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BMJ. Jun 12, 2004; 328(7453): 1415–1416.
PMCID: PMC421783

Gastrointestinal bleeding after the introduction of COX 2 inhibitors: ecological study

Muhammad Mamdani, senior scientist,1 David N Juurlink, clinical pharmacologist,2 Alex Kopp, analyst,1 Gary Naglie, Mary Trimmer chair in geriatric medicine research,3 Peter C Austin, scientist,1 and Andreas Laupacis, chief executive officer1

Recent evidence suggests a lower risk of upper gastrointestinal haemorrhage for selective cyclo-oxygenase-2 (COX 2) inhibitors compared with non-selective non-steroidal anti-inflammatory drugs (NSAIDs) at the patient level,1-3 although COX 2 inhibitors are likely not devoid of gastrointestinal toxicity. At the population level, however, the widespread proliferation of COX 2 inhibitors might lead to an increase in the overall numbers of people exposed to anti-inflammatory drugs with uncertain implications on rates of population-wide gastrointestinal events. We did an ecological study to examine temporal changes in the use of NSAIDs and upper gastrointestinal haemorrhage hospitalisation rates among a population of older individuals after the introduction of COX 2 inhibitors.

Participants, methods, and results

We did a population based cross sectional time series analysis using administrative healthcare databases covering more than 1.3 million residents of Ontario, Canada, aged at least 66 years.4 This population has universal access to hospital care, doctors' services, and prescription drugs on a formulary. The study's timeframe was divided into 15 intervals of six months from 1 September 1994 to 28 February 2002. Rofecoxib and celecoxib were introduced on the provincial drug formulary in April 2000 and meloxicam was introduced in March 2001. The prevalence of use of NSAIDs in each interval was determined by dividing the unique number of individuals dispensed any NSAID (either non-selective NSAIDs or COX 2 inhibitors) by the total number of individuals alive at the beginning of the interval. Similarly, we examined hospitalisation rates for upper gastrointestinal haemorrhage. As secondary endpoints, we examined hospitalisations for myocardial infarction and heart failure. We standardised all rates for age and sex. As supplementary analyses, we also examined changes in the use of gastroprotective agents, oral corticosteroids, prescription aspirin, and warfarin, since these factors may be strongly related to upper gastrointestinal haemorrhage. We used time series analysis involving autoregressive integrated moving average models to evaluate changes over time with the package SAS 8.2 (SAS, Cary, NC).5

The prevalence of use of NSAIDs among Ontario's population of older people increased from 14.0% just before the introduction of COX 2 inhibitors to 19.8% by the end of the observation period (figure; P < 0.01), representing an absolute increase of more than 90 000 additional individuals annually using NSAIDs, entirely attributable to the use of COX 2 inhibitors rather than switching from non-selective NSAIDs to COX 2 inhibitors. The rate of hospitalisation for upper gastrointestinal haemorrhage was decreasing before the introduction of COX 2 inhibitors, but increased from about 15.4 to 17.0 per 10 000 older persons after their introduction (figure; P < 0.01), representing an absolute increase of more than 650 upper gastrointestinal haemorrhage hospitalisations annually. Other than a small but statistically significant increase in the prevalence of gastroprotective agent use, we saw no significant differences in the use of drugs that might affect upper gastrointestinal risk over expected projections. Also, we saw no significant differences in hospitalisation rates for myocardial infarction or heart failure greater than expected projections.

Figure 1
Age and sex standardised prevalence of the use of NSAIDs and hospitalisation rates for upper gastrointestinal haemorrhage over time among elderly people in Ontario


In this population based study a 41% rise in NSAID use, entirely due to increased use of COX 2 inhibitors, was accompanied by a 10% increase in hospitalisation rates for upper gastrointestinal haemorrhage. Although we cannot prove causation, we believe that the striking temporal correlation, biological plausibility, and lack of any other trends that would explain the association strongly suggest that the two events are directly related. Coding practices for hospital admissions for upper gastrointestinal haemorrhage period did not change significantly during our study. However, we could not evaluate whether the potential improvement in population level pain relief offsets the increase in hospitalisations for upper gastrointestinal haemorrhage.

The findings of this study suggest that even if a new drug is associated with lower side effects than previous drugs in its class at the patient level, a marked increase in its use can be associated with an apparently paradoxical adverse impact on the population.


Contributors: MM, DNJ, GN, PCA, and AL designed the study; MM, DNJ, PCA, and AK did the study. GN, PCA, and AL advised and supervised. PCA gave statistical advice. MM is guarantor. Funding: MM is supported by a New Investigator award from the New Emerging Teams of the Canadian Institutes of Health Research (CIHR). DNJ is supported by a New Investigator award from the CIHR and by the University of Toronto Drug Safety Research Group. GN is supported by the Mary Trimmer Chair in Geriatric Medicine Research at the University of Toronto. AL is a senior scientist of the CIHR. This study was supported by a CIHR operating grant (MOP-49527) and a CIHR Chronic Disease New Emerging Team programme grant (NET-54010). The NET programme receives joint sponsorship from the Canadian Diabetes Association, the Kidney Foundation of Canada, the Heart and Stroke Foundation of Canada, and the CIHR Institutes of Nutrition, Metabolism and Diabetes and Circulatory and Respiratory Health.

Competing interests: MM has done research in an unrelated content area upon the request of an academic institution whose funding was supported by Pharmacia in the past three years, but none of the funding for this study was provided by any pharmaceutical company.

Ethical approval: Sunnybrook and Women's College Health Sciences Centre Ethics Review Board.

This article was posted on bmj.com on 11 May 2004: http://bmj.com/cgi/doi/10.1136/bmj.38068.716262.F7


1. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343: 1520-8. [PubMed]
2. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs non-steroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib long-term arthritis safety study. JAMA 2000;284: 1247-55. [PubMed]
3. Mamdani M, Rochon PA, Juurlink DN, Kopp A, Anderson GM, Naglie G, et al. Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ 2002;325: 624. [PMC free article] [PubMed]
4. Williams JI, Young W. A summary of studies on the quality of health care administrative databases in Canada. In: Goel V, Williams JI, Anderson GM, Blackstein-Hirsh P, Fooks C, Naylor CD, eds. Patterns of health care in Ontario: the ICES practice atlas. 2nd ed. Ottawa: Canadian Medical Association, 1996: 339-45.
5. Pindyck RS, Rubinfeld DL. Econometric models and economic forecasts. 4th ed. New York: Irwin McGraw-Hill, 1998: ch 15.

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