Study suggests cardiovascular benefit with TNF-alpha blockade



Patients with rheumatoid arthritis who began taking a tumor necrosis factor–alpha blocking agent had a lower cardiovascular event risk during the subsequent 6 months than did those who took a nonbiologic disease-modifying antirheumatic drug in a large, observational study of several administrative and health plan datasets.

The incidence rate for a composite cardiovascular endpoint through the first 6 months of follow-up was 2.52/100 person-years in 11,587 subjects with rheumatoid arthritis (RA) who added a TNF-alpha blocker to their treatment regimen, compared with a rate of 3.05/100 person-years in 8,656 subjects with RA who added a nonbiologic DMARD, Dr. Daniel H. Solomon of Brigham and Women’s Hospital, Boston, and his colleagues reported.

The findings were most pronounced among those aged 65 years and older (hazard ratio, 0.52), and the benefits waned after 6 months.

"In both the first exposure carried forward and the as-treated analyses, the cardiovascular event–free survival curves diverged over the first 6 months. The hazard ratio for the TNF-alpha blocking agent, compared with the nonbiologic DMARD in the first exposure, carried forward was 0.80, and the as-treated analysis at 6 months was 0.71. However, by 12 months the curves appeared to converge with the hazard ratios approaching the null," the investigators explained (Am. J. Med. 2013;126:730.e9-17).

The study involved participants older than 16 years (mean age of 56 years) in several U.S. insurance programs. Those included in the current study – which was part of a larger study collaborative known as SABER (Safety Assessment of Biologic Therapy) – were RA patients using methotrexate who were either adding or switching to a TNF-alpha blocker or a nonbiologic DMARD.

The study’s primary endpoint consisted of a composite cardiovascular outcome of myocardial infarction, stroke, or coronary revascularization; each of these components alone represented a secondary study endpoint.

"While statins and aspirin may reduce cardiovascular risk in part through their anti-inflammatory properties, targeting cytokines known to be part of cardiovascular disease is an attractive therapeutic option."

"The component cardiovascular outcomes followed a similar pattern (to the composite outcome), except stroke, where the incidence rates were similar across exposures," the investigators noted.

Despite the limitations inherent in an observational study, the findings may have important clinical implications, they said.

"As greater evidence accumulates for the role of inflammation in atherosclerosis, consideration has been given to the use of immunosuppressive treatment regimens in cardiovascular disease. While statins and aspirin may reduce cardiovascular risk in part through their anti-inflammatory properties, targeting cytokines known to be part of cardiovascular disease is an attractive therapeutic option. Because the use of potent immunosuppressive agents is common in a systemic inflammatory condition such as rheumatoid arthritis, studying the effect of these agents on cardiovascular disease may provide important insights into the potential role of this strategy in the general population."

The results of the current study generally agree with prior findings demonstrating a link between TNF-alpha blocker use and reduced risk of cardiovascular outcomes.

"TNF-alpha appears to affect several aspects of cardiovascular disease, such as plaque stabilization, endothelial function, and postinfarct remodeling. Thus, one would anticipate that blockade of TNF-alpha would reduce ischemic cardiovascular outcomes. This finding supports the inflammatory underpinnings of cardiovascular disease and highlights a potential role for immunosuppression in cardiovascular risk reduction," they wrote, concluding that randomized controlled clinical trials testing targeted immunosuppression to reduce cardiovascular risk are warranted.

This study was supported by the Agency for Healthcare Research and Quality and the Food and Drug Administration. Dr. Solomon reported receiving research grants from Abbott, Amgen, and Lilly, and serving in unpaid roles on two Pfizer trials. He also directed an educational course supported by Bristol-Myers Squibb, and serves as a consultant to the Consortium of Rheumatology Researchers of North America Inc. (CORRONA). Other study authors reported receiving research grants from, and/or serving as a consultant for Amgen, Abbott, BMS, Centocor, Genentech/Roche, Janssen, Pfizer, UCB, and CORRONA.

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