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The balance between severe cardiovascular and gastrointestinal events among users of selective and non-selective non-steroidal anti-inflammatory drugs
  1. M W van der Linden1,
  2. S van der Bij1,
  3. P Welsing2,
  4. E J Kuipers3,4,
  5. R M C Herings1,5
  1. 1
    PHARMO Institute for Drug Outcomes Research, Utrecht, The Netherlands
  2. 2
    Pfizer BV, Capelle aan den Ijssel, The Netherlands
  3. 3
    Department of Gastroenterology & Hepatology, Erasmus MC, Rotterdam, The Netherlands
  4. 4
    Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
  5. 5
    Department of Health Policy & Management, Erasmus Medical Centre, Rotterdam, The Netherlands
  1. M W van der Linden, PHARMO Institute, Papendorpseweg 65, 3528 BJ Utrecht, PO Box 85222, 3508 AE Utrecht, The Netherlands; michiel.van.der.linden{at}


Objective: To simultaneously assess cardiovascular (CV) and gastrointestinal (GI) risk with traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and cyclo-oxygenase 2 (COX-2) inhibitors.

Methods: Using the PHARMO Record Linkage System, including drug-dispensing and hospitalisation data of >2 million residents of The Netherlands, subjects with first hospitalisation for acute myocardial infarction (AMI), CV and GI events were identified. Use of COX-2 inhibitors and traditional non-selective NSAIDs was classified into remote, recent and current. Cases were matched to controls in a 1:4 ratio on age and event date. Multivariate analyses adjusted for gender, history of hospitalisations and medications.

Results: Compared to remote use, AMI risk was increased among current users of COX-2 inhibitors combined (adjusted odds ratio (OR) 1.73, 95% CI 1.37 to 2.19) and tNSAIDs combined (OR 1.41, 95% CI 1.23 to 1.61). AMI risk with celecoxib (OR 2.53, 95% CI 1.53 to 4.18), rofecoxib (OR 1.60, 95% CI 1.22 to 2.10), ibuprofen (OR 1.56, 95% CI 1.19 to 2.05) and diclofenac (OR 1.51, 95% CI 1.22 to 1.87) was significantly increased. CV risk with current use of individual COX-2 inhibitors and tNSAIDs was significantly increased (OR from 1.17 to 1.64), as was GI risk with current use of rofecoxib (OR 1.99, 95% CI 1.51 to 2.63), naproxen (OR 4.44, 95% CI 3.36 to 5.86), ibuprofen (OR 1.90, 95% CI 1.40 to 2.58), diclofenac (OR 4.77, 95% CI 3.94 to 5.76), other tNSAIDs (OR 2.59, 95% CI 2.08 to 3.21), but not celecoxib (OR 1.36, 95% CI 0.70 to 2.66). Compared to current use of celecoxib and AMI risk was significantly decreased with current use of naproxen (OR 0.48, 95% CI 0.26 to 0.87) only. GI risk was increased with current naproxen (OR 3.26, 95% CI 1.59 to 6.70) and diclofenac (OR 3.50, 95% CI 1.76 to 6.98).

Conclusions: AMI and CV risk increased similarly with individual COX-2 inhibitors and tNSAIDs, whereas GI risk was found to be greater with naproxen and diclofenac. Residual confounding and “channelling” cannot be excluded.

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  • Competing interests: None declared.

  • Funding: This study was supported by Pfizer BV, Capelle a/d Ijssel, The Netherlands. The sponsor assisted in the interpretation of the data and writing of the report but was not involved in the study design, nor in the collection, analysis of data or in the decision to submit the paper for publication.

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