Researchers examine combined effect of aspirin, COX-2 drugs on adverse events

Physicians recommend that patients taking traditional NSAIDs and aspirin stagger treatments.

Issue: February 2008

Nora G. Singer, MD
Nora G. Singer

While NSAIDs have been shown to be effective for the treatment of osteoarthritis, the safety of some of these drugs have come under fire. Now, researchers are investigating the role aspirin may play in some of the adverse events seen with these treatments.

According to the 2000 American College of Rheumatology (ACR) guidelines, non-selective NSAIDs and COX-2 inhibitors were indicated for patients with moderate to severe osteoarthritic pain. However, recent reports of adverse cardiovascular events have diminished some rheumatologist’s emphasis on selective NSAIDs, Nora G. Singer, MD, said during her presentation at Osteoarthritis and Synovitis: The link between pathogenesis, detection and treatment, a post-ACR educational symposium.

Initial safety studies demonstrated lower rates of gastrointestinal events with COX-2 inhibitors (coxibs) compared to non-selective NSAIDs. In the Celecoxib Long-term Arthritis Safety Study (CLASS), investigators found a 52% reduction in the annualized incidence of symptomatic ulcers and ulcer complication rates among patients who took 400 mg of celecoxib (Celebrex, Pfizer) and no aspirin compared to those who received non-selective NSAIDs. Similarly, investigators in the Vioxx Gastrointestinal Outcome Research Study (VIGOR) discovered a 53% reduction in ulcer complication rates with 50 mg of rofecoxib (Vioxx, Merck & Co.) compared to 500 mg of naproxen (Aleve, Bayer Healthcare).

“Of note, these patients were not on aspirin and this was the highest dosage of which rofecoxib was approved,” Singer said.

GI events

The study also revealed fewer upper and lower gastrointestinal (GI) events in the rofecoxib-treated group. The investigators found 34 serious upper GI events and 24 lower events in the naproxen-treated group, while there were only 15 serious upper and 11 lower GI events in the rofecoxib cohort.

Despite these advantages, news of increased cardiovascular adverse events caused patients and physicians to question the safety of COX-2 inhibitors, Singer said. In the VIGOR study, investigators discovered a 0.4% rate of myocardial infarction in 4,047 rofecoxib-treated patients compared to a 0.1% rate in 4,029 patients treated with naproxen. According to the VIGOR study authors, up to 4% of patients met criteria for American Society of Anesthesiologists cardioprotective regimen, but were not administered. These patients accounted for 38% of the overall myocardial infarctions seen.

“Originally, it was attributed to the fact that it was thought that naproxen perhaps had a protective effect in VIGOR and that accounted for the difference,” Singer said.

She also noted that the study was planned to detect cardiovascular safety as a primary outcome measure and therefore could not have been expected to have been powered to detect events rarer than its primary outcome measure, namely GI events.

“In addition, in VIGOR none of the patients were on aspirin,” Singer said. “Therefore, it may have been that in VIGOR, which was a trial of rheumatoid arthritis patients (RA), that there were high-risk patients who really should have been on aspirin as the VIGOR authors pointed out.”

However, the CLASS trial included more OA than RA patients and also consisted of patients who did and did not take aspirin. In that study, investigators found the same overall myocardial infarction rate of 0.3% in both the celecoxib and traditional NSAID-treated groups. They also discovered a lower rate in celecoxib patients who were not taking aspirin (<00.1%) and a 0.1% rate in non-aspirin NSAID patients.

In 2004, the manufactures of rofecoxib voluntarily withdrew the drug due to an increased risk of cardiovascular events seen in an adenomatous polyp prevention study, Singer said. In a randomized trial examining the rate of adenomatous polyposis coli (APC) in patients taking a placebo, 200 mg of celecoxib twice daily, or 400 mg of celecoxib twice daily, investigators discovered significantly higher rates of cardiovascular events in both of the celecoxib cohorts compared to the placebo group.

“When the APC data became available, the trial was stopped and subsequently, [a] second adenomatous polyp trial that did not show differences between placebo and celecoxib was also stopped because the first trial had been stopped,” Singer said.

Aspirin

A recent meta-analysis using a Medicare California database to assess the risk of acute myocardial infarction with various NSAIDs revealed a 1.08 relative risk with naproxen, a 1.11 risk with ibuprofen and a 1.71 risk with indomethacin in arthritic adults.

“Whether or not this had to do with interference from aspirin was a major question,” Singer said. She noted that laboratory studies have shown that when ibuprofen interacts with aspirin, the aspirin cannot inactivate COX-1.

A retrospective Canadian database study examining the incidence of recurrent acute myocardial infarction in 18,503 patients revealed that the benefits of aspirin were abrogated by consistent ibuprofen use. The investigators found that patients who took aspirin and ibuprofen for more than 60 days showed a 1.83 times higher adjusted hazards ratio for recurrent acute myocardial infarction compared to patients taking aspirin alone.

“This really led many physicians to recommend that if a patient is on a traditional nonsteroidals and they are taking aspirin, that they do it an hour before or 4 hours after,” Singer said.

For more information:

Nora G. Singer, MD, is an associate professor at Case Medical Center, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106; 216-844-3237; e-mail: ngs@po.cwru.edu.

Reference:

Singer NG. Current therapies for osteoarthritis and synovitis: Examining recent data. Presented at Osteoarthritis and synovitis: The link between pathogenesis, detection and treatment. A post-ACR symposium. Nov. 11, 2007. Boston.