Rofecoxib, diclofenac and indomethacin increase risk of CVD

Clinical Question

Which NSAIDs increase the risk of cardiovascular disease (CVD)?

Bottom Line

Rofecoxib (Vioxx), diclofenac (Voltaren, Cataflam), and indomethacin (Indocin) are associated with a significant increased risk of CVD. It is likely that all NSAIDs carry some risk, but the risks may vary between medicines. Current evidence does not point to an increased risk for low dose (over the counter) ibuprofen and this remains safe to use at recommended doses. (LOE = 2a-)


McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase. A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006;296:1633-44.  [PMID:16968831]

Study Design

Systematic review




Various (meta-analysis)


Recent evidence that rofecoxib (Vioxx) increases the risk of CVD has raised concern about other nonsteroidal anti-inflammatory drugs (NSAIDs). These investigators searched multiple databases including MEDLINE, EMBASE, the Cochrane Library, abstracts of scientific meetings and bibliographies of relevant studies for reports on cardiovascular events and NSAID use. Of 7086 potentially eligible titles, 17 case-control including 86,193 cases and 6 cohort studies including 75, 520 users met study criteria. Most exclusions were a result of reports not providing sufficient information on study outcomes or the drugs of interest. The mean age of study participants was rarely less than 55 years, and in most cases was grater than 60 years. Two individuals independently extracted data and assessed study quality with disagreements resolved by consensus. Individual studies underwent assessment using a standardized instrument. All studies scored well (7-8 points in total from a possible 9). As expected, rofecoxib use significantly increased the risk of CVD, with risk being highest with doses in excess of 25 mg/day. Diclofenac (Voltaren, Cataflam) and indomethacin (Indocin) were also associated with a significantly increased risk of CVD. Data on meloxicam (Mobic) came from 3 trials, only one of which showed a statistically significant elevated risk. Authors of the article state that these data do not allow definite conclusions about the risk of meloxicam. Celecoxib (Celebrex), naproxen, piroxicam and inbuprofen exposure did not increase CVD risk. Stay tuned, however, as more studies are forthcoming shortly. In a related study in the same journal (Zhang J, Ding E, Song Y. JAMA;296:1619-32), only rofecoxib was associated with a significant increased risk of renal events and heart arrhythmia. Celecoxib (Celebrex) was significantly associated with a reduced risk of renal dysfunction.