BERLIN – Treatment with a drug that blocked the action of tumor necrosis factor led to a significant reduction of cardiovascular events in patients with rheumatoid arthritis, compared with treatment with methotrexate or other nonbiologic disease modifying antirheumatic drugs, in a review of more than 100,000 patients treated during routine practice, according to Dr. Michael T. Nurmohamed.
Although this finding adds to the accumulating circumstantial evidence that treating patients with rheumatoid arthritis (RA) with a drug that blocks tumor necrosis factor (TNF) reduces their cardiovascular disease risk better than does treatment with disease-modifying antirheumatic drugs (DMARDs), current evidence does not yet clearly support an early start to anti-TNF treatment to maximize cardiovascular risk reduction, Dr. Nurmohamed said in an interview at the annual European Congress of Rheumatology.
"However, the literature does indicate that effective inflammatory suppression is essential [for patients with RA], and that if this is not achieved within a reasonable time frame with high-dose methotrexate or another DMARD then treatment with a biological, anti-TNF drug should be considered," he noted.
"The rheumatologic aim of treatment should be minimal RA disease activity and preferably remission. An additional aim of treatment might be cardiovascular risk reduction. If anti-TNF treatment stops when an RA patient achieves disease remission, we need to know whether the arterial inflammatory process also stays in remission. Investigations of this are now underway, and these studies may reveal new biomarkers of cardiovascular risk in RA patients. Until these results are available, cardiovascular risk management in patients with RA should follow EULAR recommendations (Ann. Rheum. Dis. 2010;69:325-31)," said Dr. Nurmohamed, a rheumatologist at VU University Medical Centre in Amsterdam.
"It appears that in patients with RA, atherosclerotic plaques rupture earlier," he said in an interview. "We know that inflammation is very important in that process. It might be that when you treat patients with an anti-TNF drug or other anti-inflammatory, you reduce the inflammatory content of the plaque. Therefore the plaque ruptures later. That may be the way that anti-TNF drugs lower myocardial infarctions," according to Dr. Nurmohamed.
The new results he reported came from a review of 109,462 United States patients diagnosed with RA who had filled at least one prescription for an anti-TNF drug, methotrexate, or another DMARD, and were included in a database maintained by Thomson Reuters MarketScan The researchers reviewed the patient records following the date when they filled their index prescription until they developed a cardiovascular event, ended their enrollment in their health plan, or until 6 months after they stopped taking their index drug, whichever came first. The review included 48,210 patient-years of follow-up while on treatment with an anti-TNF drug, 13,540 patient-years of treatment with methotrexate, and 7,320 patient-years of treatment with another nonbiologic DMARD. The database included more than 75,000 patient-years of follow-up when patients received monotherapy with one of these three treatments, according to Dr. Nurmohamed.
During follow-up, 1,743 patients (1.6%) had a cardiovascular event, a myocardial infarction (MI), unstable angina, heart failure, or stroke. Events primarily occurred as MI, unstable angina, or heart failure. Dr. Nurmohamed said that he and his associates then ran a series of Cox proportional hazard models that assessed the outcomes from cumulative exposure to the various treatments and controlled for patient demographics, use of cardiovascular medications, smoking, comorbidities, hypertension, diabetes, history of cardiovascular events, and medical-resource use.
The analyses showed that for every 6 months of treatment with an anti-TNF drug, the rate of all cardiovascular events fell by 13%, compared with patients not treated with an anti-TNF drug. Six months of anti-TNF-drug treatment cut the rate of MIs specifically by 20%, compared with nonuse of an anti-TNF drug. Both effects were statistically significant.
The analyses also showed that the cardiovascular-event effect of anti-TNF drugs was cumulative. A year of use cut the cardiovascular event rate by 24%, 2 years cut the rate by 42%, and 3 years cut the rate by 56%, compared with patients who did not receive an anti-TNF drug, Dr. Nurmohamed reported. This cumulative effect was not surprising because "prolonged inflammatory suppression will lead to more pronounced risk reduction," he said.
The analyses also showed that the cardiovascular-risk reduction of treatment with an anti-TNF drug, compared with patients who did not get this drug class, was a statistically significant 14% in patients who were at least 50 years old, and a significant 15% in patients with no prior exposure to methotrexate. The analyses failed to find a significant impact on cardiovascular disease from treatment with methotrexate or other nonbiologic DMARDs.