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Higher Risk of Major Adverse Cardiovascular Events and Cancers with Tofacitinib

EMA starts safety review of Janus kinase inhibitors used for inflammatory disorders
28 Feb 2022
Population Risk Factor

The European Medicines Agency (EMA) announced on 11 February 2022 that its Pharmacovigilance Risk Assessment Committee (PRAC) has started a review of the safety of Janus kinase (JAK) inhibitors used to treat several chronic inflammatory disorders, in particular rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, ulcerative colitis and atopic dermatitis. The review was prompted by the final results from a clinical study of the JAK inhibitor tofacitinib (Xeljanz).

The study results showed that patients taking tofacitinib for rheumatoid arthritis and who were at risk of heart disease were more likely to experience a major cardiovascular problem (such as heart attack, stroke or death due to cardiovascular disease) and had a higher risk of developing cancer than those treated with medicines belonging to the class of TNF-alpha inhibitors. The study also showed that compared with TNF-alpha inhibitors, tofacitinib was associated with a higher risk of death due to any cause, serious infections and venous thromboembolism (VTE).

In addition, preliminary findings from an observational study involving another JAK inhibitor, baricitinib (Olumiant), also suggest an increased risk of major cardiovascular problems and VTE in patients with rheumatoid arthritis treated with baricitinib compared with those treated with TNF-alpha inhibitors.

In the treatment of inflammatory disorders, baricitinib and other JAK inhibitors work in a similar way to tofacitinib. PRAC will therefore carry out a review to determine whether these risks are associated with all JAK inhibitors authorised in the EU for the treatment of inflammatory disorders and whether the marketing authorisation for these medicines should be amended.

Some measures to minimise these risks are already in place for tofacitinib as a result of a review finalised in 2020, which analysed the interim results of study A3921133. In addition, the product information for tofacitinib was further updated in 2021 to reflect the increased risk of major cardiovascular problems and cancer observed after the release of additional data from this study.

On 27 January 2022, the findings from a randomised, open-label, non-inferiority, post-authorisation, safety endpoint study that involved patients with active rheumatoid arthritis despite methotrexate treatment, who were 50 years of age or older and had at least one additional cardiovascular risk factor and who were randomly assigned in a 1:1:1 ratio to receive tofacitinib at a dose of 5 mg or 10 mg twice daily or a TNF inhibitor were published in The New England Journal of Medicine. The study co-primary endpoints were adjudicated major adverse cardiovascular events and cancers, excluding non-melanoma skin cancer.

In total, 1455 patients received tofacitinib at a dose of 5 mg twice daily, 1456 received tofacitinib at a dose of 10 mg twice daily, and 1451 received a TNF inhibitor. During a median follow-up of 4.0 years, the incidences of major adverse cardiovascular events and cancer were higher with the combined tofacitinib doses (3.4% [98 patients] and 4.2% [122 patients], respectively) than with a TNF inhibitor (2.5% [37 patients] and 2.9% [42 patients]).

The hazard ratios were 1.33 (95% confidence interval [CI] 0.91 to 1.94) for major adverse cardiovascular events and 1.48 (95% CI 1.04 to 2.09) for cancers.

The non-inferiority of tofacitinib was not shown.

The incidences of adjudicated opportunistic infections (including herpes zoster and tuberculosis), all herpes zoster (non-serious and serious), and adjudicated non-melanoma skin cancer were higher with tofacitinib than with a TNF inhibitor.

Efficacy was similar in all three groups, with improvements from month 2 that were sustained through study completion.

The study authors concluded that in a cardiovascular risk–enriched population, risks of major adverse cardiovascular events and cancers were higher with tofacitinib and did not meet non-inferiority criteria. Several adverse events were more common with tofacitinib.


Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med 2022;386:316-326.

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