High-dose nonselective NSAIDs pose cardiovascular risk
Last Updated: 2006-06-19 16:00:17 -0400 (Reuters Health)
NEW YORK (Reuters Health) - The use of selective cyclooxygenase-2 (COX-2) inhibitors and nonselective nonsteroidal anti-inflammatory agents (NSAIDs) has been associated with an increased risk of cardiovascular disease. Now, investigators in Denmark have found that all doses of selective COX-2 inhibitors and higher doses of nonselective NSAIDs are also associated with an increased risk of mortality in patients with established cardiovascular disease.
"Patients who have already suffered a heart attack appear be more vulnerable to the harmful effect of these medications," said lead author Dr. Gunnar H. Gislason said in press release from the American Heart Association.
To investigate the relationship between hospitalization, mortality and the use of these agents in patients with established cardiovascular disease, Dr. Gislason's team extracted data from the Danish National Patient Registry for the 58,432 patients, 30 years of age or older, who had survived a first acute MI between 1994 and 2002.
The researchers then evaluated the Danish Registry of Medicinal Product Statistics for information regarding prescriptions of selective COX-2 inhibitors and other NSAIDs, the dosage, and length of prescription. The upper limit of low dosage was defined as the lower recommended daily dosage for each drug.
They report their findings in the June 19th early online issue of Circulation: Journal of the American Heart Association.
During follow-up, 9773 patients had another MI (18.6%) and 16,561 died (28.3%).
Patients who used any selective COX-2 inhibitor or other nonselective NSAID had higher mortality rates compared with patients who did not use any of these drugs, although the risk was highest for the selective COX-2 inhibitors. For rofecoxib up to 25 mg/day, and celecoxib up to 200 mg/day (both considered to be low dose), the adjusted hazard ratios (AHR) were 2.49 and 1.92 for mortality and 1.68 and 1.47 for MI, respectively.
For these two drugs at higher doses, the adjusted hazard ratios for death were 5.26 and 4.69 for each, and for repeat MI, 1.27 and 1.64.
For high daily doses of more than 1200 mg of ibuprofen, the adjusted hazard ratio for death was 2.20, and for doses of diclofenac greater than 100 mg/day it was 4.44. For repeat MI, the corresponding adjusted hazard ratios were1.22 and 1.89, respectively.
A statistical analysis "demonstrated a clear dose-related response in the increase in the risk of death for all drugs," the investigators report.
They estimated that the number of patients needed to treat with each drug for 1 year to cause 1 additional death was 13 for rofecoxib 25 mg, 14 for celecoxib 200 mg, 45 for ibuprofen 1600 mg, and 24 for diclofenac 100 mg.
Given the results from this and other studies, Dr. Gislason's team concludes: "selective COX-2 inhibitors and nonselective NSAIDs should be used with particular caution in patients with a prior MI."
In a related editorial, physicians based at the New York University School of Medicine discuss these findings and suggest that "When pain demands treatment, a conversation that elicits patient preferences should help guide the first agents of choice.
Dr. Judith S. Hochman and Dr. Nirav R. Shah conclude: "High dose aspirin (up to 1500 mg/day) is associated with protection from cardiovascular events, but also with gastrointestinal toxicity," for which they recommend proton pump inhibitors.
Circulation 2006;113.
