Frequent, Low-Dose Erythropoietin A Mechanistic Approach to Mitigate Adverse Cardiovascular Effects of Erythropoietin
Condition: Anemia; CKD; Atherosclerosis; Cardiovascular
MeSH terms: Atherosclerosis
Intervention: Low dose erythropoietin; High dose erythropoietin
Intervention description: Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly; Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks
Intervention MeSH terms: Epoetin Alfa
Phase: Phase 4
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients will be randomly assigned two different erythropoietin dosing strategies. One group will be given more frequent, low-doses of EPO and the other group will be given the same, cumulative dose given every 2 weeks.
Masking: Single (Outcomes Assessor)
Masking description: The outcome is the progression of carotid plaque. John Forder, PhD, who will read the MRIs will be blinded to the subject and treatment group.
Enrollment: 5.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: erythropoietin

Summary:

      Although several large well designed clinical trials have shown that erythropoietin which is
      commonly used to treat anemia associated with kidney disease, increases the risk of stroke
      and heart disease, the mechanism for this increased risk is unknown. The investigators'
      preliminary studies show that the adverse effects of erythropoietin are from activation of
      the heterodimeric erythropoietin/ beta common receptor which only occurs with high doses of
      erythropoietin. The investigators propose a clinical trial of 120 patients assigned to low
      doses of erythropoietin given more frequently or the same cumulative dose of erythropoietin
      administered as a high dose once every two weeks and assess effects on the beta common
      receptor activation, inflammation and vascular disease as evidence by MRI of the carotid
      arteries.
    

Eligibility criteria:

        Inclusion Criteria:

        The investigators will enroll Veterans who fulfill the following criteria:

          -  stage 3, 4, or 5 CKD (estimated glomerular filtration rate of less than 60 ml/min/1.73
             m2) on at least two separate occasions greater than 3 months apart; and

          -  candidates for EPO therapy as per the National Kidney Foundation's Kidney Disease
             Outcomes Quality Initiative guidelines (hemoglobin < 10 gm/dL and anemia of CKD).

        Exclusion Criteria:

        The investigators will exclude any Veteran who meets any of the following criteria:

          1. pregnant, planning to become pregnant in the next year, or breast feeding;

          2. uncontrolled hypertension (blood pressure > 180/100 mm Hg despite optimal
             antihypertensive medications);

          3. active gastrointestinal bleeding (visible blood or positive tests for stool occult
             blood accompanied by a decrease in hemoglobin);

          4. likely to have EPO resistance;

          5. an adverse cardiovascular event in the prior three months;

          6. active or recent (within the last 3 months) severe, systemic infection;

          7. active inflammatory disease such as lupus, rheumatoid arthritis, or vasculitis
             requiring immunosuppressive or immunomodulatory medications;

          8. history of solid organ transplantation;

          9. expected off-dialysis survival of less than one year (as determined by the estimated
             glomerular filtration slope and the treating physician;

         10. active cancer (undergoing chemotherapy or radiation within the last 3 months) or
             primary bone marrow disease such as myelofibrosis; or

         11. a contraindication for an MRI or individuals who cannot comply with the study
             protocol. The investigators will exclude healthy subjects that meet a, b, f, g, h, or
             j.