Tofacitinib May Increase Risk for Cardiovascular Outcomes in Patients With RA With CV Risk Factors or History of CVD

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Based on results from the ORAL Surveillance trial, researchers of this study assessed the risk for cardiovascular outcomes with tofacitinib in patients with rheumatoid arthritis.

Janus kinase inhibitor tofacitinib is not associated with an increased risk for cardiovascular (CV) outcomes in patients with rheumatoid arthritis (RA); however, patients with CV risk factors or a history of cardiovascular disease (CVD) may be at an elevated risk, according to study results published in Annals of the Rheumatic Diseases.

Recent reports from the ORAL Surveillance postmarketing safety trial indicated an increased risk for major adverse cardiovascular events with tofacitinib compared with tumor necrosis factor inhibitors (TNFis) in patients with RA who were 50 years and older and had at least 1 risk factor for CVD.

To address this, a large observational study (Safety of Tofacitinib in Routine Care Patients with RA [STAR-RA]; Identifier: NCT004772248) was conducted to further examine the CV safety of tofacitinib in patients with RA in the real-world setting.

Using claims data from several databases, patients with RA who were initiated with treatment with tofacitinib or TNFis were selected for inclusion in the current analysis. Researchers identified 2cohorts of patients to compare CV outcomes in tofacitinib vs TNFis: a “real-world evidence” cohort that included all patients with RA and a “randomized controlled trial (RCT)-duplicate cohort” that mimicked the inclusion and exclusion criteria of the ORAL Surveillance trial and allowed direct comparison of results.

Hazard ratios (HRs) for myocardial infarction and stroke were estimated using Cox proportional hazards models with propensity score fine stratification weighting and accounting for 76 potential confounders. Effect estimates were pooled across the databases using fixed effects models with inverse-variance weighting.

The real-world evidence cohort included 102,263 patients (12,852 [12.6%] initiated tofacitinib). The pooled weighted HR for CV outcomes comparing tofacitinib with TNFis was 1.01 (95% CI, 0.83-1.23). 

In the RCT-duplicate cohort, a total of 35,070 patients were included (3497 [10.0%] initiated tofacitinib). The pooled weighted HR for this cohort was 1.24 (95% CI, 0.90-1.69), which closely compared with results from the ORAL Surveillance trial (HR, 1.33; 95% CI, 0.91-1.94).

Study limitations included potential confounding by factors not found in the claims databases, exposure misclassification from incomplete medication adherence, and a lack information on newer Janus kinase inhibitors (baricitinib and upadacitinib).

“Overall, in this multidatabase population-based study, we did not find evidence for an increased risk of CV outcomes with tofacitinib, in comparison with TNFi, among patients with RA treated in the real-world setting,” the researchers concluded. However, concordant with results from ORAL Surveillance safety trial, tofacitinib, in comparison with TNFi, was associated with an elevated risk of CV outcomes, though statistically non-significant, in patients with RA with CV risk factors or a history of CVD.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Khosrow-Khavar F, Kim SC, Lee H, Lee SB, Desai RJ. Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in routine care patients with rheumatoid arthritis (STAR-RA) study. Ann Rheum Dis. Published online January 13, 2022. doi:10.1136/annrheumdis-2021-221915