Evidence continues to accumulate that the potent anti-inflammatory effect of drugs that block tumor necrosis factor can significantly dampen cardiovascular-disease risk in patients with rheumatoid arthritis, even though definitive proof from a prospective trial is still lacking.
Two recent pieces of suggestive evidence came from a meta-analysis of four placebo-controlled trials of adalimumab (Humira) that together included nearly 2,500 patients with rheumatoid arthritis, and from two prospective cohort studies of 828 RA patients that compared the outcomes of those treated with either adalimumab or etanercept (Enbrel) to the outcomes of similar patients who did not receive an anti–tumor necrosis factor drug.
In both studies, treatment with an anti-TNF agent was linked to a statistically significant cut in cardiovascular (CV) events of about 50%.
These results support another recent, similar finding reported in June at the Annual European Congress of Rheumatology in London. In that study, analysis of medical records from more than 109,000 U.S. patients with RA showed that every 6 months of treatment with an anti-TNF drug reduced the rate of CV events by 13%, compared with RA patients who did not receive a TNF blocker.
The meta-analysis of four trials included data collected in the ARMADA (Arthritis Rheum. 2003;48:35-45), DEO19 (Arthritis Rheum. 2004;50:1400-11), PREMIER (Arthritis Rheum. 2006;54:26-37), and OPTIMA (Ann. Rheum. Dis. 2012 May [doi: 10.1136/annrheumdis-2011-201247]) trials. Collectively, these four studies included 1,411 RA patients treated with both adalimumab and methotrexate, and 1,036 patients who received methotrexate but no anti-TNF drug. At baseline, patients in these two treatment groups had similar demographic and CV disease risk profiles.
Mitchel L. Zoler/IMNG Medical Media
Dr. Gerd Burmester
During study periods that ranged from 16 to 104 weeks, the incidence of major adverse CV events was 1.3% in patients who received adalimumab, and 2% in those who didn’t. This difference represents a statistically significant, 2/3 drop in the risk for a major CV event in a proportional-hazard model, said Dr. Gerd Burmester, lead investigator for the analysis and a rheumatologist and professor of medicine at Charité Hospital in Berlin. His analysis also showed a statistically significant risk reduction with adalimumab in the rate of nonfatal myocardial infarction, but no significant effect of adalimumab on the rates of nonfatal myocardial infarction or nonfatal stroke compared with patients not receiving adalimumab.
A limitation of the analysis was that none of the four trials was powered to assess CV outcomes, Dr. Burmester said.
The second study used data collected from two cohorts: the CARRÉ (Cardiovascular Research and Rheumatoid Arthritis) study, a prospective Dutch cohort study of 309 randomly selected RA patients who were not treated with a TNF blocker; and the Biologics cohort, which involves 519 Dutch RA patients who have been followed since they began treatment with an anti-TNF drug for the first time, either adalimumab or etanercept.
During follow-up, there were 8 CV events per 1,000 patient-years in the cohort receiving an anti-TNF drug, compared with 23 events per 1,000 patient-years in patients not on an anti-TNF agent, a statistically significant reduction. In a proportional hazards model that adjusted for baseline differences in age and gender, treatment with an anti-TNF agent reduced the rate of CV events by about half, a statistically significant effect, said Dr. Alper M. van Sijl, a researcher at the Reade Centre for Rehabilitation and Rheumatology at the VU Medical Center in Amsterdam.
"Our observations confirm the association between strong suppression of inflammation [with an anti-TNF drug] and curbing the cardiovascular risk in RA," said Dr. van Sijl and his colleagues. But they cautioned that because of the design of the study it remains unclear whether this was a real effect of the anti-TNF drugs, or a bias to treat patients with lower CV disease risk with a TNF blocker.
Dr. Burmester said that he has been a consultant to, served as a speaker for, and received research support from Abbott, the company that markets adalimumab. Dr. van Silj said that he had no disclosures.