Olumiant® ▼ (baricitinib)

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Olumiant® ▼ (baricitinib): Incidence of Arterial Thombotic Events in the Clinical Development Program

Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, some fatal, have occurred in patients treated with BARI. Patients with symptoms of thrombosis should be evaluated promptly.

Arterial Thrombotic Events in the Rheumatoid Arthritis Clinical Development Program

Arterial Thrombotic Event Risk in Patients With Rheumatoid Arthritis

Patients with RA have increased cardiovascular risk, including arterial and venous occlusive events.1-6

Compared with patients without RA, patients with RA have a 1.5 times greater risk of CVD, including

  • myocardial infarction

  • stroke

  • heart failure, and

  • peripheral vascular disease.7

That increased risk exists even in patients without traditional risk factors for CVD such as

  • smoking

  • hypertension

  • diabetes, and

  • hyperlipidemia.7

Exclusion Criteria Potentially Related to Arterial Thrombotic Events in the Baricitinib Clinical Development Program

In the 4 phase 3 BARI clinical trials, RA-BEGIN, RA-BEAM, RA-BUILD, and RA-BEACON, eligibility criteria relating to ATEs excluded patients who

  • have screening electrocardiogram abnormalities that, in the opinion of the investigator or the sponsor, are clinically significant and indicate an unacceptable risk for the patient’s participation in the study, such as Fridericia’s corrected QT interval >500 milliseconds

  • within 12 weeks of study entry have experienced 

    • myocardial infarction

    • unstable ischemic heart disease

    • stroke, or

    • have New York Heart Association stage IV heart failure.8

Incidence of Arterial Thrombotic Events in the Baricitinib Clinical Development Program

Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, some fatal, have occurred in patients treated with BARI. 8

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.8

The majority of events classified as ATEs were also classified as MACE.8

  • 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, 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.9

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).9

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).8,10

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.8

Two patients in the BARI 2-mg and 2 patients in the BARI 4-mg group reported an ATE from the 4-study extended dataset. The IR was 0.25 and 0.25 per 100 PYE for the BARI 2-mg and the BARI 4-mg groups, respectively.8

All BARI RA Dataset

The All BARI RA analysis set included 3770 patients with RA who received BARI 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, RA-BALANCE). Data includes a long-term extension study (RA-BEYOND) with

  • 13,148 PYE,

  • median exposure of 4.2 yrs,

  • maximum exposure of 8.4 yrs, and

  • data through 01 September 2019.11,12

At all BARI doses with a maximum exposure of 8.4 years,  69 patients reported an ATE with an IR of 0.52 per 100 PYE.8

This IR of 0.52 is consistent with data presented the previous All BARI RA integrated data with 10,127 total PYE (median 3.1 years, maximum 6.9 years) as depicted over time intervals inFigure 1.8,9

Figure 1. Arterial Thrombotic Event* Incidence Rates Over Time in the All BARI RA Dataset 8

Abbreviations: ATE = arterial thromboembolism; BARI = baricitinib; MACE = major cardiovascular event; MedDRA = Medical Dictionary for Regulatory Activities; MI = myocardial infarction; PYE = patient years exposure; RA = rheumatoid arthritis.

* ATE included positively adjudicated MI and thrombotic stroke, which were also counted as MACE, plus MedDRA preferred terms indicative of other acute ATE; adjudicated in phase 3 for applicable event types.

In an analysis from the All BARI RA integrated dataset with 7,860 total PYE, the incidence of ATE was associated with common risk factors for CVD such as older age, male gender, obesity, hypertension and hypercholesterolemia as shown in Table 1.8,10

Table 1. Characteristics of Patients Who Reported an ATE in the All BARI RA Dataset With 7,860 Total PYE8,10

Patient Characteristic

All BARI RA Dataset (N=3492)

n (%)

With ATE (N=35)

n (%)

Age, y

18-49

1270 (36.4)

6 (17.1)

50-59

1125 (32.2)

9 (25.7)

60

1097 (31.4)

20 (57.1)

Gender

Male

732 (21.0)

14 (40.0)

Female

2760 (79.0)

21 (60.0)

BMI

Underweight (<18.5 kg/m2)

142 (4.1)

1 (2.9)

Normal or Underweight (≥18.5 and <20 kg/m2)

1245 (35.7)

7 (20.0)

Overweight (≥25 and <30 kg/m2)

1040 (29.8)

12 (34.3)

Obese (≥30 kg/m2)

1061 (30.4)

15 (42.9)

Missing

4 (0.1)

0

Cigarette Smoking

573 (16.4)

11 (31.4)

ASCVDa

92 (2.6)

3 (8.6)

CD MedDRA SOC

347 (9.9)

13 (37.1)

Hypertension

1270 (36.4)

20 (57.1)

Diabetes

192 (5.5)

2 (5.7)

Hypercholesterolemia

1713 (49.1)

26 (74.3)

Abbreviations: ASCVD = arteriosclerotic cardiovascular event; ATE = arterial thromboembolism; BARI = baricitinib; BMI = body mass index; CD MedDRA SOC = cardiac disease MedDRA system organ class; RA = rheumatoid arthritis.

a Defined at baseline by medical history of myocardial infarction, coronary artery bypass, stroke, transient ischemic attack, or peripheral vascular disease.

Information from the label

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib. 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. If clinical features of DVT/PE occur, baricitinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.13

DVT and PE are listed as uncommon in the table of adverse reactions in the summary of product characteristics.13

Arterial thrombotic events are not listed among the adverse events listed in the summary of product characteristics.13

References

1. Choi HK, Rho YH, Zhu Y, et al. The risk of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a UK population-based outpatient cohort study. Ann Rheum Dis 2013;72(7):1182-1187. http://dx.doi.org/10.1136/annrheumdis-2012-201669

2. Holmqvist ME, Neovius M, Eriksson J, et al. Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization. JAMA. 2012;308(13):1350-1356. http://dx.doi.org/10.1001/2012.jama.11741

3. Davies R, Galloway JB, Watson KD, et al. Venous thrombotic events are not increased in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2011;70(10):1831-1834. http://dx.doi.org/10.1136/ard.2011.153536

4. Romero-Díaz J, García-Sosa I, Sánchez-Guerrero J. Thrombosis in systemic lupus erythematosus and other autoimmune diseases of recent onset. J Rheumatol. 2009;36(1):68-75. http://www.jrheum.org/content/36/1/68.long

5. Ogdie A, Kay McGill N, Shin DB, et al. Risk of venous thromboembolism in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a general population-based cohort study. Eur Heart J. 2018;39(39):3608-3614. http://dx.doi.org/10.1093/eurheartj/ehx145

6. Kim SC, Schneeweiss S, Liu J, Solomon DH. Risk of venous thromboembolism in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2013;65(10):1600-1607. http://dx.doi.org/10.1002/acr.22039

7. Mackey RH, Kuller LH, Moreland LW. Update on cardiovascular disease risk in patients with rheumatic diseases. Rheum Dis Clin N Am. 2018;44(3):475-487. https://doi.org/10.1016/j.rdc.2018.03.006

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

9. Genovese MC, Smolen JS, Tsutomu 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

10. Taylor PC, Weinblatt ME, Burmester GR, et al. Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis [published online January 21, 2019]. Arthritis Rheumatol. https://dx.doi.org/10.1002/art.40841

11. Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis [abstract]. Ann Rheum Dis. 2020;79(suppl 1):638. http://scientific.sparx-ip.net/archiveeular/?c=a&view=4&item=2020FRI0123

12. Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis. Poster presented at: European League Against Rheumatism Virtual Congress; June 3-6, 2020.

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

Glossary

ATE = arterial thrombotic event

BARI = baricitinib

CVD = cardiovascular disease

IR = incidence rate

MACE = major adverse cardiovascular event

MedDRA = Medical Dictionary for Regulatory Activities

MI = myocardial infarction

PYE = patient-years of exposure

RA = rheumatoid arthritis

TEAE = treatment-emergent adverse event

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Date of Last Review: June 08, 2020

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