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Marchioli R, et al. "Cardiovascular events and intensity of treatment in polycythemia vera". The New England Journal of Medicine. 2013. 368(1):22-33.
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Clinical Question

In adult patients with JAK2-positive polycythemia vera being treated with phlebotomy and/or hydroxyurea, does intensive hematocrit lowering (target <45%) versus a less-intensive strategy (target 45-50%) reduce mortality from cardiovascular or major thrombotic events?

Bottom Line

Among patients with JAK2-positive polycythemia vera (PV), maintaining a target hematocrit of <45% has a significantly lower rate of fatal and non-fatal cardiovascular or thrombotic events, when compared to a target hematocrit of 45-50%.

Major Points

Polycythemia vera (PV) is a myeloproliferative disorder (MPN) characterized by overproduction of erythrocytes — and to a lesser extent, granulocytes and platelets — and is driven by a mutation in the JAK2 tyrosine kinase in nearly all cases. PV is associated with arterial and venous thrombotic events, related to increased blood viscosity. Lowering the hematocrit has long been shown to have beneficial effect, but quantifying the benefit and establishing a therapeutic target has largely been based on observational data.[1] In fact, results from prior PV trials show mixed results of the influence of targeting a lower hematocrit on reducing thrombotic events.[2][3]

Published in 2013, the Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) enrolled 365 patients with JAK2-positive PV, and randomized patients to treatment with aspirin, phlebotomy, and hydroxyurea, targeting a hematocrit of either <45% or 45-50%. Treatment decisions were left to investigator discretion, although investigators were encouraged to use hydroxyurea in high-risk patients (age >65 or prior thrombosis) or those with symptomatic splenomegaly or thrombocytosis. The primary outcome was the composite endpoint of cardiovascular death or thrombotic event (stroke/TIA, ACS, arterial thrombosis, or DVT/PE). Slow enrollment resulted in approximately one-third of the planned accrual. At a median follow-up of 31 months, the intensive (<45%) group had fewer fatal cardiovascular or thrombotic events (1.1 vs. 4.4 per 100 patient-years). Rates of non-fatal thrombotic events were also significantly decreased. There was no difference in bleeding, evolution to myelofibrosis, myelodysplastic syndrome, or acute leukemia. Subgroup analyses showed no significant differences amongst prespecified groups including sex, prior thrombotic episodes, and concurrent antiplatelet and anticoagulant therapy.


BSCH Guidelines for PV (2005, adapted)[4]

  • The Hct should be maintained at <45% by phlebotomy. (Grade B)


  • Multicenter, non-blinded, randomized, controlled trial
  • N=365 patients with JAK2-positive PV
    • Low hematocrit (<45%) group (n=182)
    • High hematocrit (45-50%) group (n=183)
  • Setting: 26 centers in Italy
  • Enrolment: 2008-2012
  • Mean follow-up: 31 months
  • Analysis: Intention-to-treat
  • Primary outcome: Composite endpoint of death from cardiovascular or thrombotic cause (stroke, ACS, PE)


Inclusion Criteria

  • Polycythemia vera by WHO 2008 criteria
  • Presence of JAK2 mutation (V617F or exon 12)

Exclusion Criteria

  • Liver dysfunction (AST or ALT >2.5×ULN )
  • Renal dysfunction (Cr >2 mg/dL or >177 μmol/L)
  • Pregnancy, lactation or unwillingness to use contraception for females of child-bearing age
  • Prior intolerance to hydroxyurea therapy
  • Serious comorbidities likely to significantly limit life expectancy
  • Any other condition felt to limit adherence to treatment protocol

Baseline Characteristics

  • Mean age: 64.5 years
  • Female: 38%
  • Time from diagnosis to enrollment: mean 4.3 years, 50% within 2 years
  • Hematologic values at enrolment
    • Hematocrit: 47.4%
    • WBC count (per mm2): 9,300
    • Platelet count (per mm2): 406,000
  • Prior thrombotic episodes
    • Arterial: 17.3%
    • Venous: 12.3%
  • Antithrombotic therapy
    • Antiplatelet agent: 84.4%
    • Vitamin K antagonist: 13.4%
  • Cytoreductive method
    • Phlebotomy: 68% (median 2 procedures in prior 6 months)
    • Hydroxyurea: 52.6% (median dose 750 mg per day)
    • Other (pipobroman, IFN, busulfan): 7.1%
  • Baseline treatment for CV risk factors
    • Hypertension: 48.2%
    • Dyslipidemia: 12.9%
    • Diabetes: 4.7%


  • Randomized to intensive (hematocrit <45%) versus non-intensive target (hematocrit 45-50%)
    • Stratified by referring medical center and high-risk features (age <65 or ≥65, prior thrombotic event, splenomegaly, progressive thrombocytopenia)
  • Random assignment to achieve hematocrit targets via phlebotomy, cytoreductive therapy, or combination. Choice of best therapeutic option then left to discretion of investigator, with high-risk patients recommended to have cytoreductive therapy
    • Phlebotomy 2-4 times per week (250 or 500 mL) until target reached
    • Hydroxyurea started at 500-1,000 mg per day, with weekly CBC monitoring to target platelet count of under 400,000/mL. Dose reductions performed if leukocyte count fell under 3,500/mL
  • Low-dose aspirin was administered to all patients who had no contraindication to its use
  • Other cytoreductive therapy permitted at physician's discretion
  • Permanent discontinuation or change in hematocrit target was considered if in the best interest in the patient


Comparisons are intensive vs. non-intensive hematocrit group.

Primary Outcome

Cardiovascular death or major thrombotic event
2.7% vs. 9.8% (HR 3.91; 95% CI 1.45-10.53; P=0.007)
1.1 vs. 4.4 events per 100 person-years

Secondary Outcomes

Cardiovascular events
4.4% vs. 10.9% (HR 2.69; 95% CI 1.19-6.12; P=0.02)
Progression to myelofibrosis, myelodysplastic syndrome, or leukemia
0.5-3.3%, no statistically significant difference between groups

Adverse Events

  • Low hematocrit group
    • Discontinuation of assigned treatment: 2.2%
    • Serious adverse events: 1 patient (bone fracture)
  • High hematocrit group
    • Discontinuation of assigned treatment: 2.7%
    • Serious adverse events: 3 patients (diarrhea, dizziness, bronchitis)


  • Trial closed after 365 patients were enrolled, earlier than the planned 1,000 patients and 5 year follow up due to slow accrual and competing trials with JAK2 inhibitors
  • High hematocrit group had a significantly higher leukocyte count and a lower proportion of participants on hydroxyurea therapy, which could have been confounding variables influencing the outcomes, however there was no difference in platelet count
  • Proportion of patients in target hematocrit range: approximately 75%


Sponsored by the Italian Medicines Agency. Treatments provided through the national health system. No major conflicts of interest stated.

Further Reading

  1. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011; 29:761-70.
  2. Di Nisio M, Barbui T, Di Gennaro L, et al. The haematocrit and platelet target in polycythemia vera. Br J Haematol 2007; 136:249-59.
  3. Fruchtman SM, Mack K, Kaplan ME, Peterson P, Berk PD, Wasserman LR. From efficacy to safety: a Polycythemia Vera Study Group report on hydroxyurea in patients with polycythemia vera. Semin Hematol 1997;34:17-23.
  4. McMullin MF, et al. Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. 2005;130(2):174-195.