Cardiovascular Events and Polycythemia Vera

Polycythemia vera is a rare hematologic neoplasm characterized by clonal proliferation of multipotent bone marrow progenitors, leading to abnormal production of erythroid cells and an increased red-cell mass. Acquired mutations in JAK2 (JAK2 V617F and exon 12 mutations) are found in nearly all patients with polycythemia vera. Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of <45%, but this therapeutic strategy has not been tested in a randomized clinical trial. Major causes of death and complications include thrombosis, bleeding, and hematologic transformation into overt myelofibrosis or acute leukemia.

In this large-scale, multicenter, prospective, randomized clinical trial, called the Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) study, the investigators, from Italy, compared the efficacy of conventional treatment (phlebotomy, hydroxyurea, or both) aimed at maintaining the recommended hematocrit target of <45%, compared with a level of 45% to 50%, for the prevention of thrombotic events in patients with polycythemia vera. Study results were published online in the New England Journal of Medicine [2012.doi.10.1056/NEJMoa1208500].

A total of 365 patients from 26 centers in Italy were enrolled in the study between May 2008 and February 2012. At enrollment, the patients were stratified according to the presence or absence of a history of thrombosis, age group (<65 years or ≥65 years), and referring medical center. Patients were randomly assigned in a 1:1 ratio to undergo phlebotomy, receive hydroxyurea, or both, with one group receiving more aggressive therapy for a hematocrit target of <45% (low-hematocrit group) and the other group receiving less aggressive therapy for a hematocrit target of 45% to 50% (high-hematocrit group).

Primary composite end point was time until death from cardiovascular causes or thrombotic events (stroke, acute coronary syndrome, transient ischemic attack, pulmonary embolism, abdominal thrombosis, deep-vein thrombosis, or peripheral arterial thrombosis). Secondary end point was the total rate of cardiovascular events, defined as the primary end point plus superficial-vein thrombosis. Additional end points were incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, total and nonfatal major hemorrhage (any hemorrhage requiring transfusion, hospitalization, or both), and minor bleeding.

Of the total study population, 182 were randomly assigned to the low-hematocrit group and 183 to the high-hematocrit group. The intention-to-treat analysis included all 365 patients. All patients carried the JAK2 V617F mutation (with the exception of 10, of whom 5 carried a JAK2 exon 12 mutation and 5 had an unknown mutation status). Of the 365 patients, 245 (67.1%) were at high risk due to being ≥65 years of age or experiencing previous thrombosis; 91 patients (24.9%) had had thrombotic events >12 months before undergoing randomization, and 63 of these events (60.0%) were arterial thromboses. Fifty-five percent of the patients had hypertension and 17% had hypercholesterolemia. The most common therapies at enrollment were antiplatelet agents (84.4%) — most frequently aspirin (76.4%) — phlebotomy (68.0%), hydroxyurea (52.6%), and antihypertensive medication (48.2%). Patients were followed for a mean (±SD) of 28.9±10.9 months (range, 1.5-48.1).

After a median of 31 months of follow-up, 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 [HR] in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.4-10.53; P=.007).

The incidence of death from cardiovascular causes or major thrombosis was 1.1 per 100 person-years in the low-hematocrit group and 4.4 per 100 person-years in the high-hematocrit group. Total cardiovascular events occurred in 4.4% of patients in the low-hematocrit group and 10.9% of those in the high-hematocrit group (HR, 2.69; 95% CI, 1.19-6.12; P=.02).