Direct Oral Anticoagulants As Secondary Prophylaxis in Classical Myeloproliferative Neoplasms

Introduction: Thrombosis is a major cause of morbidity and mortality in patients with classical myeloproliferative neoplasms (MPN), which include polycythemia vera, essential thrombocythemia and primary myelofibrosis. One third of patients with MPN suffer a thrombotic event, either arterial or venous. Despite this, there are no strong data to guide either the selection or duration of anticoagulants for MPN. Warfarin has been primarily used for long-term anticoagulation and is associated with a clear reduction in overall thrombotic events, however 20% of patients will have a recurrent thrombotic event despite ongoing warfarin anticoagulation, corresponding to a failure rate of 4-8% pt-yrs (AnnHematol 2015;94:911-918, Haematologica2008;93:372-380). The overall objective of this study was to evaluate recurrent thrombotic and major bleeding events in MPN-associated thrombosis treated with DOAC versus warfarin.

Methods: The primary outcome was to compare the rate of thrombotic events in patients treated with DOAC versus warfarin for secondary thromboprophylaxis (treatment of first clot) among MPN patients. The secondary outcome compared the rate of bleeding events between the two groups. Electronic medical records for patients with a classical MPN diagnosis by PSVG criteria at the University of North Carolina Hospitals were queried to evaluate DOAC or warfarin medication orders between January 1, 2010 and May 31, 2017. Demographic laboratory data, concomitant medications, and incidence and severity of thrombotic or bleeding events were recorded for each MPN patient treated with a DOAC, warfarin, or aspirin. Descriptive statistics were used to characterize the population. Categorical variables were summarized as counts and percentages, while continuous variables were summarized as medians with first to third quartiles. The annual incidence of secondary thrombosis (ie: recurrent event) was calculated by dividing the number of events by the total number of patient-years (pt-yrs). 95% confidence intervals and comparisons were made using a Mid-P exact test. For all analyses, results were deemed significant if P<0.05.

Results: We identified 38 total patients diagnosed with a classical MPN, who started either warfarin (n=33), a DOAC (n=4), or aspirin (n=1) for secondary thromboprophylaxis. Median age was 56 years (range 15-98), 40% were male, and 90% Caucasian. No significant differences in the baseline characteristics were observed (Table). For all patients, the initial thrombotic event occurred two years or less prior to the MPN diagnosis. Cytoreductive therapy with either hydroxyurea or anagrelide was used as additional secondary therapy in 28 patients. Patients who received cytoreductive therapy had similar rates of a second thrombus compared to those who did not. Six of the 34 patients who started on either warfarin or aspirin switched to a DOAC, where two of the six were switched after a bleeding event, and none experienced a second thrombus. Seventeen of the 33 patients who started on warfarin, experienced a clot while on therapy with total follow-up of 116.7 pt-yrs. Of those 17 patients, 4 switched to a DOAC and none experienced another thrombotic event at follow-up of 23.7 pt-yrs. The rate of secondary thrombus while on DOAC was 4.2 per 100 pt-yrs (95% CI: 0.2-20.8) compared with a warfarin rate of 14.6 per 100 pt-yrs (95% CI: 8.8-22.9), P=0.2. Eleven bleeding events occurred at a rate of 4.2 per 100 pt-yrs (95% CI: 0.2-20.8) on DOAC compared to 8.6 per 100 pt-yrs (95% CI: 4.4-15.3) on warfarin. This did not lead to a therapy switch in the one DOAC patient, but did lead to a switch in three of 10 warfarin patients (Table).

Conclusion: These data suggest that DOACs are comparable to warfarin for preventing recurrent thrombotic events in MPN patients, with a similar risk of bleeding. There was a trend toward fewer thrombotic events in real world MPN-associated thrombosis treated with DOAC versus warfarin, though the small patient numbers do not allow definitive conclusions. Our data adds to the limited published experience using DOACs in MPN and strengthen rationale to pursue future prospective lines of inquiry that evaluate DOACs for secondary thromboprophylaxis in MPN patients.

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