Cardiovascular safety of JAK inhibitors: reassuring results from a real-world study

The incidence of major adverse cardiovascular events (MACE) with the use of JAK inhibitors (JAKi) in registries was not higher compared to therapy with TNF inhibitors (TNFi) in patients with rheumatoid arthritis (RA). Moreover, the risk was not elevated in the subgroup of patients with cardiovascular (CV) risk factors.

The objective of the “JAK-pot” study presented by statistician Mr Romain Aymon (Geneva University Hospital, Switzerland) was to assess the incidence of MACE in RA patients treated with JAKi, compared with biologic agents in a large, multi- country, real-world population [1]. “With our subgroup analysis, we wanted to replicate the main inclusion criteria of the ORAL Surveillance study”, Mr Aymon explained. In the post- authorisation safety trial ORAL Surveillance (NCT02092467), an increased risk of MACE and venous thromboembolism was found during therapy with tofacitinib versus TNFi in patients with RA and at least 1 additional CV risk factor [2]. It led to issued warnings from both European and US authorities, which raised concern about the safety of JAKi.

The data of the “JAK-pot” study was derived from 14 registries from an international collaboration. Patients starting JAKi, TNFi, or biological DMARDs with other modes of action (OMA, namely abatacept, rituximab, sarilumab, or tocilizumab) were included. A sub-analysis was performed on patients of at least 50 years old and with 1 or more CV risk factors, mimicking the ORAL Surveillance inclusion criteria. The exposure period was from treatment initiation until the first of either: 3 months after discontinuation, start of a new treatment, end of participation in the register, or end of the study period.

Across the 50,325 treatment initiations considered, 182 incident MACE were reported. The study did not find a significantly higher risk of MACE in RA patients treated with JAKi compared with TNFi. “The crude incidence rates for JAKi were lower than for TNFi,” Mr Aymon said. However, the adjusted regression analysis demonstrated no significant difference in the incidence of MACE between JAKi versus TNFi (IRR 0.87; 95% CI 0.56–1.35) and OMA versus TNFi (IRR 1.05; 95% CI 0.74–1.49; see Figure).

Figure: Adjusted IRR for MACE according to treatments in the “JAK-pot” study [1].



TNFi, TNF inhibitors; JAKi, JAK inhibitors; OMA, DMARDs with other modes of action; IRR, incidence rate ratio; CI, confidence interval.

The ORAL Surveillance duplicate cohort accounted for 38.4% of treatment courses and had a higher incidence of MACE in each treatment group. But, similarly to the overall population, there was no significant difference in the incidence rates of MACE observed between JAKi versus TNFi (IRR 0.78; 95% CI 0.44–1.38) and OMA versus TNFi (IRR 0.84; 95% CI 0.53–1.32). “There were no differences in any outcomes, only maybe a small venous thromboembolic event signal in the ORAL Surveillance duplicate cohort,” Mr Aymon concluded.

1. Aymon R, et al. Incidence of major adverse cardiovascular events in patients with rheumatoid arthritis treated with JAK-inhibitors compared to bDMARDs: data from an international collaboration of registries (the "JAK-pot" study). OP0219, EULAR 2023, 31 May–3 June, Milan,
2. Ytterberg SR, et N Engl J Med. 2022;386:316-26.

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Posted on 31 July 202316 February 2024