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A Comparison of Reported Gastrointestinal and Thromboembolic Events Between Rofecoxib and Celecoxib Using Observational Data

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Abstract

Background and objectives: Rofecoxib, a selective cyclo-oxygenase (COX)-2 inhibitor, was a widely marketed drug that was used for relief of pain and inflammation in arthritic conditions. It was withdrawn from the market worldwide in September 2004 because of an increased risk of cardiovascular events. Celecoxib, which belongs to the same class of drugs, is now under scrutiny for the risk of similar events. The objective of our study was to compare the incidence of gastrointestinal (GI) [symptomatic and complicated upper GI] events and thromboembolic (cardiovascular, cerebrovascular and peripheral venous) events reported for patients prescribed rofecoxib or celecoxib in primary care.

Methods: A retrospective analysis of selected events was conducted using data collected from previously conducted prescription-event monitoring (PEM) studies for rofecoxib and celecoxib. PEM is an observational cohort technique. Exposure data were derived from dispensed prescriptions for rofecoxib (July–November 1999) and celecoxib (May–December 2000) that were written by primary care general practitioners in England. Outcome data were clinical events and information on potential risk factors reported on simple questionnaires (posted to prescribers approximately 9 months after the date of the first prescription). Incidence rates of the first event during treatment within each thromboembolic and GI group were calculated during the 270 days after the patient started receiving either of the drugs; crude and adjusted rate ratios (RR) were calculated for rofecoxib compared with celecoxib using Poisson regression modelling.

Results: The rofecoxib and celecoxib PEM cohorts contained 15 268 and 17 458 patients, respectively. For the GI event groups, the adjusted RRs for rofecoxib compared with celecoxib were: 1.21 (95% CI 1.09, 1.36) for symptomatic upper GI events and 1.60 (95% CI 0.95, 2.70) for complicated upper GI conditions. For the thromboembolic event groups, the adjusted RRs were: 1.04 (95% CI 0.50, 2.17) for cardiovascular thromboembolic events; 1.43 (95% CI 0.86, 2.38) for cerebrovascular thromboembolic events; and 0.36 (95% CI 0.01, 1.34) for peripheral venous thromboembolic events.

Conclusions: This study was a retrospective comparison of PEM studies conducted for rofecoxib and celecoxib. For symptomatic upper GI events, a 21% increase in the relative rate was found for rofecoxib users compared with celecoxib users after adjusting for identified risk factors. For complicated upper GI events, no statistically significant difference in the incidence was observed between rofecoxib and celecoxib users after adjusting for identified risk factors. For the three thromboembolic event groups, no evidence of a statistically significant difference between rofecoxib and celecoxib users was found after adjusting for identified risk factors.

This study contributes to the understanding of the association between COX-2 inhibitors and thromboembolic events. However, it should be borne in mind that we had information on only a limited number of confounding variables for thromboembolic events. Further research is required to fully understand the risks and benefits of using celecoxib and other COX-2 inhibitors. Meanwhile, doctors should be cautious when prescribing these products, particularly to patients with risk factors for developing thromboembolic events.

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References

  1. Langman MJ, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994 Apr 30; 343(8905): 1075–8

    Article  PubMed  CAS  Google Scholar 

  2. Hawkey CJ. COX-2 inhibitors. Lancet 1999 Jan 23; 353(9149): 307–14

    Article  PubMed  CAS  Google Scholar 

  3. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001 Aug 9; 345(6): 433–42

    Article  PubMed  CAS  Google Scholar 

  4. FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004 Oct 21; 351(17): 1709–11

    Article  PubMed  CAS  Google Scholar 

  5. Maxwell SR, Webb DJ. COX-2 selective inhibitors: important lessons learned. Lancet 2005 Feb 5; 365(9458): 449–51

    PubMed  Google Scholar 

  6. US FDA. FDA Issues Public Health Advisory on Vioxx as its Manufacturer Voluntarily Withdraws the Product, 2004 Sep 30 [online]. Available from URL: http://www.fda.gov/bbs/topics/news/2004/NEW01122.html [Accessed 2005 Feb 2]

  7. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000 Nov 23; 343(21): 1520–8

    Article  PubMed  CAS  Google Scholar 

  8. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005 Feb 5; 365(9458): 475–81

    PubMed  CAS  Google Scholar 

  9. Ray WA, Stein CM, Daugherty JR, et al. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002 Oct 5; 360(9339): 1071–3

    Article  PubMed  CAS  Google Scholar 

  10. Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004 May 4; 109(17): 2068–73

    Article  PubMed  CAS  Google Scholar 

  11. Kimmel SE, Berlin JA, Reilly M, et al. Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. Ann Intern Med 2005 Feb 1; 142(3): 157–64

    PubMed  CAS  Google Scholar 

  12. Levesque LE, Brophy JM, Zhang B. The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med 2005 Apr 5; 142(7): 481–9

    PubMed  CAS  Google Scholar 

  13. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005 Mar 17; 352(11): 1092–102

    Article  PubMed  CAS  Google Scholar 

  14. Juni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004 Dec 4; 364(9450): 2021–9

    Article  PubMed  CAS  Google Scholar 

  15. White WB, Faich G, Whelton A, et al. Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol 2002 Feb 15; 89(4): 425–30

    Article  PubMed  CAS  Google Scholar 

  16. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005 Mar 17; 352(11): 1071–80

    Article  PubMed  CAS  Google Scholar 

  17. Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005 Mar 17; 352(11): 1081–91

    Article  PubMed  CAS  Google Scholar 

  18. Shakir SA. PEM in the UK. In: Mann RD, Andrews E, editors. Pharmacovigilance. 1st ed. Chichester (UK): John Wiley & Sons Ltd, 2002: 333–44

    Chapter  Google Scholar 

  19. Layton D, Riley J, Wilton LW, et al. Safety profile of rofecoxib as used in general practice in England: results of a prescription-event monitoring study. Br J Clin Pharmacol 2002; 55: 166–74

    Article  Google Scholar 

  20. Layton D, Wilton LV, Shakir SA. Safety profile of celecoxib as used in general practice in England: results of a prescription-event monitoring study. Eur J Clin Pharmacol 2004 Sep; 60(7): 489–501

    Article  PubMed  CAS  Google Scholar 

  21. Sweetman SC, editor. Martindale. 33rd ed. London: Pharmaceutical Press, 2002

    Google Scholar 

  22. Layton D, Heeley E, Hughes K, et al. Comparison of the incidence rates of selected gastrointestinal events reported for patients prescribed rofecoxib and meloxicam in general practice in England using prescription-event monitoring (PEM) data. Rheumatology (Oxford) 2003 May; 42(5): 622–31

    Article  CAS  Google Scholar 

  23. Laporte JR, Ibanez L, Vidal X, et al. Upper gastrointestinal bleeding associated with the use of NSAIDs: newer versus older agents. Drug Saf 2004; 27(6): 411–20

    Article  PubMed  CAS  Google Scholar 

  24. Altman R, Luciardi HL, Muntaner J, et al. The antithrombotic profile of aspirin: aspirin resistance, or simply failure? Thromb J 2004 Jan 14; 2(1): 1

    Article  PubMed  Google Scholar 

  25. Layton D, Heeley E, Hughes K, et al. Comparison of the incidence rates of thromboembolic events reported for patients prescribed rofecoxib and meloxicam in general practice in England using prescription-event monitoring (PEM) data. Rheumatology (Oxford) 2003 Nov; 42(11): 1342–53

    Article  CAS  Google Scholar 

  26. Layton D, Hughes K, Harris S, et al. Comparison of the incidence rates of selected gastrointestinal events reported for patients prescribed celecoxib and meloxicam in general practice in England using prescription-event monitoring (PEM) data. Rheumatology (Oxford) 2003 Nov; 42(11): 1332–41

    Article  CAS  Google Scholar 

  27. Layton D, Hughes K, Harris S, et al. Comparison of the incidence rates of thromboembolic events reported for patients prescribed celecoxib and meloxicam in general practice in England using prescription-event monitoring (PEM) data. Rheumatology (Oxford) 2003 Nov; 42(11): 1354–64

    Article  CAS  Google Scholar 

  28. Mamdani M, Rochon PA, Juurlink DN, et al. Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ 2002 Sep 21; 325(7365): 624–7

    Article  PubMed  CAS  Google Scholar 

  29. Norgard B, Pedersen L, Johnsen SP, et al. COX-2-selective inhibitors and the risk of upper gastrointestinal bleeding in high-risk patients with previous gastrointestinal diseases: a population-based case-control study. Aliment Pharmacol Ther 2004 Apr 1; 19(7): 817–25

    Article  PubMed  CAS  Google Scholar 

  30. Battistella M, Mamdami MM, Juurlink DN, et al. Risk of upper gastrointestinal hemorrhage in warfarin users treated with non-selective NSAIDs or COX-2 inhibitors. Arch Intern Med 2005 Jan 24; 165(2): 189–92

    Article  PubMed  CAS  Google Scholar 

  31. Wolfe F, Anderson J, Burke TA, et al. Gastroprotective therapy and risk of gastrointestinal ulcers: risk reduction by COX-2 therapy. J Rheumatol 2002 Mar; 29(3): 467–73

    PubMed  CAS  Google Scholar 

  32. McAdam BF, Catella-Lawson F, Mardini IA, et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A 1999 Jan 5; 96(1): 272–7

    Article  PubMed  CAS  Google Scholar 

  33. Clark DW, Layton D, Shakir SAW. Do some inhibitors of cyclooxygenase-2 (COX-2) increase the risk of thromboembolic events? Linking pharmacology with pharmacoepidemiology. Drug Saf 2004; 27(2): 427–56

    Article  PubMed  CAS  Google Scholar 

  34. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001 Aug 22; 286(8): 954–9

    Article  PubMed  CAS  Google Scholar 

  35. Harrison-Woolrych M, Herbison P, McLean R. Incidence of thrombotic cardiovascular events in patients taking celecoxib compared with those taking rofecoxib: interim results from the New Zealand Intensive Medicines Monitoring Programme. Drug Saf 2005; 28(5): 435–42

    Article  PubMed  CAS  Google Scholar 

  36. Chenevard R, Hurlimann D, Bechir M, et al. Selective COX-2 inhibition improves endothelial function in coronary artery disease. Circulation 2003 Jan 28; 107(3): 405–9

    Article  PubMed  Google Scholar 

  37. Widlansky ME, Price DT, Gokce N, et al. Short- and long-term COX-2 inhibition reverses endothelial dysfunction in patients with hypertension. Hypertension 2003 Sep; 42(3): 310–5

    Article  PubMed  CAS  Google Scholar 

  38. US FDA. FDA Public Health Advisory. FDA announces important changes and additional warnings for COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs), 2005 Apr 7 [online]. Available from URL: http://www.fda.gov/cder/drug/advisory/COX2.htm [Accessed 2005 Apr 15]

  39. European Medicines Agency. European Medicines Agency statement on the suspension of use of Bextra, 2005 Apr 7 [online]. Available from URL: http://www.emea.eu.int/pdfs/human/press/pus/12163705en.pdf [Accessed 2005 Jul 21]

  40. Medsafe. Press releases. Stringent conditions for COX-2 inhibitors, 2005 Apr 29 [online]. Available from URL: http://www.medsafe.govt.nz/search.htm [Accessed 2005 Jul 21]

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Acknowledgements

The Drug Safety Research Unit (DSRU) is an independent charity that works in association with the University of Portsmouth. It receives unconditional donations from pharmaceutical companies and has received such funds from the manufacturers of rofecoxib and celecoxib. The companies have no control on the conduct or the publication of the studies conducted by the DSRU. Professor Shakir has received lecturing fees from Pfizer. Dr Wilton and Professor Shakir have received support to attend scientific meetings from Pfizer. Dr Kasliwal, Ms Layton and Mr Harris have no conflicts of interest that are directly relevant to the content of this study.

We are grateful to the general practitioners in England, the Prescription Pricing Authority and the health authorities of England for their important participation in the prescription-event monitoring studies for rofecoxib and celecoxib. We also thank Dr Ruth Pickering for her guidance in statistical analysis, Mr Shayne Freemantle for data management and Dr Patrick Waller for commenting on this manuscript.

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Authors and Affiliations

  1. Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, SO31 1AA, UK

    Rachna Kasliwal, Deborah Layton, Lynda Wilton & Saad AW Shakir

  2. University of Portsmouth, Portsmouth, UK

    Deborah Layton, Lynda Wilton & Saad AW Shakir

  3. University of Southampton, Southampton, UK

    Scott Harris

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  1. Rachna Kasliwal
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  2. Deborah Layton
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  5. Saad AW Shakir
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Correspondence to Rachna Kasliwal.

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Kasliwal, R., Layton, D., Harris, S. et al. A Comparison of Reported Gastrointestinal and Thromboembolic Events Between Rofecoxib and Celecoxib Using Observational Data. Drug-Safety 28, 803–816 (2005). https://doi.org/10.2165/00002018-200528090-00005

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