Anti-TNFs Associated With Reduced Cardiovascular Risk in RA

Kate Johnson

June 12, 2012

June 11, 2012 (Berlin, Germany) — In patients with rheumatoid arthritis (RA), tumor necrosis factor (TNF) inhibitors are associated with a significantly lower risk for cardiovascular events than non-TNF agents, according to research presented here at the European League Against Rheumatism Congress 2012.

"The longer the exposure [to TNF inhibitors], the greater the reduction," said lead researcher Michael Nurmohamed, MD, from the VU University Medical Center and Jan van Breemen Research Institute in Amsterdam, the Netherlands.

The study used a composite cardiovascular risk model that included myocardial infarction, unstable angina, congestive heart failure, and stroke; the findings showed no reduced risk for stroke alone, said Dr. Nurmohamed, explaining that "the underlying mechanisms have not been completely elucidated."

The researchers identified 109,462 adults from the US Thomson Reuters MarketScan database (2003 to 2010) with at least 2 International Classification of Diseases, Ninth Revision (ICD-9) code diagnoses of RA who had filled at least 1 prescription for anti-TNF therapy (n = 38,758), methotrexate (n = 45,016), or another nonbiologic disease-modifying antirheumatic drug (DMARD; n = 25,688).

Patients were followed from their index prescription date until their first inpatient cardiovascular diagnosis, to the end of their health plan enrollment, or for 6 months after the discontinuation of the index drug, whichever came first.

The analysis involved 105,920 patient-years of follow-up — 48,621 patient-years of exposure to anti-TNF therapies (31,466 as monotherapy), 35,480 patient-years of exposure to methotrexate (18,325 as monotherapy), and 52,994 patient-years of exposure to other nonbiologic DMARDs (9441 as monotherapy).

A total of 1743 patients (1.6%) had a cardiovascular event after their index prescription. The analysis showed that anti-TNF agents were associated with a reduced risk, compared with patients without anti-TNF exposure (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.80 to 0.96; = .005), after controlling for the cumulative amount of methotrexate and other nonbiologic DMARD exposure. Neither methotrexate (HR, 0.98) nor other nonbiologic DMARDs (HR, 1.00) had a significant impact on risk for a cardiovascular event. When the cardiovascular composite was broken down, the risk for myocardial infarction was most reduced with anti-TNF use (HR, 0.80; 95% CI, 0.67 to 0.95; = .013).

After adjustment for a number of factors — baseline demographics (1 year before index prescription); the use of concomitant RA therapies (methotrexate, nonbiologic DMARDs, or corticosteroids), cardiovascular-related medications, or smoking deterrents; comorbidities such as dyslipidemia, hypertension, or diabetes; and history of cardiovascular events — multivariate regression analysis predicted a risk reduction of 24%, 42%, and 56%, in the first, second, and third years, respectively, of cumulative anti-TNF use, compared with the use of the other therapies, Dr. Nurmohamed reported.

A subgroup analysis of patients 50 years and older revealed a cumulative reduction in cardiovascular events associated with each additional 6 months of anti-TNF therapy (HR, 0.86; 95% CI, 0.77 to 0.96; =.007). The same was true for a subgroup analysis of patients not previously treated with methotrexate (HR, 0.85; 95% CI, 0.73 to 0.98; P =.022).

Decreased Cardiovascular Risk an "Added Bonus," But Not for Congestive Heart Failure

"RA and heart disease have a common origin; the systemic inflammation involved in RA is thought to promote cardiovascular disease and even cardiovascular death. Studies have shown that within the first 10 years of being diagnosed with RA, the risk of a heart attack almost doubles," said Dr. Nurmohamed in a press release. "Because anti-TNFs are now the treatment of choice for patients who are unstable on methotrexate, the decreased cardiovascular risk observed in the study is an added bonus to an already successful class of drugs."

Anti-TNF therapies are contraindicated in people with existing heart failure, said session moderator Deborah Symmons, MD, from the epidemiological unit at Arthritis Research UK in Manchester, United Kingdom. "I don't think, on the basis of this, we could say use [anti-TNFs] in everyone, but obviously...[they are] showing benefit [in cardiovascular risk]," she told Medscape Medical News.

Dr. Symmons noted that it remains unclear why the benefit of anti-TNFs are specific to the heart and not the brain. "You would expect, if it was a mechanistic effect on atherosclerosis, that you would also see a reduction in stroke," she said. However, "stroke is a rarer outcome in this period of follow-up.... It may be that if there's a beneficial effect, it takes longer to become apparent. This is still only in the first 3 years of treatment.... It may be that if you are going to have a stroke, it was set in motion long before and it will take 10 years to see any benefit."

Dr. Nurmohamed reports receiving grants and research support from, being a consultant for, and serving on the speakers bureau for Abbott. Several coauthors are under contract with or are employees of Abbott and shareholders in the company. Dr. Symmons has disclosed no relevant financial relationships.

European League Against Rheumatism (EULAR) Congress 2012: Abstract OP0002. Presented June 6, 2012.


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