The selective COX-2 inhibitor etoricoxib and the non-selective agent diclofenac have comparable rates of thrombotic cardiovascular events when used for arthritis-related pain, according to a presentation at a Late-Breaking Clinical Trials session at the American Heart Association meeting.

Results of the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) Study Program: Cardiovascular Outcomes Following Long-term Treatment with Etoricoxib versus Diclofenac in Patients with Osteoarthritis and Rheumatoid Arthritis were published online by Lancet.

Etoricoxib, the selective COX-2 inhibitor investigated in this study, is approved for use in 60 countries, although not the United States. Diclofenac, which is available in the United States, affects both enzymes, but has substantially more COX-2 (physiologically desirable) inhibition than agents such as ibuprofen, aspirin or naproxen. To date, drugs with more enzyme selectivity have also had more thrombotic adverse events.

"We saw that the risk of serious blood clotting or thrombotic events was similar with diclofenac and the newer COX-2 inhibitor etoricoxib," said Christopher P. Cannon, MD, co-chair of the study. "So, for people who need to take one of this type of agents long term, either one will have the same risk profile for thrombotic events such as heart attack or stroke."

The primary endpoint -- the rate of any thrombotic cardiovascular event -- was 1.24 events per 100 patient years for etoricoxib and 1.30 events per 100 patient years for diclofenac. These rates were not different when tested statistically, said Cannon, who is also a cardiologist at Brigham and Women's Hospital and an associate professor of medicine at Harvard Medical School.

The MEDAL program -- the largest randomized trial performed in arthritis patients -- involved 34,701 patients with osteoarthritis or rheumatoid arthritis in 38 countries. The participants, all age 50 years or older, were randomized to two daily doses of etoricoxib, 60 or 90 milligrams (mg), or a 150 mg daily dose of diclofenac, and then followed for an average of 18 months.

Researchers also found that rates of complicated upper gastrointestinal events, life-threatening events including bleeding or ulcers leading to perforation or obstruction were virtually the same with both medications, about 1 per 300 patient years. Congestive heart failure was rare, but higher in the etoricoxib 90 mg group.

Higher-dose etoricoxib had more discontinuations due to edema and both doses had higher rates of discontinuation due to hypertension. Meanwhile, diclofenac patients had higher discontinuations for gastrointestinal and adverse liver events.

Because all of the patients in the MEDAL study had debilitating arthritis, there was no placebo group. Consequently, this study may provide a glimpse of real-world risks in patients who must take pain medication long term, but it cannot provide an absolute risk compared to people of the same age who do not take such a drug.

In addition to the absence of a placebo group, there was no comparison with a group of patients given other less-selective drugs in combination with a proton pump inhibitor (PPI) -- a combination that may treat pain while minimizing bleeding.

The study should be interpreted with caution, said American Heart Association president-elect Daniel Jones, MD.

"The MEDAL trial does not indicate that etoricoxib is safe just because it has a similar risk profile to diclofenac," Jones said. "It does not appear that either of these medications would be among the first choices for pain relief with regard to safety, especially in individuals with or at risk for cardiovascular disease. Of note, the higher rates of edema and hypertension in the etoricoxib group may represent important limitations to its use."

The American Heart Association recommends physicians weigh the benefits and risks before prescribing any pain killer. Because the risks of adverse effects of COX-2 inhibitors are likely greatest in patients with -- or at high risk for -- cardiovascular disease, the association suggests limiting the use of COX-2 drugs to patients who have no appropriate alternatives.