Meta-analysis queries VTE risk associated with JAK inhibitors in clinical trials
medwireNews: A meta-analysis of randomized controlled trials (RCTs) has found no significant association between Janus kinase (JAK) inhibitor use and the risk for venous thromboembolism (VTE) among patients with immune-mediated inflammatory diseases.
“There remains considerable uncertainty about any link between JAK [inhibitor] therapy and VTE events,” say Mark Yates (King's College London, UK) and co-authors, noting that regulatory agencies in the USA and Europe have added warnings about VTE risk to the labels for approved JAK inhibitors “based upon a small number of randomised controlled trials” and long-term extension studies (LTEs).
The meta-analysis included 42 placebo-controlled phase 2 and 3 RCTs of tofacitinib, baricitinib, upadacitinib, or filgotinib, involving a total of 12,207 participants treated with a JAK inhibitor and 5062 given placebo. In all, 29 trials involved patients with inflammatory arthritis, seven involved people with psoriasis, and six involved those with inflammatory bowel disease. LTEs were excluded from the meta-analysis.
Yates and team report that 15 VTE events occurred over 6542 patient exposure–years (PEY) to a JAK inhibitor, compared with four events during 1578 PEY to placebo, equating to rates per 100 PEY of 0.23 and 0.25, respectively, and a nonsignificant incidence rate ratio (IRR) of 0.68.
These findings “confirm that VTE risk is unlikely to be substantially increased in those on JAK [inhibitor] therapy compared to placebo,” write the study authors in Arthritis & Rheumatology. However, they say that “given the low event rates and thus precision of the data, a true effect involving a small increase in risk cannot be ruled out, and neither can small to large protective effects.”
The researchers also caution that “[t]he studies included in this meta-analysis are RCTs with tight inclusion/exclusion criteria that limits the external validity of findings.”
“Patients at the highest risk of VTE, such as older ages and those with multi-morbidity, may be under represented in the RCTs so extrapolation of the findings to these populations must be done cautiously.”
They note that an “important additional study is currently ongoing to look at the long-term safety of tofacitinib in patients at increased risk of cardiovascular disease,” and interim analysis of the data from this study led the US and European regulatory agencies to issue safety alerts warning against the use of tofacitinib at the higher dose of 10 mg twice daily due to VTE and infection risk.
“When the full study is published it will provide important additional information pertaining to the risk of VTE with JAK [inhibitor] therapy,” they add.
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