Higher Bleeding Rates Found with Direct Oral Anticoagulants in Myeloproliferative Neoplasm Patients

In this study we evaluated thrombosis and bleeding outcomes in myeloproliferative neoplasm (MPN) patients treated with direct oral anticoagulants (DOACs). We found an unexpected high cumulative incidence of bleeding, emphasizing the need for continued rigorous evaluation of DOACs in MPNs.

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Myeloproliferative neoplasms (MPNs) are a type of chronic leukemia that are characterized by increased risk of thrombosis and bleeding. The most common MPNs include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Data regarding the choice of anticoagulation is unclear in MPNs, with expert consensus guidelines recommending case-by-case evaluation for the selection and duration of anticoagulation in MPN thrombosis. The historic standard anticoagulant has been vitamin K antagonists (VKAs) such as warfarin. However, VKAs have several limitations, including a narrow therapeutic window, a need for frequent monitoring, dietary restrictions, and multiple drug interactions.

Direct oral anticoagulants (DOACs) have emerged as the first-line treatment for venous thrombosis and atrial fibrillation in general populations. DOACs have also recently been studied in cancer populations, with similar or improved efficacy in preventing recurrent blood clots compared to low molecular weight heparin (LMWH), although increased bleeding is seen especially in certain DOACs and malignancies.1,2 MPNs have not been included in these trials, and these patients have unique risks for thrombosis and bleeding. This includes clonal abnormalities in hematopoietic and endothelial cells that further predispose to thrombosis and bleeding, unusual sites of thrombosis, frequent need for anti-platelet therapy, and predisposition to arterial events.

Recent retrospective studies have demonstrated increasing comfort and use of DOACs in MPN populations. Recurrent thrombosis rates are reported to be 5-9% in this population, and appear similar between DOACs and warfarin.3,4 Bleeding rates also appear comparable at about 1-3%.3,4 However, these studies are overall relatively few, and especially in the absence of randomized trials the safety and efficacy of DOACs remain unclear.

For these reasons we conducted a retrospective analysis of MPN patients placed on DOAC to evaluate thrombosis and bleeding outcomes and practice patterns of use. Recurrent thrombosis was defined as either an arterial or venous thrombosis that occurred after DOAC initiation, and bleeding was defined as major or clinically relevant non-major bleeding by International Society on Thrombosis and Hemostasis (ISTH) criteria.5

We included 133 MPN patients seen across our institution who were treated with either apixaban, rivaroxaban, edoxaban, or dabigatran for venous/arterial thrombosis or atrial fibrillation. Our study included 76 patients with PV, 35 patients with ET, 11 patients with MF, and 11 patients with unclassifiable MPN. Most patients (56%) were treated with venous thrombosis, followed by atrial fibrillation (35%) and arterial thrombosis including stroke (9%). The vast majority of patients (89%) had a JAK2 V617F mutation. 56% of patients had a prior history of thrombosis at time of DOAC initiation, and 23% had previously been treated with warfarin.

We first found that practice patterns with DOAC use was heterogenous, even within our institution. The median duration of anticoagulation was 37 months, with 15% of patients having completed a finite course of anticoagulation. Approximately 10% of patients had their dose of anticoagulation subsequently reduced. Half of patients were also on concomitant antiplatelet therapy, while 80% were on cytoreduction.

The 1-year cumulative incidence of recurrent thrombosis in this cohort was 5.5%, which appears similar to recurrent thrombotic events in the literature.3,4 Surprisingly, we found a much higher incidence of bleeding, with 1-year cumulative incidence of bleeding of 12.3%. This is in comparison to the 1-3% bleeding rates found in the literature.3,4 Thrombosis and bleeding rates were not different between the patients treated for venous thrombosis or patients treated for atrial fibrillation. Prior history of thrombosis, use of dabigatran or edoxaban and younger age were associated with higher risk of recurrent thrombosis, while leukocytosis was associated with a higher risk of bleeding.

We unexpectedly found a higher bleeding rate in this cohort of MPN patients treated on DOAC, which emphasizes the need for continued rigorous evaluation of DOAC use in this population. Many of the bleeding events in our cohort were non-trivial, including 6 major bleeding events and 4 that contributed to patient death. Given that we are a tertiary referral center, the higher bleeding rate may reflect increased patient complexity that can predispose to further complications. Previous studies have identified concomitant aspirin use as a risk factor for increased bleeding,6 although in our analysis only a higher white blood cell count was significant. Interestingly, we found a higher risk of thrombosis in younger patients, which may be driven by the young unclassifiable MPN patients in our cohort that had abdominal thrombosis and need for TIPS revisions.

Overall, our study emphasizes that MPN patients need to be carefully monitored for bleeding complications, especially if prescribed DOAC. The high bleeding rate in our cohort demonstrates that DOAC safety and efficacy should be investigated further in MPNs, with the gold standard being randomized controlled trials.

 

  1. Agnelli G, Becattini C, Meyer G, et al. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. N Engl J Med 2020; 382(17): 1599-607.
  2. Young AM, Marshall A, Thirlwall J, et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J Clin Oncol 2018; 36(20): 2017-23.
  3. Barbui T, De Stefano V, Carobbio A, et al. Direct oral anticoagulants for myeloproliferative neoplasms: results from an international study on 442 patients. Leukemia 2021.
  4. Hamulyák EN, Daams JG, Leebeek FWG, et al. A systematic review of antithrombotic treatment of venous thromboembolism in patients with myeloproliferative neoplasms. Blood Advances 2021; 5(1): 113-21.
  5. Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, Subcommittee on Control of A. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13(11): 2119-26.
  6. Zwicker JI, Paranagama D, Lessen DS, Colucci PM, Grunwald MR. Hemorrhage in patients with polycythemia vera receiving aspirin with an anticoagulant: a prospective, observational study. Haematologica 2021.

Joan How

MD, Brigham and Women's Hospital