HJ, Cho YK, Bang CS, Kim BJ, Jung HK, Kim BW, Lee YC. [Clinical Guidelines for Drug-induced Peptic Ulcer, 2020 Revised Edition]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2021; 76:108-133. [PMID: 32969360 DOI: 10.4166/kjg.2020.76.3.108] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/08/2020] [Accepted: 07/08/2020] [Indexed: 12/18/2022]
Abstract
The Korean guidelines for nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcers were previously developed under co-work with the Korean College of Helicobacter and Upper Gastrointestinal Research and Korean Society of Gastroenterology at 2009. On the other hand, the previous guidelines were based mainly on a literature review and expert opinions. Therefore, the guidelines need to be revised. In this study, a guideline development committee for drug-induced peptic ulcers was organized under the Korean College of Helicobacter and Upper Gastrointestinal Research in 2017. Nine statements were developed, including four for NSAID, three for aspirin and other antiplatelet agents, and two for anticoagulants through de novo processes based on evidence-based medicine, such as a literature search, meta-analysis, and the consensus was established using the modified Delphi method. The primary target of this guideline was adult patients taking long-term NSAIDs, aspirin, or other antiplatelet agent and anticoagulants. The revised guidelines reflect the consensus of expert opinions and are intended to assist relevant clinicians in the management and prevention of drug-induced peptic ulcers and associated conditions.
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Affiliation(s)
- Moon Kyung Joo
- Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Chan Hyuk Park
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Joon Sung Kim
- Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae Myung Park
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Yong Ahn
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Bong Eun Lee
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
| | - Jeong Hoon Lee
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyo-Joon Yang
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yu Kyung Cho
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chang Seok Bang
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Beom Jin Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Hye-Kyung Jung
- Department of Internal Medicine, College of Medicine, Ewha Woman's University, Seoul, Korea
| | - Byung-Wook Kim
- Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yong Chan Lee
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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Pal A, Shenoy S, Gautam A, Munjal S, Niu J, Gopalakrishnan M, Gobburru J. Pharmacokinetics of DFN-15, a Novel Oral Solution of Celecoxib, Versus Celecoxib 400-mg Capsules: A Randomized Crossover Study in Fasting Healthy Volunteers. Clin Drug Investig 2018; 37:937-946. [PMID: 28748412 PMCID: PMC5602059 DOI: 10.1007/s40261-017-0548-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Background COX-2 inhibitors can be effective for acute migraine, but none is supplied in a rapidly absorbed, ready-to-use oral liquid formulation. DFN-15, a novel oral liquid formulation of celecoxib, is being developed for the acute treatment of migraine with or without aura. Clinical studies with this formulation are ongoing. Objectives The objectives of the present study were to compare the bioavailability of DFN-15 with that of the commercial formulation of celecoxib 400-mg oral capsules (Celebrex®) and to determine the dose proportionality of DFN-15 in healthy fasted volunteers. Methods This single-dose randomized crossover study in 16 healthy fasted volunteers evaluated the pharmacokinetics and relative bioavailability of DFN-15 at doses of 120, 180, and 240 mg against the commercial formulation of celecoxib 400-mg oral capsules and determined the dose proportionality of DFN-15. Results The maximum observed plasma concentrations (Cmax) of celecoxib after the administration of DFN-15 120, 180, and 240 mg (1062–1933 ng/ml) were higher than for the 400-mg oral capsules (611 ng/ml). The median time to peak concentration (Tmax) was within 1 h for DFN-15 and 2.5 h for the oral capsules. The pharmacokinetics of DFN-15 were dose proportional from 120 to 240 mg. Partial area under the plasma concentration–time curves (AUCs) from 15 min to 2 h for DFN-15 120 mg were at least threefold higher than for the oral capsules, and the relative bioavailability of DFN-15 was approximately 140% that of the oral capsules. DFN-15 was well tolerated, with no new or unexpected adverse events. Conclusions Based on a faster rate of absorption and increased bioavailability, DFN-15 is being evaluated as an abortive medication for acute treatment in patients with migraine.
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Affiliation(s)
- Arindam Pal
- Proprietary Products, Dr. Reddy’s Laboratories Ltd., Innovation Plaza, Survey Nos. 42, 44, 45 and 54, Quthubullapur, Bachupally, RR Dist, Hyderabad, Telangana 500090 India
| | - Srinivas Shenoy
- Proprietary Products, Dr. Reddy’s Laboratories Ltd., Innovation Plaza, Survey Nos. 42, 44, 45 and 54, Quthubullapur, Bachupally, RR Dist, Hyderabad, Telangana 500090 India
| | - Anirudh Gautam
- Proprietary Products, Dr. Reddy’s Laboratories SA, Elisabethenanlage 11, 4051 Basel, Switzerland
| | - Sagar Munjal
- Dr. Reddy’s Laboratories, Inc., 107 College Road East, Princeton, NJ 08540 USA
| | - Jing Niu
- Center for Translational Medicine, University of Maryland, Baltimore, MD USA
| | | | - Joga Gobburru
- Center for Translational Medicine, University of Maryland, Baltimore, MD USA
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Goy J, Paikin J, Crowther M. Rofecoxib does not appear to increase the risk of venous thromboembolism: A systematic review of the literature. Thromb Res 2014; 134:997-1003. [DOI: 10.1016/j.thromres.2014.08.030] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 08/24/2014] [Accepted: 08/27/2014] [Indexed: 11/27/2022]
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Andrew Moore R. Endoscopic ulcers as a surrogate marker of NSAID-induced mucosal damage. Arthritis Res Ther 2013; 15 Suppl 3:S4. [PMID: 24267380 PMCID: PMC3891314 DOI: 10.1186/ar4176] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The characteristic of a biomarker that makes it a useful surrogate is the ability to identify a high risk of clinically important benefits or harms occurring in the future. A number of definitions or descriptions of surrogate definition have been put forward. Most recently the Institute of Medicine of the National Academy of Sciences in the USA has put forward an evaluation scheme for biomarkers, looking at validation (assay performance), qualification (assessment of evidence), and utilisation (the context in which the surrogate is to be used). This paper examines the example of endoscopy as a surrogate marker of NSAID-induced mucosal damage using the Institute of Medicine criteria. The article finds extensive evidence that the detection of endoscopic ulcers is a valid marker. The process of qualification documents abundant evidence showing that endoscopic ulcers and serious upper gastrointestinal damage are influenced in the same direction and much the same magnitude by a variety of risk factors and interventions. Criticisms of validation and qualification for endoscopic ulcers have been examined, and dismissed. Context is the key, and in the context of serious NSAID-induced upper gastrointestinal harm, endoscopic ulcers represent a useful surrogate. Generalisability beyond this context is not considered.
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Datto C, Hellmund R, Siddiqui MK. Efficacy and tolerability of naproxen/esomeprazole magnesium tablets compared with non-specific NSAIDs and COX-2 inhibitors: a systematic review and network analyses. Open Access Rheumatol 2013; 5:1-19. [PMID: 27790020 PMCID: PMC5074787 DOI: 10.2147/oarrr.s41420] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs), such as non-selective NSAIDs (nsNSAIDs) or selective cyclooxygenase-2 (COX-2) inhibitors, are commonly prescribed for arthritic pain relief in patients with osteoarthritis (OA), rheumatoid arthritis (RA), or ankylosing spondylitis (AS). Treatment guidelines for chronic NSAID therapy include the consideration for gastroprotection for those at risk of gastric ulcers (GUs) associated with the chronic NSAID therapy. The United States Food and Drug Administration has approved naproxen/esomeprazole magnesium tablets for the relief of signs and symptoms of OA, RA, and AS, and to decrease the risk of developing GUs in patients at risk of developing NSAID-associated GUs. The European Medical Association has approved this therapy for the symptomatic treatment of OA, RA, and AS in patients who are at risk of developing NSAID-associated GUs and/or duodenal ulcers, for whom treatment with lower doses of naproxen or other NSAIDs is not considered sufficient. Naproxen/esomeprazole magnesium tablets have been compared with naproxen and celecoxib for these indications in head-to-head trials. This systematic literature review and network meta-analyses of data from randomized controlled trials was performed to compare naproxen/esomeprazole magnesium tablets with a number of additional relevant comparators. For this study, an original review examined MEDLINE®, Embase®, and the Cochrane Controlled Trials Register from database start to April 14, 2009. Using the same methodology, a review update was conducted to December 21, 2009. The systematic review and network analyses showed naproxen/esomeprazole magnesium tablets have an improved upper gastrointestinal tolerability profile (dyspepsia and gastric or gastroduodenal ulcers) over several active comparators (naproxen, ibuprofen, diclofenac, ketoprofen, etoricoxib, and fixed-dose diclofenac sodium plus misoprostol), and are equally effective as all active comparators in treating arthritic symptoms in patients with OA, RA, and AS. Naproxen/esomeprazole magnesium tablets are therefore a valuable option for treating arthritic symptoms in eligible patients with OA, RA, and AS.
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Do COX-2 inhibitors raise blood pressure more than nonselective NSAIDs and placebo? An updated meta-analysis. J Hypertens 2010; 27:2332-41. [PMID: 19887957 DOI: 10.1097/hjh.0b013e3283310dc9] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Both COX-2 selective inhibitors (coxibs) and nonselective (ns)-NSAIDs elevate blood pressure (BP) and this may contribute to excess cardiovascular (CV) events. A number of recent large-scale randomized clinical trials (RCTs) comparing coxibs (including newer agents, lumiracoxib and etoricoxib) to both ns-NSAIDs and placebo have been reported, permitting an update to earlier BP analyses of these agents. DATA SOURCES/SYNTHESIS Our search yielded 51 RCTs involving coxibs published before April 2008 with a total of 130 541 participants in which BP data were available. The Der Simonian and Laird random effects method for dichotomous variables was used to produce risk ratios (RR) for development of hypertension. RESULTS For coxibs versus placebo, there was a RR of 1.49 (1.18-1.88, P = 0.04) in the development of new hypertension. For coxibs versus ns-NSAIDs, the RR was 1.12 (0.93-1.35, P = 0.23). These results were mainly driven by rofecoxib, with a RR of 1.87 (1.63-2.14, P = 0.08) versus placebo, and etoricoxib, with a RR of 1.52 (1.39-1.66, P = 0.01) versus ns-NSAID. CONCLUSION On the basis of this updated meta-analysis, coxibs appear to produce greater hypertension than either ns-NSAIDs or placebo. However, this response was heterogeneous, with markedly raised BP associated with rofecoxib and etoricoxib, whereas celecoxib, valdecoxib and lumiracoxib appeared to have little BP effect. The relationship of this increased risk of hypertension to subsequent adverse CV outcomes requires further investigation and prospective RCTs.
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Ross JS, Madigan D, Hill KP, Egilman DS, Wang Y, Krumholz HM. Pooled analysis of rofecoxib placebo-controlled clinical trial data: lessons for postmarket pharmaceutical safety surveillance. ARCHIVES OF INTERNAL MEDICINE 2009; 169:1976-85. [PMID: 19933959 PMCID: PMC2830805 DOI: 10.1001/archinternmed.2009.394] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND In September 2004, rofecoxib was voluntarily withdrawn from the worldwide market. Our objective was to determine whether and when analysis of published and unpublished placebo-controlled trials could have revealed cardiovascular risk associated with rofecoxib before its withdrawal as an example to inform future postmarket pharmaceutical safety surveillance efforts. METHODS We conducted a cumulative subject-level pooled analysis of data from all randomized, placebo-controlled trials of rofecoxib conducted by the manufacturer before September 2004. Our main outcome measurement was incidence of any investigator-reported death from any cause or cardiovascular thromboembolic (CVT) adverse event. RESULTS We identified 30 randomized, placebo-controlled trials of rofecoxib that enrolled a combined 20 152 subjects. Trial duration ranged from 4 weeks to 4 years; enrollment ranged from 17 to 2586 subjects prescribed either rofecoxib or placebo; and rofecoxib dose ranged from 12.5 mg to 50 mg. As of December 2000, 21 of these trials had been completed (70%), and the risk of a CVT adverse event or death was greater among subjects assigned to the rofecoxib group (rate ratio [RR], 2.18; 95% confidence interval [CI], 0.93-5.81) (P = .07), raising concerns from a safety standpoint. Subsequently collected data through June 2001 showed that rofecoxib was associated with a 35% increased risk of a CVT adverse event or death (RR, 1.35; 95% CI, 1.00-1.96) (P = .05). Analyzing data available as of April 2002, we found a 39% increased risk (RR, 1.39; 95% CI, 1.07-1.80) (P = .02), and using data available as of September 2004, we found a 43% increased risk (RR,1.43; 95% CI, 1.16-1.76) (P < .001). CONCLUSION Cumulative pooled analysis of all randomized, placebo-controlled trials demonstrates a trend toward increased cardiovascular risk associated with rofecoxib compared with placebo as early as December 2000, the comparison reaching a P value of .05 by June 2001, nearly 3(1/2) years before the manufacturer's voluntary market withdrawal.
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Affiliation(s)
- Joseph S Ross
- Department of Geriatrics and Palliative Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1070, New York, NY 10029, USA.
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Rostom A, Muir K, Dube C, Lanas A, Jolicoeur E, Tugwell P. Prevention of NSAID-related upper gastrointestinal toxicity: a meta-analysis of traditional NSAIDs with gastroprotection and COX-2 inhibitors. DRUG HEALTHCARE AND PATIENT SAFETY 2009; 1:47-71. [PMID: 21701610 PMCID: PMC3108684 DOI: 10.2147/dhps.s4334] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2009] [Indexed: 12/26/2022]
Abstract
Background: Traditional NSAIDs (tNSAIDs) and COX-2 inhibitors (COX-2s) are important agents for the treatment of a variety or arthritic conditions. The purpose of this study was to systematically review the effectiveness of misoprostol, H2-receptor antagonists (H2RAs), and proton pump inhibitors (PPIs) for the prevention of tNSAID related upper gastrointestinal (GI) toxicity, and to review the upper gastrointestinal (GI) safety of COX-2s. Methods: An extensive literature search was performed to identify randomized controlled trials (RCTs) of prophylactic agents used for the prevention of upper GI toxicity, and RCTs that assessed the GI safety of the newer COX-2s. Meta-analysis was performed in accordance with accepted techniques. Results: 39 gastroprotection and 69 COX-2 RCTs met inclusion criteria. Misoprostol, PPIs, and double doses of H2RAs are effective at reducing the risk of both endoscopic gastric and duodenal tNSAID-induced ulcers. Standard doses of H2RAs are not effective at reducing the risk of tNSAID-induced gastric ulcers, but reduce the risk of duodenal ulcers. Misoprostol is associated with greater adverse effects than the other agents, particularly at higher doses. COX-2s are associated with fewer endoscopic ulcers and clinically important ulcer complications, and have fewer treatment withdrawals due to GI symptoms than tNSAIDS. Acetylsalicylic acid appears to diminish the benefit of COX-2s over tNSAIDs. In high risk GI patients, tNSAID with a PPI or a COX-2 alone appear to offer similar GI safety, but a strategy of a COX-2 with a PPI appears to offer the greatest GI safety. Conclusion: Several strategies are available to reduce the risk of upper GI toxicity with tNSAIDs. The choice between these strategies needs to consider patients’ underlying GI and cardiovascular risk.
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Affiliation(s)
- Alaa Rostom
- University of Calgary, Calgary, Alberta, Canada
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Cheetham TC, Levy G, Niu F, Bixler F. Gastrointestinal safety of nonsteroidal antiinflammatory drugs and selective cyclooxygenase-2 inhibitors in patients on warfarin. Ann Pharmacother 2009; 43:1765-73. [PMID: 19809010 DOI: 10.1345/aph.1m284] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The interaction between warfarin and nonsteroidal antiinflammatory drugs (NSAIDs) is well known. However, warfarin and NSAIDs are still commonly prescribed together. Selective cyclooxygenase-2 (COX-2) inhibitors, a newer class of NSAID, offer potential advantages over the nonselective NSAIDs in patients treated with warfarin. OBJECTIVE To study the rates of hospitalization for gastrointestinal (GI) bleeding events in 3 groups of patients: those taking warfarin only, those taking warfarin plus a nonselective NSAID, and those taking warfarin plus a selective COX-2 inhibitor. METHODS This was a retrospective cohort analysis in a large nonprofit health maintenance organization. All warfarin users from January 1, 2000, to December 31, 2005, were eligible for inclusion in the study. Eligible patients were grouped by their exposure time to warfarin only, warfarin plus nonselective NSAIDs, or warfarin plus selective COX-2 inhibitor. The study endpoint was hospitalization for a GI bleed. Patients were matched using a propensity scoring methodology. A multivariate Cox proportional hazards model was used to estimate the hazard ratio for GI bleeding between patient cohorts, controlling for age, sex, baseline medical conditions, prior history of GI bleeding, and prescription drug use. RESULTS The eligible population consisted of 35,548 patients undergoing 46,214 courses of warfarin therapy. The adjusted hazard ratio for hospital-associated GI bleeding in the warfarin plus nonselective NSAID group versus warfarin alone was 3.58 (95% CI 2.31 to 5.55; p < 0.01) and for warfarin plus selective COX-2 inhibitor versus warfarin alone was 1.71 (95% CI 0.60 to 4.84; p = 0.31). For nonselective NSAIDs plus warfarin versus selective COX-2 inhibitor plus warfarin, the adjusted hazard ratio was 3.69 (95% CI 1.42 to 9.60; p = 0.01). CONCLUSIONS In general, nonselective NSAIDs and selective COX-2 inhibitors should be avoided in patients taking warfarin. In situations where patients require NSAIDs and cannot be managed using other therapies, our results suggest that selective COX-2 inhibitors are associated with fewer hospitalizations for GI bleeding.
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Affiliation(s)
- T Craig Cheetham
- Pharmacy Analytical Services, Kaiser Permanente, Downey, CA, USA
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Yuan YH, Wang C, Yuan Y, Hunt RH. Meta-analysis: incidence of endoscopic gastric and duodenal ulcers in placebo arms of randomized placebo-controlled NSAID trials. Aliment Pharmacol Ther 2009; 30:197-209. [PMID: 19438429 DOI: 10.1111/j.1365-2036.2009.04038.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND The safety of NSAIDs is often evaluated by comparison with placebo in clinical trials. AIM To investigate the incidence of gastric and duodenal ulcers (GDU) in placebo arms in NSAID trials over the last three decades. METHODS Randomized placebo-controlled trials of oral NSAIDs from 1975 to 2006 were systematically reviewed. The pooled incidence of GDU in placebo arms was calculated and compared. Meta-regression was used to identify risk factors related to the incidence of the placebo ulcer at the study level. RESULTS Thirty-six studies met inclusion criteria (duration of 6.5 days to 24 weeks). In total, 3.29% GDUs were reported in 36 placebo arms. The incidence of GDU in placebo arms was 0, 4.20% and 3.03% in the studies from 1975-1989, 1990-1999 and 2000-2006 respectively (P > 0.05). Eligible subjects with previous GI events and eligible subjects on co-therapy with low-lose aspirin/corticosteroids were associated with the increase in placebo ulcer incidence after adjusting for other factors. CONCLUSIONS The incidence of GDU in placebo arms has not changed significantly over the last three decades, although has decreased in the past 10 years. Studies show that previous GI events and co-therapy with low-dose aspirin/corticosteroids were associated with increasing GDU in placebo arms.
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Affiliation(s)
- Y-H Yuan
- Farncombe Family Digestive Health Research Institute, Division of Gastroenterology, Department of Medicine, McMaster University Health Science Centre, Hamilton, Canada
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Scott PA, Kingsley GH, Scott DL. Non-steroidal anti-inflammatory drugs and cardiac failure: meta-analyses of observational studies and randomised controlled trials. Eur J Heart Fail 2008; 10:1102-7. [DOI: 10.1016/j.ejheart.2008.07.013] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2008] [Revised: 05/27/2008] [Accepted: 07/15/2008] [Indexed: 11/24/2022] Open
Affiliation(s)
- Paul A Scott
- Department of Cardiology; Southampton University Hospital; Southampton SO16 6YD UK
| | - Gabrielle H. Kingsley
- Department of Rheumatology; Kings College London School of Medicine; London SE5 9RS UK
- Department of Rheumatology; University Hospital Lewisham; London SE13 6LH UK
| | - David L Scott
- Department of Rheumatology; Kings College London School of Medicine; London SE5 9RS UK
- Department of Rheumatology; Kings College Hospital; London SE5 9RS UK
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Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs worldwide, but they can cause serious gastrointestinal (GI) side effects. NSAIDs are capable of damaging the whole gastrointestinal tract. Cyclooxygenase-2 (COX-2) inhibitors (coxibs) have been developed with the aim of maintaining the anti-inflammatory benefits but reducing gastrotoxicity. There is a good evidence that these drugs effectively prevent gastroduodenal ulcers and ulcer complications. Little is known about the side effects of these agents in the small and large intestine. There is an increasing evidence that COX-2 is constitutively expressed in the gastrointestinal tract and is important for the maintenance of bowel integrity. There have also been growing concerns about the potential for coxibs to increase the frequency of adverse cardiovascular events. The purpose of this review is to summarize recent knowledge about the safety profile of selective COX-2 inhibitors.
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Affiliation(s)
- Gábor Lakatos
- Semmelweis Egyetem, Altalános Orvostudományi Kar II. Belgyógyászati Klinika, Budapest.
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Kiltz U, Zochling J, Schmidt WE, Braun J. Use of NSAIDs and infection with Helicobacter pylori--what does the rheumatologist need to know? Rheumatology (Oxford) 2008; 47:1342-7. [PMID: 18477642 DOI: 10.1093/rheumatology/ken123] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVES NSAID-induced gastroduodenal lesions are a frequent and potentially serious health problem in patients with rheumatic diseases. Helicobacter pylori (H. pylori) has also been recognized as a major risk factor for the development of ulcer disease. However, the role of H. pylori in the pathogenesis of NSAID-induced gastroduodenal lesions has remained controversial, and there is currently no clear consensus on the management of NSAID users who are infected with H. pylori. METHODS To clarify this situation we have performed a systematic literature search to find randomized controlled trials comparing the efficacy of eradication in patients receiving NSAIDs to prevent ulcer development. RESULTS Seven randomized controlled trials and one meta-analysis were identified. There were three papers on NSAID-naive patients. According to this data, NSAID-naive users benefit from testing for H. pylori infection and subsequent H. pylori eradication therapy prior to the initiation of NSAID. In contrast, H. pylori eradication alone does not protect chronic NSAID users with recent ulcer complications from further gastrointestinal (GI) events. To prevent recurrent ulcer bleeding long-term acid suppressive therapy is needed. CONCLUSIONS In conclusion, ulcer risk reduction after H. pylori eradication therapy is clearly more marked in patients beginning NSAID therapy than in patients who were already receiving and tolerating NSAID therapy. Thus, the management of H. pylori infection and the prevention of GI complications in NSAID users need to be individualized on the basis of recently published data.
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Affiliation(s)
- U Kiltz
- Rheumazentrum Ruhrgebiet, St. Josefs Hospital, Landgrafenstr. 15, 44652 Herne, Germany.
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Abstract
BACKGROUND Over the past few years, major changes have taken place in the treatment of gastroduodenal peptic ulcer. AIM To evaluate risk factors associated with the incidence of peptic ulcer in inpatients. METHODS From 2001 to 2004, the number of prescriptions of H2-antagonists and proton pump inhibitors (PPIs) in each department of Verona University Hospital was monitored. Over the same period we prospectively recorded the number of upper endoscopies per department for inpatients with a diagnosis of peptic ulcer. RESULTS We analyzed 4943 inpatients. A significantly decreasing trend in H(2)-antagonist prescriptions (r=-0,88; P<0.001) and an increasing trend in PPI prescriptions (r=0.97; P<0.001) were observed. The endoscopic incidence of duodenal ulcers decreased linearly from 2001 to 2004 as follows: 6.5% (94/1439) in 2001, 5.6% (82/1473) in 2002, 4.5% (63/1411) in 2003, and 3.1% (22/702) (P<0.001) in 2004. Gastric ulcer incidence, sex, age, indication for endoscopy, use of nonsteroidal anti-inflammatory drugs (NSAIDs), presence of Helicobacter pylori (32%), and smoking and drinking habits showed no significant changes over the study period. Considering time-dependent variables, multivariate regression analysis identified only PPI use and NSAID use as factors predictive of duodenal ulcer but not of gastric ulcer. CONCLUSIONS In inpatients, PPIs are associated with a reduced risk of duodenal ulcer, whereas NSAIDs are associated with an increased risk. Gastric ulcer was not associated with any increased or degreased risk with the 2 above-mentioned variables.
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Abstract
BACKGROUND In clinical trials of peptic ulcer prevention, the most appropriate definition of an ulcer remains challenging. AIMS To evaluate the ulcer definitions used in clinical trials of ulcer prevention among non-steroidal anti-inflammatory drug users and to determine whether any specific definition is preferred. METHODS A systematic literature search of the PubMed, Medline and EMBASE databases was conducted. Results were limited to full papers published in English from June 1987 to June 2007 that met the following criteria: randomized, controlled non-steroidal anti-inflammatory drug trials of > or =8 weeks' duration, with a primary end point of ulcer upon endoscopy. RESULTS Forty five publications met the inclusion criteria and were reviewed. Overall, an ulcer diameter of > or =3 mm was used in 25 publications and most included a description of ulcer depth. Of the remainder, ulcer was defined as any lesion with unequivocal/observable depth (with no lower limit for ulcer diameter; five publications) or an excavated mucosal break >3 mm (one publication), whereas nine defined a minimum ulcer size of > or =5 or >5 mm. Ulcer definition was unclear in the remaining five publications. CONCLUSION In clinical trials of ulcer prevention among non-steroidal anti-inflammatory drug users, a gastric or duodenal lesion > or =3 mm in diameter with significant depth is the preferred definition.
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Affiliation(s)
- N D Yeomans
- School of Medicine, University of Western Sydney, Sydney, NSW, Australia.
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18
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Laine L, White WB, Rostom A, Hochberg M. COX-2 selective inhibitors in the treatment of osteoarthritis. Semin Arthritis Rheum 2008; 38:165-87. [PMID: 18177922 DOI: 10.1016/j.semarthrit.2007.10.004] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2007] [Revised: 09/29/2007] [Accepted: 10/21/2007] [Indexed: 01/31/2023]
Abstract
OBJECTIVES To assess the efficacy of cyclooxygenase-2 selective inhibitors (coxibs) in osteoarthritis (OA) and their gastrointestinal, cardiovascular, renovascular, and hepatic side effects compared with traditional nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen. METHODS Bibliographic database searches for randomized controlled trials, meta-analyses, and literature reviews. RESULTS Coxibs are comparable to traditional NSAIDs, providing moderate benefit for OA patients in pain and function versus placebo. NSAIDs, including coxibs, are superior to acetaminophen for OA, particularly in patients with moderate to severe pain. Coxibs decrease gastroduodenal ulcers (74% relative risk reduction) and ulcer complications (61% reduction) versus traditional NSAIDs. Meta-analysis of randomized trials indicates that coxibs increase the risk of myocardial infarctions approximately twofold versus placebo and versus naproxen, but do not increase the risk versus nonnaproxen NSAIDs. NSAIDs, including coxibs, commonly cause fluid retention and increase blood pressure and uncommonly induce congestive heart failure or significant renal dysfunction; risk factors include advanced age, hypertension, and heart or kidney disease. NSAIDs are a rare cause of clinical hepatotoxicity (<1 liver-related death per 100,000 NSAID users in clinical studies). Increased rates of aminotransferase elevations occur with rofecoxib (2%) and high-dose lumiracoxib (3%), and postmarketing cases of clinical liver injury with lumiracoxib have been reported recently. CONCLUSIONS Coxibs are as effective as traditional NSAIDs and superior to acetaminophen for the treatment of OA. Coxibs cause fewer gastrointestinal complications than traditional NSAIDs. Coxibs increase cardiovascular risk versus placebo and naproxen-but probably not versus nonnaproxen NSAIDs. Blood pressure commonly increases after initiation of selective or nonselective NSAIDs, especially in hypertensive patients.
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Affiliation(s)
- Loren Laine
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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19
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de Leest HTJI, Steen KSS, Lems WF, Bijlsma JWJ, van de Laar MAFJ, Huisman AM, Vonkeman HE, Houben HHML, Kadir SW, Kostense PJ, van Tulder MW, Kuipers EJ, Boers M, Dijkmans BAC. Eradication of Helicobacter pylori does not reduce the incidence of gastroduodenal ulcers in patients on long-term NSAID treatment: double-blind, randomized, placebo-controlled trial. Helicobacter 2007; 12:477-85. [PMID: 17760715 DOI: 10.1111/j.1523-5378.2007.00543.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND Helicobacter pylori and nonsteroidal antiinflammatory drugs (NSAIDs) are the major causes of gastroduodenal ulcers. Studies on the benefit of eradication of H. pylori in NSAID users yielded conflicting results. OBJECTIVE To investigate whether H. pylori eradication in patients on long-term NSAIDs reduces the incidence of gastroduodenal ulcers. METHODS Patients on long-term NSAID treatment and who are H. pylori positive on serologic testing, were randomly assigned to either H. pylori eradication (omeprazole, amoxicillin, and clarithromycin) or placebo. Primary endpoint was the presence of endoscopic gastric or duodenal ulcers 3 months after randomization. RESULTS One hundred sixty-five (48%) of a total of 347 patients were on gastroprotective medication. At endoscopy, gastroduodenal ulcers were diagnosed in 6 (4%) and 8 (5%) patients in the eradication and placebo group, respectively (p = .65). During follow-up of 12 months, no symptomatic ulcers or ulcer complications developed. No significant differences were found in the development of gastroduodenal erosions, dyspepsia, or in quality of life. CONCLUSION H. pylori eradication therapy in patients on long-term NSAID treatment had no beneficial effect on the occurrence of ulcers, erosions, or dyspepsia. Ulcer rates in both study arms are remarkably low, in both patients with and without gastroprotective therapy.
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Affiliation(s)
- Helena T J I de Leest
- Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands.
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Morrison A, Ramey DR, van Adelsberg J, Watson DJ. Systematic review of trials of the effect of continued use of oral non-selective NSAIDs on blood pressure and hypertension. Curr Med Res Opin 2007; 23:2395-404. [PMID: 17714606 DOI: 10.1185/030079907x219553] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVE To investigate the effects of continued use of non-selective NSAIDs (nsNSAIDs) on blood pressure and hypertension. RESEARCH DESIGN AND METHODS This was a systematic review of randomized clinical trials of oral nsNSAIDs used for at least a 4-week duration. Searches were conducted of PubMed and the Cochrane Database of Systematic Reviews, using key terms for nsNSAIDs and blood pressure or hypertension, to identify articles published in the English language peer-reviewed literature through March 2007. MAIN OUTCOME MEASURES Change from baseline to end of study in systolic blood pressure (SBP) and diastolic blood pressure (DBP), and the incidence of hypertension. Pooled statistics were computed using fixed and random-effects analyses. RESULTS Thirty-two articles were included. The mean change (95% confidence interval [CI]) in blood pressure (in mmHg) from baseline to end of study for five trials of ibuprofen was 3.54 (2.70, 4.39) for SBP and 1.16 (0.68, 1.64) for DBP (p < 0.001 for both changes). Results of four trials of indomethacin were similar to those for ibuprofen: 2.90 (-0.28, 6.08) for SBP (p = 0.07) and 1.58 (0.29, 2.87) for DBP (p = 0.02). Mean changes from baseline for two trials of diclofenac were -0.46 (-1.48, 0.56) for SBP (p = 0.38) and -0.56 (-1.19, 0.07) for DBP (p = 0.08) and were similar to those for placebo. Changes from baseline in SBP were positive but not statistically significant for naproxen, sulindac, and nabumetone. Compared with placebo, the risk ratio (95% CI) for hypertension was 2.85 (1.44, 5.65; p = 0.003) in two ibuprofen trials. CONCLUSIONS Continued use of ibuprofen increases blood pressure and raises the incidence of hypertension. There appears to be heterogeneity in such effects with continued use of other nsNSAIDs but, due to limitations in the data, results for naproxen, sulindac, and nabumetone are inconclusive.
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García-Hernández L, Déciga-Campos M, Guevara-López U, López-Muñoz FJ. Co-administration of rofecoxib and tramadol results in additive or sub-additive interaction during arthritic nociception in rat. Pharmacol Biochem Behav 2007; 87:331-40. [PMID: 17570478 DOI: 10.1016/j.pbb.2007.05.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2006] [Revised: 05/01/2007] [Accepted: 05/07/2007] [Indexed: 11/23/2022]
Abstract
Over the decades, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used analgesics in the management of acute and chronic pain. In order to assess a possible antinociceptive interactions, the antinociceptive effects of rofecoxib p.o., a preferential inhibitor of cyclooxygenase-2, and tramadol-hydrochloride p.o., an atypical opioid analgesic, administered either separately or in combination, were determined using a rat model of arthritic pain. The data were interpreted using the surface of synergistic interaction (SSI) analysis and an isobolographic analysis to establish the nature of the interaction. The SSI was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Female rats received orally rofecoxib alone (1.0, 1.8, 3.2, 5.6, 10.0, 17.8, 31.6 and 56.2 mg/kg), tramadol alone (1.8, 3.2, 5.6, 10.0, 17.8, 31.6 and 56.2 mg/kg) or 12 different combinations of rofecoxib plus tramadol. Five combinations exhibited various degrees of sub-additive (i.e. less than the sum of the effects produced by the each drug alone) antinociceptive effects (3.2 mg/kg tramadol with 7.8 mg/kg rofecoxib; 5.6 mg/kg tramadol with either 10.0 or 17.8 mg/kg rofecoxib; 10.0 mg/kg tramadol with either 10.0 or 17.8 mg/kg rofecoxib), whereas the other 7 combinations showed additive antinociceptive effects (i.e. the sum of the effects produced by each agent alone). Three combination of rofecoxib+tramadol (10.0+5.6, 10.0+10.0, and 17.8+5.6 mg/kg respectively) presented high sub-additive interactions (P<0.002: Q=9.5). The combination rofecoxib (17.8 mg/kg)+tramadol (10.0 mg/kg) caused gastric injuries less severe than those observed with indomethacin, but more severe than those obtained with rofecoxib or tramadol in single administration. The antinociceptive interaction of rofecoxib and tramadol suggests that combinations with these drugs may have no clinical utility in pain therapy.
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Rostom A, Muir K, Dubé C, Jolicoeur E, Boucher M, Joyce J, Tugwell P, Wells GW. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane Collaboration systematic review. Clin Gastroenterol Hepatol 2007; 5:818-28, 828.e1-5; quiz 768. [PMID: 17556027 DOI: 10.1016/j.cgh.2007.03.011] [Citation(s) in RCA: 168] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Nonselective non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 inhibitors (COX-2s) are used to treat a variety of arthritic and inflammatory conditions. The aim of this study was to assess the upper gastrointestinal (GI) harms of the long-term use of COX-2s, compared with nonselective NSAIDs and placebo, in arthritis sufferers. METHODS A systematic review of randomized controlled trials (RCTs) was conducted. Searches were conducted in (1) Cochrane Central Register of Controlled Trials (CENTRAL), (2) the Cochrane Collaboration Library (2005), (3) MEDLINE (to December 2006), and (4) Excerpta Medica Database (EMBASE) (to June 2005). Reference lists from trials and abstracts of conference proceedings were searched by hand, and experts were contacted to identify further relevant trials. RCTs of celecoxib, rofecoxib, etoricoxib, valdecoxib, and lumiracoxib were included if they reported on endoscopic ulcers, clinically important ulcer complications, or adverse gastrointestinal (GI) symptoms with the use of these COX-2s, compared with placebo or with nonselective NSAIDs. Study selection and data extraction were performed in duplicate by independent reviewers. Data were analyzed by using Review Manager 4.2 in accordance with accepted meta-analysis techniques. RESULTS Compared with nonselective NSAIDs, COX-2s produced significantly fewer gastroduodenal ulcers (relative risk, 0.26; 95% confidence interval, 0.23-0.30) and clinically important ulcer complications (relative risk, 0.39; 95% confidence interval, 0.31-0.50), as well as fewer treatment withdrawals caused by GI symptoms. The co-administration of acetylsalicylic acid appears to reduce the GI safety of COX-2s in subgroup analyses. CONCLUSIONS COX-2s appear to offer greater upper GI safety and are better tolerated than nonselective NSAIDs. The co-administration of acetylsalicylic acid might reduce the safety advantage of COX-2s over that of nonselective NSAIDs.
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Affiliation(s)
- Alaa Rostom
- Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.
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Bjarnason I, Scarpignato C, Takeuchi K, Rainsford KD. Determinants of the short-term gastric damage caused by NSAIDs in man. Aliment Pharmacol Ther 2007; 26:95-106. [PMID: 17555426 DOI: 10.1111/j.1365-2036.2007.03348.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND The short-term gastric damage seen with non-steroidal anti-inflammatory drugs (NSAIDs) in man may involve inhibition of cyclooxygenase (COX-1) and COX-2 as well as the topical irritancy, which is dependant on the acidity (pKa) and/or lipophilicity (log P(7.4)). AIM To study the quantitative relationship between NSAID-induced short-term gastric damage, their physicochemical properties and contrasting roles of COX-1 and COX-2 inhibition. METHODS We identified studies that allowed a qualitative comparison of the gastric injury (Lanza scores) induced by NSAIDs with their pKa and log P(7.4). Damage was correlated with gastric COX inhibition and potency to inhibit COX-1 and 2 and their COX-2/COX-1 selectivity ratio. RESULTS The gastric damage correlates significantly with pKa (r = -0.69; P < 0.01), log P (r = -0.58, P < 0.05) and potency of the NSAIDs to inhibit COX-1 (r = -0.61, P < 0.02), but not with COX-2 inhibition or COX-2/COX-1 selectivity. CONCLUSION Against a background of COX-1 and COX-2 inhibition, the physicochemical properties of NSAID appear to play an important role in short-term gastric damage.
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Affiliation(s)
- I Bjarnason
- Department of Medicine, Guy's, King's, St Thomas' Medical School, London, UK.
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Lanas A, Baron JA, Sandler RS, Horgan K, Bolognese J, Oxenius B, Quan H, Watson D, Cook TJ, Schoen R, Burke C, Loftus S, Niv Y, Ridell R, Morton D, Bresalier R. Peptic ulcer and bleeding events associated with rofecoxib in a 3-year colorectal adenoma chemoprevention trial. Gastroenterology 2007; 132:490-7. [PMID: 17258718 DOI: 10.1053/j.gastro.2006.11.012] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2006] [Accepted: 10/12/2006] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Our aim was to establish the incidence of symptomatic upper gastrointestinal ulcers, ulcer perforation, ulcer obstruction, or bleeding episodes (PUBs) associated with the use of selective cyclooxygenase-2 inhibitors at standard clinical doses compared with placebo. We report here on the PUB outcomes associated with the use of rofecoxib 25 mg in a 3-year, multicenter, double-blind, placebo-controlled trial designed to determine the effect of rofecoxib on the risk of recurrent neoplastic polyps of the colon. METHODS A total of 2587 patients with a history of colorectal adenomas underwent randomization to 25 mg/day of rofecoxib or to placebo. Investigator-reported PUBs were adjudicated by an external blinded committee. Kaplan-Meier and Cox proportional hazards techniques were used to estimate incidence and relative risks of PUBs in an intention-to-treat analysis. RESULTS Patients assigned to rofecoxib had a higher incidence of confirmed PUBs than those randomized to placebo (.88 vs .18 events per 100 patient-years; relative risk, 4.9; 95% confidence interval, 1.98-14.54). The incidence of confirmed complicated PUBs (ulcer perforation, obstruction, or bleeds) was low, but was numerically higher in the rofecoxib than in the placebo group (.23 vs .06 events per 100 patient-years; relative risk, 3.8; 95% confidence interval, .72-37.46; P = .14). Rofecoxib increased the incidence of confirmed PUBs vs placebo in both low-dose aspirin users and nonusers. CONCLUSIONS Among patients with a history of colorectal adenomas, the long-term use of 25 mg/day of rofecoxib was associated with an increased risk of clinically relevant upper gastrointestinal events when compared with placebo.
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Affiliation(s)
- Angel Lanas
- Department of Medicine, University Clinic Hospital, Instituto Aragones de Ciencias de la Salud (CIBER HEPAD) Zaragoza, Spain.
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Chelly JE, Nissen CW, Rodgers AJ, Smugar SS, Tershakovec AM. The efficacy of rofecoxib 50 mg and hydrocodone/acetaminophen 7.5/750 mg in patients with post-arthroscopic pain. Curr Med Res Opin 2007; 23:195-206. [PMID: 17207303 DOI: 10.1185/030079907x162647] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVE To compare the efficacy and tolerability of rofecoxib, hydrocodone/acetaminophen 7.5 mg/750 mg (H/A) and placebo in treating pain after arthroscopy of the knee. METHODS A randomized, double-blind, placebo-controlled, single dose study enrolling patients experiencing moderate or severe pain after knee arthroscopy. Patients with moderate-to-severe postoperative pain received either rofecoxib 50 mg (n = 151), H/A (n = 145), or placebo (n = 147). Pain was measured over 24 h. The primary endpoint was total pain relief at 6 h for rofecoxib 50 mg compared with placebo. RESULTS H/A (p = 0.003), but not rofecoxib (p = 0.256) was significantly more effective than placebo for total pain relief at 6 h (TOPAR6). Although analgesic onset and peak were significantly better for H/A than for both rofecoxib (p < 0.01, p < 0.05, respectively) and placebo (p < 0.05, p < 0.001, respectively), rofecoxib patients used significantly less rescue analgesia (p < 0.001) over 24 h. Rofecoxib also provided better Brief Pain Inventory Severity (p = 0.008) and Interference Domain (p = 0.045) scores at 24 h compared to placebo and had lower 24-h Pain Severity scores than H/A (p < 0.05). Treatments were generally well tolerated, with no significant difference in the frequency of patient-reported adverse events between groups. CONCLUSIONS Rofecoxib 50 mg did not provide significantly different pain relief than placebo at 6 h, and the primary endpoint TOPAR was not attained, although it did show several efficacy benefits at 24 h, including a significant opioid-sparing effect. All treatments were well tolerated, with no significant differences observed. The limited efficacy of rofecoxib in this study contrasts to the results of previous surgical studies evaluating rofecoxib, and may be partially explained by the postoperative dosing in this arthroscopic surgical model.
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Affiliation(s)
- Jacques E Chelly
- University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Salpeter SR, Gregor P, Ormiston TM, Whitlock R, Raina P, Thabane L, Topol EJ. Meta-analysis: cardiovascular events associated with nonsteroidal anti-inflammatory drugs. Am J Med 2006; 119:552-9. [PMID: 16828623 DOI: 10.1016/j.amjmed.2005.10.056] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2005] [Revised: 10/28/2005] [Accepted: 10/29/2005] [Indexed: 02/06/2023]
Abstract
PURPOSE We performed a meta-analysis of randomized controlled trials to assess the effect of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) on cardiovascular events in trials of joint disease and Alzheimer's disease. METHODS We performed comprehensive searches of MEDLINE, EMBASE, CINAHL and Cochrane databases from 1966 to July 2005, and references of identified articles and reviews. We included randomized placebo-controlled trials of at least 6 weeks duration that evaluated nonselective NSAIDs in trials of joint disease or Alzheimer's disease, and reported at least one cardiovascular event or death. The outcome measured was the composite of death, myocardial infarction or cerebrovascular accident, with the pooled results reported as odds ratios (OR). Subgroup analyses evaluated the difference between trials of joint disease and Alzheimer's disease, and for naproxen and non-naproxen NSAIDs. RESULTS Pooled data from 13 trials with 7718 participants showed that nonselective NSAIDs had no significant effect on cardiovascular events (OR 1.3; 95% confidence interval [CI], 0.8 to 2.1). No significant effect was seen for joint disease trials (OR 0.6; 95% CI, 0.2 to 1.7) or Alzheimer disease trials (OR 1.6; 95% CI, 0.9 to 2.7). There was no significant difference in results for naproxen and non-naproxen NSAIDs. CONCLUSION Nonselective NSAIDs have no significant effect on cardiovascular events or death in trials of joint disease and Alzheimer disease, but a small adverse effect could not be excluded. An indication for risk was present in trials of Alzheimer's disease but not in joint disease trials. There was no significant adverse or cardioprotective effect of naproxen.
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Barton GR, Avery AJ, Whynes DK. Accounting for the increase in NSAID expenditure: substitution or leakage? COST EFFECTIVENESS AND RESOURCE ALLOCATION 2006; 4:9. [PMID: 16737538 PMCID: PMC1501056 DOI: 10.1186/1478-7547-4-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2005] [Accepted: 05/31/2006] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND National Institute of Health and Clinical Excellence (NICE) guidance stated that a new form of non-steroidal anti-inflammatory drug (NSAID) (selective COX-2 inhibitors) should only be an option for arthritis patients at high risk of a gastro-intestinal (GI) event. Total expenditure on NSAIDs has risen by 57% over five years, to 247 pounds sterling million in 2004. We assess whether this expenditure increase can be accounted for by substitution--an increased prescribing of two (more expensive) selective COX-2 inhibitors (celecoxib and rofecoxib) and a simultaneous equivalent reduction in the prescribing volume of three (cheaper) older NSAIDs (diclofenac, ibuprofen and naproxen). METHODS Quarterly prescription data was collated from January 1999 to September 2004. Over this period, the level of correlation between the total prescribing volumes for i) celecoxib and rofecoxib, and ii) diclofenac, ibuprofen, and naproxen were compared, the change in total expenditure on the five NSAIDs was also estimated. The latter was apportioned into that which was estimated to have arisen due to i) substitution, and ii) increased NSAID prescription volume. RESULTS Total prescription volumes for the two NSAID groups were negatively correlated (r = -0.97, p < 0.001). In the last quarter there were 1.23 million prescriptions for celecoxib and rofecoxib, and 0.46 million fewer prescriptions for naproxen, diclofenac, and ibuprofen (than in the first quarter, when celecoxib and rofecoxib were not prescribed). Total expenditure for the five NSAIDs was 32.7 pounds sterling million higher in the last quarter, than the first, 12.2 pounds sterling million of which was estimated to be due to substitution, and 20.4 pounds sterling million due to increased volume. CONCLUSION The introduction of celecoxib and rofecoxib was associated with a reduction in the prescription volume for naproxen, diclofenac, and ibuprofen. However, overall quarterly prescription volume for these five NSAIDs increased by 0.76 million, and we estimate that quarterly expenditure increased by 20.4 pounds sterling million more than would have been expected if overall NSAID volume had remained constant. This suggests that the prescription of both celecoxib and rofecoxib may have 'leaked' to population groups who would not previously have received an older NSAID.
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Affiliation(s)
- Garry R Barton
- School of Economics, University of Nottingham, Nottingham, NG7 2RD, UK
| | - Anthony J Avery
- Division of Primary Care, Medical School, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - David K Whynes
- School of Economics, University of Nottingham, Nottingham, NG7 2RD, UK
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Riley AF, Wakely LA, Patel HY, Neveldsen B, Purdie GL, Wells AP. Use of a cyclo-oxygenase 2 inhibitor for prophylaxis of cystoid macular oedema following cataract surgery: a randomized placebo-controlled trial. Clin Exp Ophthalmol 2006; 34:299-304. [PMID: 16764647 DOI: 10.1111/j.1442-9071.2006.01213.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND To assess the efficacy of Celecoxib, a cyclo-oxygenase 2 (COX-2) inhibitor, as prophylaxis for cystoid macular oedema after routine cataract surgery. METHODS A prospective, randomized, double-blind placebo-controlled trial of 69 hospital patients undergoing cataract surgery. Celecoxib 200 mg twice daily or placebo was given immediately after surgery for 14 days. Optical coherence tomography was used to quantify macular thickness before surgery and on day 1, week 2 and week 6 after surgery. RESULTS Sixty-nine patients were enrolled, of which 33 received placebo and 36 received active drug. Clinically apparent cystoid macular oedema occurred in four of the treatment group and two of the placebo group (P = 0.68). No difference in best-corrected visual acuity was seen at 6 weeks (P = 0.37). Covariate analysis of the results at 2 weeks and 6 weeks showed a macular thickness of 3% less in the treatment group compared with placebo (P = 0.050). CONCLUSION Celecoxib may decrease macular thickening following routine cataract surgery at 2 and 6 weeks after surgery as measured by Stratus OCT III. No difference in best-corrected visual acuity or clinically apparent cystoid macular oedema was seen. Further investigation of COX-2 inhibitors in a larger prospective randomized trial is required.
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Affiliation(s)
- Andrew F Riley
- Ophthalmology Unit, Department of Surgery and Anaesthesia, Wellington School of Medicine, University of Otago, Wellington, New Zealand
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Spiegel BMR, Farid M, Dulai GS, Gralnek IM, Kanwal F. Comparing rates of dyspepsia with Coxibs vs NSAID+PPI: a meta-analysis. Am J Med 2006; 119:448.e27-36. [PMID: 16651060 DOI: 10.1016/j.amjmed.2005.11.020] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2005] [Revised: 11/20/2005] [Accepted: 11/21/2005] [Indexed: 11/28/2022]
Abstract
PURPOSE Because dyspeptic symptoms are far more prevalent than ulcer complications in users of nonsteroidal anti-inflammatory drugs (NSAIDs), economic models indicate that dyspepsia rates (not ulcer complications) are the major determinant of cost-effectiveness in treating arthritis. We performed a meta-analysis to compare rates of dyspepsia for two common therapies in high-risk patients with arthritis: cyclooxygenase-2 inhibitor (Coxib) alone and combination therapy with a nonselective NSAID and a proton pump inhibitor (PPI) (NSAID+PPI). METHODS We performed a systematic review to identify trials comparing either a Coxib versus NSAID or NSAID+PPI versus NSAID in chronic arthritis. We selected studies that report incident dyspepsia, defined a priori as "epigastric pain," "dyspepsia," and "nausea." We then performed meta-analysis to compare the relative risk reduction and absolute risk reduction of dyspepsia for Coxib versus NSAID and NSAID+PPI versus NSAID. RESULTS Meta-analysis of 26 studies comparing dyspepsia between Coxibs and NSAIDs revealed a 12% relative risk reduction for Coxibs with an absolute risk reduction of 3.7%. Meta-analysis of four studies comparing dyspepsia between the NSAID+PPI combination and NSAIDs alone revealed a 66% relative risk reduction for NSAID+PPI with an absolute risk reduction of 9%. Compared with the NSAID strategy, the number needed to treat to prevent dyspepsia was 27 for Coxibs and 11 for NSAID+PPI. CONCLUSION NSAID+PPI affords greater risk reduction for dyspepsia than Coxibs when compared with the common baseline of NSAIDs. Because there are limited head-to-head data comparing Coxibs versus NSAID+PPI, these data provide the best indirect evidence that NSAID+PPI may be superior to Coxibs in minimizing incident dyspepsia.
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Affiliation(s)
- Brennan M R Spiegel
- Division of Gastroenterology and Hepatology, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, Calif 90073, USA.
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Chua SS, Paraidathathu T. Utilisation of non-steroidal anti-inflammatory drugs (NSAIDs) through community pharmacies in Malaysia. Asia Pac J Public Health 2006; 17:117-23. [PMID: 16425656 DOI: 10.1177/101053950501700210] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
This study was conducted to evaluate the use of non-steroidal anti-inflammatory drugs (NSAIDs) by consumers who obtained these drugs from community pharmacies. Factors that influenced community pharmacists in their choice of NSAIDs were also determined. Personal interviews were conducted on consumers who visited the 25 participating community pharmacies throughout Malaysia. Of the 389 respondents, 49% requested for an NSAID by name, 42% asked the pharmacist to recommend a medication and 9% had a doctor's prescription. NSAIDs were mainly purchased for joint/shoulder pain and the most commonly dispensed was diclofenac. Elderly respondents were more likely to be dispensed a selective COX-2 inhibitor than those below 60. NSAIDs were recommended based mainly on the pharmacist's perception of their efficacy, cost and safety. Community pharmacists play an important role in assisting patients in choosing the most appropriate NSAID for their health problems.
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Affiliation(s)
- S S Chua
- Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
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Perić A, Toskić-Radojicić M. Analysis of the use and adverse effects of non-steroidal anti-inflammatory drugs: A pilot study. VOJNOSANIT PREGL 2006; 63:271-7. [PMID: 16605193 DOI: 10.2298/vsp0603271p] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background/Aim. The use and adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in outpatients with rheumatic diseases has not yet been studied enough. The aim of this study was to evaluate the data about the efficacy and safety of NSAIDs obtained from the questionnaires submitted to the outpatients receiving these drugs. Methods. The patients who had been prescribed any of NSAIDs within the period from June to September, 2004 were included in the study. The answers obtained from the questionnaires were statistically analyzed by means of ?2-test. Results. At the time of the study, 150 patients had been prescribed ibuprofen or some other NSAID. Out of the total number of dispensed questionnaires (n = 150), only 45 (30%) were shown to be correctly filled-in. Their analysis showed that 64.4% of the patients had suffered from rheumatic diseases for more than five years, and had regularly used NSAIDs. The average age of these patients was about 70 years, and the number of females was double as high as that of the males. The most frequently used NSAIDs were diclofenac and ibuprofen (46.14%, and 23.24%, respectively). According to the answers given by the patients, the most often adverse reactions were gastric complaints such as nausea (11.1%), and stomach pain (8.9%). Due to this, the majority of the patients (64.4%) used some of the antiulcer drugs, most often ranitidine (31.1%). Conclusion. The results of this pilot study revealed that among the outpatients suffering from rheumatic diseases, the number of females was double as high as the number of males, that these patients were of the mean age of 70 years, and that their diseases lasted longer than five years. Gastric complains such as nausea and gastric pain of mild intensity were the most often adverse effects of NSAIDs reported by our patients. It could be the consequence of the predominant use of diclofenac and ibuprofen, NSAIDs with mild to moderate ulcerogenic potential, as well as the concomitant use of H2-receptor antagonists.
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Affiliation(s)
- Aneta Perić
- Vojnomedicinska akademija, Institut za farmaciju, Beograd.
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Naesdal J, Brown K. NSAID-associated adverse effects and acid control aids to prevent them: a review of current treatment options. Drug Saf 2006; 29:119-32. [PMID: 16454539 DOI: 10.2165/00002018-200629020-00002] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
NSAIDs are central to the clinical management of a wide range of conditions. However, NSAIDs in combination with gastric acid, which has been shown to play a central role in upper gastrointestinal (GI) events, can damage the gastroduodenal mucosa and result in dyspeptic symptoms and peptic lesions such as ulceration.NSAID-associated GI mucosal injury is an important clinical problem. Gastroduodenal ulcers or ulcer complications occur in up to 25% of patients receiving NSAIDs. However, these toxicities are often not preceded by indicative symptoms. Data obtained from the Arthritis, Rheumatism, and Aging Medical Information System have shown that 50-60% of NSAID-associated peptic ulcer cases can remain clinically silent and do not present until complications occur. Therefore, prophylactic treatment to prevent GI complications may be necessary in a substantial proportion of NSAID users, especially those in groups associated with a high risk of developing these complications. Use of cyclo-oxygenase (COX)-2 selective NSAIDs, also known as 'coxibs', substantially reduces the incidence of upper GI toxicities seen with non-selective NSAIDs. However, there are concerns regarding the cardiovascular safety of coxibs. For this reason, the US FDA recommends minimal use of coxibs and only when strictly necessary. Additionally, rofecoxib has been removed from the US market and sales of valdecoxib have been suspended. Furthermore, upper GI toxicities still occur in patients receiving coxibs. Therefore, cotherapies are required to prevent and/or heal upper GI effects associated with NSAID use. Effective prophylactic and treatment strategies include misoprostol, histamine H(2) receptor antagonists and proton pump inhibitors (PPIs). The key role that gastric acid plays in upper GI adverse events among NSAID users suggests that it is important to choose the most effective agent for acid control to alleviate symptoms, heal mucosal erosions and improve the reduced quality of life in this patient population. PPIs provide effective acid suppression, which is essential to avoid GI mucosal injury, and they are, therefore, capable of dramatically decreasing the morbidity and mortality associated with this disorder. Since many serious GI complications are not heralded by any previous symptoms, physicians need to be aware of risk factor profiles that predispose patients to serious GI problems. Physicians also need to initiate the appropriate preventative acid suppressive therapy to minimise the burden of NSAID-associated GI adverse effects.
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Papatheodoridis GV, Archimandritis AJ. Role of Helicobacter pylori eradication in aspirin or non-steroidal anti-inflammatory drug users. World J Gastroenterol 2005; 11:3811-6. [PMID: 15991274 PMCID: PMC4504877 DOI: 10.3748/wjg.v11.i25.3811] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H pylori) infection and the use of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin at any dosage and formulation represent well-established risk factors for the development of uncomplicated and complicated peptic ulcer disease accounting for the majority of such cases. Although the interaction between H pylori and NSAID/aspirin use in the same individuals was questioned in some epidemiological studies, it has now become widely accepted that they are at least independent risk factors for peptic ulcer disease. According to data from randomized intervention trials, naive NSAID users certainly benefit from testing for H pylori infection and, if positive, H pylori eradication therapy prior to the initiation of NSAID. A similar strategy is also suggested for naive aspirin users, although the efficacy of such an approach has not been evaluated yet. Strong data also support that chronic aspirin users with a recent ulcer complication should be tested for H pylori infection and, if positive, receive H pylori eradication therapy after ulcer healing, while they appear to benefit from additional long-term therapy with a proton pump inhibitor (PPI). A similar approach is often recommended to chronic aspirin users at a high risk of ulcer complication. H pylori eradication alone does not efficiently protect chronic NSAID users with a recent ulcer complication or those at a high-risk, who certainly should be treated with long-term PPI therapy, but H pylori eradication may be additionally offered even in this setting. In contrast, testing for H pylori or PPI therapy is not recommended for chronic NSAID/aspirin users with no ulcer complications or those at a low risk of complications.
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Affiliation(s)
- George-V Papatheodoridis
- Second Academic Department of Internal Medicine, Medical School of Athens University, Hippokration General Hospital of Athens, 114 Vas. Sophias Ave., Athens 115 27, Greece.
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Wedmore IS, Johnson T, Czarnik J, Hendrix S. Pain management in the wilderness and operational setting. Emerg Med Clin North Am 2005; 23:585-601, xi-xii. [PMID: 15829399 DOI: 10.1016/j.emc.2004.12.017] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The wilderness and operational setting places unique constraints on one's ability to treat pain. In this article we will discuss methods for treating pain both in the wilderness and operational setting. By operational we mean the austere deployed military setting, to include both noncombat and combat operations. The authors combined experience with wartime trauma pain management consists of experience in Operation "Just Cause" (Panama Invasion), Operation "Desert Storm" (Persian Gulf War), Operation "Uphold Democracy" (Haiti liberation), Operation "Enduring Freedom" (Afghanistan conflict), and Operation "Iraqi Freedom" (Iraq conflict).
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Affiliation(s)
- Ian S Wedmore
- University of Washington School of Medicine, Madigan Army Medical Center, Ft. Lewis, WA 98431, USA.
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Hawkey C, Talley NJ, Yeomans ND, Jones R, Sung JJY, Långström G, Naesdal J, Scheiman JM. Improvements with esomeprazole in patients with upper gastrointestinal symptoms taking non-steroidal antiinflammatory drugs, including selective COX-2 inhibitors. Am J Gastroenterol 2005; 100:1028-36. [PMID: 15842575 DOI: 10.1111/j.1572-0241.2005.41465.x] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Upper gastrointestinal (GI) symptoms are common in patients using non-steroidal antiinflammatory drugs (NSAIDs) including selective cyclooxygenase (COX)-2 inhibitors and may be acid related. We therefore assessed esomeprazole treatment for upper GI symptoms in these patients. METHODS A total of 794 and 848 continuous NSAID users, free of gastroduodenal ulcers, erosive esophagitis, and Helicobacter pylori, were enrolled into two identical, multinational, multicenter double-blind studies (NASA1, SPACE1). Moreover, 608 and 556 patients were randomized to receive 4 wk esomeprazole 20 mg, or 40 mg, or placebo once daily. The primary variable was the patient-reported change in the upper GI symptom (pain, discomfort, or burning in the upper abdomen) score on a 7-graded severity scale (0-6) from the 7 days prior to treatment to the last 7 days in the study. RESULTS Esomeprazole was associated with highly significant symptom improvement compared to placebo. Symptom improvements were 2.30 mean [SD 1.63] on esomeprazole 20 mg and 2.03 [1.56] on esomeprazole 40 mg versus 1.64 [1.57] on placebo in NASA1 and 2.17 [1.34] and 2.12 [1.48]versus 1.56 [1.26], respectively, in SPACE1 (all placebo comparisons at least p < 0.001). Esomeprazole-improved symptoms in patients taking selective COX-2 inhibitors, with changes of 2.21 [1.46] and 1.92 [1.38]versus 1.64 [1.46] in NASA1 and 2.20 [1.26] and 2.24 [1.62]versus 1.58 [1.37] in SPACE1 (all placebo comparisons at least p < 0.05), as well as those on non-selective NSAIDs. Esomeprazole was well tolerated and associated with significant improvements in HRQL. CONCLUSION Esomeprazole 20 mg and 40 mg improve upper GI symptoms associated with continuous, daily NSAID therapy, including selective COX-2 inhibitors.
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Affiliation(s)
- Chris Hawkey
- Institute of Clinical Research Trials Unit, University Hospital, Nottingham, UK
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Misra UK, Jose M, Kalita J. Rofecoxib versus ibuprofen for acute treatment of migraine: a randomised placebo controlled trial. Postgrad Med J 2005; 80:720-3. [PMID: 15579612 PMCID: PMC1743152 DOI: 10.1136/pgmj.2003.012393] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND Rofecoxib is a potent cyclo-oxygenase-2 inhibitor with a long duration of action. Its role in migraine has not been systematically evaluated. AIM To study the efficacy of rofecoxib in migraine. METHOD In a randomised placebo controlled trial rofecoxib 25 mg, ibuprofen 400 mg, and placebo were compared regarding their efficacy in relieving acute migraine attack. Migraine patients with 2-6 attacks per month were recruited. Headache severity, functional disability, and severity of associated symptoms were graded on a 0-3 scale. The primary endpoint was pain relief at two hours. Relief of associated symptoms and sustained pain relief for 24 hours were also noted. RESULT One hundred and twenty four patients were randomised into rofecoxib (42), ibuprofen (40), and placebo (42) groups. One hundred and one patients were followed up: 33 on rofecoxib, 35 ibuprofen, and 33 placebo. Patients' ages ranged from 16-62 (mean 31.4) years, and 83 were females. Pain relief at two hours was noted in 45.5% on rofecoxib, 55.6% on ibuprofen, and 9.1% in the placebo group. The associated symptoms at two hours were reduced in 39.4% on rofecoxib, 50% on ibuprofen, and 9.1% in the placebo group. Sustained 24 hour pain relief was noted in 36.4% on rofecoxib, 41% on ibuprofen, and 6.1% in the placebo group. In the ibuprofen group, five patients had abdominal pain but there were no side effects in those on rofecoxib or in the control group. Both rofecoxib and ibuprofen were significantly effective in relieving pain, associated symptoms at two hours, and in sustained pain relief. There was no significant difference between rofecoxib and ibuprofen in aborting acute migraine attacks. CONCLUSIONS Both ibuprofen and rofecoxib were superior to placebo in aborting an acute migraine attack, and there was no significant difference in their efficacy in an acute migraine attack.
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Affiliation(s)
- U K Misra
- Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
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Moore RA, Derry S, Makinson GT, McQuay HJ. Tolerability and adverse events in clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-analysis of information from company clinical trial reports. Arthritis Res Ther 2005; 7:R644-65. [PMID: 15899051 PMCID: PMC1174947 DOI: 10.1186/ar1704] [Citation(s) in RCA: 163] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2004] [Revised: 01/21/2005] [Accepted: 01/28/2005] [Indexed: 02/01/2023] Open
Abstract
The objective was to improve understanding of adverse events occurring with celecoxib in the treatment of osteoarthritis and rheumatoid arthritis. Data were extracted from company clinical trial reports of randomised trials of celecoxib in osteoarthritis or rheumatoid arthritis lasting 2 weeks or more. Outcomes were discontinuations (all cause, lack of efficacy, adverse event, gastrointestinal adverse event), endoscopically detected ulcers, gastrointestinal or cardio-renal events, and major changes in haematological parameters. The main comparisons were celecoxib (all doses) versus placebo, paracetamol (acetaminophen) 4,000 mg daily, rofecoxib 25 mg daily, or nonsteroidal anti-inflammatory drugs (NSAIDs) (naproxen, diclofenac, ibuprofen, and loxoprofen). For NSAIDs, celecoxib was compared both at all doses and at licensed doses (200 to 400 mg daily). Thirty-one trials included 39,605 randomised patients. Most patients had osteoarthritis and were women of average age 60 years or above. Most trials lasted 12 weeks or more. Doses of celecoxib were 50 to 800 mg/day. Compared with placebo, celecoxib had fewer discontinuations for any cause or for lack of efficacy, fewer serious adverse events, and less nausea. It had more patients with dyspepsia, diarrhoea, oedema, more adverse events that were gastrointestinal or treatment related, and more patients experiencing an adverse event. There were no differences for hypertension, gastrointestinal tolerability, or discontinuations for adverse events. Compared with paracetamol, celecoxib had fewer discontinuations for any cause, for lack of efficacy, or diarrhoea, but no other differences. Compared with rofecoxib, celecoxib had fewer patients with abdominal pain and oedema, but no other differences. Compared with NSAIDs, celecoxib had fewer symptomatic ulcers and bleeds, endoscopically detected ulcers, and discontinuations for adverse events or gastrointestinal adverse events. Fewer patients had any, or a gastrointestinal, or a treatment-related adverse event, or vomiting, abdominal pain, dyspepsia, or reduced haemoglobin or haematocrit. Discontinuations for lack of efficacy were higher. No differences were found for all-cause discontinuations, serious adverse events, hypertension, diarrhoea, nausea, oedema, myocardial infarction, cardiac failure, or raised creatinine. Company clinical trial reports present much more information than published papers. Adverse event information is clearly presented in company clinical trial reports, which are an ideal source of information for systematic review and meta-analysis.
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Affiliation(s)
- R Andrew Moore
- Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe NHS Trust, Oxford, UK
| | - Sheena Derry
- Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe NHS Trust, Oxford, UK
| | - Geoffrey T Makinson
- Department of Outcomes Research and Evidence-based Medicine, Pfizer Ltd, Walton Oaks, Surrey, UK
| | - Henry J McQuay
- Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe NHS Trust, Oxford, UK
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Affiliation(s)
- E M Lima Rodríguez
- Medicina Familiar y Comunitaria, Hospital Perpetuo Socorro, Badajoz, España
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Edwards JE, McQuay HJ, Moore AR. Efficacy and safety of valdecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. Pain 2004; 111:286-296. [PMID: 15363872 DOI: 10.1016/j.pain.2004.07.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2004] [Revised: 06/30/2004] [Accepted: 07/06/2004] [Indexed: 11/20/2022]
Abstract
Our objective was to determine the efficacy and safety of valdecoxib (a cyclo-oxygenase 2 inhibitor) in the treatment of arthritis. Randomised, controlled trials comparing 10 or 20mg valdecoxib with placebo or non-steroidal anti-inflammatory drugs (NSAIDs) in patients with active osteoarthritis or rheumatoid arthritis. The manufacturer provided clinical trial reports. Data were combined through meta-analysis. Main outcomes were patient global rating of arthritis, arthritis pain, Western Ontario and McMaster Universities indices for osteoarthritis, American College of Rheumatology indices for rheumatoid arthritis, discontinuation, endoscopic ulcers, clinically significant upper gastrointestinal or renal events. Nine trials (five in osteoarthritis, four in rheumatoid arthritis) were included with 5726 patients. Overall, valdecoxib 10 and 20mg were superior to placebo and equivalent in efficacy to maximum daily doses of NSAIDs. Significantly fewer discontinuations because of gastrointestinal adverse events (4% versus 8%), or endoscopic ulcers of 3mm or more (5% versus 13%) occurred with valdecoxib compared with NSAIDs. Clinically significant upper gastrointestinal events occurred in 2/2733 (0.1%) with valdecoxib compared with 8/1846 (0.4%) with NSAIDs. Rates of clinically significant renal events were the same (2-3%) for valdecoxib and NSAIDs. At an appropriate dose valdecoxib was as effective as NSAIDs in osteoarthritis and rheumatoid arthritis. There were fewer gastrointestinal adverse event withdrawals and endoscopically detected ulcers. Convincing evidence of reduced major gastrointestinal adverse events could not be addressed by the trials.
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Affiliation(s)
- Jayne E Edwards
- Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe Hospital, The Churchill, Headington, Oxford OX3 7LJ, UK
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Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004; 364:2021-9. [PMID: 15582059 DOI: 10.1016/s0140-6736(04)17514-4] [Citation(s) in RCA: 535] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND The cyclo-oxygenase 2 inhibitor rofecoxib was recently withdrawn because of cardiovascular adverse effects. An increased risk of myocardial infarction had been observed in 2000 in the Vioxx Gastrointestinal Outcomes Research study (VIGOR), but was attributed to cardioprotection of naproxen rather than a cardiotoxic effect of rofecoxib. We used standard and cumulative random-effects meta-analyses of randomised controlled trials and observational studies to establish whether robust evidence on the adverse effects of rofecoxib was available before September, 2004. METHODS We searched bibliographic databases and relevant files of the US Food and Drug Administration. We included all randomised controlled trials in patients with chronic musculoskeletal disorders that compared rofecoxib with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo, and cohort and case-control studies of cardiovascular risk and naproxen. Myocardial infarction was the primary endpoint. FINDINGS We identified 18 randomised controlled trials and 11 observational studies. By the end of 2000 (52 myocardial infarctions, 20742 patients) the relative risk from randomised controlled trials was 2.30 (95% CI 1.22-4.33, p=0.010), and 1 year later (64 events, 21432 patients) it was 2.24 (1.24-4.02, p=0.007). There was little evidence that the relative risk differed depending on the control group (placebo, non-naproxen NSAID, or naproxen; p=0.41) or trial duration (p=0.82). In observational studies, the cardioprotective effect of naproxen was small (combined estimate 0.86 [95% CI 0.75-0.99]) and could not have explained the findings of the VIGOR trial. INTERPRETATION Our findings indicate that rofecoxib should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarise the accumulating evidence need to be clarified.
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Affiliation(s)
- Peter Jüni
- Department of Social and Preventive Medicine, University of Berne, Berne, Switzerland
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Abstract
Rofecoxib is an inhibitor of the enzyme cyclo-oxygenase 2 (COX-2) used as an analgesic and anti-inflammatory agent especially in rheumatoid arthritis and osteoarthritis. The adverse effects are generally less than with other anti-inflammatory drugs (NSAIDs), and no oral adverse reactions have been reported in the literature. We present three cases of oral lesions caused by rofecoxib. Extensive erosions appeared, which in all cases resolved on withdrawal of the drug.
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Affiliation(s)
- J V Bagán
- Valencia University, University General Hospital, Valencia, Spain.
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Abstract
PURPOSE OF REVIEW This review reports and attempts to place in some context current key observations in the literature, as they relate to peptic ulcer disease. RECENT FINDINGS Focus areas in this review are general, the usefulness of symptom-based triage in management decision making and critical review of current practice as it relates to foregut malignancy; Helicobacter pylori, important observations regarding gastric cancer prevention are presented, the role of the organism in "acid rebound" is discussed, and further evidence to support the role of H. pylori eradication in peptic ulcer disease is provided; medication, a number of studies comparing steady state and onset of action efficacy of current proton pump inhibitors at a gastric pH level are reviewed and a new agent is introduced. Problems with and strategies for the safe use of antithrombotic agents are reviewed, and exciting data with regard to a new class of nonsteroidal antiinflammatory drug are provided, now at the "proof of concept" stage. SUMMARY The review period's main "new" information relates to the nonsteroidal antiinflammatory drugs in which a number of exciting agents are being developed. Although inconclusive, the observations with regard to the effect of H. pylori eradication on gastric carcinogenesis is likely to lead to more work in this field.
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Affiliation(s)
- Japie A Louw
- Gastroenterology Division, Department of Medicine, Queen's University, Kingston, Ontario, Canada.
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Miura S, Tatsuguchi A, Wada K, Takeyama H, Shinji Y, Hiratsuka T, Futagami S, Miyake K, Gudis K, Mizokami Y, Matsuoka T, Sakamoto C. Cyclooxygenase-2-regulated vascular endothelial growth factor release in gastric fibroblasts. Am J Physiol Gastrointest Liver Physiol 2004; 287:G444-51. [PMID: 15246970 DOI: 10.1152/ajpgi.00537.2003] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
VEGF is a highly specific stimulator of endothelial cells and may play an important role in angiogenesis in the process of tissue regeneration. We previously showed that cyclooxygenase-2 (COX-2) expressed in mesenchymal cells of the ulcer bed is involved in the ulcer repair process. To clarify the role of COX-2 in angiogenesis during gastric ulcer healing, we investigated the relation between COX-2 expression and VEGF production in human gastric fibroblasts in vivo and in vitro. Gastric fibroblasts were cultured in RPMI 1640 with and without IL-1alpha or IL-1beta in the presence or absence of NS-398, a selective COX-2 inhibitor. Supernatant VEGF and PGE(2) concentrations were measured by enzyme-linked immunosorbent assay. COX-2 expression in fibroblasts was determined by Western blot analysis. VEGF and COX-2 expression in surgical resections of human gastric ulcer tissue was examined immunohistochemically. IL-1 dose dependently enhanced VEGF release in cultured gastric fibroblasts after a 24-h stimulation. IL-1 also stimulated PGE(2) production in gastric fibroblasts via COX-2 induction. NS-398 significantly suppressed VEGF and PGE(2) release from IL-1-stimulated gastric fibroblasts; concurrent addition of PGE(2) restored NS-398-inhibited VEGF release. COX-2 and VEGF immunoreactivity were colocalized in fibroblast-like cells in the ulcer bed of gastric tissues. These results suggest that COX-2 plays a key role in VEGF production in gastric fibroblasts stimulated by IL-1 in vitro and that angiogenesis induced by the COX-2-VEGF pathway might be involved in gastric ulcer healing.
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Affiliation(s)
- Shuhei Miura
- Third Dept. of Internal Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
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Kivitz AJ, Nayiager S, Schimansky T, Gimona A, Thurston HJ, Hawkey C. Reduced incidence of gastroduodenal ulcers associated with lumiracoxib compared with ibuprofen in patients with rheumatoid arthritis. Aliment Pharmacol Ther 2004; 19:1189-98. [PMID: 15153172 DOI: 10.1111/j.1365-2036.2004.01956.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Lumiracoxib (Prexige; Novartis Pharma AG, Basel, Switzerland) is a cyclooxygenase-2 selective inhibitor associated with improved gastrointestinal safety compared with nonsteroidal anti-inflammatory drugs, in patients with osteoarthritis. AIM To compare the gastroduodenal safety of lumiracoxib with ibuprofen and celecoxib in patients with rheumatoid arthritis. METHODS A total of 893 patients with rheumatoid arthritis were randomized to lumiracoxib 400 mg once daily, lumiracoxib 800 mg once daily, ibuprofen 800 mg three times daily or celecoxib 200 mg twice daily for 13 weeks, in a double-blind randomised controlled clinical trial. The primary endpoint was the cumulative incidence of gastroduodenal ulcers over 13 weeks. RESULTS The incidence of gastroduodenal ulcers >/=3 mm with lumiracoxib 400 mg once daily (2.8%) or lumiracoxib 800 mg once daily (4.3%) was significantly lower than with ibuprofen (13.6%, all P < 0.01) and not different from celecoxib (1.9%). The incidence of adverse events was similar for lumiracoxib 400, 800 mg and celecoxib (78, 75 and 77%, respectively) and higher with ibuprofen (86%). Discontinuation for adverse events was highest for ibuprofen (12.5% vs. 7.9-8.8% for the other groups). CONCLUSIONS Lumiracoxib demonstrated gastroduodenal safety superior to ibuprofen and similar to celecoxib in patients with rheumatoid arthritis.
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Affiliation(s)
- A J Kivitz
- Altoona Center for Clinical Research, Duncansville, PA, USA
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Merle V, Thiéfin G, Czernichow P. Épidémiologie des complications gastro-duodénales associées aux anti-inflammatoires non stéroïdiens. ACTA ACUST UNITED AC 2004; 28 Spec No 3:C27-36. [PMID: 15366672 DOI: 10.1016/s0399-8320(04)95276-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Nonsteroidal anti-inflammatory agents (NSAIDs) are among the most widely prescribed drugs worldwide. In France, about 25% of individuals aged 40 years or older are treated with NSAIDs at least one week in the year. Although the therapeutic benefits of these drugs are substantial, their use is limited by their gastroduodenal toxicity. Dyspepsia occurs in about 30% of patients receiving NSAIDs, an approximately two-fold enhancement of risk compared with control subjects. Asymptomatic endoscopic lesions are observed in 20 to 80% of patients, depending on population characteristics, individual NSAIDs and definitions of endoscopic lesions. The risk of symptomatic ulcer, complicated ulcer (haemorrhage, perforation, stenosis) and death related to ulcer complication is multiplied by 4 in patients treated with NSAIDs. Established risk factors for NSAID-induced gastroduodenal complications are age, ulcer history, heavy alcohol consumption, individual NSAIDs, dose, association with corticoid or aspirin or anticoagulants (ulcer haemorrhage) while the role of treatment duration and Helicobacter pylori infection are controversial.
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Affiliation(s)
- Véronique Merle
- Reseau de Recherche sur le Systeme de Soins, Université de Rouen, Département d'Epidémiologie et de Santé Publique CHU, Hôpitaux de Rouen
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Thiéfin G, Jolly D. Impact de l’infection à Helicobacter pylori sur le risque de complications gastro-duodénales des traitements anti-inflammatoires non stéroïdiens. ACTA ACUST UNITED AC 2004; 28 Spec No 3:C45-57. [PMID: 15366674 DOI: 10.1016/s0399-8320(04)95278-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
The interaction of Helicobacter pylori (H. pylori) and non steroidal anti-inflammatory drugs (NSAIDs) on the development of gastro-duodenal ulcers and their complications is complex and controversial. From a clinical point of view, the question is whether or not H. pylori infection should be tested and eradicated in patients treated or about to be treated by NSAIDs or low-dose aspirin. Contradictory results have been reported in epidemiological studies. Recent data suggest that H. pylori-NSAID interaction may be different depending on the type of treatment, non aspirin NSAIDs or low-dose aspirin, the gastric or duodenal localization of ulcer and the strains of H. pylori. Controlled randomized studies suggest that eradication of H. pylori may be beneficial in NSAID-naïve patients but not in those already on long term NSAID therapy. Recommendations are proposed for different subgroups of patients. In NSAID users presenting with gastro-duodenal ulcer or complications, H. pylori screening and eradication are indicated. In patients treated or about to be treated by NSAIDs, the "test and treat" H. pylori strategy is recommended if there is a history of gastroduodenal ulcer or complications. Whether this strategy should be generalized preventively in patients without ulcer history is still controversial and deserves further studies.
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Affiliation(s)
- Gérard Thiéfin
- Service d'Hépato-Gastroentérologie, CHU Robert-Debré, rue Général-Koenig, 51092 Reims Cedex.
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Yuan Y, Hunt RH. Assessment of the safety of selective cyclo-oxygenase-2 inhibitors: where are we in 2003? Inflammopharmacology 2003; 11:337-54. [PMID: 15035788 DOI: 10.1163/156856003322699528] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide despite their well-documented adverse gastrointestinal (GI) effects. The risk of developing a severe GI event varies from patient to patient and NSAID to NSAID. Selective cyclo-oxygenase-2 inhibitors (coxibs) have been designed to have similar efficacy but less GI toxicity than traditional NSAIDs, and have been shown to have an improved GI tolerability and less adverse events across a range of different GI safety assessments. In clinical trials, particularly VIGOR and CLASS, rofecoxib and celecoxib, respectively, significantly reduce the risk of ulcers and ulcer complications than nonselective NSAID comparators with ulcer rates comparable to placebo. The real benefit of a coxib comes from the sparing of the thromboxane and hence preservation of normal platelet function. Thus, there is less risk of bleeding with selective inhibition of COX-2, which is the most common and serious complication of non-selective NSAIDs. Moreover, bleeding can occur anywhere in the GI tract. Although some concern has been raised about the cardiovascular safety of coxibs, when used in recommended doses, there is no convincing evidence that patients treated with a coxib have an increased risk of cardiovascular thrombotic events. Different approaches have been advocated to minimize NSAID-related GI toxicity. Choice of less harmful NSAIDs such as coxib has been one of the strategies promoted in guidelines. The introduction of coxibs with a higher benefit-risk ratio has dramatically changed the therapeutic scenario for anti-inflammatory treatment in the clinical practice.
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Affiliation(s)
- Yuhong Yuan
- Division of Gastroenterology, Room 4W8A, Department of Medicine, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada
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Abstract
Recent experimental studies may undermine our understanding of the gastrointestinal side effects of non-steroidal anti-inflammatory drugs and cast a shadow on the original concept that underpins the development of the recent addition to the clinical anti-inflammatory armamentarium, the COX-2 selective inhibitors. But is this just a passing cloud or a total eclipse of the COX theory?
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Affiliation(s)
- B J R Whittle
- William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine, Charterhouse Square, London EC1M 6BQ, UK.
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