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New analysis assesses the safety of tofacitinib regarding extended MACE

Presented by
Prof. Maya Buch, University of Manchester, United Kingdom
ACR 2022
ORAL Surveillance
A new post-hoc analysis of the ORAL Surveillance study revealed that the risk of a composite of all ischaemic cardiovascular (CV) events and heart failure with tofacitinib appears similar to that with TNF inhibitors. However, the totality of CV risk was elevated with the higher tofacitinib dose versus the TNF inhibitor, most likely due to a higher incidence of venous thromboembolic events (VTE) in patients with rheumatoid arthritis (RA) treated with the JAK inhibitor.

The black box warning of the FDA for JAK inhibitors issued in January 2022 was prompted by the recently published ORAL Surveillance trial (NCT02092467), a post-authorisation safety study of tofacitinib in 2 doses versus TNF inhibitors [1]. This study found an increased risk of major adverse cardiovascular events (MACE) and VTE with tofacitinib versus TNF inhibitors in patients with RA and at least 1 additional CV risk factor [1]. In addition, a post-hoc analysis of this trial revealed a higher risk of MACE with tofacitinib versus TNF inhibitors in patients with a history of atherosclerotic CV disease (ASCVD) [2]. In both these analyses, MACE consisted of a 3-component endpoint (MACE-3): CV death, non-fatal myocardial infarction, and non-fatal stroke.

A new post-hoc analysis presented by Prof. Maya Buch (University of Manchester, United Kingdom) expanded the 3 MACE components by evaluating the risk of all adjudicated CV events with tofacitinib compared with TNF inhibitors [3]. Extended MACE endpoints were based on MACE-3 and sequentially added adjudicated ischaemic CV events, in particular: hospitalisation for unstable angina (in MACE-4), coronary revascularisation procedures (MACE-5), transient ischaemic attack (MACE-6), peripheral vascular disease (MACE-7), and hospitalisation for heart failure (MACE-8). For example, MACE-4 included the risk of MACE-3 plus unstable angina, MACE-5 represented the risk of MACE-4 plus coronary revascularisation procedures, and so on. The totality of CV risk was defined by MACE-8 plus VTE.

“Baseline characteristics were well balanced, with hypertension being the most frequent comorbidity,” Prof. Buch explained. When the researchers analysed the risk of extended MACE endpoints, they noticed that the risk diminished from MACE-4 to -7 with tofacitinib versus TNF inhibitors. “In MACE-7, there was no significant difference compared with TNF inhibitors,” Prof. Buch said. The risk of MACE-8 was similar between both tofacitinib doses and TNF inhibitors. However, the risk of MACE-8 plus VTE was only similar with tofacitinib 5 mg versus TNF inhibitors (HR 1.12; 95% CI 0.82-1.52) but higher with tofacitinib 10 mg versus TNF inhibitors (HR 1.38; 95% CI 1.02-1.85), driven by an increase in VTE.

Whereas the cumulative probability of MACE-3 differed significantly between tofacitinib and TNF inhibitors, the curves of MACE-8 were largely superimposed with only a slight difference in the high tofacitinib dose. However, across extended MACE endpoints, the risk was also numerically higher with tofacitinib versus TNF inhibitors with a history of ASCVD.

A limitation of the analysis was that only low numbers could be included in individual CV events.

“This data highlights the need for a better understanding of the risk of individual CV events in patients with RA,” Prof. Buch concluded.

    1. Ytterberg SR, et al. N Engl J Med. 2022;386:316-26.
    2. Charles-Schoeman et al. Ann Rheum Dis. 2022:ard-2022-222259. Epub ahead of print.
    3. Buch M, et al. Risk of extended major adverse cardiovascular event endpoints with tofacitinib vs TNF inhibitors in patients with rheumatoid arthritis: a post hoc analysis of a phase 3b/4 randomised safety study. L06, ACR Convergence 2022, 10–14 November, Philadelphia, USA.

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