Olumiant ® (baricitinib)

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What is the incidence of arterial thrombotic events in the Olumiant® (baricitinib) rheumatoid arthritis clinical trials?

At all baricitinib doses with a maximum exposure of 9.3 years, 72 (1.9%) patients reported an arterial thrombotic event with an EAIR of 0.48 per 100 PYE.

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Arterial Thrombotic Events in the Rheumatoid Arthritis Clinical Development Program

Incidence of Arterial Thrombotic Events in the Baricitinib Clinical Development Program

Arterial thrombotic events included

  • positively adjudicated cardiovascular events of myocardial infarction and ischemic stroke as well as
  • the following MedDRA preferred terms indicative of ATEs
    • amaurosis
    • cardiac ventricular thrombosis
    • cerebrovascular accident
    • hemiparesis
    • peripheral arterial occlusive disease
    • peripheral artery thrombosis
    • peripheral embolism
    • retinal artery embolism
    • retinal vascular thrombosis
    • transient ischemic attack, and
    • vertebral artery thrombosis.1

The majority of events classified as ATEs were also classified as MACE.1

7-Study Placebo-Controlled Dataset

The 7-study pooled dataset included patients with RA randomized to BARI 4 mg (N=1142, PYE=471.8) or placebo (N=1215, PYE=450.8) from 3 phase 2 studies and 4 phase 3 studies (RA-BEAM, RA-BUILD, RA-BEACON and RA-BALANCE). Patients in the placebo group could have been taking background MTX or other conventional DMARDs. Evaluation time periods included through

  • the 12-week placebo-controlled period in phase 2 studies
  • 16 weeks of assigned treatment before any opportunity for rescue therapy in phase 3 studies, and
  • 24 weeks of assigned treatment or until rescue in phase 3 studies.2

Data from BARI 2 mg (N=479, PYE=185.8) is derived from 4 of these studies in which both BARI 2 mg and BARI 4 mg were options during randomization (2 phase 2 studies as well as RA-BUILD and RA-BEACON).2

Through week 24, TEAEs of ATE were reported for

  • 2 patients in the placebo group (IR=0.4)
  • 2 patients in the BARI 2-mg group (IR=1.0), and
  • 2 patients in the BARI 4-mg group (IR=0.4).1,3

4-Study Extended Dataset

The extended dataset included patients with RA randomized to BARI 4 mg (N=479, PYE=781.1) or BARI 2 mg (N=479, PYE=774.9) from 2 phase 2 and 2 phase 3 studies (RA-BUILD, RA-BEACON) and 1 long term extension study (RA-BEYOND). The evaluation time periods included randomization through last available observation incorporating extension data through 01 September 2019 unless otherwise specified. Data were censored at rescue or dose change.1

    Five patients in the BARI 2-mg and 4 patients in the BARI 4-mg group reported an ATE from the 4-study extended dataset. The EAIR was 0.63 and 0.50 for the BARI 2-mg and the BARI 4-mg groups, respectively.1

    All-BARI-RA Dataset

    The All-BARI-RA analysis set included 3770 patients with RA who received baricitinib at a variety of doses from 1 phase 1, 3 phase 2, and 5 phase 3 studies (RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, and RA-BALANCE). Data include a long-term extension study (RA-BEYOND) with

    • 14,744 patient-years of exposure (PYE) to baricitinib
    • 15,114 patient-years (PY) overall observation including time on baricitinib and follow up
    • median exposure of 4.6 years, and
    • maximum exposure of 9.3 years.4

    At all BARI doses with a maximum exposure of 9.3 years, 72 (1.9%) patients reported an ATE with an EAIR of 0.48 per 100 PYE.1 Of these 72 patients who reported 1 or more ATE,

    • 36 patients had ischemic/embolic stroke or transient ischemic attack (27 events were positively adjudicated ischemic stroke [EAIR=0.19])
    • 32 patients had MI (24 events were positively adjudicated [EAIR=0.17])
    • 4 patients had peripheral artery embolism/thrombosis (EAIR=0.03), and
    • 1 patient had retinal artery embolism (EAIR=0.01).1

    Of the total ATE cases, 83% met serious criteria (60/72) and there were 10 deaths including

    • acute MI (5 patients)
    • MI (2 patients)
    • ischemic stroke (2 patients), and
    • basilar artery thrombosis (1 patient).1

    The IRs per 100 patient-years at risk of ATE by 48-week interval beyond 336 weeks of baricitinib treatment showed that the IRs were stable over time. Events were not found to cluster around the time of baricitinib treatment initiation and also did not increase with longer baricitinib exposure duration (Incidence Rate of ATE by Time Period in Patients in the All-BARI-RA Analysis Set).1

    Incidence Rate of ATE by Time Period in Patients in the All-BARI-RA Analysis Set1

    Abbreviations: ATE = arterial thrombotic event; BARI = baricitinib; n = number of patients in the specified category; NAR = number of patients at risk; PYR = patient-years at risk; RA = rheumatoid arthritis.

    Incidence of Arterial Thromboembolism According to Baricitinib Dose

    In the All-BARI-RA dataset, EAIRs per 100 PYE were calculated for ATEs in the baricitinib 2-mg and baricitinib 4-mg subsets. The EAIRs per 100 PYE for ATE were similar between patients in the baricitinib 2-mg and baricitinib 4-mg subgroups of the All-BARI-RA dataset (Exposure-Adjusted Incidence Rates of Arterial Thromboembolisms in the Baricitinib 2-mg and Baricitinib 4-mg Subsets of the All-BARI-RA Analysis Set).4

    Exposure-Adjusted Incidence Rates of Arterial Thromboembolisms in the Baricitinib 2-mg and Baricitinib 4-mg Subsets of the All-BARI-RA Analysis Seta1

     

    Ever on BARI 2 mg
    (N=1077)
    PYE=2678
    EAIR (95% CI)

    Ever on BARI 4 mg
    (N=3401)
    PYE=11,872
    EAIR (95% CI)

    All BARI RA
    (N=3770)
    PYE=14,744
    EAIR (95% CI)

    ATE

    0.41 (0.21-0.73)

    0.49 (0.37-0.63)

    0.48 (0.37-0.60)

    Abbreviations: ATE = arterial thrombotic events; BARI = baricitinib; EAIR = exposure-adjusted incidence rate; N = number of patients in the safety analysis set; PYE = patient-years of exposure; PY = patient-years; RA = rheumatoid arthritis.

    aEAIRs were calculated in a subset of data from All-BARI-RA that included patients who had ever taken baricitinib 2-mg or 4-mg, based on the dose at the time of the event.

    Risk Factors for Arterial Thromboembolism

    In an analysis from the All-BARI-RA integrated dataset, patients with ATE were older, more likely to be male, and had been diagnosed with RA longer than those without ATE. The incidence of ATE was also associated with common risk factors for CVD including smoking, hypertension, diabetes, atherosclerotic disorder, and hypercholesterolemia at the start of baricitinib treatment (Cardiovascular Risk Factors Present at Baseline for Patients With and Without ATE in the All-BARI-RA Analysis Set).1,3

    Cardiovascular Risk Factors Present at Baseline for Patients With and Without ATE in the All-BARI-RA Analysis Set1

    CV Risk Factor at Baseline

    Patients With ATE 
    (n=72)

    Patients Without ATE 
    (n=3698)

    IR per 100 PYR (95% CI) for Patients With Risk Factors

    Mean age, years

    59.8

    52.3

    NR

    Male, %

    31 (43.1)

    756 (20.4)

    0.96 (0.65-1.36)

    Mean duration since RA diagnosis, years

    10.1

    7.7

    NR

    Hypercholesterolemia,a n (%)

    48 (66.7)

    1755 (47.5)

    0.69 (0.51-0.91)

    HDL cholesterol <40 mg/d, n (%)

    8 (11.1)

    300 (8.1)

    0.62 (0.27-1.22)

    DM, n (%)

    13 (18.1)

    322 (8.7)

    1.06 (0.56-1.81)

    Hypertension, n (%)

    39 (54.2)

    1299 (35.1)

    0.75 (0.53-1.02)

    Cardiac disorder (SOC), n (%)

    23 (31.9)

    347 (9.4)

    1.70 (1.08-2.55)

    ASCVD, n (%)

    6 (8.3)

    87 (2.4)

    1.94 (0.71-4.22)

    Current smoker, n (%)

    23 (31.9)

    580 (15.7)

    0.85 (0.54-1.27)

    Overweight, n (%)

    28 (39.4)

    1091 (29.5)

    0.62 (0.41-0.89)

    Obese, n (%)

    26 (36.6)

    1074 (29.1)

    0.60 (0.39-0.88)

    Baseline use of systemic corticosteroids, n (%)

    44 (61.1)

    1880 (50.8)

    0.56 (0.41-0.75)

    Treatment-emergent thrombocytosis,b n (%)

    4 (5.6)

    164 (4.4)

    0.56 (0.15-1.44)

    Having any of 5 risk factors (current smoker, hypertension, HDL cholesterol <40 mg/dL, DM, ASCVD), n (%)

    ≥1

    55 (76.4)

    1917 (51.8)

    0.68 (0.52-0.89)

    ≥2

    24 (33.3)

    555 (15.0)

    1.07 (0.69-1.59)

    ≥3

    8 (11.1)

    105 (2.8)

    1.84 (0.80-3.63)

    Abbreviations: ASCVD = arteriosclerotic cardiovascular disease; ATE = arterial thrombotic events; BARI = baricitinib; CV = cardiovascular; DM = diabetes mellitus; HDL = high-density lipoprotein; IR = incidence rate; LDL = low-density lipoprotein; n = number of patients in the specified category; NR = not reported; PYR = patient-years at risk; RA = rheumatoid arthritis; SOC = system organ class.

    aHypercholesterolemia was defined by baseline total cholesterol ≥200 mg/dL or LDL ≥130 mg/dL, or event with relevant preferred terms.

    bFor “patients with ATE,” thrombocytosis was defined as an increase in platelet count from the originating study maximum baseline value of ≤600 billion cells/L to any postbaseline value >600 billion cells/L prior to the ATE onset. For “patients without ATE” and “All BARI RA,” thrombocytosis was defined as an increase in platelet count from the originating study maximum baseline value of ≤600 billion/L to any postbaseline value >600 billion cells/L in the treatment period.

    Information from the label

    Arterial thrombotic events are not specifically mentioned in the Summary of Product Characteristics, but please note the following related to DVT and PE.5

    Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib.5

    Baricitinib should be used with caution in patients with risk factors for DVT/PE, such as

    • older age,
    • obesity,
    • a medical history of DVT/PE, or
    • patients undergoing surgery and immobilisation.5

    If clinical features of DVT/PE occur, baricitinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.5

    DVT and PE are listed as uncommon in the table of adverse reactions in the Summary of Product Characteristics.5

    References

    1Data on file, Eli Lilly and Company and/or one of its subsidiaries.

    2Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis. Lancet Rheumatol. 2020;2(6):E347-E357. https://doi.org/10.1016/S2665-9913(20)30032-1

    3Taylor PC, Weinblatt ME, Burmester GR, et al. Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis. Arthritis Rheumatol. 2019;71(7):1042-1055. https://dx.doi.org/10.1002/art.40841

    4Taylor PC, Takeuchi T, Burmester GR, et al. Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database. Ann Rheum Dis. Published online October 27, 2021. https://doi.org/10.1136/annrheumdis-2021-221276

    5Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

    Date of Last Review: 01 December 2021


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