STAR-RA CV Risk Study Design | Xeljanz® (tofacitinib citrate)

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XELJANZ® (tofacitinib citrate) Prescribing Information and Maxtrex (methotrexate) Prescribing Information. Adverse event reporting can be found at the bottom of the page.

Tofacitinib should only be used if no suitable treatment alternatives are available in patients:

65 years of age and older;
patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors (such as current or past long-time smokers);
patients with malignancy risk factors (e.g. current malignancy or history of malignancy)

These risks are considered class effects and relevant across all approved indications of JAKi in inflammatory and dermatologic diseases.

STAR-RA Cardiovascular (CV) Risk Study Design

Real World Evidence for Rheumatoid Arthritis

Study Population

Baseline Characteristics

Study Endpoints

Study Limitations

ORAL Surveillance Study

Please see the Oral Surveillance page (linked below) for more information on: study design, baseline characteristics, coprimary endpoints, and adverse events of special interest, before reading the real-world evidence content.

ORAL Surveillance page

StudyObjective

The STAR-RA study examines the risk of CV outcomes with XELJANZ (tofacitinib citrate) vs TNFi in patients with RA treated in routine clinical care settings¹.

3 US claims databases were used: Medicare, Optum, MarketScan

A 'real-world evidence (RWE) cohort' consisting of routine care patients and a 'randomised controlled trial (RCT)-duplicate cohort' mimicking inclusion and exclusion criteria of the ORAL surveillance trial were used to calibrate results against the trial findings¹.

Considering the increased risk of serious infections, myocardial infarction, and malignancies with Xeljanz in patients 65 years of age and older, Xeljanz should only be used in these patients if no suitable treatment alternatives are available.

This study was not sponsored by Pfizer.

StudyPopulation

New users of XELJANZ or TNFi‡ with ≥365 days continuous enrolment up to the cohort entry date.

RWE Overall Cohort¹

≥18 years old (≥65 in Medicare)

Sample:

Optum: N=28,568 (13.2% on XELJANZ)

MarketScan: N=34,083 (15.6% on XELJANZ)

Medicare: N=39,612 (9.5% on XELJANZ)

RWE 'RCT Duplicate' Cohort^1,2

Mimicking eligibility criteria of the ORAL Surveillance study¹ (Phase IIIb/IV randomized, open-label, noninferiority, post-authorization, safety endpoint-driven study^2§)

•≥50 years old (≥65 in Medicare)

•≥1 MTX dispensation in 6 months prior to cohort entry date

•≥1 CV risk factor including history of smoking, hypertension, dyslipidemia, diabetes mellitus, IHD, or family history of IHD

Sample:

•Optum: N=6878 (11.6% on XELJANZ)

•MarketScan: N=8071 (14.3% on XELJANZ)

•Medicare: N=20,121 (7.7% on XELJANZ)

Baseline Characteristics

RWE OVERALL COHORT

Demographics and RA treatment use¹

	Optum			MarketScan			Medicare (≥65 years old)
Demographics and RA treatment use	XELJANZ (N=3761)	TNFi‡ (N=24,688)	St dif (%)	XELJANZ (N=5298)	TNFi‡ (N=28,727)	St dif (%)	XELJANZ (N=3782)	TNFi‡ (N=35,816)	St dif (%)
Age, mean±SD	56.8±12.5	57.1±13.2	-2.6	54.7±11.5	55.0±12.0	-1.9	72.1±5.6	72.2±5.6	-1.3
Female, n (%)	3043 (80.9)	20,046 (81.2)	-0.7	4333 (81.8)	23,503 (81.8)	-0.1	3134 (82.9)	29,819 (83.3)	-1.0
No. of unique bDMARDs, mean±SD	1.6±0.7	1.6±0.7	2.4	1.8±0.8	1.8±0.8	1.6	1.6±0.7	1.6±0.7	2.2
No. of distinct csDMARDs, mean±SD	1.0±0.8	1.0±0.8	0.3	1.0±0.8	1.0±0.8	1.8	1.1±0.8	1.1±0.8	0.8
Any csDMARD use, n (%)	2723 (72.4)	17,851 (72.3)	0.2	3989 (75.3)	21,451 (74.7)	1.4	2889 (76.4)	27,253 (76.1)	0.7
MTX, n (%)	1731 (46.0)	11,244 (45.5)	1.0	2722 (51.4)	14,582 (50.8)	1.2	1954 (51.7)	18,239 (50.9)	1.5
Prior GC use (last 365 days), n (%)	2814 (74.8)	18,489 (74.9)	-0.2	3896 (73.5)	21,185 (73.7)	-0.5	2846 (75.3)	26,944 (75.2)	0.1

CV disease risk factors, n(%)¹

	Optum			MarketScan			Medicare (≥65 years old)
CV disease risk factors, n (%)	XELJANZ (N=3761)	TNFib (N=24,688)	St dif (%)	XELJANZ (N=5298)	TNFib (N=28,727)	St dif (%)	XELJANZ (N=3782)	TNFib (N=35,816)	St dif (%)
Obesity	882 (23.5)	5876 (23.8)	–0.8	810 (15.3)	4392 (15.3)	0.0	581 (15.4)	5446 (15.2)	0.4
Smoking	749 (19.9)	4925 (20.0)	–0.1	465 (8.8)	2566 (8.9)	–0.6	972 (25.7)	9180 (25.6)	0.2
Atrial fibrillation	154 (4.1)	1038 (4.2)	–0.6	140 (2.6)	752 (2.6)	0.1	397 (10.5)	3723 (10.4)	0.3
Coronary artery disease	381 (10.1)	2564 (10.4)	–0.8	425 (8.0)	2394 (8.3)	–1.1	904 (23.9)	8477 (23.7)	0.5
Type 2 diabetes mellitus	805 (21.4)	5353 (21.7)	–0.7	835 (15.8)	4563 (15.9)	–0.3	1162 (30.7)	10,918 (30.5)	0.5
Heart failure	192 (5.1)	1324 (5.4)	–1.2	175 (3.3)	960 (3.3)	–0.2	450 (11.9)	4267 (11.9)	0.0
Hypertension	1966 (52.3)	13,075 (53.0)	–1.4	2355 (44.5)	12,922 (45.0)	–1.1	3110 (82.2)	29,417 (82.1)	0.3
Hyperlipidemia	1619 (43.0)	10,706 (43.4)	–0.6	2002 (37.8)	10,937 (38.1)	–0.6	2569 (67.9)	24,187 (67.5)	0.8
Stroke or transient ischemic attack	92 (2.4)	605 (2.5)	0.0	113 (2.1)	620 (2.2)	–0.2	134 (3.5)	1255 (3.5)	0.2
Peripheral vascular disease	163 (4.3)	1103 (4.5)	–0.6	141 (2.7)	776 (2.7)	–0.3	442 (11.7)	4166 (11.6)	0.2
Venous thromboembolism	102 (2.7)	699 (2.8)	–0.7	141 (2.7)	765 (2.7)	0.0	103 (2.7)	996 (2.8)	–0.4

Other comorbidities¹

	Optum			MarketScan			Medicare (≥65 years old)
Other comorbidities	XELJANZ (N=3761)	TNFib (N=24,688)	St dif (%)	XELJANZ (N=5298)	TNFib (N=28,727)	St dif (%)	XELJANZ (N=3782)	TNFib (N=35,816)	St dif (%)
Chronic liver disease, n (%)	273 (7.3)	1792 (7.3)	0.0	315 (5.9)	1696 (5.9)	0.2	317 (8.4)	2985 (8.3)	0.2
Chronic kidney disease (Stage 3+), n (%)	212 (5.6)	1428 (5.8)	−0.6	168 (3.2)	926 (3.2)	−0.3	442 (11.7)	4207 (11.7)	−0.2
COPD, n (%)	599 (15.9)	3992 (16.2)	−0.7	629 (11.9)	3454 (12.0)	−0.5	1041 (27.5)	9955 (27.8)	−0.6
Inflammatory bowel disease, n (%)	63 (1.7)	415 (1.7)	0.0	68 (1.3)	353 (1.2)	0.5	50 (1.3)	461 (1.3)	0.3
Psoriasis, n (%)	170 (4.5)	1100 (4.5)	0.3	169 (3.2)	885 (3.1)	0.6	119 (3.1)	1028 (2.9)	1.6
Cancer (excluding NMSC), n (%)	484 (12.9)	3267 (13.2)	−1.1	692 (13.1)	3783 (13.2)	−0.3	789 (20.9)	7438 (20.8)	0.2
Combined comorbidity index; mean ± SD	1.2±2.0	1.2±2.0	−0.8	0.7±1.5	0.7±1.5	−0.7	1.8±2.4	1.9±2.4	−0.4
Frailty score, mean ± SD	0.2±0.0	0.2±0.0	−0.8	0.1±0.0	0.1±0.0	−1.5	0.2±0.0	0.2±0.0	0.0

RWE 'RCT DUPLICATE' COHORT

Demographics and RA treatment use¹

CV disease risk factors¹

Other comordities¹

Studymethod + Analytical approach

Study Method¹

Data collected from November 2012 to June 2020 (Optum), to December 2018 (MarketScan), and to December 2017 (Medicare)

Statistical analysis

PS fine stratification weighting used to account for measured confounders (76 covariates included [75 in MarketScan])
Standardized differences used to assess balance in each covariate between treatment groups before and after PS fine stratification weighting (<10% represents adequate covariate balance)
Adjusted HRs estimated using a Cox proportional hazards model
Crude and weighted differences in rates between XELJANZ and TNFi assessed using Poisson regression
Effect estimates pooled across databases using a fixed-effects model with inverse variance weighting

Sensitivity analyses

Prespecified subgroup analyses conducted based on age (≤65 and >65 years), sex, and baseline CV disease (overall RWE cohort only)
Risk of CV outcomes examined by stratifying by unique number of previous agents of bDMARDs (ie, 0 vs ≥1)

Scroll left to view table

StudyEndpoints

Primary Outcomes¹

Composite CV outcome of hospitalization for MI or stroke

Secondary Outcomes¹

MI
Stroke
Hospitalization for heart failure
Coronary revascularization
All-cause mortality

StudyLimitations

US claims data on the risk of CV outcomes with XELJANZ: Study limitations

The specific geographic population may not be representative of the worldwide population (eg, patient characteristics, healthcare access)¹
Residual confounding is possible because the study databases do not report RA disease activity¹
Doses of MTX were not accounted for in the analyses
Other JAK inhibitors, eg, baricitinib or upadacitinib, were not assessed in this analysis and the results of this study cannot necessarily be extrapolated beyond XELJANZ¹
Exposure misclassification was possible due to incomplete adherence to the study drug; a claim does not indicate that the patient took the medication^1,3
Administrative claims may contain missing data and/or coding errors because their primary use is to obtain payment for services and medications administered³
Data may not be representative of patients without insurance¹
No analyses specific to dose
Comparisons between the RWE study and ORAL Surveillance study results should be interpreted with caution due to differences in trial design, populations and methodology (eg, STAR-RA only looked at a US patient population, had a shorter length of follow-up, and not all the ORAL Surveillance inclusion and exclusion criteria can be adequately represented in claims data)^1,2
Some covariates in the matching model are colinear, eg, use of glucocorticoids is included for those with prior use in the last 365 days or recent use in the last 60 days, which may limit the accuracy of propensity score weighting¹
As patients in the databases are de-identified, it is not possible to confirm that all patients across the three databases are completely independent of each other¹

Explore More

Updated regulatory guidance on JAK inhibitors with James Galloway

Visit our dedicated Expert Opinion page to learn more about the regulatory guidance on JAK inhibitors by watching our video with James Galloway.

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STAR-RA Cardiovascular Risk Outcomes

Read next page of STAR-RA cardiovascular risk outcomes

§ Eligibility criteria for ORAL Surveillance included: patients ≥50 years of age; taking MTX without adequate control of symptoms; moderate to severe RA, including ≥6 tender or painful joints and ≥6 swollen joints (28-joint count) ≥1 CV risk factor.² See cited publication for full eligibility criteria and study design.
‡TNFi: infliximab, adalimumab, certolizumab pegol, etanercept, and golimumab

CV=cardiovascular; JAK=Janus kinase; MTX=methotrexate; ORAL=Oral Rheumatoid Arthritis Trial; RA=rheumatoid arthritis; RCT=randomized controlled trial; RWE=real-world evidence; STAR-RA=Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis; US=United States; HR=hazard ratio; PS=propensity score; bDMARD=biologic disease-modifying antirheumatic drug; HZ=herpes zoster; IHD=ischemic heart disease; MI=myocardial infarction; MTX=methotrexate

Additional Prescribing information:
Enbrel (etanercept): https://www.pfizerpiindex.co.uk/enbrel
Inflectra (infliximab): https://www.pfizerpiindex.co.uk/inflectra

References

1. Khosrow-Khavar F, et al. Ann Rheum Dis. 2022;81(6):798-804
2. Ytterberg SR, et al. N Engl J Med. 2022;386(4):316-326.
3. Harnett J, et al. J Manag Care Spec Pharm. 2016;22(12):1457-1471.

XELJANZ Risk Minimisation Programme (RMP) materials, including a Patient Alert Card, Prescriber Checklists and a Prescriber Brochure are available from https://www.medicines.org.uk/emc/. Patients treated with XELJANZ should be given the Patient Alert Card.

PP-XEL-GBR-4465. May 2023

Real-World Evidence: STAR-RA

CV Risk Study Design CV Risk Study Outcomes Malignancy Risk Study Design Malignancy Risk Study Outcomes

Explore more Real-World Evidence in RA

RA Insights - Using Real-World Evidence (RWE) on JAK inhibitors for shared decision making

In this episode, Dr Ai Lyn Tan and Dr Sarah Mackie highlight the recent real-world evidence on shared decision making, treatment persistence and second-line treatment strategies in the context of Rheumatoid Arthritis (RA) with Janus Kinase inhibitors.

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