Abstract:Patients with myeloproliferative neoplasms (MPNs), polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have an increased risk of thrombosis. Risk of recurrent thrombosis can be reduced with antithrombotic therapy and/or cytoreduction, but the optimal long-term management in patients with MPN with a history of venous thromboembolism (VTE) is unknown, and clinical practice is heterogeneous. We performed a systematic review and meta-analysis of randomized trials and observational studies eval… Show more
“…Almost all patients were receiving cytoreductive drugs (Table S2 ) so that we were unable to confirm the conclusion of a recent meta-analysis [ 14 ] that the risk of recurrence after VTE in MPN was lowest for patients receiving oral anticoagulation plus cytoreduction. Therefore, studies in this setting are urgently needed considering that the IR of recurrent VTE in the present series of MPN patients receiving a DOAC is twice as high as in non-MPN patients treated with DOACs for more than 3 months after the acute VTE event (3.4% versus 1.5% pts-yr, respectively) [ 15 ].…”
In the Philadelphia-negative myeloproliferative neoplasms (MPN), the major burden of disease is the elevated risk of thrombosis [1]. Moreover, MPN patients are concomitantly prone to bleeding [1], making antithrombotic therapy challenging. Regarding atrial fibrillation (AF), very scarce data are available about treatment outcomes with vitamin-K antagonists (VKAs) or direct oral anticoagulants (DOACs) [2,3]. On the other hand, VKAs partially prevent recurrent venous thromboembolism (VTE), and the incidence of either recurrent thrombosis and major bleeding is still unacceptable high [4].DOACs emerged as a treatment of choice for secondary prevention of VTE and thrombosis prophylaxis in AF in the general population, and may be an attractive alternative to VKAs in MPN. However, evidence of their efficacy and safety in MPN is very limited and based on few retrospective observational studies [3,[5][6][7], and on scattered information from controlled trials of DOACs versus VKAs.
“…Almost all patients were receiving cytoreductive drugs (Table S2 ) so that we were unable to confirm the conclusion of a recent meta-analysis [ 14 ] that the risk of recurrence after VTE in MPN was lowest for patients receiving oral anticoagulation plus cytoreduction. Therefore, studies in this setting are urgently needed considering that the IR of recurrent VTE in the present series of MPN patients receiving a DOAC is twice as high as in non-MPN patients treated with DOACs for more than 3 months after the acute VTE event (3.4% versus 1.5% pts-yr, respectively) [ 15 ].…”
In the Philadelphia-negative myeloproliferative neoplasms (MPN), the major burden of disease is the elevated risk of thrombosis [1]. Moreover, MPN patients are concomitantly prone to bleeding [1], making antithrombotic therapy challenging. Regarding atrial fibrillation (AF), very scarce data are available about treatment outcomes with vitamin-K antagonists (VKAs) or direct oral anticoagulants (DOACs) [2,3]. On the other hand, VKAs partially prevent recurrent venous thromboembolism (VTE), and the incidence of either recurrent thrombosis and major bleeding is still unacceptable high [4].DOACs emerged as a treatment of choice for secondary prevention of VTE and thrombosis prophylaxis in AF in the general population, and may be an attractive alternative to VKAs in MPN. However, evidence of their efficacy and safety in MPN is very limited and based on few retrospective observational studies [3,[5][6][7], and on scattered information from controlled trials of DOACs versus VKAs.
“…However, in the studies cited above, treatment with anticoagulants did not significantly increase the incidence of major bleeding events, supporting long-term use of oral anticoagulants (OAC or DOAC) in PV patients who have a history of thrombotic events. This is supported by a high safety profile of direct oral anticoagulants (DOAC) in recent studies on MPN and cancer patients (Hamulyak et al 2021 ; Huenerbein et al 2021 ; Raskob et al 2018 ). Fig.…”
Purpose
Patients with polycythemia vera (PV) show an elevated incidence of thromboembolic complications and decreased survival when compared to age-matched healthy individuals. Hypercellularity as indicated by elevated hematocrit, pathophysiological changes induced by the JAK2 driver mutation and cardiovascular risk factors contribute to the increased incidence of thromboembolic events. Higher age and a history of thromboembolic events define a high-risk population of PV patients. Depending on the individual risk profile, phlebotomy or pharmacologic cytoreduction is recommended in combination with low-dose acetylsalicylic acid. Stringent cytoreduction is required for effective risk reduction. However, in recent reports, the rate of thromboembolic complications in PV patients under cytoreductive therapy appears still elevated compared to healthy individuals. This study reports on a chart review to assess for cytoreductive therapy of 1440 PV patients in real life.
Methods
Forty-two eligible hematologists/oncologists in private practice treating patients with MPN were recruited to participate in a paper–pencil-based survey conducted between January 2019 and March 2020 in Germany. Physicians were asked to report primary documented data obtained from patient charts. Descriptive analyses were conducted to assess for patient characteristics, treatment modalities, risk factors and thromboembolic complications.
Results
Data were collected from the patient charts of 1440 individuals diagnosed with PV. The patient population was older than those reported in multicenter trials with a median age of 72.2 years at the time of reporting and 63.5 years at diagnosis. Age was the main factor accounting for high-risk status with 84.7% of patients being above the age of 60 followed by thromboembolic complications reported in 21.3% of patients. The use of pharmacologic cytoreduction was highly variable between participating centers with an average of 60.7% and a range of 10.1–100%. Hydroxyurea was the most frequently used drug followed by ruxolitinib, while interferons were reported for a minority of patients. For 35.4% of patients a persistent need for phlebotomy in addition to cytoreductive treatment was reported. Although presence of high-risk criteria and insufficient disease control were reported as main triggers to initiate pharmacologic cytoreduction, 28.1% had elevated hematocrit values (> 45%) and 38.6% showed persistence of elevated leukocyte count (> 109/l) while on cytoreductive treatment. In contrast, physician-reported symptom burden was lower than published in clinical trials and patient-reported outcomes. The rate of patients experiencing thromboembolic complications was 32.2% at any time and 14.3% after diagnosis with most patients receiving acetylsalicylic acid and 10.8% remaining on oral anticoagulants or heparin.
Conclusions
Cytoreductive treatment of high-risk PV in real life is highly variable regarding indication for cytoreduction and definition of therapy resistance. This study highlights the need for (i) improved risk stratification for thromboembolic events, (ii) consequent indication of pharmacologic cytoreduction in high-risk PV and (iii) attention to signs of therapy resistance that can trigger an earlier and stringent switch to second line agents.
“…More including patients on DOACs have emerged. A meta-analysis of the antithrombotic treatment of VTE in MPN patients pooled 10 studies with a total of 738 MPN patients and found that 22.6% of evaluable patients had a recurrent thrombotic event, including 55 of 313 (18%) on VKA and 5 of 63 (8%) on DOACs [30]. An observational multicenter study of 442 MPN patients on DOACs for either VTE or atrial fibrillation was recently published and found an incidence rate of 4.5% recurrent thromboses per patient year [31].…”
Myeloproliferative neoplasms (MPNs) are characterized by an increased risk of thrombosis and bleeding. Vitamin K antagonists (VKAs) are the historic anticoagulant recommended for use in MPNs. Direct oral anticoagulants (DOACs) are being increasingly used in general and cancer populations. However, DOAC safety and efficacy in MPN patients remains unclear. We characterized real-world practice patterns of DOAC use in MPN patients and evaluated thrombosis and bleeding risk. We conducted a retrospective cohort study of 133 MPN patients prescribed DOACs for venous thromboembolism (VTE), atrial fibrillation, or arterial thromboembolism (ATE). Practice patterns including duration of anticoagulation, dosing, and concomitant use of antiplatelet/cytoreductive agents, were heterogeneous among MPN patients. The 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. In comparison, reported bleeding rates in MPN patients on DOAC and VKAs are 1–3%. On multivariable analysis, prior history of thrombosis, use of dabigatran or edoxaban, and younger age were significantly associated with a higher risk of recurrent thrombosis, while leukocytosis was associated with a higher risk of bleeding on DOAC. The higher-than-expected bleeding rate found in our study indicates the continued need for rigorous evaluation of DOACs in this population.
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