For RA Cardioprotection, Biologics Found Equal to Methotrexate

BOSTON, Nov. 29 -- The biologic agents used to treat rheumatoid arthritis are no better or worse for the heart than methotrexate, according to a case-control study.

Compared with methotrexate, biologics for RA conferred no more or less risk of cardiovascular events, although oral glucocorticoid monotherapy increased the odds by 50% and other cytotoxic agents raised the risk by 80%, said Daniel H. Solomon, M.D., M.P.H., of Brigham and Women's Hospital here, and colleagues.

Their study, reported in the December issue of Arthritis & Rheumatism, compared stroke and heart attack rates in 3,501 primarily frail older patients, enrolled in a state prescription drug assistance program and Medicare, who were taking RA drugs.

Biologic agents Humira (adalimumab), Enbrel (etanercept), Remicade (infliximab) and Kineret (anakinra) as a group carried the same risk as methotrexate (odds ratio 1.0, 95% confidence interval 0.5 to 1.9), which was not significantly changed by combination with methotrexate (OR 0.8, 95% CI 0.3 to 2.0) or with other immunosuppressive agents (OR 1.2, 95% CI 0.7 to 2.2).

Oral glucocorticoid monotherapy significantly increased cardiovascular event risk compared with methotrexate (OR 1.5, 95% CI 1.1 to 2.1), with a similar trend when combined with other drugs (OR 1.3, 95% CI 0.8 to 2.0).

The cytotoxic immunosuppressive agents azathioprine, cyclosporine, and Arava (leflunomide) increased cardiovascular event risk the most of any group of agents whether as monotherapy or in combination treatment (both OR 1.8, 95% CI 1.1 to 3.0).

The noncytotoxic agents, which included gold, Plaquenil (hydroxychloroquine) and Azulfidine (sulfasalazine), did not significantly increase cardiovascular event risk compared with methotrexate (OR 1.2, 95% CI 0.8 to 1.7).

Previous studies have identified cardiovascular benefits for various agents in reducing event rates, surrogate measures and even death, but an investigation of all available immunosuppressive agents across a broad spectrum of patients with RA was lacking.

So, the researchers examined cardiovascular risk for the medications compared to methotrexate. Using RA patients not on immunosuppressive agents as the reference group would not have been appropriate, the authors wrote, because those patients may have disease remission, mild disease, or no actual RA.

The study included patients with a RA diagnosis on at least two office visits and a filled immunosuppressive medication prescription within three months. Among these were 946 cases who had been hospitalized for a cardiovascular event (438 for myocardial infarction, 639 for stroke) during the approximately two-year follow-up period.

The researchers compared each of the cases with 10 age- and sex-matched controls with RA who had not had a cardiovascular event by the time of the patient's index event.

Both groups were predominantly white (93% to 94%) and female (89% to 92%). Rheumatologic care was similar between groups though cases were more likely to have been hospitalized in the year prior to their RA diagnosis (37% versus 31%) and, as might be expected, had more cardiovascular comorbidities and medications than the control group.

In the prescription assistance program, patients received all medications for a copay of without restrictions on the use of immunosuppressive agents. Each medication treatment category was mutually exclusive such that "other cytotoxic agents" included monotherapy and combination therapy but not combinations with methotrexate, biologics or glucocorticoids.

When the investigators analyzed the event rates for myocardial infarction and stroke separately, the results were similar to those of the composite findings but with widely overlapping confidence intervals. Analyses looking at glucocorticoids according to average daily dosage and cumulative dosage revealed no gradient of cardiovascular risk.

The study was limited by lack of data on important cardiovascular risk factors such as smoking and Framingham risk score and out-of-hospital events.

Also, there were no data on underlying RA severity. If patients with more severe disease who were more likely to develop cardiovascular events preferentially were channeled to the more potent methotrexate and biologic agents, there may have been a false bias against these medications.

"When studying the cardiovascular effects of an immunosuppressive agent," Dr. Solomon and colleagues wrote, "it is difficult to disentangle the effects of the medications from the underlying [RA] and its severity."

They noted that the increased cardiovascular risk found for the cytotoxic agents other than methotrexate may have been due to drug-induced hypertension, but may also reflect suboptimal control of inflammation by these agents compared to methotrexate.

Randomized, controlled studies should be done to better understand the effects of immunosuppressive agents on cardiovascular outcomes among patients with rheumatoid arthritis, the investigators concluded.

The study was supported by the Engalitcheff Arthritis Outcomes Initiative. Other relevant grant support was provided by the Arthritis Foundation, NIH, Merck, Pfizer, and Savient.

Michael, E. Weinblatt, M.D., a co-author, reported receiving consulting fees from Abbott (more than ,000) and from Amgen, Wyeth, Centocor, Bristol-Myers Squibb, VCB, Genentech, and Roche (less than ,000 each).