Selective COX-2 inhibitors associated with slightly increased risk for adverse cardiovascular events in postmenopausal women

Postmenopausal women who used selective COX-2 inhibitors and NSAIDs with more COX-2 than COX-1 inhibition had a modestly increased risk for cardiovascular events, a study concluded.

Researchers reviewed data from the Women's Health Initiative to examine the primary outcome of total cardiovascular disease, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. A secondary analysis considered the association of selective COX-2 inhibitors, nonselective agents with relatively more COX-2 inhibition, and nonselective agents with relatively more COX-1 inhibition.

Selective COX-2 inhibitors included rofecoxib and celecoxib. Nonselective NSAIDs with relatively more COX-2 included naproxen, and nonselective NSAIDs with relatively more COX-1 inhibition included ibuprofen. Results appeared online July 8 at Circulation: Cardiovascular Quality and Outcomes.

There were 160,801 participants (1,793,222 person-years), with a mean follow-up of 11.2 years in the analysis. Among this cohort, 53,142 reported regular NSAID use at some point in time.

The primary outcome occurred in 12,733 cases, or an overall incidence rate of 71 events per 10,000 person-years.

The unadjusted hazard ratio (HR) for an event associated with any type of NSAID use was 1.16 (95% CI, 1.11 to 1.21; P<0.001), and the adjusted HR was 1.10 (95% CI, 1.06 to 1.15; P<0.001). Selective COX-2 inhibitors were associated with a modest risk for cardiovascular events (HR, 1.13; 95% CI, 1.04 to 1.23; P=0.004), as was celecoxib alone (HR, 1.13; 95% CI, 1.01 to 1.27; P=0.031).

Agents with more COX-2 inhibition than COX-1 inhibition also showed increased risk (HR, 1.17; 95% CI, 1.10 to 1.24; P<0.001), as did naproxen (HR, 1.22; 95% CI, 1.12 to 1.34; P<0.001). There was no similar risk elevation for agents with more COX-1 inhibition than COX-2 inhibition (HR, 1.01; 95% CI, 0.95 to 1.07; P=0.884) or for ibuprofen alone (HR, 1.00; 95% CI, 0.93 to 1.07; P=0.996).

The authors noted that although the risk for cardiovascular disease appeared slightly higher with nonselective NSAIDs with relatively more COX-2 than COX-1 inhibition than for COX-2 selective agents, the magnitude of risk with these 2 classes of agents was similar. However, COX-2 selective agents seemed to be associated with a greater hazard for stroke, compared to nonselective NSAIDs with relatively more COX-2 inhibition, which were associated with a greater hazard for myocardial infarction.

The authors wrote that they didn't find a higher cardiovascular risk with medications that had more COX-1 than COX-2 inhibition, which may indicate that such agents have a better cardiovascular safety profile for long-term use in postmenopausal women.