VTE in global registry data more common in JAK inhibitor-treated RA patients

The occurrence of major cardiovascular events (MACEs) and venous thromboembolism (VTE) in JAK inhibitor-treated patients with rheumatoid arthritis (RA) was the focus of a large register-based study. It found an increase of VTE with JAK inhibition, as well as MACEs, the latter only in cases reported by physicians.

“With the recently published ORAL Surveillance study, some concerns have been raised about cardiovascular and thromboembolic risks associated with tofacitinib in comparison to anti-TNF,” Prof. Adeline Ruyssen-Witrand (Toulouse University Hospital, France) said, referring to a post-authorisation trial in older patients with RA (NCT02092467) [1,2]. Due to these safety warnings, the French study analysed data from The World Health Organization Global Individual Case Safety Report (VigiBase®), which encompasses worldwide data on side effects [1]. In VigiBase®, physicians and non-physicians can submit cases.

Prerequisites for case selection were patients with RA aged 18–75 years, who had adverse events related to JAK inhibitors or anti-TNF medication. MACEs, i.e. myocardial infarction, stroke, and cardiovascular death, as well as VTE in terms of pulmonary embolism and deep vein thrombosis, were classified as events of interest. Out of 16 million declared cases between 2011 and 2022, 50,694 were RA patients on JAK inhibitors, and 239,914 received anti-TNFs.

The analysis revealed MACEs in 817 JAK inhibitor-treated patients and 3,379 patients treated with anti-TNF, with 23% and 33% registered by physicians, respectively. As for VTE, reports were found in 596 and 818 cases in patients treated with JAK inhibitors and anti-TNFs, respectively, with 46% and 38% entering the database upon physician notification. Overall, most patients were 60 years of age or older.

The study found no increase in MACEs with JAK inhibition in the disproportionality analysis in the entire population. “However, after stratification on the source of reporting, meaning physician versus non-physician, we could observe a slight increase of reported MACEs with JAK inhibitors in comparison with anti-TNF, as well as an increase of myocardial infarction, in the physician reports,” Prof. Ruyssen-Witrand said. This was significantly indicated by adjusted reporting odds ratios (ROR) of 1.45 (MACEs) and 1.70 (myocardial infarction) in the physician-reported subgroups.

Regarding VTE, an increased risk associated with JAK inhibitors was found in the main analysis (ROR 3.48) and also after stratification according to physician (ROR 8.51) and non-physician reports (ROR 1.96). At further stratification according to the date of declaration in VigiBase®, there was an increase after the authority alerts. However, Prof. Ruyssen-Witrand underlined that in the year prior to these alerts, the study results already revealed an increase in risk for the 2 events with JAK inhibitors compared with anti-TNFs, with an odds ratio of 1.24 for MACEs and 1.84 for VTE.

Nonetheless, the selective outcome reporting might be a study limitation, giving a negative bias against JAK inhibitors. Prof. Ruyssen-Witrand concluded that this kind of analysis can be very useful for clinicians to detect early safety signals after a new drug marketing use, especially when focusing on physician-declared cases.

1. Ruyssen-Witrand A, et al. Comparison of major cardiovascular and thromboembolic events in safety reports between rheumatoid arthritis patients treated with JAK-inhibitors versus anti-TNF: results from VigiBase®. OP0268, EULAR 2022 Congress, 1–4 June, Copenhagen, Denmark.
2. Ytterberg SR, et al. N Engl J Med. 2022;386:316–326.

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Posted on 21 July 202220 February 2024