High Incidence of Bleeding Found with Direct Oral Anticoagulant Use in Myeloproliferative Neoplasm Patients
Authors: How Chi-Joan , Story Charlotte McIlwaine , Ren Siyang , Neuberg Donna S. , Rosovsky Rachel P. , Hobbs Gabriela , Connors Jean M. 
Published: November 2021

Abstract

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are at increased risk of arterial (ATE) and venous thromboembolism (VTE). There are no clear guidelines regarding selection of anticoagulation (AC) in MPN patients. Direct oral anticoagulants (DOACs) are increasingly used in the general population to treat a variety of conditions including VTE, ATE, and atrial fibrillation (AF). Data on the safety and efficacy of DOACs in MPNs limited. We conducted a multi-center, retrospective analysis of DOAC use in MPN patients to characterize real-world practice patterns and evaluate thrombosis and bleeding risks.
METHODS: We retrospectively analyzed 133 MPN patients prescribed DOACs across the Massachusetts General Brigham / Dana Farber Harvard Cancer Center system from 1995 to 2020. Patients were identified using ICD-9 and 10 codes in the electronic medical record. Patient and treatment characteristics were described with summary statistics. We calculated cumulative incidence functions of VTE and ATE, and major and clinically relevant non-major bleeding (CRNMB) by ISTH criteria, using death on DOAC as a competing risk. A Gray's test was used to compare cumulative incidence between groups. Analysis of risk factors associated with bleeding/thrombosis was carried out by univariate and multivariable Fine-Gray models.
RESULTS: Baseline characteristics are displayed in Table 1. Seventy-five (56.4%) MPN patients were prescribed DOAC for VTE, 46 (34.6%) for AF, 7 (5.3%) for stroke, and 5 for other ATE (3.8%). The median age at DOAC initiation was 71; the AF population was significantly older than patients with VTE (75 vs 59, p&lt;0.001). Fifty-seven percent of patients (N = 76) had a diagnosis of PV, with 89% (N = 118) of patients carrying a JAK2 driver mutation. Apixaban was the most commonly prescribed DOAC (N = 83, 62.4%). Nearly half (N = 59, 45%) of patients had a prior VTE/ATE at DOAC initiation, and 23% (N = 31) of patients were switched from warfarin. Among the VTE-treated patients, 43% of events were deep vein thrombosis (N = 39), 31% (N = 28) were pulmonary embolism, 21% (N = 19) were splanchnic vein thrombosis (SVT), and 4.4% (N=4) were other VTE.
Table 2 displays practice patterns of DOAC use in MPN patients. The median duration of AC was 37.0 months for all patients, with no difference (p=0.01) between patients treated for AF (42.3 months) and VTE (37.0 months). Twenty-one percent of VTE-treated patients completed a finite course of AC of 6 months median duration. Fifteen percent (N = 11) of VTE-treated and 4.3% (N = 2) of AF patients had reduction to prophylactic dosing. Fifty percent (N = 66) of patients took aspirin and AC concurrently; 83% (N = 110) of patients took cytoreduction with AC.
After a median follow-up of 37 months, we found 12 thrombotic (7 arterial, 3 venous, 2 TIPS occlusions) and 28 bleeding (6 major with 4 contributing to patient death, 2 CRNMB) events on DOAC. The estimated 1-year cumulative incidence of thrombosis and bleeding on DOAC was 5.5% (1.5%-9.5%) and 12.3% (6.4%-18.2%), respectively (Figure 1). Thrombosis and bleeding rates were not significantly different between patients treated for VTE versus AF.
Prior history of thrombosis and use of dabigatran or edoxaban were significantly associated with increased thrombosis on both univariate and multivariable analysis (p&lt;0.05). Age ≤ 65 also emerged as a risk factor for recurrent thrombosis in multivariate analysis (p=0.04). Use of dabigatran or edoxaban trended toward increased bleeding, but otherwise we found no significant risk factors for bleeding at α=0.05 level, including concomitant aspirin use.
DISCUSSION: DOACs are increasingly prescribed in MPN patients for a wide range of indications, with heterogeneity in practice patterns. In our cohort, 1-year thrombosis and bleeding incidence rates on DOAC were 5.5% and 12.3%, respectively. While our 5.5% thrombosis rate is similar to recurrent thrombosis rates reported in MPN patients on DOACs and VKA, our 12.3% bleeding rate appears much higher. This may be related to the complexity of patients seen at our tertiary referral center. The higher-than-expected bleeding rate found in our study indicates the continued need for rigorous evaluation of DOACs in this population, with the gold standard being randomized controlled trials comparing DOAC with warfarin.
Figure 1 Figure 1.

Disclosures
Neuberg: Madrigal Pharmaceuticals: Other: Stock ownership; Pharmacyclics: Research Funding. Rosovsky: Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hobbs: Bayer: Research Funding; Merck: Research Funding; AbbVie.: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Incyte Corporation: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding. Connors: Abbott: Consultancy; Bristol-Myers Squibb: Honoraria; takeda: Honoraria; Alnylam: Consultancy; Pfizer: Honoraria; CSL Behring: Research Funding.