A systematic review of case-control and cohort studies regarding the risk of selective and non-selective COX-2 inhibitors was recently published in the JAMA. The analysis has confirmed the findings of numerous randomised control trials regarding the cardiovascular risk associated with the use of rofecoxib. Other findings included that both randomised and non randomised evidence seems to point to diclofenac increasing the risk of cardiovascular events. Celebrex (celecoxib) however, did not appear to be associated with increased risk when used at doses around 200mg/day, but there was possible risk with higher doses. Use of ibuprofen also appeared to have little effect on cardiovascular events.
Following the removal of rofecoxib from world markets in October 2004, there has been increasing interest in the cardiovascular effects of other, selective as well as non-selective, cyclooxygenase 2 (COX-2) inhibitors. A recent article, authored by Patricia McGettigan and David Henry and published in the JAMA, systematically reviewed numerous case-control and cohort design studies that looked at the cardiovascular events associated not only with the more recent agents such as Vioxx (rofecoxib) and Celebrex (celecoxib), but also with some older and more easily available agents including diclofenac and ibuprofen.Data was obtained through a search of the electronic databases including MEDLINE, EMBASE and Cochrane Library, using search terms such individual drug names, therapeutic class as well as cardiovascular and cerebrovascular outcome terms among many others. Each study was assessed in terms of selection criteria for both cases and controls, as well as the adequacy of expose to the agent of interest.The majority of studies used information collected from large electronic databases or electronic medical records and used drug dispensation as an indication of consumption. Disadvantages of this system included the lack of information regarding the use of non-prescription medications, alcohol and tobacco as well as possible misclassification of clinical outcomes and comorbid states.Of 7086 articles returned on initial search, 233 articles were selected for further evaluation, and after application of inclusion criteria, 23 studies were eligible for inclusion. In total, this amounted to case-control analyses of 86,193 cardiovascular events (usually myocardial infarction or sudden cardiovascular death) and at least 628,000 controls.The case-control and cohort studies combined risk estimates were as follows:
- All Rofecoxib: 1.35 (1.15-1.59)
- Rofecoxib ≤ 25 mg/d: 1.33 (1.00-1.79)
- Rofecoxib > 25 mg/d: 2.19 (1.64-2.91)
- All Celecoxib: 1.06 (0.91-1.23)
- Meloxicam: 1.25 (1.00-1.55)
- Naproxen: 0.97 (0.87-1.07)
- Diclofenac: 1.40 (1.16-1.70)
- Ibuprofen: 1.07 (0.97-1.18)
- Indomethacin: 1.30 (1.07-1.60)
- Any/Other NSAID: 1.10 (1.00-1.21)
- Piroxicam:1.06 (0.70-1.59)
When compared with any nonselective NSAID, the relative risk for rofecoxib was 1.21 (1.13-1.29) and for celecoxib was 0.95 (0.85-1.05). An early risk was especially evident with use of rofecoxib, with higher risk in the first 30 days of treatment. This was not seen with celecoxib and in a comparison of the use between the two agents, the risk ratio for acute myocardial infarction with first time use of rofecoxib was 1.43 (1.12-1.83).Data on aspirin use, and whether it was cardioprotective when used in conjunction with rofecoxib or other risk-inducing drugs, was insufficient to provide an adequate analysis; however there was no evidence that ibuprofen had any interaction with low-dose aspirin, as had been previously suggested.In comment, the authors noted that their data confirmed the elevated risk with rofecoxib and that it is dose related. They also assert that while doses of 200mg/d of celecoxib were not associated with increased risk, the data did not exclude an increased risk with higher doses. Naproxen was not associated with any cardioprotection, the removal of which had previously been suggested as a mechanism for the increased cardiovascular events associated with rofecoxib.Of the other nonselective NSAIDs, diclofenac was seen to have the highest risk and, unlike celecoxib, appears to be harmful at commonly used dosages. The authors conclude that this is grounds for diclofenac to have its regulatory status reviewed.
- McGettigan P, Henry D. A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2. JAMA. 2006;296(13):1633-44.