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Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data

Author

Ann Rheum Dis. 2020 Aug 5;annrheumdis-2019-216761.doi: 10.1136/annrheumdis-2019-216761. Online ahead of print.

Philip Mease 1, Christina Charles-Schoeman 2, Stanley Cohen 3, Lara Fallon 4, John Woolcott 5, Huifeng Yun 6, Joel Kremer 7, Jeffrey Greenberg 8, Wendi Malley 8, Alina Onofrei 8, Keith S Kanik 9, Daniela Graham 9, Cunshan Wang 10, Carol Connell 11, Hernan Valdez 12, Manfred Hauben 13 14, Eric Hung 13, Ann Madsen 15, Thomas V Jones 16, Jeffrey R Curtis 17

Author Information

1 Rheumatology Clinical Research Division, Swedish Medical Center/Providence St. Joseph Health and University of Washington, Seattle, Washington, USA pmease@philipmease.com.

2 Division of Rheumatology, University of California, Los Angeles, California, USA.

3 Metroplex Research Center, Dallas, Texas, USA.

4 Inflammation and Immunology - Global Medical Affairs, Pfizer Inc, Kirkland, Quebec, Canada.

5 Inflammation and Immunology, Pfizer Inc, Collegeville, Pennsylvania, USA.

6 Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

7 Albany Medical College and The Center for Rheumatology, Albany, New York, USA.

8 Corrona LLC, Waltham, Massachusetts, USA.

9 Inflammation and Immunology TA, Pfizer Inc, Groton, Connecticut, USA.

10 Statistics, Global Product Development, Pfizer Inc, Groton, Connecticut, USA.

11 Clinical Development & Operations, Pfizer Inc, Groton, Connecticut, USA.

12 Global Product Development, Inflammation and Immunology, Pfizer Inc, New York, New York, USA.

13 Worldwide Safety, Pfizer Inc, New York, New York, USA.

14 Department of Medicine, NYU Langone Health, New York, New York, USA.

15 Global Medical Epidemiology, Pfizer Inc, New York, New York, USA.

16 Worldwide Medical and Safety, Pfizer Inc, Collegeville, Pennsylvania, USA.

17 Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Abstract

Objectives: Tofacitinib is a Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis, and has been investigated in psoriasis (PsO). Routine pharmacovigilance of an ongoing, open-label, blinded-endpoint, tofacitinib RA trial (Study A3921133; NCT02092467) in patients aged ≥50 years and with ≥1 cardiovascular risk factor identified a higher frequency of pulmonary embolism (PE) and all-cause mortality for patients receiving tofacitinib 10 mg twice daily versus those receiving tumour necrosis factor inhibitors and resulted in identification of a safety signal for tofacitinib. Here, we report the incidence of deep vein thrombosis (DVT), PE, venous thromboembolism (VTE; DVT or PE) and arterial thromboembolism (ATE) from the tofacitinib RA (excluding Study A3921133), PsA and PsO development programmes and observational studies. Data from an ad hoc safety analysis of Study A3921133 are reported separately within.

Methods: This post-hoc analysis used data from separate tofacitinib RA, PsO and PsA programmes. Incidence rates (IRs; patients with events per 100 patient-years' exposure) were calculated for DVT, PE, VTE and ATE, including for populations stratified by defined baseline cardiovascular or VTE risk factors. Observational data from the US Corrona registries (including cardiovascular risk factor stratification), IBM MarketScan research database and the US FDA Adverse Event Reporting System (FAERS) database were analysed.

Results: 12 410 tofacitinib-treated patients from the development programmes (RA: n=7964; PsO: n=3663; PsA: n=783) were included. IRs (95% CI) of thromboembolic events among the all tofacitinib cohorts' average tofacitinib 5 mg and 10 mg twice daily treated patients for RA, respectively, were: DVT (0.17 (0.09-0.27) and 0.15 (0.09-0.22)); PE (0.12 (0.06-0.22) and 0.13 (0.08-0.21)); ATE (0.32 (0.22-0.46) and 0.38 (0.28-0.49)). Among PsO patients, IRs were: DVT (0.06 (0.00-0.36) and 0.06 (0.02-0.15)); PE (0.13 (0.02-0.47) and 0.09 (0.04-0.19)); ATE (0.52 (0.22-1.02) and 0.22 (0.13-0.35)). Among PsA patients, IRs were: DVT (0.00 (0.00-0.28) and 0.13 (0.00-0.70)); PE (0.08 (0.00-0.43) and 0.00 (0.00-0.46)); ATE (0.31 (0.08-0.79) and 0.38 (0.08-1.11)). IRs were similar between tofacitinib doses and generally higher in patients with baseline cardiovascular or VTE risk factors. IRs from the overall Corrona populations and in Corrona RA patients (including tofacitinib-naïve/biologic disease-modifying antirheumatic drug-treated and tofacitinib-treated) with baseline cardiovascular risk factors were similar to IRs observed among the corresponding patients in the tofacitinib development programme. No signals of disproportionate reporting of DVT, PE or ATE with tofacitinib were identified in the FAERS database.

Conclusions: DVT, PE and ATE IRs in the tofacitinib RA, PsO and PsA programmes were similar across tofacitinib doses, and generally consistent with observational data and published IRs of other treatments. As expected, IRs of thromboembolic events were elevated in patients with versus without baseline cardiovascular or VTE risk factors, and were broadly consistent with those observed in the Study A3921133 ad hoc safety analysis data, although the IR (95% CI) for PE was greater in patients treated with tofacitinib 10 mg twice daily in Study A3921133 (0.54 (0.32-0.87)), versus patients with baseline cardiovascular risk factors treated with tofacitinib 10 mg twice daily in the RA programme (0.24 (0.13-0.41)).