Bleeding rate higher than expected with DOACs in myeloproliferative neoplasms
Click Here to Manage Email Alerts
Direct oral anticoagulant use appeared linked to high incidence of bleeding among patients with myeloproliferative neoplasms, according to study results presented at ASH Annual Meeting & Exposition.
“As this is still a single-institution, retrospective study, our results should be interpreted with caution; however, it does emphasize that more rigorous studies evaluating the safety of [direct oral anticoagulants (DOACs) for patients with myeloproliferative neoplasms] are needed,” Chi-Joan How, MD, instructor in medicine at Brigham and Women’s Hospital, told Healio. “Patients who are started on DOACs need to be closely monitored for bleeding and have their bleeding risks identified.”
DOACs are being used more frequently to treat multiple conditions — such as VTE, atrial fibrillation and arterial thromboembolism — in the general population and among individuals with cancer. However, limited data exist about the safety and efficacy of these agents for people with myeloproliferative neoplasms.
Individuals with myeloproliferative neoplasms are at higher risk for arterial and venous thromboembolism, but no clear guidelines exist for anticoagulation selection in this population.
“DOACs are being increasingly used in the myeloproliferative neoplasms population given that they’re easier to use than warfarin, which is the historic standard in myeloproliferative neoplasms,” How said. “However, there really isn't any good data guiding DOAC use in this specific population, and myeloproliferative neoplasms have unique bleeding and thrombosis risk that may be different even from other cancer populations. We, therefore, wanted to perform a retrospective study of [patients with myeloproliferative neoplasms] treated with DOACs for a variety of indications and assess real-world practice patterns of DOAC use and thrombosis/bleeding outcomes.”
The analysis included 133 patients (median age, 71 years; range, 21-95; 56.4% women) within the Massachusetts General Hospital, Brigham and Women’s Hospital and Dana-Farber Cancer Institute system prescribed DOACs between 1995 and 2020.
Types of myeloproliferative neoplasms in the cohort included polycythemia vera (57.1%), essential thrombocythemia (26.3%), myelofibrosis (8.3%) and myeloproliferative neoplasms not otherwise specified (8.3%). Most patients had JAK2 mutations (88.7%).
The majority of patients received apixaban (Eliquis; Bristol Myers Squibb, Pfizer; 62.4%) or rivaroxaban (Xarelto, Janssen; 31.6%), whereas 5.3% received dabigatran (Pradaxa, Boehringer Ingelheim) and 0.8% received edoxaban (Savaysa, Daiichi Sankyo).
Indications for anticoagulation included VTE (56.4%), atrial fibrillation (34.6%) and stroke (9.1%). The most common events among patients with VTE included deep vein thrombosis (43%), pulmonary embolism (31%) and splanchnic vein thrombosis (21%).
More than half (55.6%) of the cohort had no prior history of VTE or atrial thromboembolism, 26.3% had history of atrial thromboembolism only, 12.8% had history of VTE, and 5.3% had history of both. Less than one-third of the cohort had received prior anticoagulation (warfarin, 23.3%; fondaparinux, 4.5%; low-molecular-weight heparin, 3%; other, 0.8%).
Researchers calculated cumulative incidence function of VTE and arterial thromboembolism, as well as major bleeding and clinically relevant non-major bleeding per International Society on Thrombosis and Haemostasis criteria. They used death while on DOACs as a competing risk.
Median duration of anticoagulation was 37 months, with no significant difference between those treated for atrial fibrillation and those treated for VTE. Twenty patients (15%) completed a finite course of anticoagulation, 13 (9.8%) had a reduction to prophylactic dosing, 66 (49.6%) took aspirin concurrently with anticoagulation, and 110 (82.7%) underwent cytoreduction with anticoagulation.
After median follow-up of 37 months, researchers reported 12 thrombotic events (arterial, n = 7; venous, n = 3; transjugular intrahepatic portosystemic shunt occlusions, n = 2). They reported 28 bleeding events, six of them major. Four of the major bleeding events contributed to patient death; the other two were clinically relevant non-major bleeding events.
Investigators estimated a 5.5% (95% CI, 1.5-9.5) 1-year cumulative incidence of thrombosis, similar to what had been reported in prior literature. They estimated a 12.3% (95% CI, 6.4-18.2) 1-year cumulative incidence of bleeding, considerably higher than the previously reported rates of 1% to 3%.
“As our retrospective study is at a tertiary referral center, many of the patients are likely more complex and sicker and, therefore, at higher risk for bleeding than in other studies in the literature,” How said. “In addition, bleeding outcomes — even when defined by standard recommended measures — are often more subjective to report, and so there can be variability between studies.”
Univariate and multivariable analysis showed use of dabigatran or edoxaban, as well as prior history of thrombosis, appeared significantly associated with increased thrombosis risk (P < .05). Multivariate analysis revealed age younger than 65 years as a risk factor for recurrent thrombosis (P = .04).
Researchers observed a trend toward increased bleeding with dabigatran or edoxaban, but otherwise they identified no significant risk factors for bleeding.
The higher-than-expected bleeding rate indicates the continued need for rigorous evaluation, How said.
“This is an active area of investigation and opens up many more questions: Which MPN patients are at higher risk for bleeding? What can we as providers do to prevent bleeding risk?” How said. “A randomized trial would be the gold standard to evaluate DOAC safety and efficacy in this specific population.”
Perspective
Back to Top
John Mascarenhas, MD
This study describes outcomes of patients with myeloproliferative neoplasms treated at a single institution over a 20-year period while receiving direct oral anticoagulant therapy for various indications. The main point is that incidence of thrombosis of approximately 5% is similar to other reports. However, incidence of bleeding was nearly 12%, which would appear higher than other reports of bleeding risk while receiving anticoagulation in a similar setting. This seems unusually high to me based on my personal experience — which is relatively extensive — and our recently published retrospective review of more than 400 patients with myeloproliferative neoplasms treated with a DOAC across multiple institutions. Results of that review showed the annual risk for bleeding was 2% to 3%, with the highest risks among those who received dabigatran and those who had a myelofibrosis diagnosis.
One needs to carefully weigh the potential risks and benefits of anticoagulation and be very vigilant when anticoagulating a patient with a myeloproliferative neoplasm in the setting of atrial fibrillation, venous or arterial thrombosis, and especially myelofibrosis, thrombocytopenia or splanchnic vein thrombosis, where esophageal variceal bleeding can be a major source of morbidity and mortality. Also, the potential for a drug-drug interaction can lead to increased risks for bleeding.
A randomized prospective study is needed to determine relative benefit in terms of hazard for thrombosis and bleeding among the various DOACs and warfarin. The additional benefit of cytoreductive therapy while receiving anticoagulation is not fully clear and may be different depending on primary or secondary prophylaxis and arterial vs. venous origin.
Reference:
Barbui T, et al. Leukemia. 2021;doi: 10.1038/s41375-021-01279-1.
The Tisch Cancer Institute
Icahn School of Medicine at Mount Sinai
Collapse
How C-J, et al. Abstract 3632. Presented at: ASH Annual Meeting & Exposition; Dec. 11-14, 2021; Atlanta.
Click Here to Manage Email Alerts