Impact of cytoreduction on thrombotic and bleeding outcomes in patients with myeloproliferative neoplasms and atrial fibrillation

Abstract Background Myeloproliferative neoplasms (MPNs), such as polycythemia vera (PV) and essential thrombocythemia (ET) have an increased risk of arterial and venous thrombotic complications. Cytoreductive therapies are indicated in MPN to reduce thrombotic risk. Atrial fibrillation (AF) is the most common arrhythmia in adults and significantly increases the risk of stroke and thromboembolic events, including in patients with MPN. However, AF is not currently taken into consideration with regards to initiation of cytoreductive therapy for PV or ET. There is a lack of data on the specific impact of cytoreduction on thrombotic outcomes in patients with MPN and AF. Methods We conducted a retrospective, observational study employing the TriNetX Analytics Network, which includes de-identified health records from over 100 international health care organizations. We included patients with preexisting non-valvular atrial fibrillation and polycythemia vera (PV) or essential thrombocythemia (ET) indexed at MPN diagnosis between 2015-2024. We excluded patients with valvular heart disease, prior thrombotic events, myelofibrosis, or other myeloid neoplasms. We employed propensity score matching (1:1) based on demographics, comorbidities (such as hypertension, diabetes, chronic kidney disease, hyperlipidemia, obesity, and heart failure), baseline hematocrit and platelet count, MPN subtype, and relevant medications (including antithrombotics) to create two comparable cohorts; 1) received pharmacologic cytoreductive therapy within 3 months of index diagnosis (including hydroxyurea, ruxolitinib, anagrelide or interferon alpha) 2) patients who did not receive cytoreductive therapy. Study horizon was two years from index MPN diagnosis. A Cox regression model was used to compare the cohorts for the primary outcome of ischemic stroke, as well as secondary outcomes including arterial thrombosis (stroke, myocardial infarction, and peripheral arterial embolism) and venous thrombosis (pulmonary embolism, deep vein thrombosis, and abdominal thrombosis). Kaplan-Meier analysis was used to evaluate survival. Results We included 1,382 patients (691 in each cohort) with median follow-up of 24 months. The average age at the index event was 77.2 ± 9.3 years, 74.5% White and 50.3% female. The majority had ET (65.1%) followed by PV (38.0%). Antithrombotics at index included aspirin (34.8%), direct oral anticoagulants (39.5%), warfarin (13.5%) and low molecular weight heparin (11.9%). In the cytoreductive group, hydroxyurea was the most frequent therapy (89.4%) followed by anagrelide (6.8%) and ruxolitinib (5.9%). The cohorts were well balanced after matching, with all standardized mean differences < 0.01 for demographics, comorbidities, laboratory values, MPN subtype, and concomitant medication use. The incidence of ischemic stroke was 16.6 and 26.0 per 1,000 patient-years in patients receiving cytoreduction and those who did not receive cytoreduction, respectively. Cytoreduction was associated with a numerically lower risk of stroke, although the difference was not statistically significant (HR 0.64 [95% CI: 0.38–1.08]). Furthermore, cytoreduction was associated with a statistically lower risk of composite arterial thrombosis (HR 0.66 [95% CI: 0.46-0.96]). The incidence of composite venous thrombosis was 16.6 per 1000 patient-years in both cohorts. The risk of composite venous thrombosis (HR 1.01 [95% CI: 0.57-1.80]) did not differ between the cytoreduction and non-cytoreduction groups. There were also no significant differences for individual venous thrombotic outcomes including PE (HR 1.5 [95% CI: 0.62-3.7]), DVT (HR 0.69 [95% CI: 0.32-1.49]). Cytoreductive therapy was not associated with significant difference in mortality at 2 years (HR 0.87, [95% CI 0.64-1.17]) Conclusion In this propensity score–matched analysis of patients with MPN and AF, arterial thrombotic events were more frequent than venous thrombotic complications. Cytoreductive therapy at MPN diagnosis was not associated with a significant reduction in the primary outcome of ischemic stroke among patients with concomitant AF and MPN. However, it was associated with a lower risk of composite arterial events. These findings suggest that risk-adapted use of cytoreductive therapy in MPN could help reduce thrombotic complications in patients with coexisting high-risk conditions such as AF.