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Comparative Risk of Thrombotic and Cardiovascular Events with Tofacitinib and Anti-TNF Agents in Patients with Inflammatory Bowel Diseases

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Abstract

Background

Tofacitinib and inflammatory bowel disease (IBD) have been associated with increased risks for thromboembolic and cardiovascular events, but drug attributable risk is unknown.

Methods

We conducted a retrospective cohort study in a US claims database. We identified patients with IBD by International Classification of Disease (ICD) codes, stipulated 180 days of continuous enrollment prior to tofacitinib or anti-tumor necrosis factor (TNF) initiation to determine new users. Primary outcomes were ICD codes for venous thromboembolism (VTE) and cardiovascular (CV) events. We constructed propensity score (PS)-weighted Cox proportional hazard models to estimate hazard ratios (HRs) and time-to-event outcomes comparing tofacitinib and anti-TNF. We conducted a subgroup analysis of patients ≥ 50 years.

Results

We identified 305 patients with IBD initiating tofacitinib and compared them with 19,096 initiating anti-TNFs. After weighting, balance was achieved across all demographic covariates. VTE occurred in 5% of patients treated with tofacitinib and 4% of anti-TNF users; in a PS-weighted cohort, tofacitinib did not confer a significantly elevated VTE risk compared with anti-TNF therapy (HR: 1.72, 95% CI: 0.74–3.01). A major CV event (MACE) occurred in 2% of tofacitinib users and 1% of anti-TNF users; tofacitinib also did not confer a significantly elevated risk for MACE (HR: 2.50, 95% CI: 0.37–6.18). Those with a Charlson comorbidity index ≥ 2 had greater risks for thromboembolic and cardiovascular events. Similar findings were noted in patients ≥ 50 years.

Conclusions

In this large, active comparator, study, we demonstrate that tofacitinib was not associated with a higher risk of adverse thrombotic events compared with anti-TNFs in patients with IBD.

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References

  1. Sandborn WJ, Su C, Sands BE et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2017;376:1723–1736.

    Article  CAS  Google Scholar 

  2. Flanagan ME, Blumenkopf TA, Brissette WH et al. Discovery of CP-690,550: a potent and selective janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection. J Med Chem 2010;53:8468–8484.

    Article  CAS  Google Scholar 

  3. Administration FaD. Initial safety trial results find increased risk of serious heart-related problems and cancer with arthritis and ulcerative colitis medicine, Xeljanz, Xeljanz XR, 2021.

  4. Sandborn WJ, Panés J, Sands BE et al. Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme. Alimentary Pharmacol Ther 2019;50:1068–1076.

    Article  CAS  Google Scholar 

  5. Sandborn WJ, Panés J, D’Haens GR et al. Safety of tofacitinib for treatment of ulcerative colitis, based on 4.4 years of data from global clinical trials. Clin Gastroenterol Hepatol 2019;17:1541–1550.

    Article  CAS  Google Scholar 

  6. Deepak P, Alayo QA, Khatiwada A, et al. Safety of tofacitinib in a real-world cohort of patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2020.

  7. Lair-Mehiri L, Stefanescu C, Vaysse T et al. Real-world evidence of tofacitinib effectiveness and safety in patients with refractory ulcerative colitis. Dig Liver Dis 2020;52:268–273.

    Article  CAS  Google Scholar 

  8. Weisshof R, Aharoni Golan M, Sossenheimer PH et al. Real-world experience with tofacitinib in IBD at a tertiary center. Dig Dis Sci 2019;64:1945–1951.

    Article  CAS  Google Scholar 

  9. Chaparro M, Garre A, Mesonero F et al. Tofacitinib in ulcerative colitis: real-world evidence from the ENEIDA registry. J Crohn’s Colitis 2021;15:35–42.

    Article  Google Scholar 

  10. Honap S, Chee D, Chapman TP et al. Real-world effectiveness of tofacitinib for moderate to severe ulcerative colitis: a multicentre UK experience. J Crohn’s Colitis 2020;14:1385–1393.

    Article  Google Scholar 

  11. Fenster M, Alayo QA, Khatiwada A et al. Real-world effectiveness and safety of tofacitinib in crohn’s disease and IBD-U: a multicenter study from the TROPIC consortium. Clin Gastroenterol Hepatol 2021;19:2207-2209.e3.

    Article  CAS  Google Scholar 

  12. Kappelman MD, Horvath-Puho E, Sandler RS et al. Thromboembolic risk among Danish children and adults with inflammatory bowel diseases: a population-based nationwide study. Gut 2011;60:937–943.

    Article  Google Scholar 

  13. Sleutjes JAM, Van Lennep JER, Van Der Woude CJ et al. Thromboembolic and atherosclerotic cardiovascular events in inflammatory bowel disease: epidemiology, pathogenesis and clinical management. Ther Adv Gastroenterol 2021;14:175628482110321.

    Article  Google Scholar 

  14. Alotaibi GS, Wu C, Senthilselvan A et al. The validity of ICD codes coupled with imaging procedure codes for identifying acute venous thromboembolism using administrative data. Vascul Med 2015;20:364–368.

    Article  Google Scholar 

  15. Wahl PM, Rodgers K, Schneeweiss S et al. Validation of claims-based diagnostic and procedure codes for cardiovascular and gastrointestinal serious adverse events in a commercially-insured population. Pharmacoepidemiol Drug Saf 2010;19:596–603.

    Article  Google Scholar 

  16. Quan H, Sundararajan V, Halfon P et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care 2005;43:1130–1139.

    Article  Google Scholar 

  17. Gasparini A. comorbidity: an R package for computing comorbidity scores. J Open Source Softw 2018;3:648.

    Article  Google Scholar 

  18. Pfizer I. Phase 3B/4 randomized safety endpoint study of 2 doses of tofacitinib in comparison to a tumor necrosis factor (TNF) inhibitor in subjects with rheumatoid arthritis, 2014, March - 2020, July.

  19. Kotyla PJ, Engelmann M, Giemza-Stokłosa J et al. Thromboembolic adverse drug reactions in janus kinase (JAK) inhibitors: does the inhibitor specificity play a role? Int J Mol Sci 2021;22:2449.

    Article  CAS  Google Scholar 

  20. Tang Y, Liu W, Wang W et al. Inhibition of JAK2 suppresses myelopoiesis and atherosclerosis in apoe−/− mice. Cardiovasc Drugs Therapy 2020;34:145–152.

    Article  CAS  Google Scholar 

  21. Scott IC, Hider SL, Scott DL. Thromboembolism with janus kinase (JAK) inhibitors for rheumatoid arthritis: How real is the risk? Drug Saf 2018;41:645–653.

    Article  CAS  Google Scholar 

  22. Gladman DD, Charles-Schoeman C, McInnes IB et al. Changes in lipid levels and incidence of cardiovascular events following tofacitinib treatment in patients with psoriatic arthritis: a pooled analysis across phase iii and long-term extension studies. Arthritis Care Res 2019;71:1387–1395.

    Article  CAS  Google Scholar 

  23. Sands BE, Taub PR, Armuzzi A et al. Tofacitinib treatment is associated with modest and reversible increases in serum lipids in patients with ulcerative colitis. Clin Gastroenterol Hepatol 2020;18:123-132.e3.

    Article  CAS  Google Scholar 

  24. Yates M, Mootoo A, Adas M et al. Venous thromboembolism risk with JAK inhibitors: a meta-analysis. Arthritis Rheumatol 2021;73:779–788.

    Article  CAS  Google Scholar 

  25. Desai RJ, Pawar A, Weinblatt ME et al. Comparative risk of venous thromboembolism in rheumatoid arthritis patients receiving tofacitinib versus those receiving tumor necrosis factor inhibitors: an observational cohort study. Arthritis Rheumatol 2019;71:892–900.

    Article  CAS  Google Scholar 

  26. Ha C, Ullman T, Siegel C et al. Patients enrolled in randomized controlled trials do not represent the inflammatory bowel disease patient population. Clin Gastroenterol Hepatol 2012;10:1002–1007.

    Article  Google Scholar 

  27. Taxonera C, Olivares D, Alba C. Real-world effectiveness and safety of tofacitinib in patients with ulcerative colitis: systematic review with meta-analysis. Inflamm Bowel Dis. 2021.

  28. Curtis JR, Schulze-Koops H, Takiya L et al. Efficacy and safety of tofacitinib in older and younger patients with rheumatoid arthritis. Clin Exp Rheumatol 2017;35:390–400.

    PubMed  Google Scholar 

  29. Asscher VER, Biemans VBC, Pierik MJ et al. Comorbidity, not patient age, is associated with impaired safety outcomes in vedolizumab- and ustekinumab-treated patients with inflammatory bowel disease-a prospective multicentre cohort study. Aliment Pharmacol Ther 2020;52:1366–1376.

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

BK has served on an advisory board for Pfizer, Inc, and is supported by a grant from the National Institutes of Health. He supported by a grant from the Crohn’s and Colitis Foundation (568375). AN has served on scientific advisory boards of Gilead, Ikena therapeutics, and Sun Pharma and is supported by grants from the National Institute of Health, Crohn’s and Colitis Foundation and Chleck Family Foundation. The other authors have no personal or funding interests to declare.

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Authors and Affiliations

  1. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Bharati D. Kochar & Ashwin N. Ananthakrishnan

  2. Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA

    David Cheng

  3. Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA

    Tianxi Cai

  4. Boston, USA

    Ashwin N. Ananthakrishnan

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  1. Bharati D. Kochar
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Correspondence to Ashwin N. Ananthakrishnan.

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Conflict of interest

Ananthakrishnan has served on the scientific advisory boards of Gilead, Ikena therapeutics, and Sun Pharma. Kochar has served on an advisory board for Pfizer, Inc. The other authors have no conflicts of interest.

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Kochar, B.D., Cheng, D., Cai, T. et al. Comparative Risk of Thrombotic and Cardiovascular Events with Tofacitinib and Anti-TNF Agents in Patients with Inflammatory Bowel Diseases. Dig Dis Sci 67, 5206–5212 (2022). https://doi.org/10.1007/s10620-022-07404-z

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  • DOI: https://doi.org/10.1007/s10620-022-07404-z

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