Clopidogrel (Plavix) and aspirin are two antithrombotic agents (blood thinners) commonly
used in patients with previous thrombotic events (stroke or heart attack). Thrombosis is the
formation of a blood clot in a blood vessel. Patients with polycythemia vera are routinely
treated with aspirin which has been shown to be effective in reducing their thrombotic risk.
However, in polycythemia vera patients with previous thrombosis, a further benefit might be
obtained by using the combination of aspirin and clopidogrel which is routinely used in
patients with recent acute myocardial ischemia (reduced blood supply to the heart muscle).
The study will assess whether this combination therapy greatly increases the risk of
bleeding versus aspirin alone, if clopidogrel reduces biological factors that might lead to
a stroke or heart attack, and whether a high number of patients with polycythemia vera are
resistant to clopidogrel.
Approximately 200 subjects will be enrolled to the Myeloproliferative Disorders-Research
Consortium (MPD-RC) study in Europe and the United States with participation expected to
last for 7 months (6 months of receiving study medication plus a 30 day follow-up visit).
Inclusion Criteria
Patients are included in the study if all of the following criteria are met:
1. A documented diagnosis of polycythemia vera established within 5 years of
registration. There must be documentation that the patient has met the revised WHO
criteria for the diagnosis of polycythemia vera. Patients must meet the 2 major
criteria and 1 of the minor criteria. To verify that the criteria have been met, the
appropriate laboratory or pathology reports must be submitted demonstrating that the
patient has documentation of these diagnostic criteria.
Major Criteria:
- Hemoglobin >18. 5 g/dl in men, >16. 5 g/dl in women or other evidence of increased
red cell volume.
- Presence of JAK2V617F or other functionally similar mutation such as JAK2 exon
12 mutation
Minor Criteria:
- Bone marrow biopsy showing hypercellularity for age with trilineage growth
(panmyelosis) with prominent erythroid, granulocyte, and megakaryocytic
proliferation.
- Serum erythropoietin level below the reference range for normal.
- Endogenous erythroid colony formation in vitro.
2. High cardiovascular risk due to having experienced a prior vascular event such as an
ischemic stroke, myocardial infarction or venous thromboembolism. Objective
documentation of these events must be accurately reviewed and registered. Stroke and
pulmonary embolism must be documented by an imaging study, deep vein thrombosis by
ultrasound or other objective methods, myocardial infarction by typical ECG changes
and/or an increase in serum troponin. Minor thrombotic events such as transient
ischemic attacks, superficial thrombophlepitis or atypical microcirculatory
disturbances alone or in combination are considered to qualifying events.
3. No contraindication to aspirin use such as allergy, a history of a previous
hemorrhagic stroke or a major gastrointestinal bleed in the previous three months.
4. Use of hydroxyurea as a cytoreductive agent.
5. Signed informed consent: Patients must have signed consents for both the ISCLAP
protocol and for the mandatory correlative biomarker MPD-RC 107 protocol in order to
be eligible.
6. Serum bilirubin levels less and or equal to 2 times the upper limit of the normal
range for the laboratory (ULN).
7. Serum glutamic-pyruvic transaminase (SGPT) alanine aminotransferase [ALT]) levels and
serum aspartate aminotransferase (AST) less and or equal 2 x ULN.
8. Serum creatinine levels less and or equal 1. 5 x ULN.
9. Women of childbearing potential must have a negative serum or urine pregnancy test
prior to clopidogrel treatment and should be advised to avoid becoming pregnant.
Women of childbearing potential must practice effective methods of contraception
(those generally accepted as standard of care measures). Women of child bearing
potential are women who have not been menopausal for 12 months or who have not
undergone previous surgical sterilization. If the subject is a woman of childbearing
potential, she must use a medically acceptable form of contraception during the study
period and for 30 days thereafter.
10. Age greater than or euql to 18 years to 81 years of age. Exclusion Criteria
Subjects are excluded from participating in this study if 1 or more of the following
criteria are met:
1. Therapy with clopidogrel within the last 12 months.
2. Any history of prior treatment with aspirin which has resulted in a significant
clinical adverse event requiring the discontinuation of aspirin therapy (e. g.
bleeding, GI intolerance, etc. or intolerance to aspirin.
3. Patients requiring anticoagulation treatment with warfarin, heparin or low molecular
weight heparin for any medical condition.
4. Nursing and pregnant females. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her physician
immediately.
5. History of a major bleeding event (requiring blood transfusion or hospitalization,
bleeding at a critical site, or life-threatening).
6. Clinical indication for the use of clopidogrel and/or a different antithrombotic
regimen.
7. History of active substance or alcoholic abuse within the last year.
8. Known hypersensitivity or contraindication to study treatments.
9. Chronic viral hepatitis or chronic liver disease from any other cause associated with
a MELD score equal to or higher than 8.
10. Presence of any disease (e. g. cancer) that is likely to significantly shorten life
expectancy.
11. > 81 years of age
12. New York Heart Association (NYHA) Grade II or greater congestive heart failure.
13. A history of gastrointestinal bleeding in the last 12 months.
14. Major surgical procedure, open biopsy, or significant traumatic injury within 28
days, or anticipation of the need for major surgical procedure during the course of
the study.
15. Biopsy or other minor surgical procedure, excluding placement of a vascular access
device or bone marrow biopsy, within 7 days prior to study enrollment.
16. Ongoing serious, non-healing wound, ulcer, or bone fracture.
17. Treatment with a CYP3A4 inhibitor, including azole antifungals (topicals are
permitted); protease inhibitors; nefazodone; cyclosporine; erythromycin;
clarithromycin; and troleandomycin.
18. Serum AST greater than or equal to 2 x ULN Serum ALT greater than or equal 2 x ULN
Total Bilirubin greater than or equal 2 X ULN Serum creatinine greater than or equal
1. 5 X ULN
19. Patients with a diagnosis of polycythemia vera > 5 years from the time of
registration
20. Patients who do not have high risk polycythemia vera as defined by experiencing a
thrombotic event (see section 3. 1) occurring since the initial
diagnosis of PV.
