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NSAID use linked to higher stroke risk in Danish study.

STOCKHOLM -- Treatment with various types of nonsteroidal anti-inflammatory drugs was linked with a significantly higher risk for strokes in a review of a million people from the Danish general population during 1997-2005.

"Commonly used NSAIDs such as diclofenac and ibuprofen were associated with an increased risk of hemorrhagic and ischemic stroke," and the link showed a dose-response relationship, reported Dr. Gunnar H. Gislason.

The public needs "increased awareness about the cardiovascular risk of NSAIDs, even in healthy people," said Dr. Gislason, a cardiologist at Gentofte Hospital in Hellerup, Denmark.

The study focused on three nonselective NSAIDs, ibuprofen, diclofenac, and naproxen; and on two COX-2 selective NSAIDs, rofecoxib (Vioxx) and celecoxib (Celebrex). The results showed significant links between use of all of these drugs except naproxen and an increased risk for fatal and nonfatal strokes. In general, naproxen use did not show significant links with stroke incidence.

The study used data collected in Danish national prescription, patient, and mortality records. In Denmark, all five NSAID formulations examined in the analysis are available only by prescription, Dr. Gislason said. The database included 4.6 million people as of January 1, 1997, the entire population of Danish citizens aged 10 or older as of that date.

The analysis focused on the 1.5 million people who had no hospitalizations during the 5 years prior to January 1997, and further focused on the 1 million people with one or more filled prescriptions for a selected list of drugs during the 2 years prior to January 1997. The median age of these 1 million people from the general Danish population was 39 in January 1997, and 58% were men.

During the 9 years of follow-up, 55% of the study group never used an NSAID, 17% filled one prescription, 14% filled two or three prescriptions, and 14% filled four or more prescriptions for NSAIDs. Ibuprofen was the most commonly prescribed NSAID, used by 29% of the study population, followed by diclofenac, used by 17%, and naproxen, used by 4%. Both rofecoxib and celecoxib were each used by about 2% (total exceeds 45% because some people used more than one NSAID). The total, average duration of use for each drug was small, ranging from an average of 13 days for rofecoxib to 24 days for naproxen.

In a multivariate analysis that controlled for age, gender, comorbidities, and concomitant medications, people treated with ibuprofen, diclofenac, rofecoxib, or celecoxib had a statistically significant, increased risk for fatal or nonfatal stroke. The increased risk ranged from about 30% higher among all ibuprofen users to about double in all diclofenac users. The two coxibs each linked with about an 80% increased risk. The only NSAID studied without a significantly linked risk was naproxen.

In general, the risk increased at higher dosages. For example, among ibuprofen users who averaged 1,200 mg/day or less had about a 20% increased risk for fatal or nonfatal stroke on the days they took the drug. People who took more than 1,200 mg a day had an average increased risk of about 80%. Both increases were statistically significant.

A second analysis showed significantly increased risks for ischemic stroke among ibuprofen and diclofenac users, but not among users of naproxen, rofecoxib, or celecoxib.


NSAID, CVD Link Long Suspected

If one extrapolates the results to the United States, this is a major and concerning public health finding. The data show that people should not take these drugs casually, but rather should think about whether the drugs are really needed. The link between NSAID use and increased stroke risk is not a surprise. A lot of observational data show links between NSAID use and cardiovascular disease events, but those data have been discounted because people's recollection of over-the-counter drug use is often fuzzy.

This is the first time I know of where well-documented NSAID use showed similar relationships. Additional studies should determine if risks exist at OTC dosages of the drugs, and whether the COX-2 specific drugs pose a greater stroke risk compared with the nonselective NSAIDs. The only way to definitively assess the stroke risk from these drugs would be in a large, randomized trial.

ROBERT M. CALIFF, M.D., is the Donald F. Fortin, M.D. professor of cardiology at Duke University in Durham, N.C. Dr. Califf had no relevant disclosures.

Disclosures: Dr. Gislason had no relevant disclosures.


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Title Annotation:CLINICAL ROUNDS
Author:Zoler, Mitchel L.
Publication:OB GYN News
Date:Oct 1, 2010
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