Temporal Relationship between Use of NSAIDs, Including Selective COX-2 Inhibitors, and Cardiovascular Risk

Background and Objective: The search for NSAIDs with less gastrointestinal toxicity led to the introduction of the selective cyclo-oxygenase-2 (COX-2) inhibitors. However, following their introduction into the market, concerns have developed regarding their safety, particularly their cardiovascular safety. The purpose of this study was to assess the cardiovascular risk (events included were myocardial infarction, stroke and myocardial infarction-related deaths) associated with long-term (>180 days of exposure) and short-term (≤180 days of exposure) use of non-selective NSAIDs, including ‘preferential COX-2 inhibitors’ (i.e. etodolac, nabumetone and salsalate), and selective COX-2 inhibitors.

Methods: A retrospective analysis of the Veterans Integrated Service Network 17 Veterans Affairs (VA) database was conducted. Medicare data and Texas Department of Health mortality data were incorporated to capture events occurring outside the VA healthcare network. Patients ≥35 years of age who received celecoxib, rofecoxib, ibuprofen, etodolac and naproxen from 1 January 1999 through 31 December 2001, were included. Multivariate Cox proportional hazard models were used to analyse the relationship between cardiovascular risk and NSAID use, including selective COX-2 inhibitor use, while adjusting for various risk factors.

Results: We identified 12 188 exposure periods (11 930 persons) and 146 cardiovascular events over the entire study period. Compared with long-term ibuprofen use, long-term use of celecoxib (adjusted hazard ratio [HR] 3.64; 95% CI 1.36, 9.70) and rofecoxib (adjusted HR 6.64; 95% CI 2.17, 20.28) was associated with a significant increase in cardiovascular risk. When restricted to patients ≥65 years of age, the cardiovascular risks associated with long-term celecoxib (adjusted HR 7.36; 95% CI 1.62, 33.48) and rofecoxib (adjusted HR 13.24; 95% CI 2.59, 67.68) use increased. Short-term use of celecoxib (adjusted HR 0.75; 95% CI 0.42, 1.35) and rofecoxib (adjusted HR 0.85; 95% CI 0.39, 1.86) was not associated with any significant change in cardiovascular risk when compared with short-term ibuprofen use. Neither long- nor short-term exposure to naproxen and etodolac was associated with cardionegative or cardioprotective effects when compared with ibuprofen use.

Conclusions: The findings of this observational study, along with recent clinical trial results, suggest that prolonged exposure to selective COX-2 inhibitors may be associated with an increased risk of adverse cardiovascular outcomes.