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CYTO-PV

Cardiovascular Events and Intensity of Treatment in Polycythemia Vera

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Year of Publication: 2013

Authors: Roberto Marchioli, Guido Finazzi, Giorgina Specchia, ..., Tiziano Barbui

Journal: The New England Journal of Medicine

Citation: N Engl J Med 2013;368:22-33

Link: https://doi.org/10.1056/NEJMoa1208500

Clinical Question

Does maintaining a hematocrit target of less than 45% versus 45-50% reduce cardiovascular death and major thrombotic events in patients with polycythemia vera?

Bottom Line

In patients with polycythemia vera, maintaining a hematocrit target of less than 45% significantly reduced cardiovascular death and major thrombosis compared to a target of 45-50%.

        Major Points
        First randomized trial to test current hematocrit recommendations in polycythemia vera
Primary endpoint occurred in 2.7% of intensive vs 9.8% of standard treatment group
Hazard ratio of 3.91 (95% CI 1.45-10.53, p=0.007) favoring intensive control
Study closed early due to clear benefit in the intensive treatment group
No significant increase in adverse events with intensive treatment

      

Design

Study Type: Randomized controlled trial

Randomization: 1

Blinding: Open-label

Enrollment Period: May 2008 to February 2012

Follow-up Duration: Median 31 months

Centers: 26

Countries: Italy

Sample Size: 365

Analysis: Intention-to-treat analysis using Kaplan-Meier method and Cox proportional-hazards models

Inclusion Criteria

Adults with diagnosis of polycythemia vera according to WHO 2008 criteria
Presence of JAK2 V617F or exon 12 mutation
Being treated with phlebotomy, hydroxyurea, or both

Exclusion Criteria

Substantial liver disease (ALT or AST >2.5 times upper normal limit)
Renal disease (creatinine >2 mg/dL or 177 μmol/L)
History of active substance or alcohol abuse within past year
Pregnancy, lactation, or lack of contraception in women of childbearing age
Life-threatening condition or disease likely to substantially shorten life expectancy
Previous side effects while receiving hydroxyurea
Any condition that could result in poor protocol adherence

Arms

Field	Control	Low-hematocrit group
Intervention	Less intensive treatment with target hematocrit 45-50% using phlebotomy, hydroxyurea, or both	More intensive treatment with target hematocrit <45% using phlebotomy, hydroxyurea, or both
Duration	Median 31 months	Median 31 months

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Time until death from cardiovascular causes or major thrombotic events (stroke, acute coronary syndrome, transient ischemic attack, pulmonary embolism, abdominal thrombosis, deep-vein thrombosis, or peripheral arterial thrombosis)	Primary	18/183 (9.8%)	5/182 (2.7%)	3.91	0.007
Total cardiovascular events (primary endpoint plus superficial-vein thrombosis)	Secondary	20/183 (10.9%)	8/182 (4.4%)	2.69	0.02
All-cause death	Secondary	6/183 (3.3%)	3/182 (1.6%)	2.15	0.28
Cardiovascular death	Secondary	4/183 (2.2%)	0/182 (0%)
Bleeding	Adverse	5/183 (2.7%)	2/182 (1.1%)	2.53	0.27
Myelofibrosis	Adverse	2/183 (1.1%)	6/182 (3.3%)	0.34	0.18
Myelodysplasia or acute leukemia	Adverse	1/183 (0.5%)	2/182 (1.1%)	0.52	0.59

Subgroup Analysis

No significant interaction found for effect of study-group assignment across prespecified subgroups including age, sex, previous thrombosis, platelet counts, white-cell counts, splenomegaly, and medication use

Criticisms

Study closed early before reaching planned recruitment target due to slow enrollment
Not all patients maintained assigned hematocrit targets during study
Follow-up period too short to assess long-term transformation rates
Open-label design could introduce bias
Higher use of hydroxyurea in low-hematocrit group may have contributed to benefit beyond hematocrit control

Funding

Italian Medicines Agency (AIFA) and Special Program Molecular Clinical Oncology 5x1000 of Associazione Italiana per la Ricerca sul Cancro–Gruppo Italiano Malattie Mieloproliferative

Based on: CYTO-PV (The New England Journal of Medicine, 2013)

Authors: Roberto Marchioli, Guido Finazzi, Giorgina Specchia, ..., Tiziano Barbui

Citation: N Engl J Med 2013;368:22-33

Content summarized and formatted by NeuroTrials.ai.

CYTO-PV

(2013)

Objective

To compare the efficacy of maintaining hematocrit <45% versus 45-50% for preventing thrombotic events in polycythemia vera patients

Study Summary

• Patients with hematocrit target <45% had significantly lower rate of cardiovascular death and major thrombosis (2.7% vs 9.8%)
• Hazard ratio of 3.91 favoring intensive hematocrit control
• Study supports current guidelines for tight hematocrit control in polycythemia vera

Intervention

More intensive treatment (target hematocrit <45%) versus less intensive treatment (target hematocrit 45-50%) using phlebotomy, hydroxyurea, or both

Inclusion Criteria

Adults with JAK2-positive polycythemia vera according to WHO 2008 criteria

Study Design

Arms: Low-hematocrit group (target <45%) vs High-hematocrit group (target 45-50%)

Patients per Arm: 182 vs 183

Outcome

• Primary endpoint occurred in 2.7% of low-hematocrit vs 9.8% of high-hematocrit group (HR 3.91, p=0.007)
• Total cardiovascular events: 4.4% vs 10.9% (HR 2.69, p=0.02)
• No significant difference in adverse events between groups

Bottom Line

In patients with polycythemia vera, maintaining a hematocrit target of less than 45% significantly reduced cardiovascular death and major thrombosis compared to a target of 45-50%.

Major Points

First randomized trial to test current hematocrit recommendations in polycythemia vera
Primary endpoint occurred in 2.7% of intensive vs 9.8% of standard treatment group
Hazard ratio of 3.91 (95% CI 1.45-10.53, p=0.007) favoring intensive control
Study closed early due to clear benefit in the intensive treatment group
No significant increase in adverse events with intensive treatment

Study Design

Study Type: Randomized controlled trial
Randomization: Yes
Blinding: Open-label
Sample Size: 365
Follow-up: Median 31 months
Centers: 26
Countries: Italy

Primary Outcome

Definition: Time until death from cardiovascular causes or major thrombotic events (stroke, acute coronary syndrome, transient ischemic attack, pulmonary embolism, abdominal thrombosis, deep-vein thrombosis, or peripheral arterial thrombosis)

Control	Intervention	HR/OR	P-value
18/183 (9.8%)	5/182 (2.7%)	3.91 (1.45-10.53)	0.007

Limitations & Criticisms

Study closed early before reaching planned recruitment target due to slow enrollment
Not all patients maintained assigned hematocrit targets during study
Follow-up period too short to assess long-term transformation rates
Open-label design could introduce bias
Higher use of hydroxyurea in low-hematocrit group may have contributed to benefit beyond hematocrit control

Citation

N Engl J Med 2013;368:22-33

View Original Publication →

CYTO-PV

Cardiovascular Events and Intensity of Treatment in Polycythemia Vera

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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