Intended for healthcare professionals

Primary Care

Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis

BMJ 2005; 331 doi: (Published 01 December 2005) Cite this as: BMJ 2005;331:1310
  1. Julia Hippisley-Cox (julia.hippisley-cox{at}, professor of clinical epidemiology and general practice1,
  2. Carol Coupland, senior lecturer in medical statistics1,
  3. Richard Logan, professor of clinical epidemiology2
  1. 1Division of Primary Care, University of Nottingham, Nottingham NG2 7RD
  2. 2Division of Epidemiology and Public Health, University of Nottingham
  1. Correspondence to: J Hippisley-Cox
  • Accepted 21 October 2005


Objective To determine the risk of an adverse upper gastrointestinal event in patients taking different cyclo-oxygenase-2 inhibitors compared with non-selective non-steroidal anti-inflammatory drugs.

Design Nested case-control study.

Setting 367 general practices contributing to the UK QRESEARCH database, spread throughout every strategic health authority and each health board in England, Wales, and Scotland.

Participants Patients aged 25 or more with a first ever diagnosis of an adverse upper gastrointestinal event (peptic ulcer or haematemesis) between 1 August 2000 and 31 July 2004 and up to 10 controls per case matched for age, sex, calendar time, and practice.

Main outcome measures Unadjusted and adjusted odds ratios for adverse upper gastrointestinal events associated with celecoxib, rofecoxib, ibuprofen, diclofenac, naproxen, other selective and non-selective non-steroidal anti-inflammatory drugs, and aspirin.

Results The incidence of adverse upper gastrointestinal events was 1.36 per 1000 person years (95% confidence interval 1.34 to 1.39). We identified 9407 incident cases and 88 867 matched controls. Increased risks of adverse gastrointestinal events were associated with current use of cyclo-oxygenase-2 inhibitors and with conventional non-steroidal anti-inflammatory drugs. Risks were reduced after adjustment for confounders but remained significantly increased for naproxen (adjusted odds ratio 2.12, 95% confidence interval 1.73 to 2.58), diclofenac (1.96, 1.78 to 2.15), and rofecoxib (1.56, 1.30 to 1.87) but not for current use of celecoxib (1.11, 0.87 to 1.41). We found clinically important interactions with current use of ulcer healing drugs that removed the increased risks for adverse gastrointestinal events for all groups of non-steroidal anti-inflammatory drugs except diclofenac, which still had an increased odds ratio (1.49, 1.26 to 1.76).

Conclusion No consistent evidence was found of enhanced safety against gastrointestinal events with any of the new cyclo-oxygenase-2 inhibitors compared with non-selective non-steroidal anti-inflammatory drugs. The use of ulcer healing drugs reduced the increased risk of adverse gastrointestinal outcomes with all groups of non-steroidal anti-inflammatory drugs, but for diclofenac the increased risk remained significant.


  • Contributors JHC initiated and designed the study, obtained ethical approval, undertook the data extraction and manipulation, undertook the analysis, and drafted the paper. CC contributed to the study design; undertook, supervised, and checked the analysis; advised on interpretation; and contributed to drafting the paper. RL advised on analysis and interpretation and contributed to drafting the paper. JHC is the guarantor.

  • Funding None.

  • Competing interests RL has been employed on a consultancy basis at various times by Astra Zeneca; Merck, Proctor and Gamble; and Roche.

  • Ethical approval Trent multicentre research ethics committee.

  • Accepted 21 October 2005
View Full Text