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ECLAP

Efficacy and Safety of Low-Dose Aspirin in Polycythemia Vera

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Year of Publication: 2004

Authors: Raffaele Landolfi, Roberto Marchioli, Jack Kutti, ..., for the European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators

Journal: New England Journal of Medicine

Citation: N Engl J Med 2004;350:114-24

Link: https://doi.org/10.1056/NEJMoa035572

Clinical Question

Can low-dose aspirin safely prevent thrombotic complications in patients with polycythemia vera who have no contraindications to such treatment?

Bottom Line

Low-dose aspirin (100 mg daily) significantly reduces thrombotic complications by 60% in patients with polycythemia vera without significantly increasing major bleeding risk, supporting its use for primary prevention of thrombosis in this population.

Major Points

  • First randomized controlled trial of low-dose aspirin in polycythemia vera patients
  • 60% reduction in combined endpoint of MI, stroke, PE, major venous thrombosis, or CV death
  • No significant increase in major bleeding episodes (RR 1.62, 95% CI 0.27-9.71)
  • Study enrolled patients with no clear indication for aspirin (primary prevention cohort)
  • Effect size larger than typical aspirin prevention trials, possibly due to increased thromboxane synthesis in polycythemia vera

Design

Study Type: Double-blind, placebo-controlled, randomized trial

Randomization: 1

Blinding: Double-blind (patients and investigators)

Enrollment Period: About 2 years

Follow-up Duration: Mean 3 years (total 1478 person-years)

Centers: 94

Countries: Italy, Austria, Sweden, Germany, Greece, Ireland, Israel, France, Spain, Switzerland, United Kingdom, Germany

Sample Size: 518

Analysis: Intention-to-treat analysis using Kaplan-Meier survival curves, log-rank test, Cox regression models with SAS statistical software

Inclusion Criteria

  • Diagnosis of polycythemia vera based on standard clinical and laboratory criteria
  • No clear indication for aspirin treatment
  • No clear contraindication to aspirin therapy
  • Able to provide written informed consent
  • No clinically significant coexisting conditions
  • No age limits specified

Exclusion Criteria

  • Clear indication for antithrombotic therapy (742 patients, 66%)
  • Contraindication to aspirin therapy (271 patients, 24%)
  • Patient unwillingness to participate (197 patients, 18%)

Arms

FieldControlAspirin
InterventionPlacebo tablet daily for mean 3 years, with other standard treatments (phlebotomy, cytoreductive drugs, cardiovascular drugs) as requiredLow-dose aspirin 100 mg daily (enteric-coated formulation) for mean 3 years, with other standard treatments as required
DurationMean 3 yearsMean 3 years

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Combined endpoint of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causesPrimary21 events (7.9%)8 events (3.2%)0.40.03
Nonfatal MI, nonfatal stroke, or death from cardiovascular causesSecondary13 events (4.9%)5 events (2.0%)0.410.09
Major or minor thrombosisSecondary41 events (15.5%)17 events (6.7%)0.420.003
Minor thrombotic complicationsSecondary22 events (8.3%)10 events (4.0%)0.470.049
Death from any causeSecondary18 events (6.8%)9 events (3.6%)0.540.13
Any bleedingAdverse14 events (5.3%)23 events (9.1%)1.820.08
Major bleedingAdverse2 events (0.8%)3 events (1.2%)1.620.60
Minor bleedingAdverse12 events (4.5%)20 events (7.9%)1.830.10

Subgroup Analysis

Consistent beneficial effects of aspirin across subgroups defined by disease duration, cytoreductive drug use, platelet count, and hematocrit levels. Fully adjusted multivariate model showed 77% reduction in first primary endpoint (P=0.02) and 71% reduction in second primary endpoint (P=0.008).

Criticisms

  • Study was terminated early due to slow recruitment - only recruited about 25% of planned sample size
  • Wide confidence intervals around point estimates due to relatively small number of events
  • Only the second primary endpoint reached statistical significance
  • Excluded 45% of potential enrollees who had clear indications for aspirin
  • Results may not be generalizable to higher-risk polycythemia vera patients with prior thrombotic events

Funding

Supported by grant ERBBMH4CT961433 from the Biomed 2 Program of the European Union and unrestricted grants from Bayer and Bayer Italia

Based on: ECLAP (New England Journal of Medicine, 2004)

Authors: Raffaele Landolfi, Roberto Marchioli, Jack Kutti, ..., for the European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators

Citation: N Engl J Med 2004;350:114-24

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