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

Abstract

ObjectivesTofacitinib 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.MethodsThis 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.Results12 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.ConclusionsDVT, 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)).

Lessons from tofacitinib in patients with cardiovascular risk factors: increased pulmonary embolism or isolated (thrombotic) pulmonary occlusion rates?

“…As study A3921133 and the post hoc data of tofacitinib 5 show a preferential increase of PE compared with DVTs between the 5 and 10 mg groups (table 1), do we see increased i-PE, which may also explain the link to ATE risk factors? Although assignment of embolic versus thrombotic origin is challenging, increased i-PE would suggest that the safety signal of tofacitinib impacts distinctly on pulmonary arteries compared with conventional DVT/PE.…”

“…The comprehensive safety assessment of two doses of tofacitinib compared with TNF-i now provides evidence for increased VTE, especially PE rates 5 in patients with increased risks when treated with 10 mg tofacitinib. In the absence of data, no firm conclusion about any other Jak-i in patients with ATE/VTE risk factors can be drawn.…”

“…Another question arising from the study 5 is whether the increased PE especially under higher dosed tofacitinib occurred as isolated (thrombotic) or conventional PE related to DVT. Disproportional increase of PEs versus DVT and a stronger association with cardiovascular (ATE) than VTE risk in these patients suggest that there may be different types of pulmonary artery occlusions.…”

“…22 In addition to increased ATE and VTE risks in RA and other IMIDs, certain antiinflammatory agents (glucocorticoids, NSAIDs, cyclo-oxygenase-2 inhibitors and Jak-I) are associated with enhanced VTE and ATE side effects, while other compounds (TNF-i and IL-6R antagonists) do not. The study by Mease et al 5 substantially advanced knowledge about risks under different dosages of tofacitinib versus TNF-i; however, additional mechanistic and epidemiological studies are needed about drug-related risks and occurrences of DVT, DVT/PE and i-PE, not only for Jak-i. If patients can be better stratified according to vascular risks, it would not only guide therapeutic decisions based on safety considerations of DMARDs but also substantiate appropriate primary (and possibly secondary) prophylaxis.…”

“…In ARD, the study by Mease et al 5 reports post hoc data of patients with cardiovascular risk (50 years or older with at least one cardiovascular risk factor) from the tofacitinib development in the context of data submitted to the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency and other real-world data. PRAC reviewed an ongoing postauthorisation study (A3921133) in patients with RA, psoriatic arthritis (PsA) and psoriasis (PsO) with cardiovascular risk factors treated with 5 and 10 mg tofacitinib or an TNF-i, and reported increased all-cause mortality, sixfold increased PE risk with 10 mg and threefold with 5 mg (not significant) versus TNF-i.…”