• Special warnings and precautions regarding baricitinib and VTE 
• Incidence of VTE in placebo-controlled trials and long term baricitinib exposure
• Incidence of VTE
• Incidence of VTE in real-world studies
• Incidence of VTE in the rheumatoid arthritis real-world population
• Ongoing baricitinib safety trials
• References
• Appendix 1: Integrated analysis datasets used to evaluate safety in rheumatoid arthritis clinical trials
• Appendix 2: Potential risk factors for patients with and without VTE in the All-BARI-RA analysis set  

In a retrospective observational study of baricitinib in rheumatoid arthritis patients, a higher rate of venous thromboembolic events (VTE) was observed compared to patients treated with TNF inhibitors.1

In a large randomized active‑controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a dose dependent higher rate of VTE including deep venous thrombosis (DVT) and pulmonary embolism (PE) was observed with tofacitinib compared to TNF inhibitors.1

In patients with cardiovascular or malignancy risk factors baricitinib should only be used if no suitable treatment alternatives are available.1 

In patients with known VTE risk factors other than cardiovascular or malignancy risk factors, baricitinib should be used with caution.1

VTE risk factors other than cardiovascular or malignancy risk factors include1

• previous VTE,
• patients undergoing major surgery,
• immobilisation,
• use of combined hormonal contraceptives or hormone replacement therapy, and
• inherited coagulation disorder.

Patients should be re‑evaluated periodically during baricitinib treatment to assess for changes in VTE risk.1

Promptly evaluate patients with signs and symptoms of VTE and discontinue baricitinib in patients with suspected VTE, regardless of dose or indication.1

Baricitinib was evaluated in up to 14.744 patient-years of exposure and up to 9.3 years. Please find an overview about the datasets used to evaluate safety in the rheumatoid arthritis clinical trials in Appendix 1: Integrated analysis datasets used to evaluate safety in rheumatoid arthritis clinical trials. All incidence rates were calculated as number of patients with an event per 100 patient-years at risk.2

Incidence of treatment-emergent adverse VTE, DVT and PE in the baricitinib rheumatoid arthritis clinical development program shows the incidence rate of treatment emergent venous thromboembolic (VTE), pulmonary embolism (PE) and deep venous thrombosis (DVT) events in the baricitinib rheumatoid arthritis program.

The incidence rates (IR) of VTE remained stable through exposures up to 9.3 years and fell within the published IR of the rheumatoid arthritis population (0.33 to 0.79 per 100 PYE).2,4-6.

There were 4 patients who died due to pulmonary embolism. None of the deaths were reported as related to baricitinib by the investigator.3

Risk factors possibly associated with VTE events were evaluated from the ALL BARI RA dataset comparing the risks between patients with and without events and characteristics for these patients are provided in Potential Risk Factors for Patients With and Without Venous Thromboembolism in the ALL BARI RA Analysis Set (Total PYE = 14,774 PYE; Maximum Exposure = 9.3 years) .3,7

Factors from the analysis associated with an increased risk for VTE in the ALL BARI RA dataset included

• age ≥50 years
• body mass index (BMI) ≥30 
• history of
  • VTE
  • malignancy
  • chronic cardiac failure, or
  • respiratory failure
• estimated glomerular filtration rate <60 mL/min/1.73m², and
• severe mobility impairment.3,7

In the majority of patients with a reported VTE, concurrent risk factors for developing a VTE were present.3,7

In the All-BARI-RA dataset, 2619 out of 3770 patients were considered at-risk. This was defined as being ≥65 years old or having at least one of the following risk factors: atherosclerotic cardiovascular disease, diabetes mellitus, hypertension, current smoking, high-density lipoprotein cholesterol less than 40 mg/dL, body mass index at least 30, poor mobility on EuroQol-5 Dimension, and history of malignancy (Incidence of venous thromboembolic events in rheumatoid arthritis patients).8

The published incidence rate (IR) of venous thromboembolic events (VTE) among patients with rheumatoid arthritis (RA) in inpatient and outpatient settings ranges from 0.33 to 0.79 per 100 patient years of exposure (PYE).5,6,11,12

To further characterize the VTE IR found for BARI, VTE IRs for the RA population from the Food and Drug Administration's (FDA’s) Sentinel program and Truven Marketscan administrative claims data were assessed. Both Sentinel and Truven administrative claims databases contain information on patients enrolled in US health plans. A subset of the Sentinel program representing 75 million enrolled patients identified over 69,000 users of RA medications. Truven represents over 110 million patients, from which over 205,000 patients with RA medications were identified.11,13-15

While not directly comparable with results from the BARI clinical trial program, venous thromboembolism IRs for RA patients treated with conventional and biologic DMARDs from Sentinel (IR range=0.76 – 3.08) and Truven (IR range=0.76 – 2.96) appear to be within a similar range including when comparing data by age for 50 to 59 year age group.13,14,16

Two randomized, controlled, open-label, phase 3b/4 studies, RA-BRIDGE (NCT03915964) and RA-BRANCH (NCT04086745), are evaluating the safety of high- and low-dose baricitinib compared to adalimumab or etanercept in patients with rheumatoid arthritis who had an inadequate response or intolerance to at least one DMARD. The outcome measures are the time from first dose of study treatment to the first

• venous thromboembolism (primary endpoint)
• arterial thromboembolic event
• major adverse cerebro-cardiovascular event
• malignancy, excluding nonmelanoma skin cancer
• opportunistic infection, and
• serious infection.17,18

In RA-BRIDGE and RA-BRANCH, patients had at least 1 of the following baseline characteristics:

• documented evidence of a prior venous thromboembolism
• aged at least 60 years
• body mass index (BMI) ≥30 kg/m², or
• aged 50 to less than 60 years and have a BMI 25 to <30 kg/m².17,18
  

RA-BRIDGE includes an estimated enrollment of 2600 participants from sites in the United States and outside the United States. The estimated primary completion date is April 2025.18

RA-BRANCH is currently recruiting patients in the United States. The estimated enrollment will be 1300 patients and the estimated primary completion date is December 2024.17