STOCKHOLM – Treatment with various types of non-steroidal 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 [non-steroidal anti-inflammatory drugs] 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 non-selective 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 non-fatal 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 study included follow-up data through the end of 2005.
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 non-fatal 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 non-fatal 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. Again, users of ibuprofen and diclofenac faced a greater risk when taking higher dosages, defined as being more than 1,200 mg/day of ibuprofen or at least 100 mg/day diclofenac.
Dr. Gislason had no relevant disclosures.