Pos0225 risk of Major Cardiovascular Event Across Jak Inhibitor Treated Patients: Analysis of a National Claim Database

Abstract

Background:Inhibiting a specific JAK may impede more than one pathway, explaining both the efficacy and adverse effects observed with JAK inhibitors (JAKi). Among those, there have been recent concerns about potential thromboembolic risks with these drugs. As patients enrolled are not representative of all patients who may receive JAKi, data from trials are unlikely to provide definitive answers. Real impact of JAKi in real life on major cardiovascular events is not known.Objectives:To evaluate the risk of venous and arterial thromboembolic events with the use of JAKi in a real-world setting.Methods:A self-controlled case series analysis (method in which individuals act as their own control) was performed using data from the French national healthcare insurance system SNDS (“Système National des Données de Santé”), which included all anonymized individual level data about sociodemographic data, outpatient healthcare dispensed, hospital discharge summaries, and registration status for a list of 30 long term diseases. All patients treated by JAKi (baricitinib or tofacitinib) for rheumatoid arthritis, psoriasis arthritis and/or inflammatory bowel disease, and with at least one thromboembolic event (venous (VTE): deep vein thrombosis (DVT), pulmonary embolism (PE), arterial (ATE): acute coronary syndrome (ACS), myocardial infarction (MI), transient ischemic attack (TIA) and stroke) between 2017/11/01 and 2019/06/30 were included in the study. Associations were evaluated by incidence rate ratios (IRR), which compare the rate of events during exposed periods with rate of event during all other observed time periods. Exposed periods were defined as i) exposure to JAKi, ii) the month following exposure (post-exposure 1-30 days), and iii) long-term post-exposure (31 to 60 days). A pre-exposure period of 7 days was individualized to identify event-dependent probabilities of exposure and potential reverse causality bias, and all other periods were considered as non-exposed periods.Results:Among the 5,870 patients treated with JAKi between 2017/11/01 and 2019/06/30, 94 presented an incident thromboembolic event and were included. Almost two thirds were female (n=61, 64.9%), and median age was 65.4 [IQR: 55.5; 75.8] years. Most of patients have a rheumatoid arthritis (n=91, 96.8%), 62 (66.0%) were treated by baricitinib, and 32 (34.0%) by tofacitinib. Almost half (n=42, 44.7%) presented a venous thromboembolism, mainly DVT (n=31, 33.0%), and 52 (55.3%) presented an arterial thromboembolism, mainly MI (n=16, 17.0%) and stroke (n=14, 14.9%). Eleven patients (11.7%) died during the study period. The median time of occurrence of VTE was 4.3 [IQR: 2.5; 8.9] months, and 6.1 [IQR: 3.3; 9.2] months for ATE.The median duration of exposure was 6.0 [IQR: 3.3; 10.1] months for VTE, and 12.0 [IQR: 4.8; 15.3] months for ATE. The IRR for VTE and ATE were increased during exposure, and during the 30 days following exposure (Table 1). The IRR for VTE was only increased during exposure and in the early post-exposure phase contrary to the IRR for ATE that was also increased in the pre-exposure 7-Day period. Analysis conducted on survival patients confirmed results.Table 1.NPatient-yearsIRR95%CIVenous thromboembolic eventsNon-exposure (reference)83975.01-Pre-exposure to JAK-i1135.24.70.6-38.0Exposure to JAK-i272090.59.84.1-23.3Post-exposure 1-30 d5369.06.21.9-19.9Post-exposure 31-60 d1139.01.50.2-12.6Arterial thromboembolic eventsNon-exposure (reference)74076.81-Pre-exposure to JAK-i3344.111.52.8-46.8Exposure to JAK-i326363.87.42.9-18.7Post-exposure 1-30 d8659.211.53.8-34.6Post-exposure 31-60 d2132.24.30.8-22.0Conclusion:The present study found an increased risk of VTE and ATE for baricitinib and tofacitinib. The risk persists in the month following the discontinuation of treatment but disappears after day 30 post-exposure.Disclosure of Interests:Amandine Gouverneur: None declared, Jérôme Avouac Consultant of: JA has/had consultancy relationship and/or has received research funding in the area of potential treatments for rheumatoid arthritis from (last three years): Abbvie, Galapagos, Pfizer, Bristol Myers Squibb, Sanofi, Nordic Pharma, Chugai and MSD., Grant/research support from: JA has/had consultancy relationship and/or has received research funding in the area of potential treatments for rheumatoid arthritis from (last three years): Abbvie, Galapagos, Pfizer, Bristol Myers Squibb, Sanofi, Nordic Pharma, Chugai and MSD., Clément Prati: None declared, Jean-Luc Cracowski: None declared, Thierry Schaeverbeke Consultant of: TS consultancy and/or research fundings: Abbvie, Lilly, Pfizer, Galapagos, Novartis, BMS, Medac, NordicPharma, Biogen, Mylan, Janssen., Grant/research support from: TS consultancy and/or research fundings: Abbvie, Lilly, Pfizer, Galapagos, Novartis, BMS, Medac, NordicPharma, Biogen, Mylan, Janssen., Antoine Pariente Grant/research support from: AP reports acting as an independant expert towards the French Medicines Agency (Agence Nationale de Securité du Médicament et des Produits de Santé, ANSM) and the European Medicines Agency (EMA). AP coordinates the DRUGS Systematised Assessment in real-liFe EnviRonment (DRUGS-SAFER) programme funded by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM)., Marie-Elise Truchetet Consultant of: has/had consultancy relationship and/or has received research funding in the area of potential treatments for rheumatoid arthritis and spondyloarthritis and their complications from (last three years): Abbvie, Galapagos, Lilly, Medac, Novartis, Pfizer, and Roche., Grant/research support from: has/had consultancy relationship and/or has received research funding in the area of potential treatments for rheumatoid arthritis and spondyloarthritis and their complications from (last three years): Abbvie, Galapagos, Lilly, Medac, Novartis, Pfizer, and Roche.

Effective treatment of alopecia universalis with oral upadacitinib

“…This risk faded 1 month following exposure. 7 Conversel, the SELECT phase III clinical programe (5 randomized controlled trials) for rheumatoid arthritis found no difference in the rate of venous thromboembolic events among patients receiving upadacitinib, methotrexate, or adalimumab. 8 When comparing the findings of the post hoc analysis 7 to those of the SELECT phase III trial, 8 we may suggest that upadacitinib seems to have a better cardiovascular safety profile relative to baricitinib and tofacitinib.…”

“… 7 Conversel, the SELECT phase III clinical programe (5 randomized controlled trials) for rheumatoid arthritis found no difference in the rate of venous thromboembolic events among patients receiving upadacitinib, methotrexate, or adalimumab. 8 When comparing the findings of the post hoc analysis 7 to those of the SELECT phase III trial, 8 we may suggest that upadacitinib seems to have a better cardiovascular safety profile relative to baricitinib and tofacitinib. This could explain why our patient, while having a strong cardiovascular disease risk profile, was tolerating upadacitinib so well without suffering any venous thromboembolic events or adverse events.…”

Long-Term Safety, Efficacy, and Patient-Centered Outcomes of Filgotinib in the Treatment of Rheumatoid Arthritis: Current Perspectives

“…15,16,18 MACE and herpes zoster (HZ) have been reported to be associated with other JAKi treatments; however, the incidence rates for these events are similar to placebo (Table 4). 16,19,[37][38][39][40] RA patients were eligible to enroll in the LTE FINCH 4 study if they had completed 1 of the FINCH parent studies. Among patients who were MTX-IR and were rerandomized for the LTE from ADA + MTX to filgotinib + MTX or those who continued their parent-trial treatment with filgotinib 100 or 200 mg with MTX, incidence of TEAEs, serious AEs (SAEs), and ≥3-grade AEs were largely comparable (Table 5).…”

Janus Kinase Inhibitor Selectivity in Rheumatoid Arthritis: Where Do We Stand?

“…The first real-life experience with baricitinib, showing an increased risk of VTE in patients with cardiovascular risk factors may support this statement. 22,23 However, although the mechanisms of action are similar between JAKis, JAK selectivity may change the safety profile according to the JAK isoform targeted. An example might be the potential contribution of JAK2 in the occurrence of VTE.…”