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A new, and as of yet unpublished study, has raised increased concern about the relationship between rofecoxib (Vioxx), Merck's blockbuster COX-2 inhibitor, and cardiovascular events. The study, which was presented at a meeting in Bordeaux France, was financed by the FDA in collaboration with California's HMO giant Kaiser Permanente. The study was designed to determine if colecoxib, rofecoxib, ibuprofen, naproxen, or other NSAIDs increase the risk of acute myocardial infarction (AMI) or sudden cardiac death (SCD). Utilizing the 6-million member California database for Kaiser Permanente, all patients ages 18-84 who had taken a COX-2 inhibitor or non-selective NSAIDs between January 1999 and December 2001 were entered into the cohort. Controls were a risk-set match 4:1 on event date, birth year, gender and health plan region. There were 8199 acute cardiac events within the study cohort (6675 AMI, 1524 SCD). The data revealed that rofecoxib use at > 25 mg per day increased the risk of acute cardiac events 3.15 fold (OR, 3.15 [1.14-8.75]). Rofecoxib at a dose < 25mg resulted in an odds ratio of 1.29 (0.93-1.79), which was not statistically significant. When comparing low-dose rofecoxib to celecoxib (Celebrex), the risk of AMI and SCD was higher with rorecoxib (P=0.04). Other NSAIDs, including naproxen, indomethacin, and possibly diclofenac, also increased the risk of AMI and SCD. These data will be presented in this country in October at the American College of Rheumatology. Concern about the relationship between rofecoxib and cardiac events was first raised with the publication of the Vigor trial (N Engl J Med. 2000; 343:1520-1528) which showed a relative risk of cardiac events associated with rofecoxib of 2.38 (95 percent CI, 1.39-4.00; P=.002). Dr. Eric Topol and colleagues from the Cleveland clinic subsequently reevaluated these data along with the data from other studies and raised the concern of prothrombotic potential of COX-2 inhibitors, especially rofecoxib (JAMA. 2001; 286:954-959). Their concern centered of the tendency for COX-2 inhibitors to block production of prostacyclin-this blocking antiaggregatory and vasodilatory effects, while having no effect on thromboxane, which is responsible for platelet aggregation. Blockage of throboxane is a COX-1 effect and accounts for the majority of the cardioprotective effects of aspirin and other NSAIDs. Rofecoxib, the most COX-2 specific of the drugs tested, may unbalance thromboxane and protacycline accounting for the cardiovascular risk.
Some have considered a strategy of adding aspirin to a COX-2 inhibitor, but a new study suggests that aspirin negated the GI benefits of the COX-2 inhibitor, the primary benefit of COX-2 inhibitors over nonselective NSAIDs.
Researchers from USC performed a double-blind trial of rofecoxib, rofecoxib plus low-dose aspirin, ibuprofen, or placebo in patients without ulcers or erosive esophagitis. Endoscopies were performed at baseline, 6 weeks, and 12 weeks. At 12 weeks, the cumulative index of ulcers was placebo 5.8 percent, aspirin 7.3 percent, rofecoxib plus aspirin 16.1 percent;, and ibuprofen 17.1 percent (P<0.001 for rofecoxib plus aspirin and for ibuprofen vs. each of placebo and aspirin). Over the same time, rofecoxib plus aspirin and ibuprofen both significantly increased the number of erosions (both P<0.001 vs. aspirin and placebo). The authors conclude that low-dose aspirin does not significantly increase ulcer recurrence, but that the addition of a COX-2 inhibitor with aspirin increases the rate of ulceration to a rate that is similar to nonselective NSAIDs (Gastroenterology. 2004; 127:395-402).
The above article is from the publication Pharmacology Watch, October 2004.
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