Vioxx and Bextra Increase Stroke Risk

The use of rofecoxib (Vioxx; Merck) or valdecoxib (Bextra; Pfizer), but not celecoxib (Celebrex; Pfizer), increased the risk of stroke in a retrospective study of Medicaid enrollees. Results of the study, which are consistent with several, previous observational studies, were published in this month's issue of Stroke.

Investigators at Vanderbilt examined the incidence of ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage among 336,906 noninstitutionalized enrollees, aged 50-84 years, in the Tennessee Medicaid program (TennCare) from 1999 through 2004 and the use of commonly prescribed NSAIDs, including the coxibs rofecoxib, valdecoxib, and celecoxib. The adjusted* hazard ratios (HRs) for stroke among all NSAID users and among new NSAID users (to reduce bias) are shown (reference = nonusers).

Exposure	All NSAID Users (n = 94,456)	New NSAID Users
	Adjusted HR (95% CI)
Celecoxib	1.04 (0.87, 1.23)	1.12 (0.83, 1.52)
Rofecoxib	1.28 (1.06, 1.53)	1.46 (1.08, 1.98)
Valdecoxib	1.41 (1.04, 1.91)	1.39 (0.74, 2.59)
Naproxen	0.94 (0.80, 1.11)	1.02 (0.73, 1.42)
Ibuprofen	0.88 (0.73, 1.06)	1.26 (0.87, 1.81)
Diclofenac	0.94 (0.59, 1.49)	0.31 (0.04, 2.18)
Indomethacin	1.20 (0.85, 1.69)	1.29 (0.53, 3.09)
Other NSAID	1.04 (0.87, 1.23)	1.23 (0.84, 1.78)
Former NSAID	1.02 (0.94, 1.10)	1.02 (0.95, 1.10)
Former rofecoxib	1.16 (0.96, 1.39)	…
Former valdecoxib	1.17 (0.83, 1.66)	…

Hospitalization for stroke was most common among users of low-dose rofecoxib or valdecoxib. Most strokes were identified as ischemic, and the risk of hemorrhagic stroke (intracerebral and subarachnoid hemorrhages) did not differ significantly by NSAID exposure.

The investigators found that all enrollees in the TennCare program were at high risk for vascular disease, and one quarter had "serious" cardiovascular disease before entering the program. More than 60% were taking one or more antihypertensive agents at baseline. A higher percentage of coxib users had been diagnosed with atrial fibrillation and took anticoagulants or platelet inhibitors. However, aspirin use and smoking-related conditions did not differ appreciably between NSAID users and nonusers in the cohort.

Both rofecoxib and valdecoxib were withdrawn from the market (September 2004 and April 2005, respectively) owing to drug-related cardiovascular adverse effects. Celecoxib remains on the market, despite reports of increased cardiovascular risk with high dosages. The TennCare study, however, showed no significantly increased risk of stroke with the use of celecoxib.

Because NSAIDs have both antithrombotic activity (inhibition of platelet thromboxane) and prothrombotic activity (inhibition of prostacylin), the balance of these activities or the relative potency of coxibs may determine cardiovascular risk, write the authors. Other possible mechanisms include the elevation of blood pressure and the promotion of atherosclerosis.

* For age, race, sex, calendar year, residence, enrollment category, rheumatologic disease, aspirin use, smoke-related illness, outpatient visits, ED visits, hospital admissions, unique no. prescription drugs, adjusted vascular risk score, and the use of anticonvulsants, antimicrobials, bronchodilators, estrogens, and psychotropic drugs.

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