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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.
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 Medical Dictionary for Regulatory Activities 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
- A description of the cardiovascular adjudication process as well as a summary of the major cardiovascular events reported in the RA clinical development program, including positively adjudicated myocardial infarction, thrombotic and hemorrhagic stroke, and cardiovascular death, is provided in the separate medical letter titled, “Baricitinib: Major Adverse Cardiovascular Events.”
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, patient years of exposure [PYE]=450.8) from 3 phase 2 studies and 4 phase 3 studies (RA-BEAM, RA-BUILD, RA-BEACON, and RA-BALANCE). Patients could have been taking background methotrexate or other conventional disease modifying antirheumatic drugs. 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) were 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
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 exposure-adjusted incidence rates (EAIRs) were 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
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
|
Ever on BARI 2 mg |
Ever on BARI 4 mg |
All BARI RA |
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
CV Risk Factor at Baseline |
Patients With ATE |
Patients Without ATE |
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
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.5
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.5
In patients with cardiovascular or malignancy risk factors, baricitinib should only be used if no suitable treatment alternatives are available.5
In patients with known VTE risk factors other than cardiovascular or malignancy risk factors, baricitinib should be used with caution.5
VTE risk factors other than cardiovascular or malignancy risk factors include5
- 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.5
Promptly evaluate patients with signs and symptoms of VTE and discontinue baricitinib in patients with suspected VTE, regardless of dose or indication.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. 2022;81(3):335-343. 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