S1058 Risk of Myocardial Infarction, Stroke, and Thromboembolic Events in Patients With Ulcerative Colitis Treated With Tofacitinib Compared to Biologic Treatments in the United States

Introduction: There is limited information on safety events observed for tofacitinib using real-world data that includes an active comparator. In this analysis, we examined the risk of myocardial infarction or stroke (MI-S) and thromboembolic events (TE) among patients (pts) with ulcerative colitis (UC) initiating tofacitinib or biologics, using data from an adjudicated United States (US) medical and pharmacy claims database (Komodo Health). Methods: Patients with UC initiating a new treatment with tofacitinib, ustekinumab, vedolizumab, or TNFi from 31 May 2018–30 September 2022 were selected. Stabilized inverse probability treatment weights (sIPTW) were calculated using 17 covariates in the main analysis to examine the risk of MI-S and TE, and an additional 53 in a sensitivity analysis to control for additional comorbidities, UC-related measures, and health care utilization variables. Cox proportional hazards models with sIPTW were used to calculate hazard ratios (HRs) and bootstrapping to calculate 95% confidence intervals (CIs). Sub-analyses restricted to individuals with no prior history of MI-S or TE. Results: UC pts initiating new treatment were included: n=5,171 tofacitinib; n=10,424 ustekinumab; n=17,129 vedolizumab; n=29,872 TNFi. Mean age at index date was 43.1 (+ 15.1) years, and mean follow-up 359.2 (+ 323.7) days. A greater proportion of pts initiating tofacitinib had used >3 prior biologics (14.8%) compared to ustekinumab (6.8%), vedolizumab (1.4%), and TNFi (1.6%). Based on a total of 113 MI-S and 166 TE events, the incidence rates of MI-S and TE per 100 person-years were 0.13 (95% CI 0.05, 0.28) and 0.17 (95% CI 0.07, 0.34) for tofacitinib; 0.17 (95% CI 0.10, 0.27) and 0.16 (95% CI 0.09, 0.26) for ustekinumab; 0.17 (95% CI 0.12, 0.24) and 0.23 (95% CI 0.17, 0.31) for vedolizumab; and 0.19 (95% CI 0.15, 0.25) and 0.33 (95% CI 0.27, 0.40) for TNFi, respectively. In analyses restricted to pts with no history of MI-S or TE or adjusting for 70 total covariates, there were no significant differences in risk of developing MI-S or TE between treatment groups (Table 1). Conclusion: In this large US-based claims analysis adjusting for many covariates, there were no significant differences in risk of developing MI-S or TE among pts with UC initiating tofacitinib compared to biologics. These findings are important for the consideration of treatment options and discussions of risks/benefits for UC pts. Table 1. - Adjusted comparative hazard ratios of myocardial infarction or stroke and venous thromboembolism in UC patients on advanced treatments compared to tofacitinib Ustekinumab vs Tofacitinibb Vedolizumab vs Tofacitinibb TNFi (pooled) vs Tofacitinibb Myocardial Infarction or Strokea Main analysis (17 covariates)c 1.10 (0.44, 4.00) 1.66 (0.64, 6.45) 1.97 (0.83, 7.17) Main analysis + No history of MI, stroke, VTEc 1.09 (0.33, 5.46) 2.35 (0.75, 12.32) 1.75 (0.61, 10.37) Sensitivity Analysis (70 covariates)d 1.06 (0.41, 3.82) 1.45 (0.49, 6.12) 2.24 (0.86, 6.85) Thromboembolic Eventse Main analysis (17 covariates)c 0.95 (0.31, 2.86) 1.36 (0.60, 4.02) 2.10 (1.00, 5.19) Main analysis + No history of MI, stroke, VTEc 0.86 (0.11, 3.27) 1.31 (0.51, 5.17) 1.98 (0.80, 7.33) Sensitivity Analysis (70 covariates)d 0.93 (0.27, 3.08) 1.13 (0.50, 3.38) 1.91 (0.87, 5.26) Abbreviations: CI: confidence interval; TNFi: tumor necrosis factor inhibitor; UC: ulcerative colitis. Inclusion criteria for the UC overall cohort: aged ≥ 18 years, ≥ 2 outpatient (≥ 30 and ≤ 365 days apart) or ≥ 1 inpatient visit(s) with ICD-9/10 UC diagnosis (K51.X), ≥ 12 months enrollment before index (defined as date of first ICD-9/10 code for UC), and receiving UC therapy at index (tofacitinib, ustekinumab, vedolizumab, or TNFi: infliximab; adalimumab; golimumab) therapy. Exclusion criteria: tofacitinib users with prescriptions of approved JAKi other than tofacitinib at or prior to index date; other advanced treatments users with a history of JAKi use; patients with unknown gender. A patient could only be a new user once for each specific drug; however, a patient could be a new user for a second drug class category. (a) Outcomes were defined as an inpatient diagnosis of the event in the primary diagnosis field. Patients were followed from index date to the end of the study period, outcome event, treatment switch or discontinuation, or end of enrollment (whichever came first). (b) Tofacitinib was used as the reference group for all HR calculations. A HR greater than 1 suggests the comparator treatment is associated with a higher rate of the safety event compared to tofacitinib. A HR below 1 suggests the comparator treatment is associated with a lower rate of the safety event compared to tofacitinib. (c) IPTW-weighted Cox proportional hazards models were used to compare safety outcomes between tofacitinib and each comparator arm. Stabilized IPTW weights accounted for age, gender, year entered into cohort, number of prior biologics used, baseline glucocorticoid use, conventional treatment use, NSAIDs use, anti-platelet use, anti-coagulant use, statin use, oral contraceptive or hormonal therapy use, diabetes, non-alcoholic fatty liver disease, chronic kidney disease/dialysis, other immune deficiencies or immunological conditions, history of myocardial infarction, stroke, or VTE, and history of malignancy. (d) Additional adjustment covariates included Comorbidities: baseline history of atrial fibrillation, coronary artery disease, extra-intestinal manifestations, heart failure, history of C-diff, hyperlipidemia, hypertension, interstitial lung disease or chronic obstructive pulmonary disease or asthma, obesity, peripheral vascular disease, serious infection, Charlson Comorbidity Index, smoking; Medication use: antidepressants, angiotensin II receptor blockers, angiotensin converting enzyme inhibitors, antiarrhythmic drugs, beta blockers, calcium channel blockers, chronic obstructive pulmonary disease maintenance medication, diuretics, nitrates, lipid lower drugs, non-insulin diabetes medications, insulin, Cox-2 inhibitors, opioids, corticosteroid use, 5-ASA, thiopurines; Health Care Utilization: number of UC visits, number of emergency department visits, any hospitalization, recent hospitalizations (60 days), electrocardiogram, echocardiogram, colonoscopy, mammogram, PSA test, Pap smear, pneumococcal vaccine, flu vaccine, insurance type; UC-Related Measures: location of disease (pancolitis, left sided, proctosigmoiditis, proctitis, other, unspecified), anemia, weight loss, primary sclerosing cholangitis, history of colectomy, UC endoscopy, UC imaging, and intestinal polyps. (e) Thromboembolic events include pulmonary embolism and deep vein thrombosis Findings were consistent when requiring minimum treatment duration (> 6 months), and excluding those with a history of malignancy or other immune disorders. Other outcomes in this protocol included serious infections (presented separately) and malignancy (analyses ongoing).

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