Page 101 - Haematologica May 2022

Anticoagulants and hemorrhage in PV
Discussion
Management of thrombotic events in patients with MPN is challenging. Although low-dose aspirin can effectively reduce the rate of thrombotic complications in PV, the opti- mal antithrombotic approach to secondary prevention is less clear. There are no randomized studies evaluating dif- ferent antithrombotic regimens in patients with MPN, and recurrent thrombosis is common after initiation of thera- peutic anticoagulation.5,6 Combined antiplatelet and antico- agulant therapy is often prescribed in patients with MPN without knowledge of hemorrhagic risks. In this large, prospective multicenter study, we evaluated whether the addition of aspirin to an anticoagulant increased the risk of hemorrhage with PV. We observed that the combination of anticoagulant with aspirin was associated with a greater than seven-fold increased risk of severe hemorrhage com- pared with aspirin alone.
Our observation that the combination of aspirin and an anticoagulant significantly increased the risk of hemor- rhage is in keeping with the larger published experience evaluating the combination for cardiovascular indica- tions.11,12 The Augustus trial recently reported rates of hem- orrhagic outcomes in more than 4,600 patients with atrial fibrillation undergoing percutaneous coronary interven- tions who were randomized to warfarin or apixaban plus aspirin or placebo.12 The risk of major hemorrhage was sig- nificantly higher in patients receiving aspirin plus an anti- coagulant compared with an anticoagulant without aspirin (HR: 1.89; 95% CI: 1.59-2.24; P<0.001).12 There are limited published data on the safety of combined antiplatelet and antithrombotic therapy in patients with MPN. In a recent Italian cohort that included 155 patients with an MPN and history of thrombosis, the 3-year cumulative incidence of recurrent thrombosis was 18.0% accompanied by a 6.5% incidence of major hemorrhage.5 Of the 19 patients (12%) in this cohort who received combined vitamin K antago- nist with aspirin, the incidence of major hemorrhage was 3.8 per 100 patient-years (95% CI: 0.4-13.8), which was statistically similar to those who received vitamin K antag- onist alone (2.2 per 100 patient-years; 95% CI: 0.9-4.4; P=0.50).5 Older series included even fewer patients (less than 10) exposed to combined antithrombotic therapy.7
There is limited evidence regarding the safety of DOAC in combination with aspirin in patients with MPN.13,14 The administration of a DOAC with aspirin did not appear to increase the risk of hemorrhage compared with warfarin and aspirin. There is evidence in cardiology cohorts that the combination of a DOAC with aspirin may be safer than warfarin combined with aspirin.11,12 We observed a similar trend for severe hemorrhages, but the difference was not statistically significant.
Although the combination of aspirin and an anticoagu- lant significantly increased the risk of severe hemorrhage relative to aspirin alone, whether the combination therapy offers therapeutic benefit over an anticoagulant alone was not established. The indication for anticoagulant therapy was not captured, and the absence of this information pre- cludes such an efficacy analysis. Due to its over-the- counter availability, the use of aspirin may not be fully cap- tured in the medical records; therefore, the analysis was limited to patients with documented aspirin use. We also note that patients were monitored for the development of hemorrhage, which was graded by CTCAE criteria. Alternative definitions of severe hemorrhage such as those established by the International Society of Thrombosis and
Figure 2. Kaplan-Meier estimate of thrombotic event-free survival by medica- tion group at enrollment. Kaplan-Meier estimate of thrombotic event (TE)-free survival by medication groups of aspirin plus anticoagulant (blue) and aspirin alone (green).
Hemostasis (ISTH)15 were not utilized. Nevertheless, the vast majority of the hemorrhages described as severe in this cohort would be expected to meet the ISTH definition of major hemorrhage considering that grade 3 or 4 hemor- rhages per CTCAE criteria require procedural intervention or are considered life-threatening. Other limitations of this analysis include the non-randomized nature of the study, the relatively short follow-up period, and the differences in the disease and/or treatment duration.
In summary, this prospective, multicenter, observational study revealed a significant increase in the risk of hemor- rhage and severe hemorrhage attributed to the combina- tion of aspirin and anticoagulants compared with aspirin alone. In patients previously taking aspirin for cardiovascu- lar risk modification, the American Society of Hematology advises against the continuation of aspirin following the initiation of anticoagulation for treatment of VTE.16 Whether the combination of aspirin and anticoagulants offers therapeutic benefit in the management of throm- boembolic disease in PV is not established.
Disclosures
JIZ reports research funding from Incyte Corporation and Quercegen Pharmaceuticals; consultancy fees from CSL, Merck, Parexel and Sanofi; and honoraria/advisory fees from Daiichi Sankyo, Pfizer/BMS and Portola. DP and PMC are employees and shareholders of Incyte Corporation. DSL reports research funding from Astellas Pharma, Exact Sciences, Incyte Corporation and Pfizer; speakers bureau and consulting hono- raria from Bayer and Incyte Corporation; and speakers bureau participation for Amgen. MRG has provided consultancy to AbbVie, Agios, Amgen, Astellas, Cardinal Health, Bristol Myers Squibb, Daiichi Sankyo, Gilead, Incyte Corporation, Karius, Merck, Pfizer, Premier Inc., Sierra Oncology, Stemline, and Trovagene; and has received research funding from Forma Therapeutics, Genentech/Roche, Incyte Corporation and Janssen.
Contributions
PMC, DSL, MRG, DP, and JIZ participated in the clinical study design and conduct; JIZ and DP performed data analyses;
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