Brigham and Women's Hospital (BWH) studies research the impact of RA drugs on cardiovascular, cancer and infection risks.
In two ongoing lines of research especially relevant to rheumatoid arthritis (RA), Daniel Solomon, MD, MPH, Chief of Clinical Science, Division of Rheumatology, Immu-nology, and Allergy at Brigham and Women's Hospital (BWH) and colleagues have been delving into large Medicare databases to better define the relative risks and benefits of cyclooxygenase-2 inhibitors (known as coxibs or COX-2 inhibitors) and TNF-alpha antagonists (such as adalimumab, etanercept, and infliximab). For his studies, Dr. Solomon draws on his dual expertise in rheumatology and pharmacoepidemiology.
Coxibs generally cause less gastrointestinal hemorrhage than nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), but studies have raised concerns about their cardiovascular safety. Three years ago, Dr. Solomon found a slightly higher relative risk of heart attacks in people taking rofecoxib (Vioxx®), especially on higher dosages and in the first three months, compared with no elevated risk in people on celecoxib (Celebrex®) and or less selective NSAIDs, such as ibuprofen, and a reduced risk in people on naproxen. (Circulation. 2004;109: 2068-2073.)
There is growing evidence that the increased risk of cardiovascular events with coxibs is of significant concern for patients with known cardiovascular disease. Such patients should be using low-dose aspirin for cardioprotection. There is no clear gastrointestinal benefit from adding a coxib for a patient on low-dose aspirin. In fact, these patients should avoid coxibs, which may increase the risk of a future cardiovascular event, Solomon said.
RA Drugs and Cardiovascular Risk
Since then, Dr. Solomon and his colleagues have been trying to identify the subgroups of people specifically affected by the elevated risk. Preliminary evidence implicates people with known risk factors for cardiovascular disease. Aiming to find better individual risk predictors, he is working on several substudies of a large clinical trial called PRECISION, sponsored by Pfizer, designed to test the cardiovascular safety of celecoxib.
"Patients with arthritis are the biggest users of NSAIDS and coxibs," said Dr. Solomon. "These drugs are widely used and will continue to be widely used. As clinicians, we need a handle on the risk-to-benefit ratio and how to determine whether a given patient will accrue more benefit than risk. It's a complicated issue. Having patient-specific level recommendations would be tremendously useful for patients and physicians."
Cancer and Infection Risks
TNF-alpha antagonists (adalimumab/Humira®, entanercept/ Enbrel®, and infliximab/Remicade®) on the other hand, appear to be relatively safe. The drugs block the cytokine that fires up the immune system in rheumatoid arthritis, but the same molecule may be important in fighting cancer and infections, such as tuberculosis.
Dr. Solomon and his colleagues have found no relative increase in infection or cancer in people taking the drugs for as long as three years, compared with people using methotrexate. "Our results are but one piece of information in this complicated puzzle," Dr. Solomon said. "There are papers on both sides of the issue." Some of the differences in the results may be due to biases in design and analysis, which Dr. Solomon has tried to minimize with longer-term studies, validated algorithms, and comparable study groups. (Arthritis & Rheumatism.2006; Vol 54, Issue 9: 2757-64.)
"We don't know for sure how risky the TNF antagonists are," said Dr. Solomon. "Clearly, these drugs have an important role and benefit many patients. Our studies suggest the risk of infection and cancer isn't significantly increased. However, there may be an increased risk in certain patients, so we must divulge that potential problem and advise patients to have regular cancer screening and surveillance for infection."
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