Cardiovascular Safety of Tocilizumab Versus Tumor Necrosis Factor Inhibitors in Patients With Rheumatoid Arthritis: A Multi-Database Cohort Study

Seoyoung C Kim, Daniel H Solomon, James R Rogers, Sara Gale, Micki Klearman, Khaled Sarsour, Sebastian Schneeweiss, Seoyoung C Kim, Daniel H Solomon, James R Rogers, Sara Gale, Micki Klearman, Khaled Sarsour, Sebastian Schneeweiss

Abstract

Objective: While tocilizumab (TCZ) is known to increase low-density lipoprotein (LDL) cholesterol levels, it is unclear whether TCZ increases cardiovascular risk in patients with rheumatoid arthritis (RA). This study was undertaken to compare the cardiovascular risk associated with receiving TCZ versus tumor necrosis factor inhibitors (TNFi).

Methods: To examine comparative cardiovascular safety, we conducted a cohort study of RA patients who newly started TCZ or TNFi using claims data from Medicare, IMS PharMetrics, and MarketScan. All patients were required to have previously used a different TNFi, abatacept, or tofacitinib. The primary outcome measure was a composite cardiovascular end point of hospitalization for myocardial infarction or stroke. TCZ initiators were propensity score matched to TNFi initiators with a variable ratio of 1:3 within each database, controlling for >65 baseline characteristics. A fixed-effects model combined database-specific hazard ratios (HRs).

Results: We included 9,218 TCZ initiators propensity score matched to 18,810 TNFi initiators across all 3 databases. The mean age was 72 years in Medicare, 51 in PharMetrics, and 53 in MarketScan. Cardiovascular disease was present at baseline in 14.3% of TCZ initiators and 13.5% of TNFi initiators. During the study period (mean ± SD 0.9 ± 0.7 years; maximum 4.5 years), 125 composite cardiovascular events occurred, resulting in an incidence rate of 0.52 per 100 person-years for TCZ initiators and 0.59 per 100 person-years for TNFi initiators. The risk of cardiovascular events associated with TCZ use versus TNFi use was similar across all 3 databases, with a combined HR of 0.84 (95% confidence interval 0.56-1.26).

Conclusion: This multi-database population-based cohort study showed no evidence of an increased cardiovascular risk among RA patients who switched from a different biologic drug or tofacitinib to TCZ versus to a TNFi.

© 2017, The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Figures

Figure 1
Figure 1
Study design overview. Patients with rheumatoid arthritis (RA) who had not received tocilizumab (TCZ) or tumor necrosis factor inhibitors (TNFi) in the previous 365 days were enrolled in the TCZ cohort or TNFi cohort, respectively. The index date was defined as the date of first TCZ dispensing or the date of switching to a new TNFi after being treated with at least 1 other biologic drug (i.e., abatacept, TNFi, or tofacitinib). Dx = diagnosis; Rx = prescription.
Figure 2
Figure 2
Selection of the study cohort. After the inclusion and exclusion criteria were applied, the study cohort included a total of 40,119 patients with rheumatoid arthritis (RA) who started treatment with tocilizumab (TCZ) or a tumor necrosis factor inhibitor (TNFi), including 9,146 from the Medicare database, 12,826 from the PharMetrics database, and 18,147 from the MarketScan database. After propensity score (PS) matching with a variable ratio of up to 1:3, the final cohort consisted of 28,028 patients, including 9,218 TCZ initiators and 18,810 TNFi initiators. Dx = diagnosis.
Figure 3
Figure 3
Secondary end points in a 1:3 variable ratio propensity score–matched as‐treated analysis of rheumatoid arthritis patients starting treatment with tocilizumab (TCZ) or a tumor necrosis factor inhibitor (TNFi). Hazard ratios (HRs) were combined using an inverse variance‐weighted, fixed‐effects model. A “secondary definition of cardiovascular (CV) event” refers to a discharge diagnosis of myocardial infarction in the principal position for any length of hospitalization or a hospital discharge diagnosis of ischemic or hemorrhagic stroke in the principal position. “Any CV event” includes myocardial infarction, stroke, coronary revascularization, or acute coronary syndrome. 95% CI = 95% confidence interval.
Figure 4
Figure 4
Subgroup analysis in a 1:3 variable ratio propensity score–matched as‐treated analysis of rheumatoid arthritis patients starting treatment with tocilizumab (TCZ) or a tumor necrosis factor inhibitor (TNFi). Hazard ratios (HRs) were combined by an inverse variance‐weighted, fixed‐effects model. For the age

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