The new england journal of medicine n engl j med nejm.org 1 original article Cardiovascular Events and Intensity of Treatment in Polycythemia Vera Roberto Marchioli, M.D., Guido Finazzi, M.D., Giorgina Specchia, M.D., Rossella Cacciola, M.D., Ph.D., Riccardo Cavazzina, Sc.D., Daniela Cilloni, M.D., Ph.D., Valerio De Stefano, M.D., Elena Elli, M.D., Alessandra Iurlo, M.D., Ph.D., Roberto Latagliata, M.D., Francesca Lunghi, M.D., Monia Lunghi, M.D., Rosa Maria Marfisi, M.S., Pellegrino Musto, M.D., Arianna Masciulli, M.D., Ph.D., Caterina Musolino, M.D., Ph.D., Nicola Cascavilla, M.D., Giovanni Quarta, M.D., Maria Luigia Randi, M.D., Davide Rapezzi, M.D., Marco Ruggeri, M.D., Elisa Rumi, M.D., Anna Rita Scortechini, M.D., Simone Santini, M.D., Marco Scarano, Sc.D., Sergio Siragusa, M.D., Antonio Spadea, M.D., Ph.D., Alessia Tieghi, M.D., Emanuele Angelucci, M.D., Giuseppe Visani, M.D., Alessandro Maria Vannucchi, M.D., and Tiziano Barbui, M.D., for the CYTO-PV Collaborative Group* The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Marchioli at Consorzio Mario Negri Sud, Via Nazionale 8/A, 66030 Santa Maria Imbaro, Italy, or at marchioli@negrisud.it. *The investigators in the Cytoreductive Therapy in Polycythemia Vera (CYTO- PV) Collaborative Group are listed in the Supplementary Appendix, available at NEJM.org. This article was published on December 8, 2012, at NEJM.org. N Engl J Med 2012. DOI: 10.1056/NEJMoa1208500 Copyright © 2012 Massachusetts Medical Society. Abstract Background 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. Methods We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more inten- sive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treat- ment (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 hospital- izations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leuke- mic transformation, and hemorrhage. An intention-to-treat analysis was performed. Results 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 super- ficial-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. Conclusions 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.) The New England Journal of Medicine Downloaded from nejm.org at CROB - Basilicata on December 28, 2012. For personal use only. No other uses without permission. Copyright © 2012 Massachusetts Medical Society. All rights reserved.