Olumiant ® (baricitinib)

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Olumiant® (baricitinib): What was the incidence of major adverse cardiovascular events in patients with atopic dermatitis?

Of the 2636 adult patients in the AD trials treated with baricitinib over a median of 1.6 and up to 3.9 years, 7 (IR=0.15) reported MACE. Baricitinib should be used with caution in patients with risk factors for MACE.

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Incidence of Major Adverse Cardiovascular Events in the BREEZE-AD Clinical Development Program

During the atopic dermatitis (AD) clinical trials, major adverse cardiovascular events (MACE) were identified by the investigative site or through medical review and were sent to a blinded external Clinical Event Committee for adjudication.1

Positively adjudicated MACE included

  • cardiovascular (CV) death
  • myocardial infarctions, and
  • stroke.1

Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials describes the integrated safety datasets used to evaluate MACE.

The incidence of MACE across all safety datasets is presented in Major Adverse Cardiovascular Events in the Baricitinib Atopic Dermatitis Clinical Trials.

Major Adverse Cardiovascular Events in the Baricitinib Atopic Dermatitis Clinical Trials1,2

 

Placebo-Controlled
(to week 16)
n (adj %) [adj IR]a

BARI 2 mg and 4 mg Extended
(up to 3.9 years)
n [adj IR]a

All BARI AD
(up to 3.9 years)
n [IR]

 

Placebo
n=743

BARI 2 mg
n=576

BARI 4 mg
n=489

BARI 2 mg
n=584

BARI 4 mg
n=497

All doses
N=2636

MACE

0

0

0

1 [0.10]

1 [0.11]

7 [0.15]

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; IR = incidence rate; MACE = major adverse cardiovascular event.

aFor the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (example 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the adverse events to provide appropriate direct comparisons between treatment groups.

All Baricitinib-Treated Patients With Extended Period

In the All BARI AD dataset, 7 (IR=0.15) patients reported 8 MACE events.2

Of these 8 MACE events, there were

  • 2 events of CV death (1 on baricitinib 2 mg and 1 on baricitinib 4 mg)
  • 3 myocardial infarctions (2 on baricitinib 2 mg and 1 on baricitinib 4 mg), and
  • 3 strokes (2 on baricitinib 2 mg and 1 on baricitinib 4 mg).3

One patient on baricitinib 2 mg had both stroke and CV death.3

Baseline Risk Factors

Six of the 7 patients with MACE presented with at least one or more of the following CV risk factors: 

  • history of smoking
  • hypertension
  • diabetes mellitus
  • atherosclerotic cardiovascular disease (ASCVD), and
  • high-density lipoprotein cholesterol <40 mg/dL.3

The one patient with no CV risk factors at baseline had a MACE event of hemorrhagic stroke due to a ruptured cerebral aneurysm.3

Arterial Thrombotic Events

Two myocardial infarctions and one embolic stroke that were adjudicated as MACE were also counted as arterial thromboembolic event (ATE). There were 4 (IR=0.09) ATEs in the All BARI AD dataset.

Exclusion Criteria Related to Cardiovascular Events in the BREEZE-AD Clinical Development Program

In the AD phase 3 clinical trials, eligibility criteria relating to CV events 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
  • have a history of CV disease
  • have a history of recurrent (≥2) venous thromboembolisms (VTE) or are considered at high risk of venous thromboembolism (VTE) as deemed by the investigator
  • within 12 weeks of study entry have experienced
    • myocardial infarction
    • unstable ischemic heart disease
    • stroke, or
    • have New York Heart Association stage III/IV heart failure.1,3

Incidence of Cardiovascular Events in Patients With Atopic Dermatitis

Severe and predominantly active atopic eczema are independently associated with modestly increased risk of cardiovascular (CV) events (approximately 10% to 40% increased risk compared to general population).4,5

Two population-based studies in patients with atopic dermatitis (AD) reported the incidence rates (IRs) of 3 individual components commonly considered in the composite outcome of major adverse cardiovascular event (MACE)

  • myocardial infarction (MI) (IR=0.20)
  • stroke (0.27), and
  • CV death (0.29 to 0.44).4,6

Warnings and Precautions Related to Lipids

In a large randomized active-controlled study of another Janus kinase (JAK) inhibitor (tofacitinib), a higher rate of MACE, including myocardial infarction, stroke and CV death, have been observed compared with tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients 50 years and older with at least one CV risk factor. In a retrospective observational study of baricitinib in RA patients, a higher rate of MACE was observed compared to patients treated with TNF blockers.3,7  

Baricitinib should be used with caution in patients with risk factors for MACE.3

Dose dependent increases in blood lipid parameters were reported in patients treated with baricitinib.8

  • Elevations in low density lipoprotein (LDL) cholesterol decreased to pre- treatment levels in response to statin therapy.
  • Lipid parameters should be assessed approximately 12 weeks following initiation of therapy and thereafter patients should be managed according to international clinical guidelines for hyperlipidaemia.

Please refer to section 4.8 of the Olumiant Summary of Product Characteristics for further information on this topic.

Integrated Safety Datasets Table

Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials1-3,9

Analysis Set

Description

16-Week Placebo-Controlled BARI AD

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, and BREEZE-AD7

Compares BARI 2 mg, BARI 4 mg and placebo.

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 2 mg (n=576, PYE=169.1)
  • BARI 4 mg (n=489, PYE=147.1), or
  • placebo (n=743, PYE=211.8).

Treated for 0 to 16 weeks during the placebo-controlled period.

BARI 2 mg and 4 mg Extended ADa

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD7, and extension study BREEZE-AD3

Compares BARI 2 mg vs BARI 4 mg including extended evaluations

Includes patients with AD from 1 phase 2 and 4 phase 3 studies and any further exposure for those patients in the phase 3 extension study, BREEZE-AD3, who were randomized to

  • BARI 2 mg (n=584, PYE=727.1), or
  • BARI 4 mg (n=497, PYE=800.1).

Data censored at dose or treatment change (rescue, dose switch, or re-randomization to a different BARI dose or placebo) for BREEZE-AD4 and BREEZE-AD3.

All BARI AD

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, BREEZE-AD7, and extension studies BREEZE-AD3, BREEZE-AD6a

No between-group comparisons

Includes 2636 (total PYE=4628.4) patients with AD from 1 phase 2, 5 phase 3, and 2 phase 3 extension studies who received BARI at a variety of doses, including

  • BARI 1 mg (n=605, PYE=441.5)
  • BARI 2 mg (n=1703, PYE=2420.9), and
  • BARI 4 mg (n=1012, PYE=1766.8).

Includes all patients who were exposed to any BARI dose at any time during the studies, either from randomization or from switch or rescue from placebo.

 No censoring of data at dose change.

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; PYE = patient-years of exposure.

aData cut as of November 3, 2021 for BREEZE-AD3 and December 15, 2021 for BREEZE-AD4

Note: BARI 1 mg was studied in pivotal trials, however it is not approved. Please refer to section 4.2 of the Olumiant Summary of Product Characteristics for approved dosage.

References

1Bieber T, Thyssen JP, Reich K, et al. Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials. J Eur Acad Dermatol Venereol. 2021;35(2):476-485. https://doi.org/10.1111/jdv.16948

2Bieber T, Katoh N, Simpson EL, et al. Safety of baricitinib for the treatment of atopic dermatitis over a median of 1.6 and up to 3.9 years treatment: an updated integrated analysis of 8 clinical trials. Poster presented at: 31st Annual European Academy of Dermatology and Venereology Congress; September 7-10, 2022; Milan, Italy.

3Data on file, Eli Lilly and Company and/or one of its subsidiaries.

4Silverwood RJ, Forbes HJ, Abuabara K, et al. Severe and predominantly active atopic eczema in adulthood and long term risk of cardiovascular disease: population based cohort study. BMJ. 2018;361:k1786. https://doi.org/10.1136/bmj.k1786

5Yuan M, Cao WF, Xie XF, et al. Relationship of atopic dermatitis with stroke and myocardial infarction: a meta-analysis. Medicine (Baltimore). 2018;97(49):e13512. https://dx.doi.org/10.1097%2FMD.0000000000013512

6Andersen YMF, Egeberg A, Gislason GH, et al. Risk of myocardial infarction, ischemic stroke, and cardiovascular death in patients with atopic dermatitis. J Allergy Clin Immunol. 2016;138(1):310-312.e3. https://doi.org/10.1016/j.jaci.2016.01.015

7Ytterberg SR, Bhatt DL, Mikuls TR, et al; ORAL Surveillance Investigators. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386(4):316-326. http://dx.doi.org/10.1056/NEJMoa2109927

8Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

9King B, Maari C, Lain E, et al. Extended safety analysis of baricitinib 2 mg in adult patients with atopic dermatitis: an integrated analysis from eight randomized clinical trials. Am J Clin Dermatol. 2021;22(3):395-405. https://doi.org/10.1007/s40257-021-00602-x

Date of Last Review: 25 August 2022


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