Cardiovascular risks associated with Janus kinase inhibitors: peering outside the black box

Area of Science:

• Rheumatology
• Cardiovascular Safety
• Pharmacovigilance

Background:

• The cardiovascular safety of Janus kinase inhibitors (JAKinibs) is controversial following the ORAL Surveillance trial.
• The trial indicated tofacitinib was not non-inferior to tumor necrosis factor-alpha inhibitors (TNFi) for major adverse cardiovascular events (MACE) and venous thromboembolism (VTE) in rheumatoid arthritis (RA) patients with cardiovascular risk factors.

Purpose of the Study:

• To analyze the cardiovascular safety profile of JAKinibs, particularly tofacitinib, in patients with immune-mediated inflammatory diseases.
• To clarify the risks of MACE and VTE associated with JAKinibs based on available trial data and post-marketing surveillance.

Main Methods:

• Review of the ORAL Surveillance trial results and subsequent United States Food and Drug Administration (US FDA) warnings.
• Analysis of data from other trials and long-term follow-up studies of tofacitinib in various autoimmune conditions.
• Examination of post-hoc analyses from the ORAL Surveillance trial and available literature on baricitinib and upadacitinib.

Main Results:

• Tofacitinib demonstrated increased risks of MACE, VTE, and malignancy compared to TNFi in specific RA patient populations.
• Analysis of broader trial data suggests similar MACE/VTE risks for tofacitinib versus TNFi overall, but heightened risks in patients with prior cardiovascular history.
• Insufficient evidence currently exists to extend the MACE/VTE warning to baricitinib and upadacitinib based on available data.

Conclusions:

• The cardiovascular safety of JAKinibs requires careful consideration, especially in high-risk patients.
• Further post-marketing surveillance is crucial to fully elucidate the cardiovascular risks associated with JAKinibs in immune-mediated inflammatory diseases.