Diclofenac linked to increased cardiovascular risks

Diclofenac and rofecoxib were associated with increased cardiovascular mortality and morbidity and should be used with caution in most individuals, whereas naproxen may have a safer cardiovascular risk profile, Danish researchers concluded.

The researchers used their country's nationwide administrative registers to identify more than 1 million people (mean age, 39 years) who were receiving a nonsteroidal anti-inflammatory drug (NSAID), and were without hospitalizations for the previous five years or prescriptions for other cardiac drugs or analgesics for the previous two years. Results were released early online and will appear in the July issue of Circulation: Cardiovascular Quality and Outcomes.

During the study period, 56,305 individuals died, 2,204 of whom were taking an NSAID. The nonselective NSAID diclofenac (brand names include Voltaren or Cataflam) was associated with an increased risk of cardiovascular death (odds ratio [OR], 1.91; 95% CI, 1.62 to 2.42). The selective cyclooxygenase-2 inhibitor rofecoxib (Vioxx) also was associated with an increased risk (OR, 1.66; 95% CI, 1.06 to 2.59).

Ibuprofen had an increased risk of fatal or nonfatal stroke (OR, 1.29; 95% CI, 1.02 to 1.63), but naproxen (Aleve) was not associated with increased cardiovascular risk (OR for cardiovascular death, 0.84; 95% CI, 0.50 to 1.42).

Diclofenac had a dose-dependent increase of coronary death or nonfatal MI, and fatal or nonfatal stroke, which researchers found concerning because it is used in high doses more often than the other drugs. Diclofenac has a high COX-2-inhibiting selectivity, and researchers hypothesized that it may share this trait with rofecoxib, which was withdrawn from the market in 2004.

“Our results confirm this association in healthy individuals, and it is particularly worrying that diclofenac exerts the same risk for cardiovascular adverse events as rofecoxib,” the authors wrote. “This is a major public health concern because diclofenac is one of the most widely used NSAIDs worldwide and in some countries dispensed as an over-the-counter drug.”

Study strengths include its size and completeness, which was the entire population of Denmark. All NSAID use was tracked, with the exception of low-dose over-the-counter sales of ibuprofen, and a sensitivity analysis for this did not change the results. Limitations include the study's observational nature and a lack of information about the exact reason for beginning NSAID treatments, which may cause confounding by indication.