Olumiant ® (baricitinib)

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What was the incidence of major adverse cardiovascular events in the Olumiant® (baricitinib) rheumatoid arthritis clinical development program?

In the baricitinib clinical development program, treatment with baricitinib in patients with moderately to severely active rheumatoid arthritis was not associated with an increased risk of MACE.

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Incidence of Cardiovascular Events in Baricitinib Clinical Trials

Cardiovascular Risk in Patients With Rheumatoid Arthritis

Patients with RA have an increased CV risk due to the nature of RA itself.1 Accelerated atherosclerosis caused by inflammation is the hallmark of CV disease in RA.2

An assessment of CV events was incorporated into the BARI phase 3 clinical development program as an event of interest.

Exclusion Criteria Related to Cardiovascular Events in the Baricitinib Rheumatoid Arthritis Clinical Development Program

In the 4 phase 3 clinical trials, RA-BEGIN, RA-BEAM, RA-BUILD, and RA-BEACON, 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, such as Fridericia’s corrected QT interval >500 milliseconds
  • within 12 weeks of study entry have experienced
    • MI
    • unstable ischemic heart disease
    • stroke, or
    • have New York Heart Association stage IV heart failure.3

Cardiovascular Event Adjudication Process in Rheumatoid Arthritis Clinical Trials

An independent, external CEC was established to adjudicate potential CV adverse events for the BARI phase 3 clinical studies. The CEC remained blinded to treatment assignments and assessed each potential event individually.3

Potential CV events were identified to be sent for adjudication

  • by the investigator indicating that a potential event occurred, or
  • by sponsor and independent CEC review of SAE and TEAE MedDRA preferred terms according to a prespecified list to ensure that potential CV events that qualified for adjudication were sent for review.3

Positively adjudicated CV events were categorized as either

  • MACE, which included
    • CV death
    • MI
    • stroke, or
  • other CV event, which included
    • hospitalization for unstable angina
    • hospitalization for heart failure
    • serious arrhythmia
    • resuscitated sudden death
    • cardiogenic shock, or
    • coronary revascularizations.3,4

All cases of death, regardless of the investigator’s assessment as to the cause of death, were also sent for adjudication.3

Integrated Datasets Used to Evaluate Major Adverse Cardiovascular Events in Rheumatoid Arthritis Clinical Trials

The integrated datasets used to evaluate cases of MACE are described in more detail in Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials. The exposure information, including median, maximum and total PYE, and cut-off date described in the table is applicable to the data presented below unless otherwise specified.

Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials3,5,6

Analysis Set

Descriptiona

7-Study Placebo-Controlled Dataset

Studies: JADC, JADA, JADN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE

Compares BARI 4 mg vs placebo

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

  • BARI 4 mg (N=1142, [exposure through 24 weeks: PYE=471.8, median exposure=169 days, maximum exposure=211 days]), or
  • placebo (N=1215, [exposure through 24 weeks: PYE=450.8, median exposure=166 days, maximum exposure=235 days]).

Patients in the placebo group could have been taking

  • background MTX, or
  • in some studies, other conventional DMARD therapy.

Evaluation time periods included

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

BARI 2 mg Analysis Set

BARI 2 mg data is derived from 4 studies in which both BARI 2 mg (N=479, [exposure through 24 weeks: PYE=185.8, median exposure=168 days, maximum exposure=197 days]) and BARI 4 mg were options during randomization (JADA, JADN, RA-BUILD, RA-BEACON).

4-Study Extended Dataset

Studies: JADA, JADN, RA-BUILD, RA-BEACON, RA-BEYOND (extension)

Compares BARI 4 mg vs BARI 2 mg including extended evaluations

Includes patients with RA from 2 phase 2 and 2 phase 3 studies and any further exposure for those patients in the phase 3 extension study, RA-BEYOND, who were randomized to

  • BARI 4 mg (N=479, PYE=781.1, median exposure=342 days, maximum exposure=3085 days), or
  • BARI 2 mg (N=479, PYE=774.9, median exposure=257 days, maximum exposure=2370 days).

Evaluation time period included randomization through last available observation incorporating extension data through 01 September 2019 unless otherwise specified.

All BARI RA Dataset

Studies: JADB, JADC, JADA, JADN, RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE, RA-BEYOND (extension)

No between-group comparisons

Includes patients with RA (N=3770, PYE=13,148, median exposure=4.2 yrs, maximum exposure=8.4 yrs) from 1 phase 1, 3 phase 2, 5 phase 3 studies, and 1 phase 3 extension study who received BARI at a variety of doses, including

  • BARI 4 mg (n=3400)
  • BARI 2 mg (n=1077), and
  • BARI 1 mg, 7 mg, 8 mg, and 10 mg QD doses not evaluated in confirmatory studies.

Patients had to have received at least 1 dose of BARI and could have received different doses throughout the trials.

Evaluation time period is all exposure time points including after rescue or changes in study drug through 01 September 2019 unless otherwise specified.

Abbreviations: BARI = baricitinib; DMARD = disease-modifying antirheumatic drug; MTX = methotrexate; PYE = patient-years of exposure; QD = once daily; RA = rheumatoid arthritis.

aPatients with renal function impairment who were randomized to BARI 4 mg, but treated with the 2-mg dose were analyzed in the BARI 4-mg group.

Incidence of Major Adverse Cardiovascular Events in the Baricitinib Rheumatoid Arthritis Clinical Development Program

Incidence rate (IR) was calculated as the number of patients with an event per 100 PYE, with exposure censored at time of event.6

7-Study Placebo-Controlled Dataset

In the combined 7-study dataset up to week 24, the number of patients with at least 1 positively adjudicated MACE was

  • 3 (IR=0.7) in the BARI 4-mg group
  • 0 in the BARI 2-mg group, and
  • 2 (IR=0.5) in the placebo group.6

4-Study Extended Dataset

In the combined 4-study extended dataset, the number of patients with at least 1 positively adjudicated MACE was

  • 3 (0.7%; EAIR=0.40) in the BARI 2-mg group, and
  • 2 (0.5%; EAIR=0.29) in the BARI 4-mg group.3

All BARI RA Dataset

In the All-BARI-RA dataset, there were 73 MACE across all baricitinib doses and exposure durations. The incidence rate was 0.5 events per 100 patient-years at risk (PYR).7

Incidence Rate of Positively Adjudicated MACE by Time Periods in RA Clinical Studies displays the incidence rate for patients in the All-BARI-RA dataset with positively adjudicated MACE overall and by 48-week intervals. The rate of MACE does not appear to increase with duration of baricitinib exposure.7

Incidence Rate of Positively Adjudicated MACE by Time Periods in RA Clinical Studies8

Abbreviations: BARI = baricitinib; IR = incidence rate; MACE = major adverse cardiovascular events; PYE = patient-years of exposure; RA = rheumatoid arthritis.

The positively adjudicated IR for

  • stroke was 0.3 (95% CI, 0.19-0.36)
  • MI was 0.2 (95% CI, 0.11-0.25), and
  • CV death was 0.1 (95% CI, 0.08-0.21).7

Cardiovascular death included any fatal stroke and MI as well as sudden cardiac death and other cardiovascular events.3

Exposure-Adjusted Incidence Rate of Major Adverse Cardiovascular Events in the 2-mg and 4-mg Subsets of the All-BARI-RA Analysis Set7

 

Ever on BARI 2 mg
(N=1077)
PYE=2678

Ever on BARI 4 mg
(N=3401)
PYE=11,872

All-BARI-RA
(N=3770)
PYE=14,744

MACEa

0.42 (0.21-0.74)

0.54 (0.41-0.69)

0.51 (0.40-0.64)

Abbreviations: BARI = baricitinib; LTE = long-term extension; MACE = major adverse cardiovascular event; PYE = patient-years of exposure; RA = rheumatoid arthritis.

aAdjudicated MI, stroke, and cardiovascular death from phase 3 and LTE trials.

In patients with 1 or more CV risk factor (current smoker, hypertension, high-density lipoprotein (HDL <40 mg/dL), diabetes, and arteriosclerotic CV disease), the incidence rate was 0.70 events per 100 PYE (95% CI, 0.53-0.92). In patients aged 50 years or older with 1 or more CV risk factor, the incidence rate was 0.77 events per 100 PYE (95% CI, 0.56-1.04).7

References

1Kume K, Amano K, Yamada S. Tofacitinib improves arterial stiffness with methotrexate-resistant active rheumatoid arthritis. A cohort study [abstract]. Ann Rheum Dis. 2014;73(suppl 2):961. European League Against Rheumatism abstract AB0463. http://dx.doi.org/10.1136/annrheumdis-2014-eular.1019

2Sen D, Gonzalez-Mayda M, Brasington RD, Jr. Cardiovascular disease in rheumatoid arthritis. Rheum Dis Clin North Am. 2014;40(1):27-49. http://dx.doi.org/10.1016/j.rdc.2013.10.005

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

4Weinblatt M, Taylor PC, Burmester GR, et al. Cardiovascular safety – update from up to 6 years of treatment with baricitinib in rheumatoid arthritis clinical trials [abstract]. Arthritis Rheumatol. 2018;70(suppl 10):2815. https://acrabstracts.org/abstract/cardiovascular-safety-update-from-up-to-6-years-of-treatment-with-baricitinib-in-rheumatoid-arthritis-clinical-trials/

5Genovese 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. Ann Rheum Dis. 2020;79(suppl 1):638. European League Against Rheumatism abstract FRI0123. https://ard.bmj.com/content/79/Suppl_1/642.1

6Genovese 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

7Taylor 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

8Genovese 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.

Date of Last Review: 27 October 2021


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