Direct Oral Anticoagulants for Myeloproliferative Neoplasms (MPN-DOACs): Results from an International Study on 442 Patients

Background

Direct oral anticoagulants (DOACs) have emerged as a treatment of choice in patients with chronic atrial fibrillation (AF) or for secondary prevention of venous-thromboembolism (VTE). In myeloproliferative neoplasms (MPN) very small series have been reported and robust data reporting the safety/efficacy profile of these drugs is not available. We conducted an international, multi-country, retrospective study involving 19 hematologic centers from Europe, US and Canada, with the aim to describe in a large cohort of MPN patients the incidence of thrombosis and bleeding complications associated with DOAC use in real word clinical practice.

Methods

Centers reported in an electronic CRF data on 442 patients (M/F: 221/221; median age: 65 years) with a WHO diagnosis of polycythemia vera (PV, n=178), essential thrombocythemia (ET, n=172) and primary myelofibrosis (PMF, n=92) who had received DOACs (Rivaroxaban n=187; Apixaban n=157; Dabigatran n=50; Edoxaban n=48) for either primary and secondary antithrombotic prophylaxis in atrial fibrillation (AF, n=203) or secondary prophylaxis of venous thromboembolism (VTE, n=239). Eighty-two patients (18.6%) shifted to DOAC after a previous exposure to a vitamin K antagonist (VKA) mainly due to patient preference (8.4%), bleeding/thrombosis (5.2%) or INR instability (4.1%). In 60 patients, DOAC was discontinued after a median duration of 1.1 years; reasons included completion of a pre-determined duration (2.9%), patient decision (0.9%), major bleeding (2.5%) or thrombosis (2.9%), minor bleeding (0.9%), thrombocytopenia (2.0%), surgery (0.9%), or other (0.5%).

Results

Median time from MPN diagnosis to DOAC initiation was 4.4 years (range: 0-34.7 years). Concomitant therapies included antiplatelet agents (31%) and cytoreductive drugs in 90% (hydroxyurea in 87%of cases). After a median follow-up of 1.83 years, 32 major thrombotic events (rate: 3.3% pts/yr) and 26 major bleeding events (rate: 2.6% pts/yr) were reported.

1. AF. Ten thrombotic events (rate: 2.1% pts/yr) occurred in patients receiving DOACs: 4 TIA, 3 MI and 3 DVT of the lower extremities (LE); the rate was remarkably different in primary prevention (1.5% pts/yr) vs. secondary prophylaxis (i.e. after a previous thrombosis, mainly arterial: 4.6% pts/yr). This rate was almost double that reported in secondary prophylaxis in non-MPN population in randomized clinical trials (RCTs) (2.1-3.2% pts/yr). Previous arterial thrombosis was the only significant risk factor for recurrences in this subset (HR: 3.89, p=0.035).
2. VTE. Twenty-two recurrences while receiving DOACs were reported (5 arterial, 10 DVT of the LE +/- PE, 3 splanchnic vein and 4 others venous; rate: 4.5% pts/yr) and irrespective of initial site of thrombosis and type of DOACs. This rate was similar to MPN patients receiving VKAs (5.3% pts/yrs – De Stefano V et al, Leukemia 2016) but higher than in non-MPN population in RCTs (1.4-1.9% pts/yr). In univariate analysis, significant factors for recurrences were: previous arterial thrombosis (HR: 3.55, p=0.023), hypertension (HR: 2.88, p=0.021) and diabetes (HR: 3.33, p=0.018).
3. Among 26 major bleeding events, 12 were gastrointestinal, 7 intramuscular, 1 CNS and 6 in other sites. The overall rate was 2.6% patients/year, which is comparable to that reported in MPN patients under VKA (2.4% pt/yrs, De Stefano V et al, ibidem) and in non-MPN population of RCTs (1.60-3.11% pt/yrs). The frequency of major bleeding was similar in AF (3% pt/yrs) and VTE (2.3% pt/yrs) setting. In univariate analysis, significant risk factors were PMF diagnosis (HR: 2.95, p=0.007) and the use of Dabigatran in comparison to the other DOACs (HR: 2.91, p=0.016) whereas no increase was due to antiplatelet drugs.

Conclusions

This is the largest observational study describing vascular events in MPN patients receiving DOACs for prevention of thrombosis in AF or secondary prevention of VTE. Overall, the rate of re-thrombosis is similar to that reported with warfarin in MPN and double the rate of non-MPN population. The highest rate was found in patients with a previous history of arterial thrombosis and with cardiovascular risk factors. In regard to bleeding, we highlight the significant bleeding tendency in PMF and treatment with Dabigatran. In conclusion, the risk/benefit profile of DOACs in MPN is similar to that of Warfarin.