Cardiovascular Safety During Treatment With Baricitinib in Rheumatoid Arthritis

Abstract

Objective To assess the frequency of cardiovascular and venous thromboembolic events in clinical studies of baricitinib, an oral, selective JAK1 and JAK2 inhibitor approved in more than 50 countries for the treatment of moderately‐to‐severely active rheumatoid arthritis (RA). Methods Data were pooled from 9 RA studies. Placebo comparison up to 24 weeks included data from 6 studies. Randomized dose comparison between baricitinib doses of 2 mg and 4 mg used data from 4 studies and from the associated long‐term extension study. The data analysis set designated “All‐bari‐RA” included all baricitinib exposures at any dose. Results Overall, 3,492 RA patients received baricitinib (7,860 patient‐years of exposure). No imbalance compared to the placebo group was seen in the incidence of major adverse cardiovascular events (MACE) (incidence rates [IRs] of 0.5 per 100 patient‐years for placebo and 0.8 per 100 patient‐years for 4 mg baricitinib), arterial thrombotic events (ATE) (IRs of 0.5 per 100 patient‐years for placebo and 0.5 per 100 patient‐years for 4 mg baricitinib), or congestive heart failure (CHF) broad term (IRs of 4.3 per 100 patient‐years for placebo and 2.4 per 100 patient‐years for 4 mg baricitinib). Deep vein thrombosis (DVT)/pulmonary embolism (PE) were reported in 0 of 1,070 patients treated with placebo and 6 of 997 patients treated with 4 mg baricitinib during the placebo‐controlled period; these events were serious in 2 of 6 patients, while all 6 had risk factors and 1 patient developed DVT/PE after discontinuation of the study drug. In the 2 mg–4 mg‐extended data analysis set, IRs of DVT/PE were comparable between the doses across event types (IRs of 0.5 per 100 patient‐years in those receiving 2 mg baricitinib and 0.6 per 100 patient‐years in those receiving 4 mg baricitinib). In the All‐bari‐RA data analysis set, the rates were stable over time, with an IR of DVT/PE of 0.5 per 100 patient‐years. Conclusion In RA clinical trials, no association was found between baricitinib treatment and the incidence of MACE, ATE, or CHF. With regard to incidence of DVT/PE, 6 events occurred in patients treated with 4 mg baricitinib, but no cases of DVT/PE were reported in the placebo group. During longer‐term evaluation, the incidence of DVT/PE was similar between the baricitinib dose groups, with consistent IR values over time, and this was similar to the rates previously reported in patients with RA.

Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double‐Blind, Randomized Controlled Trial

“…Two GI perforations were reported in the upadacitinib arm; however, these were not spontaneous perforations, but rather 1 was a case of peritonitis and 1 was an anal abscess. In this trial, VTEs were reported in all treatment arms, consistent with the reported background risk for VTE in RA irrespective of the treatment (41)(42)(43)(44)(45). The proportion of patients with VTEs was balanced in the first 6 months of this trial across all treatment arms, including placebo and adalimumab.…”

An Integrated Analysis of the Safety of Tofacitinib in Psoriatic Arthritis across Phase III and Long-Term Extension Studies with Comparison to Real-World Observational Data

“…Patients in the A3921133 randomized, endpoint-driven postauthorization safety study had a diagnosis of RA, were aged ≥ 50 years, and had one or more cardiovascular risk factor. Based on the safety analysis of study A3921133 and knowledge of the safety profile of other Janus kinase inhibitors [49,50], venous thromboembolism events (including deep vein thrombosis and PE) were identified as an important risk for treatment with tofacitinib, irrespective of dose. Subsequently, thromboembolism was added as a warning and as an adverse drug reaction to the current product labeling for tofacitinib.…”

Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme

“…DVT/PE events have been reported in rheumatoid arthritis clinical studies of other Janus kinase inhibitors including baricitinib (all baricitinib doses: DVT IR: 0.4; PE IR: 0.2) and upadacitinib (all upadacitinib doses: DVT: 0/329 patients through Week 12; 1/498 patients through Week 24; PE: 2/329 patients through Week 12; 6/498 patients through Week 24) . All patients with DVT/PE events in the rheumatoid arthritis studies of the Janus kinase inhibitors baricitinib and upadacitinib had additional DVT/PE risk factors …”

“…doses. 5 7,8 Reported literature values for IRs of thromboembolic events among persons with rheumatoid arthritis treated with a variety of biologic and/or conventional therapies ranged between 0.04-0.79. [9][10][11][12][13][14][15][16][17][18][19][20][21][22] Rheumatoid arthritis is a known risk factor for DVT/PE events, with a risk ratio for DVT of 2.08 and a risk ratio for PE of 2.17 for rheumatoid arthritis vs nonrheumatoid arthritis, based on a metaanalysis of nine observational studies in patients with rheumatoid arthritis.…”