Outcomes of patients receiving direct oral anticoagulants for myeloproliferative neoplasm‐associated venous thromboembolism in a large tertiary centre in the UK

Abstract

Myeloproliferative neoplasms (MPN) are associated with an increased rate of venous thromboembolism (VTE), which is a major cause of morbidity and mortality, especially in the more indolent diseases of polycythaemia rubra vera (PV) and essential thrombocythaemia (ET) (Pearson, 2002; Tefferi & Barbui, 2017). Multiple factors underlie the complex pathogenesis of thrombosis in MPN including elevated blood viscosity, thrombocytosis and leucocytosis. High levels of inflammatory cytokines and adhesion molecules, circulating microparticles, enhanced thromboxane generation and/or endothelial activation ultimately will contribute to a pro-thrombotic state. Barbui et al. (2011) demonstrated a direct relationship between the presence of the JAK2 V617F mutation in MPN and C-reactive protein, whereby higher levels are associated with thrombotic events in MPN patients. These act in addition to the well-recognised thrombotic risk factors including age (>60 years), obesity and smoking, which are key contributors to the risk of thrombosis and atherosclerosis in the general population. Patients with MPN may have both arterial and venous thromboembolism with an incidence of up to 10–30%. There is also an increased risk of bleeding (Mahé et al., 2018). The prevalence of venous thromboembolic events at the time of diagnosis is higher in PV and ET (11–39% and 8–29%, respectively) compared to myelofibrosis (3–7%). Interestingly, MPN is strongly associated with the presence of thrombotic events in unusual sites such as abdominal veins (portal or hepatic vein) and cerebral venous sinus thrombosis. In particular, splanchnic vein thromboses are common in MPN and have high recurrence rates of between 15% and 20% over 10 years (Finazzi et al., 2018). Traditionally, vitamin K antagonists (VKA) have been the mainstay of anticoagulation for MPN-associated VTE and recent data suggest a high rate of recurrent VTE when they are discontinued in MPN patients (De Stefano et al., 2016). In the last five years, there has been a significant change in the use of direct oral anticoagulants (DOACs) in non-MPN associated VTE. Subgroup analyses of the EINSTEIN-DVT (deep-vein thrombosis) and EINSTEIN-PE (pulmonary embolism) studies in patients with active and/or a history of cancer at the time of VTE demonstrated that rivaroxaban is as efficacious as standard therapy (VKA and enoxaparin) in preventing thrombosis in this cohort and has reduced bleeding complications (Prins et al., 2014). Both the SELECT-D and HOKUSAI-VTE Cancer studies evaluated the use of rivaroxaban and edoxaban, respectively, in randomised controlled trials for cancer-associated VTE, including lymphoma and multiple myeloma, with similar overall outcomes for both DOACs in comparison to low molecular weight heparin, the prior standard of care (Young et al., 2018). However, limited data are available on the efficacy and safety of DOACs in the MPN setting at the present time. We present our use of these agents in our large tertiary practice and present a retrospective analysis of patients with MPN and associated VTE on treatment with a DOAC. A total of 102 patients were identified from our database as having MPN-associated VTE, with 32 of these receiving DOACs. The median age at VTE was 49·9 years (range 20‒887 years) with 14 males (43·7%). The primary diagnoses were: 12 PV, nine ET, nine myelofibrosis (MF) and two MPN/myelodysplasia overlap. A total of 25 patients were JAK2 V617F positive, one had a CALR mutation, one had MPL mutations and five were so-called ‘triple negative’, i.e. lacking detectable JAK2, CALR or MPL mutations. In total, 38 thrombotic events were recorded: 15 splanchnic (39·4%), 12 pulmonary embolism (31·5%), eight deep vein thrombosis (21%), two cerebral venous sinus thrombosis (5·3%), and one superficial thrombophlebitis (2·6%). Six patients presented with two thrombotic events. The median follow-up period was 2·1 years (range, 0·1–7·8) with 18 patients initiated on DOACs (13 rivaroxaban 20 mg daily and 5 apixaban ‒ 5 mg bd in four patients and 10 mg bd in one patient) and 14 patients changed from VKA or low molecular weight heparin (4 rivaroxaban, 9 apixaban and 1 edoxaban). Two patients used more than one DOAC in this period. A total of 25 patients were receiving long-term anticoagulation and seven had defined courses of anticoagulation because the VTE events were provoked. A total of 28 patients received cytoreductive agents or regular venesection along with anticoagulation, see details in Table 1. During the total follow-up period of patients receiving DOACs (84·7 of patients’ years cumulatively) there were no VTE recurrences in 31 patients and only one case had evidence of mesenteric ischaemia. There were no episodes of major bleeding but three patients (9·3%) had clinically relevant non-major bleeding; notably these patients were taking aspirin in addition to a DOAC. In conclusion, our results from a small cohort study showed that in those with MPN and previous VTE, the use of DOACs was associated with very low/no recurrence rates of VTE and no major bleeding complications. These data are in line with the currently limited literature whereby studies demonstrate the efficacy and safety of DOACs, with a reduction in recurrence rates of thrombosis (Ianotto et al., 2017; De Stefano et al., 2018). Our data show that those with unusual sites of VTE, including splanchnic vein thromboses and cerebral venous sinus thrombosis, had no recurrent VTE with the use of DOACs. Notably, cytoreductive measures were used in the majority of these MPN patients. Despite the limitations of our study ‒ mainly the small population of patients and the short follow-up time for the cohort ‒ our preliminary data suggest that DOACs could be efficacious and safely used in MPN patients to prevent recurrent VTE. We believe that further studies are required to confirm or refute these findings in this population and before the widespread adoption of DOACs in MPN patients with VTE. NCG and AD performed, analysed, wrote, reviewed and approved the final submitted paper; KAB, DPM, DHR, BJH, GL, CNH reviewed and approved the final submitted paper.

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