Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme

William J Sandborn, Julian Panés, Bruce E Sands, Walter Reinisch, Chinyu Su, Nervin Lawendy, Nana Koram, Haiyun Fan, Thomas V Jones, Irene Modesto, Daniel Quirk, Silvio Danese, William J Sandborn, Julian Panés, Bruce E Sands, Walter Reinisch, Chinyu Su, Nervin Lawendy, Nana Koram, Haiyun Fan, Thomas V Jones, Irene Modesto, Daniel Quirk, Silvio Danese

Abstract

Background: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC).

Aim: To report incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the tofacitinib UC programme.

Methods: DVT and PE were evaluated from one phase 2 and two phase 3 induction studies, one phase 3 maintenance study and an ongoing, open-label, long-term extension (OLE) study (September 2018 datacut). Data were analysed in induction, maintenance and overall (patients receiving ≥ 1 dose of tofacitinib 5 or 10 mg b.d. in any phase 2, 3 or OLE study) cohorts.

Results: 1157 patients (2404 patient-years' exposure; ≤ 6.1 years' tofacitinib treatment) were evaluated in the overall cohort. In induction, one placebo-treated patient had DVT and one had PE; no tofacitinib-treated patients had DVT/PE. In maintenance, one placebo-treated patient had DVT and one had PE; no tofacitinib-treated patients had DVT/PE. In the overall cohort, one patient had DVT (incidence rate [patients with events/100 patient-years; 95% CI]: 0.04 [0.00-0.23]); four had PE (0.16 [0.04-0.41]); all received predominant dose tofacitinib 10 mg b.d.; all had venous thromboembolism risk factors alongside UC.

Conclusions: In this post hoc analysis of patients with UC, during tofacitinib exposure, one patient had DVT and four had PE, all during the OLE study, on predominant dose 10 mg b.d. (83% of overall cohort patients received predominant dose 10 mg b.d.) with venous thromboembolism risk factors. This analysis is limited by small sample size and limited drug exposure; further studies are needed. ClinicalTrials.gov: NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.

© 2019 John Wiley & Sons Ltd.

References

    1. Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012;367:616‐624.
    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.
    1. Lichtenstein GR, Loftus EV Jr, Bloom S, et al. Tofacitinib, an oral Janus kinase inhibitor, in the treatment of ulcerative colitis: an interim analysis of an open‐label, long‐term extension study with up to 4.9 years of treatment [abstract]. Am J Gastroenterol. 2018;113 (Suppl): Abstract 571.
    1. US Food and Drug Administration . Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate. 2019. . Accessed May 29, 2019.
    1. Wollenhaupt J, Lee EB, Curtis JR, et al. Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open‐label, long‐term extension study. Arthritis Res Ther. 2019;21:89.
    1. Mease PJ, Kremer J, Cohen S, et al. Incidence of thromboembolic events in the tofacitinib rheumatoid arthritis, psoriasis, psoriatic arthritis and ulcerative colitis development programs [abstract]. Arthritis Rheumatol. 2017;69(Suppl 10): Abstract 16L.
    1. Taylor PC, Weinblatt ME, Burmester GR, et al. Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis. Arthritis Rheumatol. 2019;71:1042-1055.
    1. Genovese MC, Fleischmann R, Combe B, et al. Upadacitinib (ABT‐494) in patients with active rheumatoid arthritis and inadequate response or intolerance to biological dmards: a phase 3 randomized, placebo‐controlled, double‐blind study of a selective JAK‐1 inhibitor [abstract]. Arthritis Rheumatol. 2017;69(Suppl 10): Abstract 10L.
    1. Matta F, Singala R, Yaekoub AY, Najjar R, Stein PD. Risk of venous thromboembolism with rheumatoid arthritis. Thromb Haemost. 2009;101:134‐138.
    1. Davies R, Galloway JB, Watson KD, Lunt M, Symmons DP, Hyrich KL. Venous thrombotic events are not increased in patients with rheumatoid arthritis treated with anti‐TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2011;70:1831‐1834.
    1. Ramagopalan SV, Wotton CJ, Handel AE, Yeates D, Goldacre MJ. Risk of venous thromboembolism in people admitted to hospital with selected immune‐mediated diseases: record‐linkage study. BMC Med. 2011;9:1.
    1. Choi HK, Rho YH, Zhu Y, Cea‐Soriano L, Aviña‐Zubieta JA, Zhang Y. The risk of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a UK population‐based outpatient cohort study. Ann Rheum Dis. 2013;72:1182‐1187.
    1. Zoller B, Li X, Sundquist J, Sundquist K. Risk of pulmonary embolism in patients with autoimmune disorders: a nationwide follow‐up study from Sweden. Lancet. 2012;379:244‐249.
    1. Kang JH, Keller JJ, Lin YK, Lin HC. A population‐based case‐control study on the association between rheumatoid arthritis and deep vein thrombosis. J Vasc Surg. 2012;56:1642‐1648.
    1. Chung WS, Peng CL, Lin CL, et al. Rheumatoid arthritis increases the risk of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study. Ann Rheum Dis. 2014;73:1774‐1780.
    1. Kim SC, Schneeweiss S, Liu J, Solomon DH. Risk of venous thromboembolism in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2013;65:1600‐1607.
    1. Rajwanshi R, Sarsour K, Governale L, Arnieri B, Oliveri D, Berber E. Analysis of incidence rates of pulmonary embolism in the rheumatoid arthritis population compared with the non‐rheumatoid arthritis population [abstract]. Arthritis Rheumatol. 2015;67: Abstract 33.
    1. Ogdie A, Kay McGill N, Shin DB, et al. Risk of venous thromboembolism in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a general population‐based cohort study. Eur Heart J. 2018;39:3608-3614.
    1. Liang KP, Liang KV, Matteson EL, McClelland RL, Christianson TJ, Turesson C. Incidence of noncardiac vascular disease in rheumatoid arthritis and relationship to extraarticular disease manifestations. Arthritis Rheum. 2006;54:642‐648.
    1. Bacani AK, Gabriel SE, Crowson CS, Heit JA, Matteson EL. Noncardiac vascular disease in rheumatoid arthritis: increase in venous thromboembolic events? Arthritis Rheum. 2012;64:53‐61.
    1. Holmqvist ME, Neovius M, Eriksson J, et al. Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization. JAMA. 2012;308:1350‐1356.
    1. Yusuf HR, Hooper WC, Grosse SD, Parker CS, Boulet SL, Ortel TL. Risk of venous thromboembolism occurrence among adults with selected autoimmune diseases: a study among a U.S. cohort of commercial insurance enrollees. Thromb Res. 2015;135:50‐57.
    1. Ungprasert P, Srivali N, Spanuchart I, Thongprayoon C, Knight EL. Risk of venous thromboembolism in patients with rheumatoid arthritis: a systematic review and meta‐analysis. Clin Rheumatol. 2014;33:297‐304.
    1. Weng M‐T, Park SH, Matsuoka K, et al. Incidence and risk factor analysis of thromboembolic events in East Asian patients with inflammatory bowel disease, a multinational collaborative study. Inflamm Bowel Dis. 2018;24:1791‐1800.
    1. 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.
    1. Bernstein CN, Blanchard JF, Houston DS, Wajda A. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population‐based cohort study. Thromb Haemost. 2001;85:430‐434.
    1. 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.
    1. US Food and Drug Administration . XELJANZ (tofacitinib): highlights of prescribing information. 2019. . Accessed August 2, 2019.
    1. European Medicines Agency . Xeljanz (tofacitinib) ‐ summary of product characteristics. 2019. . Accessed August 2, 2019.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe