Safety of TofAcitinib in Routine Care Patients With Rheumatoid Arthritis (STAR-RA)- Cardiovascular Endpoints
Conditions: Rheumatoid Arthritis
Sponsor: Brigham and Women's Hospital

 
 
 
 
 
Safety of TofAcitinib in Routine Care Patients With Rheumatoid Arthritis 
(STAR-RA) - Cardiovascular Endpoints 
 
 
 
May 19, 2021 
 
 
NCT04772248 
 
 
 

Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA)-Cardiovascular Endpoints Protocol 
 
 
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1. Comparison Details 
a. Intended aim(s) 
 
 
 To compare the risk of cardiovascular events (including myocardial infarction or stroke), between patients treated 
with tofacitinib and patients treated with TNF inhibitors (TNFi) for rheumatoid arthritis (RA) among, 1) “real world 
evidence (RWE)” cohorts including routine care patient population from the US and, 2) “Randomized controlled trial 
(RCT) DUPLICATE” cohorts including routine care patient population who meet inclusion and exclusion criteria of 
the Safety Study Of Tofacitinib Versus Tumor Necrosis Factor (TNF) Inhibitor In Subjects With Rheumatoid Arthritis 
(“ORAL Surveillance”, NCT02092467) clinical trial.  
 
 
To examine the risk of myocardial infarction, stroke, heart failure hospitalization, coronary revascularization, and 
all-cause mortality as separated endpoints when comparing tofacitinib with TNFi in patients with RA among, 1) 
“real world evidence (RWE)” cohort including routine care patient population from the US and, 2) “Randomized 
controlled trial (RCT) DUPLICATE” cohort including routine care patient population who meet inclusion and 
exclusion criteria of the Safety Study Of Tofacitinib Versus Tumor Necrosis Factor (TNF) Inhibitor In Subjects With 
Rheumatoid Arthritis (“ORAL Surveillance”, NCT02092467) clinical trial.  
 
b. Primary endpoint  
 Major adverse cardiovascular events (MI and stroke) 
 
2. Person responsible for implementation of analysis  
Hemin Lee, MD, MPH will implement the study design and analysis in the Aetion Evidence Platform. She is not 
responsible for the validity of the design and analytic choices. All implementation steps will be recorded and the 
implementation history will be archived in the platform. Propensity score (PS) fine stratification weighting will be 
implemented using SAS statistical software (SAS Institute, Cary, NC). 
 
3. Data Source(s) 
US MarketScan, 2012-2018 
Optum, 2012-2020 
Medicare Claims Database, 2012-2017 
 

Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA)-Cardiovascular Endpoints Protocol 
 
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4. Study Design Diagrams 
Figure 1. Inclusion and Exclusion Criteria for RWE and RCT Duplicate Cohorts 
 

Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA)-Cardiovascular Endpoints Protocol 
 
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Figure 2: Study Design for RWE Cohorts  
 

Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA)-Cardiovascular Endpoints Protocol 
 
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Figure 3: Study Design for RCT-Duplicate Cohorts  
 

Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA)-Cardiovascular Endpoints Protocol 
 
 
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5. Cohort Identification  
 
a. Cohort Summary 
 
This study will employ an active comparator, new user observational cohort study design comparing initiators of 
tofacitinib to tumor necrosis factor inhibitors (infliximab, adalimumab, certolizumab pegol, etanercept, and 
golimumab).1 The patients will be required to have continuous enrollment in their health plan during the baseline period 
of 365 days before initiation of tofacitinib or TNFi (cohort entry date). Follow-up begins the day after drug initiation.  
 
There will be two independent study populations: 
 
1) Real-World Evidence (RWE) cohorts: This study population will reflect the patients diagnosed with RA who are 
routinely treated and managed in setting of clinical practice. 
 
2) RCT-duplicate cohorts: This study population will emulate “the Safety Study Of Tofacitinib Versus Tumor Necrosis 
Factor (TNF) Inhibitor In Subjects With Rheumatoid Arthritis” clinical trial (“ORAL Surveillance”, NCT02092467). 
The inclusion and exclusion criteria of this RCT will be applied to this study population. 
 
b. Inclusion and Exclusion Criteria Common to RWE and RCT-duplicate Cohorts 
 
Cohort entry date: 
 First TNFi or tofacitinib dispensation/administration date 
 
Inclusion criteria: 
 Patients treated with tofacitinib or TNF inhibitors in IBM MarketScan (2012-2018), Optum (2012-2020), and 
Medicare fee-for-service (Parts A, B and D; 2012-2017) 
 A minimum of 365 days of continuous enrollment in health plan prior to (and including) the cohort entry date 
 Two diagnosis codes for RA in any setting in 365 days baseline period (diagnosis codes between 7 and 365 days 
apart) 
 
 
 

Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA)-Cardiovascular Endpoints Protocol 
 
 
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Exclusion criteria: 
 Index drug in 365 days prior to cohort entry date (prevalent users) 
 Missing data on age or gender 
 Admission to nursing facility or hospice on or prior to cohort entry date (ever look-back) 
 TNFi users with history of any Janus kinase (JAK) inhibitors (tofacitinib, upadacitinib, or baricitinib) (ever look-back 
period) 
 TNFi users initiating with more than one TNFi on same date 
 Tofacitinib users with a prescription of baricitinib, upadacitinib (ever look-back period) 
 Tofacitinib users initiating treatment on multiple JAK inhibitors on same day (tofacitinib and baricitinib, tofacitinib 
and upadacitinib) 
 
 
c. Exclusion criteria specific to RWE cohorts 
 
 Patients less than 18 years of age (MarketScan and Optum) and 65 years of age (Medicare) at cohort entry  
 
 
d. Inclusion criteria specific to RCT-duplicate cohorts 
 
 Patients with at least one methotrexate dispensation (six months look-back period) 
 Patients with at least one cardiovascular risk factor (including smoking, hypertension, dyslipidemia, diabetes 
mellitus, ischemic heart disease, family history of ischemic heart disease) (one-year look-back period) 
 
 
e. Exclusion criteria specific to RCT-duplicate cohorts 
 
 Patients less than 50 years of age (MarketScan and Optum) and 65 years of age (Medicare) at cohort entry  
 Patients recently hospitalized with infections (30-day look-back period) 
 Pregnant patients (one year look-back period) 
 
 

Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA)-Cardiovascular Endpoints Protocol 
 
 
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6. Variables  
 
a. Exposure-related variables:  
 
Study drug:  
The study exposure of interest is initiation of tofacitinib 
 
Comparator: 
Initiators of tofacitinib will be compared to initiators of TNFi (infliximab, adalimumab, certolizumab pegol, 
etanercept, and golimumab) 
 
b. Covariates (assessed during 365 day baseline period, unless otherwise specified): 
 
Demographics and Lifestyle Factors 
Age on the cohort entry date 
Calendar year of cohort entry 
Gender 
Obesity 
Race 
Smoking 
Rheumatoid arthritis related factors 
csDMARDs use (methotrexate, hydroxychloroquine, 
leflunomide, sulfasalazine) 
Number of distinct csDMARDs  
Glucocorticoids use (365 day baseline, within 60 
days of baseline, cumulative dose) 
Number of distinct bDMARDs  
CVD factors 
Atrial Fibrillation 
Coronary Artery Disease 
Type 2 Diabetes 
 Heart Failure 
Stroke or transient ischemic attack 
Hypertension 
Hyperlipidemia 
Peripheral vascular disease 
Venous thromboembolism 
 
 
 
 
 

Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA)-Cardiovascular Endpoints Protocol 
 
 
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Comorbid conditions 
Cancer (except non-melanoma skin cancer) 
Inflammatory bowel disease 
Chronic liver disease 
Psoriasis 
Chronic kidney disease (stage 3+) 
Combined comorbidity index 
Chronic obstructive pulmonary disease 
Frailty score 
Comedication use 
Antidepressant drugs (including serotonin-
norepinephrine reuptake inhibitors, selective 
serotonin reuptake inhibitors, tricyclic 
antidepressants) 
Antihypertensive drugs (including angiotensin 
II receptor blockers, angiotensin converting 
enzyme inhibitors, beta blockers, calcium 
channel blockers, diuretics, nitrates) 
Non-steroidal anti-inflammatory drugs 
Lipid lowering drugs (Statins and non-statins) 
Selective Cox-2 inhibitors 
Anti-arrhythmic drugs 
Opioids 
Anticoagulants 
COPD drugs (bronchodilators, inhaled 
corticosteroids) 
Antiplatelets (including acetylsalicylic acid) 
Other hormonal agents/HRT 
Non-insulin diabetes medications 
 
Insulin 
Markers for healthy behavior, frailty, healthcare use 
Number of C-reactive protein tests ordered 
Echocardiogram 
Number of serum creatinine tests ordered 
Cardiac stress test 
Number of lipid tests 
Colonoscopy 
Number of outpatient visits 
Flu Shot 
Number of primary care physician visits 
Mammography 
Number of rheumatologist visits 
Pap smear 
Number of emergency department visits 
Pneumococcal vaccine 
Number of hospitalizations (any, recent) 
PSA test 
Number of hospital days 
Total distinct brand drugs used 
Cardiologist visits 
Total distinct generic drugs used 
Electrocardiogram 
Number of unique prescription medications 
                        
 

Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA)-Cardiovascular Endpoints Protocol 
 
 
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7. Outcome variables and study follow-up:  
 
 Primary outcome: Composite cardiovascular adverse events (myocardial infarction, stroke). Outcome will be 
defined by one inpatient claim.  
 
 Secondary outcomes: Inpatients claims for myocardial infarction, stroke, heart failure hospitalization, coronary 
revascularization (including coronary artery bypass grafting and percutaneous coronary intervention), all-cause 
mortality    
 
Outcome 
Codes 
Care Setting  
Position 
Myocardial 
infarction 
ICD-9 DX: 410.** (except 410.*2) 
 
ICD-10 DX: I21.0-I21.4, I22.* 
Inpatient 
Primary/ 
Secondary  
Stroke 
ICD-9 DX: 430.**, 431.**, 433.*1, 434.** (excluding 434.x0), 436.** 
 
ICD-10 DX: I60.**, I61.*, I63.*** 
Inpatient 
Primary 
Heart failure 
hospitalization 
ICD-9 DX: 398.91, 402.*1, 404.*1, 404.*3, 428.** 
 
ICD-10 DX: I09.81, I11.0, I13.0, I13.2, I50.** 
Inpatient 
Primary 
Coronary 
revascularization 
ICD-9 PX: 00.66, 36.03-36.34, (except 36.04) 
 
ICD-10 PX: 0210*, 0211*, 0212*, 0213*, 021K0Z5, 021K4Z5, 021L0Z5, 
021L4Z5, 0270***, 0271***, 0272***, 0273***, 02C0*Z6, 02C2*Z6, 
02C00ZZ, 02C03ZZ, 02C04ZZ, 02C10ZZ, 02C1*Z6, 02C13ZZ, 02C14ZZ, 
02C20ZZ, 02C23ZZ, 02C24ZZ, 02C3*Z6, 02C30ZZ, 02C33ZZ, 02C34ZZ, 
02QA0ZZ, 02QB0ZZ, 02QC0ZZ, 02QA3ZZ, 02QA4ZZ, 02QB3ZZ, 
02QB4ZZ, 02QC3ZZ, 02QC4ZZ 
 
CPT-4: 33140, 33141, 33510-33536, 33545, 33572, 92920, 92921, 
92924, 92925, 92928, 92929, 92933, 92934,92937, 92938, 92941, 
92943, 92944, 92973, 92980, 92981, 92982, 92984, 92995, 92996 
 
Inpatient 
Any 

Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA)-Cardiovascular Endpoints Protocol 
 
 
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All-cause 
mortality 
 
Inpatient (Optum 
and MarketScan) 
Any setting 
(Medicare) 
 

Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA)-Cardiovascular Endpoints Protocol 
 
 
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8. Study Follow-up Period: 
 
For the primary analysis, we will implement an as-treated exposure definition. Follow-up will start the day after initiation of 
tofacitinib and TNFi and will continue until the earliest date of the following events: 
 
 The first occurrence of the outcome of interest  
 The date of end of enrollment in the database 
 End of the study period 
 Date of treatment switch or drug discontinuation, defined as the date of the last continuous treatment episode of 
the index drug plus a defined grace period (i.e., discontinuation defined after 60 days of no prescription refills for 
the index exposure after the days supply end for the most recent dispensing) 
 Death 
 
For secondary analysis, we will implement, an intention-to-treat exposure definition. Follow-up will start the day after 
initiation of tofacitinib and TNFi and will continue until the earliest date of the following events: 
 
 The first occurrence of the outcome of interest  
 The date of end of enrollment in the database 
 End of the study period 
 Death 
 365 days after the cohort entry date 
 
 
 

Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA)-Cardiovascular Endpoints Protocol 
 
 
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9. Propensity score fine stratification analysis  
We will use a propensity-score (PS)-based approach to account for measured confounding in this study.2 The PS will be 
calculated as the predicted probability of initiating the exposure of interest (i.e., tofacitinib) conditional on baseline covariates 
using multivariable logistic regression constructed separately in each data source.3 On average, patients with similar PSs 
have similar distribution of potential confounders used to estimate the PS. We will trim non-overlapping regions of the 
propensity score distributions.3 Subsequently, we will use PS fine stratification weighting to achieve covariate balance 
between treatment groups.4 We will create 50 PS strata, based on the distribution of PS in tofacitinib-treated patients. A 
weight of one will be assigned to tofacitinib users and TNF inhibitor initiators will be weighted proportional to the distribution 
of tofacitinib initiators in the PS stratum into which they fell to achieve covariate balance (Nexposed in PS stratum i/ Ntotal)/ (Nreference 
in PS stratum i/Ntotal reference).4 This weighting strategy estimates the average treatment effect on the treated (ATT).4  
 
We will report multiple diagnostics for PS analysis in this protocol. First, the PS distribution overlap will be provided  
between two groups before weighting.4  The balance in each individual covariate between two treatment groups will also be 
reported before and after weighting using standardized differences.5,6 Distribution of PS weights will be assessed and 
truncation strategies will be considered if necessary.  
 
10. Statistical analysis plans 
Descriptive statistics, including frequencies and proportions for categorical variables and mean, median, standard deviation 
(SD), interquartile range (IQR), and range (minimum, maximum) for continuous variables, will be used to summarize 
baseline characteristics for each study cohort. Standardized differences will be used to compare characteristics before and 
after PS fine stratification weighting.5,6 Crude incidence rates and corresponding 95% confidence intervals (CI) will be 
reported for each study outcome. The primary analysis will consist of Cox proportional hazards model weighted using PS 
fine stratification weights and using an as-treated exposure definition. This model will generate weighted hazard ratio and 
95% confidence interval when comparing tofacitinib with TNFi. We will also report difference in rates when comparing 
tofacitinib with TNFi and corresponding 95% CI in the weighted population. Results will be reported independently for each 
database. Effect estimates will also be pooled across three databases using fixed effects model.  
 
We will also report cumulative incidence and the corresponding 95% CI independently for all outcomes and each study 
group. Pre-specified subgroup analysis will be conducted based on age (≤65 and > 65), sex, and baseline cardiovascular 
disease (RWE cohorts only). Secondary analysis will be conducted by using an intention-to-treat exposure definition 
whereby patients will be censored 365 days after initiation of treatment with tofacitinib or TNF inhibitors. We will also conduct 
propensity score matching where each patient initiating tofacitinib will be matched with those initiating TNFi using nearest 

Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA)-Cardiovascular Endpoints Protocol 
 
 
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neighbor greedy matching without replacement using a caliper of 0.025 on the natural scale of the PS (1:1 matching).3,7 
Standardized differences will be used to compare characteristics before and after matching. In addition, we will examine the 
risk of cardiovascular outcomes and all-cause mortality by stratifying by number of previous prescriptions of biological 
DMARDs (no previous prescriptions of bDMARDs vs ≥1 prescription of bDMARDs). Finally, sensitivity analyses will be 
conducted by restricting the TNFi comparator group to only adalimumab and etanercept users and by using herpes zoster 
as a positive control outcome.8  
 
 

Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA)-Cardiovascular Endpoints Protocol 
 
 
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11. References 
 
1. 
Lund JL, Richardson DB, Sturmer T. The active comparator, new user study design in pharmacoepidemiology: 
historical foundations and contemporary application. Curr Epidemiol Rep. 2015;2(4):221-228. 
2. 
Rosenbaum PR RD. The central role of the propensity score in observational studies for causal effects. . 
Biometrika. 1983;70(1):41-55. 
3. 
Austin PC. An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational 
Studies. Multivariate Behav Res. 2011;46(3):399-424. 
4. 
Desai RJ, Franklin JM. Alternative approaches for confounding adjustment in observational studies using weighting 
based on the propensity score: a primer for practitioners. BMJ. 2019;367:l5657. 
5. 
Franklin JM, Rassen JA, Ackermann D, Bartels DB, Schneeweiss S. Metrics for covariate balance in cohort studies 
of causal effects. Stat Med. 2014;33(10):1685-1699. 
6. 
Austin PC. Using the Standardized Difference to Compare the Prevalence of a Binary Variable Between Two 
Groups in Observational Research. Communications in Statistics - Simulation and Computation. 2008;38(6):1228-
1234. 
7. 
Austin PC. A comparison of 12 algorithms for matching on the propensity score. Stat Med. 2014;33(6):1057-1069. 
8. 
Pawar A, R D, N G, et al. Risk of admission to hospital for serious infection after initiating tofacitinib versus biologic 
DMARDs in patients with rheumatoid arthritis: a multidatabase cohort study. Lancet Rheumat. 2020;2(2):e84-e98.