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PT1

Hydroxyurea Compared with Anagrelide in High-Risk Essential Thrombocythemia

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Year of Publication: 2005

Authors: Claire N. Harrison, Peter J. Campbell, Georgina Buck, ..., Anthony R. Green

Journal: New England Journal of Medicine

Citation: N Engl J Med 2005;353:33-45

Link: https://doi.org/10.1056/NEJMoa043800

Clinical Question

Is hydroxyurea plus aspirin superior to anagrelide plus aspirin for patients with essential thrombocythemia at high risk for vascular events?

Bottom Line

Hydroxyurea plus low-dose aspirin is superior to anagrelide plus low-dose aspirin for patients with essential thrombocythemia at high risk for vascular events, with lower rates of arterial thrombosis and serious hemorrhage.

Major Points

  • Open-label randomized trial of 809 patients with high-risk essential thrombocythemia
  • Anagrelide group had significantly higher rate of primary composite endpoint (odds ratio 1.57, P=0.03)
  • Arterial thrombosis more than twice as common in anagrelide group (odds ratio 2.16, P=0.004)
  • Serious hemorrhage significantly increased with anagrelide (odds ratio 2.61, P=0.008)
  • Venous thromboembolism was lower in anagrelide group (odds ratio 0.27, P=0.006)
  • Transformation to myelofibrosis more common with anagrelide (odds ratio 2.92, P=0.01)
  • More patients withdrew from anagrelide treatment due to side effects

Design

Study Type: Randomized controlled trial

Randomization: 1

Blinding: Open-label

Enrollment Period: August 1997 to August 2002

Follow-up Duration: Median 39 months (range 12-72 months)

Centers: 138

Countries: United Kingdom, Ireland, Australia

Sample Size: 809

Analysis: Intention-to-treat analysis using Kaplan-Meier analysis and log-rank test, minimization randomization method

Inclusion Criteria

  • Essential thrombocythemia meeting Polycythemia Vera Study Group criteria
  • High risk defined as one or more: age ≥60 years, platelet count ≥1 million/mm³, history of ischemia/thrombosis/embolism, hemorrhage caused by essential thrombocythemia, hypertension requiring therapy, diabetes requiring hypoglycemic agent
  • Age ≥18 years
  • Both newly diagnosed and previously treated patients eligible

Exclusion Criteria

  • Misdiagnosis (chronic myeloid leukemia, reactive thrombocytosis, idiopathic myelofibrosis, polycythemia vera)

Arms

FieldControlAnagrelide plus aspirin
InterventionHydroxyurea 0.5-1g daily (adjusted to maintain platelet count <400,000/mm³) plus aspirin 75mg daily (100mg in Australia)Anagrelide 0.5mg twice daily (adjusted to maintain platelet count <400,000/mm³) plus aspirin 75mg daily (100mg in Australia)
DurationMedian 39 monthsMedian 39 months

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Composite of arterial thrombosis, venous thrombosis, serious hemorrhage, or death from thrombotic or hemorrhagic causesPrimary36 patients55 patients0.03
Arterial thrombosisSecondary17 patients37 patients2.160.004
Venous thromboembolismSecondary14 patients3 patients0.270.006
Serious hemorrhageSecondary8 patients22 patients2.610.008
Transformation to myelofibrosisSecondary5 patients16 patients2.920.01
Death from any causeSecondary27 patients31 patients1.15NS
Treatment withdrawalAdverse79 patients148 patients<0.001
PalpitationsAdverse7 patients63 patients<0.001
DiarrheaAdverse6 patients18 patients0.01
HeadacheAdverse8 patients51 patients<0.001
Leg ulcerAdverse20 patients9 patients0.04

Subgroup Analysis

No evidence of heterogeneity of treatment effect between subgroups of newly diagnosed vs previously diagnosed disease, previous cytoreductive therapy vs none, and previous hydroxyurea vs none

Criticisms

  • Open-label design may introduce bias
  • Higher platelet counts in anagrelide group at 3 and 6 months may have influenced early thrombotic risk
  • Trial stopped early by data monitoring committee which may affect interpretation
  • Mechanism of increased myelofibrosis transformation with anagrelide unclear
  • Aspirin contraindication led to alternative agents in some patients

Funding

United Kingdom Medical Research Council

Based on: PT1 (New England Journal of Medicine, 2005)

Authors: Claire N. Harrison, Peter J. Campbell, Georgina Buck, ..., Anthony R. Green

Citation: N Engl J Med 2005;353:33-45

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