Cardiovascular risk in rheumatoid arthritis: comparing TNF-α blockade with nonbiologic DMARDs

Abstract

Background: Elevated tumor necrosis factor (TNF)-α likely contributes to the excess cardiovascular risk observed in rheumatoid arthritis. We compared the cardiovascular risk in rheumatoid arthritis patients starting a TNF-α blocking agent versus a nonbiologic disease-modifying antirheumatic drug (nbDMARD).

Methods: Subjects with rheumatoid arthritis participating in several different US insurance programs between 1998 and 2007 who received methotrexate were eligible. Those who added a TNF-α blocking agent were compared with subjects who added a nbDMARD in Cox regression models stratified by propensity score decile and adjusted for oral glucocorticoid dosage. We examined the composite cardiovascular end point of myocardial infarction, stroke, or coronary re-vascularization after 6 months.

Results: We compared 8656 new users of a nbDMARD with 11,587 new users of a TNF-α blocking agent with similar baseline covariates. Incidence rates per 100 person-years for the composite cardiovascular end point were 3.05 (95% confidence interval [CI], 2.54-3.65) for nbDMARDs and 2.52 (95% CI, 2.12-2.98) for TNF-α blocking agents. The hazard ratio (HR) for the TNF-α blocking agent compared with nbDMARD carrying the first exposure forward was 0.80 (95%, CI 0.62-1.04), while the HR for the as-treated analysis was 0.71 (95% CI, 0.52-0.97). The potential cardiovascular benefit of TNF-α blocking agents was strongest among individuals ≥65 years of age (HR 0.52; 95% CI, 0.34 -0.77; P for interaction = 0.075).

Conclusion: Among subjects with rheumatoid arthritis, TNF-α blocking agents may be associated with a reduced risk of cardiovascular events compared with an nbDMARD. Randomized controlled clinical trials should be considered to test this hypothesis.

Keywords: Cardiovascular disease; Rheumatoid arthritis; TNF-α blocking agents.

Figure 1

demonstrates the cohort assembly.

Figure 2

illustrates the event free survival curves through 12 months of follow-up. Panel A uses a first exposure carried forward analysis and Panel B an as-treated analysis. The tables below the panels represent the number of subjects at risk for the composite cardiovascular endpoint at 90 day intervals throughout the first year. For Panel A, the log rank p-value at 180 days was 0.22 and at 365 days was 0.67. For Panel B, the log rank p-value at 180 days was 0.08 and at 365 days was 0.84.

Figure 2

illustrates the event free survival curves through 12 months of follow-up. Panel A uses a first exposure carried forward analysis and Panel B an as-treated analysis. The tables below the panels represent the number of subjects at risk for the composite cardiovascular endpoint at 90 day intervals throughout the first year. For Panel A, the log rank p-value at 180 days was 0.22 and at 365 days was 0.67. For Panel B, the log rank p-value at 180 days was 0.08 and at 365 days was 0.84.

Figure 3

represents the adjusted hazard ratios for the primary and secondary cardiovascular outcomes calculated in Cox proportional hazards regression models.

Figure 4

represents the hazard ratios for the sensitivity analyses with the study cohort stratified by database, age, gender, diabetes or cardiovascular disease, NSAID use, and statin use. These analyses were conducted using the as-treated approach.