Higher tofacitinib dose raises pulmonary embolism, VTE risks in rheumatoid arthritis
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Key takeaways:
- Patients with RA taking tofacitinib 5 mg did not have elevated risk for cardiovascular events compared with those taking TNF inhibitors.
- Venous thromboembolism risk factors are crucial to consider when choosing treatments, the researchers wrote.
Patients receiving daily tofacitinib doses of 10 mg for rheumatoid arthritis demonstrate an increased risk for venous thromboembolism and pulmonary embolism, compared with those taking TNF inhibitors, according to data.
The study, published in Arthritis & Rheumatology, also found that daily tofacitinib (Xeljanz, Pfizer) 5 mg did not significantly increase risk compared with TNF inhibitors, a dynamic that was “generally consistent” across 6-month intervals, the researchers wrote.
“The ORAL Surveillance trial found a dose-dependent increase in venous thromboembolism (VTE) and pulmonary embolism (PE) events with tofacitinib vs. TNF inhibitors,” Christina Charles-Schoeman, MD, MS, chief of the division of rheumatology at the University of California, Los Angeles, told Healio. “This prompted the current work to further understand the incidence of VTE and PE events over time as well as the individual patient factors associated with VTE risk in the trial.”
To examine VTE and pulmonary embolism incidence and risk over time in patients with RA, Charles-Schoeman and colleagues conducted a post-hoc analysis of data from the ORAL Surveillance trial. That trial had included 4,362 older patients with active RA and at least one cardiovascular risk factor. The patients had been randomly assigned to receive daily tofacitinib 5 mg (n = 1,455), daily tofacitinib 10 mg (n = 1,456) or a TNF inhibitor (n = 1,451) on a weekly or bi-weekly basis.
In the current analysis, the researchers estimated the cumulative probability of VTE in each treatment group using Kaplan-Meier analyses. Exposure-adjusted incidence rates were calculated as the number of patients with a first event of VTE, deep vein thrombosis or pulmonary embolism per 100 patient-years.
Among patients treated with tofacitinib 5 mg, the estimated cumulative probabilities for VTE, deep vein thrombosis and pulmonary embolism were 1.4%, 0.9% and 0.7%, respectively. In patients who received tofacitinib 10 mg, the estimated cumulative probabilities were 4.5%, 1.5% and 3.4%, respectively. Lastly, those treated with TNF inhibitors demonstrated probabilities of 0.8%, 0.6% and 0.3%, respectively.
According to the researchers, exposure-adjusted incidence rates for VTE, deep vein thrombosis and pulmonary embolism were “generally higher” in both tofacitinib doses vs. TNF inhibitors for up to 54 months across 6-month time intervals. In exploratory analyses, the “strongest baseline risk factors” for VTE across all treatments included history of VTE, morbid obesity (BMI 35 kg/m2), age greater than 65 years, and a history of chronic lung disease, they wrote.
“The work showed that VTE occurred throughout the trial and were not restricted to the acute phase after treatment initiation, or increased with longer treatment duration,” Charles-Schoeman said. “This signifies the importance of continued awareness and vigilance for VTE in patients with RA over time, irrespective of treatment — it is well known that RA patients have an increased VTE risk compared to the general population.
“This data emphasizes the need for clinician vigilance of both traditional VTE risk factors as well as the importance of RA disease control,” she added. “Finally, the data further highlighted the dose-dependent relationship of tofacitinib with VTE risk. The cumulative incidence of VTE and PE events were higher with tofacitinib 10mg BID vs. both tofacitinib 5mg BID and TNF inhibitors.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
Registrational clinical trials and registries of Janus kinase inhibitors did not identify a difference in the risk for major adverse cardiovascular events (MACEs), venous thromboembolism, malignancies or infections vs. biologic DMARDs.
The post-marketing ORAL Surveillance trial enrolled patients with rheumatoid arthritis aged older than 50 years with at least one cardiovascular risk factor to assess the relative risk of a JAK inhibitor vs. a TNF inhibitor.
In ORAL Surveillance, tofacitinib was not non-inferior to TNF inhibitor therapy for the occurrence of MACEs and malignancy, although this finding does not mean that tofacitinib is inferior to TNF inhibitor therapy.
Post hoc analyses of the trial data revealed that an age of 65 years or older, a history or high risk for cardiovascular disease, smoking, active RA and suboptimal treatment of cardiovascular comorbidities all increased the risk for primarily MACEs and malignancies, but also venous thromboembolism and serious infections.
The benefit-to-risk ratio of JAK inhibitors strongly favors their use in the vast majority of patients. Guidance from regulatory agencies and professional bodies on the use of JAK inhibitors should be considered carefully to ensure appropriate treatment of patients with RA.
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