More studies on risks and benefits of COX-2 inhibitors published in Archives of Internal Medicine

A group of studies published in the January 24 issue of Archives of Internal Medicine add to the growing body of medical literature about the cardiovascular risks that may be associated with the class of pain-relieving drugs known as COX-2 inhibitors. Archives of Internal Medicine is one of the JAMA/Archives journals.

The Celecoxib Rofecoxib Efficacy and Safety in Comorbodities Evaluation Trial (CRESCENT) evaluated the effects of the COX-2 inhibitors and naproxen on 24-hour blood pressure readings in patients with type 2 diabetes, hypertension, and osteoarthritis. Patients were randomly assigned to receive 200 mg of celecoxib (Celebrex; Pfizer Inc., New York) [n= 136], or 25 mg of rofecoxib once daily (Vioxx, Merck & Co., West Point, Penn.) [n = 138], or 500 mg of naproxen twice daily (Naprosyn; Roche Pharmaceuticals, Basel, Switzerland) [n = 130] for 12 weeks. A total of 65 centers from 7 countries participated in this trial from May 2001 to April 2002. Patient evaluations were conducted at the start of the study and 1, 2, 6, and 12 weeks after randomization.

“Reductions in osteoarthritis symptoms, including pain, mobility, and stiffness, were similar in all treatment groups,” the researchers found. “The mean (average) 24-hour systolic [top number in blood pressure reading] blood pressure following 6-weeks of therapy was increased significantly by refecoxib but not by celecoxib or naproxen.”

“…these results suggest the need for careful monitoring and control of blood pressure when NSAIDS (non-steroidal anti-inflammatory drugs) or COX-2 inhibitors are chosen for osteoarthritis management for patients with hypertension and type 2 diabetes and further suggest need for careful evaluation of currently available as well as future COX-2-specific inhibitors and nonspecific NSAIDs in this population,” the authors conclude.

Observational Study of Patients on COX-2 Inhibitors Does Not Show Increased Cardiovascular Risk

An observational study of 6,250 patients enrolled in the Maryland Medicaid program found that COX-2 inhibitors did not increase the risk for cardiovascular events over nonnaproxen NSAIDs in a high-risk population.

Fadia T. Shaya, Ph.D., M.P.H., from University of Maryland, Baltimore, and colleagues analyzed the claims of noninstituionalized Medicaid enrollees who received at least a 60-day supply of a COX-2 inhibitor or other prescription NSAID between June 2000 and June 2002. Naproxen users were excluded. Of the 6,250 patients, 1,005 used a COX-2 inhibitor and 5,245 used some other NSAID. The patients in the study were 70 percent female, 50 percent African American, and 30 percent were older than 50 years. “Overall, 12 percent of the patients had at least one cardiovascular thrombotic [blood clotting] event after treatment within the follow-up period,” the researchers report.

The authors conclude: “The results of this analysis do not show a difference in the rate of cardiovascular events between COX-2 inhibitors and nonnaproxen NSAIDs. Given that the study population had higher baseline cardiovascular risk, these observations provide more confidence that the widespread use of COX-2 inhibitors will not be associated with an increase in thrombotic or coronary artery events. This is particularly important because NSAIDs are often used in older, higher-risk patients.”

Patients Taking Warfarin Along With NSAIDs or COX-2 Inhibitors Have Increased Risk of Upper Gastrointentinal Hemorrhage

Patients taking warfarin at the same time as selective COX-2 inhibitors or nonselective NSAIDs have an increased risk of hospitalization for upper gastrointestinal (GI) hemorrhage, according to Canadian researchers analyzing health care databases. Warfarin is an anti-coagulant (blood thinner used to prevent clots) commonly used in patients with a variety of thromboembolic [blood vessel blocking, usually by a clot] condition.

Marisa Battistella, B.Sc.Phm., Pharm.D., from University Health Network-Toronto General Hospital, Toronto, and colleagues analyzed information from multiple linked health care databases over one year from April 1, 2000 to March 31, 2001 to identify a group of patients who were older than 66 years of age and continuously prescribed warfarin.

“During the study period, we identified 98,821 elderly patients continuously receiving warfarin,” the researchers report. “Of those 361 (0.3 percent) were admitted to the hospital with upper GI hemorrhage. After adjusting for other potential confounders, case patients were significantly more likely to be also taking nonselective NSAIDs, celecoxib, or rofecoxib prior to hospitalization relative to controls” (patients taking warfarin, but not taking NSAIDs or COX-2 inhibitors).

“Our findings suggest that the risk of upper GI hemorrhage is similarly heighted in warfarin users treated with either selective COX-2 inhibitors or nonselective NSAIDs. … physicians and pharmacists who care for elderly patients taking warfarin should be aware of the potential risks of concomitant therapy with NSAIDs or COX-2 inhibitors, particularly because the latter are among the fastest-growing class of prescription medications and have rapidly gained acceptance in clinical practice.” (Arch Intern Med. 2005; 165:189-192. Available post-embargo at www.archinternmed.com) Editor’s Note: Please see study for financial disclosures.

Editorial: Coxibs, Science, and the Public Trust

In an editorial accompanying all of the studies, Daniel H. Solomon, M.D., M.P.H., from Brigham and Women’s Hospital, Boston, and Jerry Avorn, M.D., of Harvard University School of Medicine, write that the withdrawal of rofecoxib (Vioxx) from the market in September 2004 by its manufacturer, Merck & Co., “raises many questions concerning drug policy, scientific evidence, and treatment alternatives. Several of these questions are raised by articles in this issue of the ARCHIVES.”

“Several lessons can be learned from the 5-year experience and eventual withdrawal of rofecoxib from the market. First, the current postmarketing surveillance system does not work. If the FDA is to continue to approve drugs rapidly, we should not expect that all safety issues will be understood prior to a drug’s approval.” The editorial authors add that an improved system of postmarketing surveillance is needed.

“Fortunately, many patients taking coxibs can be switched to other equally effective and evidence-based analgesic (pain relieving) regimens.”

“The market withdrawal of rofecoxib has brought to the forefront concerns about the drug safety system that have been raised before. These issues must be addressed now if we are to restore the public’s confidence in the safety of our pharmacologic armamentarium and provide physicians and patients with the data we all need to prescribe drugs safely.”