Cardiovascular Events and Intensity of Treatment in Polycythemia Vera

TLDR

Current treatment guidelines for polycythemia vera recommend keeping hematocrit below 45%, yet this strategy had never been evaluated in a randomized trial. We randomized 365 JAK2‑positive PV patients to intensive (hematocrit < 45%) or less intensive (45–50%) phlebotomy/hydroxyurea therapy and followed them for a median of 31 months, assessing a composite primary endpoint of cardiovascular death or major thrombosis and secondary endpoints of cardiovascular events, hospitalizations, cancer, disease progression, and bleeding. Intensive treatment reduced the composite primary endpoint to 2.7 % versus 9.8 % in the less intensive group (HR 3.91, P = 0.007), and lowered the combined rate of primary endpoint plus superficial‑vein thrombosis to 4.4 % versus 10.9 % (HR 2.69, P = 0.02); other secondary outcomes, including disease progression and bleeding, did not differ significantly between groups. The study was funded by the Italian Medicines Agency and others and registered at ClinicalTrials.gov (NCT01645124) and EudraCT (2007‑006694‑91).

Abstract

Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been tested in a randomized clinical trial.We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed.After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events.In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT01645124, and EudraCT number, 2007-006694-91.).