What is the recommended first‑line therapy for a patient with polycythemia vera who has already suffered an ischemic stroke to prevent further thrombotic events?

Recommended First-Line Therapy for Polycythemia Vera After Ischemic Stroke

For a patient with polycythemia vera who has suffered an ischemic stroke, the recommended first-line therapy consists of three components: (1) phlebotomy to maintain hematocrit strictly below 45%, (2) low-dose aspirin 100 mg daily, and (3) cytoreductive therapy with hydroxyurea, as this patient now meets high-risk criteria due to prior thrombosis. 1, 2, 3

Risk Stratification After Stroke

• Any history of thrombosis—including ischemic stroke—automatically classifies the patient as high-risk, regardless of age. 3, 4
• High-risk patients require all three therapeutic modalities (phlebotomy, aspirin, and cytoreductive therapy) to prevent recurrent thrombotic events. 3, 4
• The presence of prior stroke increases the urgency for aggressive management, as thrombotic risk remains substantially elevated without cytoreductive therapy. 1, 3

Component 1: Phlebotomy Target

• Maintain hematocrit strictly below 45% through therapeutic phlebotomy. 2, 3, 5
• The CYTO-PV trial definitively demonstrated that hematocrit levels of 45-50% carry significantly increased thrombotic risk compared to maintaining levels below 45%. 3, 5
• Women and African Americans may require lower targets (approximately 42%) due to physiological differences in baseline hematocrit values. 3
• Perform phlebotomy with careful fluid replacement to prevent hypotension, particularly in elderly patients or those with cardiovascular disease. 3
• Hyperviscosity from elevated hematocrit is a major factor in thrombogenesis, impairing capillary blood flow and increasing stroke risk. 6

Component 2: Aspirin Therapy

• Administer low-dose aspirin 100 mg once daily indefinitely, unless contraindications exist. 2, 3, 5
• The ECLAP trial demonstrated that aspirin 100 mg daily significantly reduces the combined endpoint of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, and cardiovascular death (RR 0.40; 95% CI 0.18-0.91; P=0.03). 2
• This dose satisfies both the polycythemia vera indication (established effective dose) and secondary stroke prevention requirements (recommended range 75-100 mg). 2
• No significant increase in major bleeding was observed with aspirin in the ECLAP trial. 2
• Contraindications to aspirin include: active bleeding, aspirin allergy/hypersensitivity, or acquired von Willebrand syndrome (particularly with extreme thrombocytosis >1,500 × 10⁹/L). 2

Component 3: Cytoreductive Therapy with Hydroxyurea

• Initiate hydroxyurea as first-line cytoreductive therapy for this high-risk patient with prior stroke. 1, 3, 4
• Hydroxyurea carries Level II, A evidence as the preferred first-line cytoreductive agent for most patients with polycythemia vera. 3
• Starting dose: 2 g/day (or 2.5 g/day if body weight >80 kg). 3
• Treatment goals: Hematocrit <45% without need for phlebotomy, platelet count ≤400 × 10⁹/L, and WBC count ≤10 × 10⁹/L. 3
• Hydroxyurea effectively controls the proliferative phase of polycythemia vera and reduces thrombotic risk beyond what phlebotomy and aspirin achieve alone. 7, 4

When to Consider Alternatives to Hydroxyurea

• Age <40 years: Use hydroxyurea with caution due to potential leukemogenic risk with prolonged exposure; consider interferon-α as first-line alternative. 3, 4
• Women of childbearing age or pregnant patients: Interferon-α is the preferred cytoreductive agent due to its safer profile and non-leukemogenic nature. 3
• Intractable pruritus: Interferon-α may be more effective than hydroxyurea for this symptom. 3

Defining Hydroxyurea Resistance or Intolerance

• Need for phlebotomy to maintain hematocrit <45% after 3 months of at least 2 g/day hydroxyurea. 3
• Uncontrolled myeloproliferation: Platelet count >400 × 10⁹/L and WBC count >10 × 10⁹/L after 3 months of at least 2 g/day. 3
• Failure to reduce massive splenomegaly or development of cytopenia/unacceptable side effects at any dose. 3
• If resistance or intolerance develops, switch to interferon-α (preferred second-line agent with non-leukemogenic profile) or consider ruxolitinib. 3, 4

Additional Secondary Prevention Measures

Cardiovascular Risk Factor Management

• Aggressively manage all modifiable cardiovascular risk factors: hypertension, hyperlipidemia, diabetes, and mandatory smoking cessation. 2, 3
• Blood pressure target: <130/80 mmHg to reduce recurrent vascular events. 3
• First-line antihypertensive agents include renin-angiotensin system blockers, calcium-channel blockers, and diuretics. 3
• Lipid management: Target LDL-C <70 mg/dL (1.8 mmol/L) for ischemic stroke patients with polycythemia vera. 3

Monitoring Strategy

• Monitor hematocrit levels and complete blood count every 3-6 months in stable patients. 3
• Assess for new thrombotic or bleeding events at each visit. 3
• Evaluate for signs/symptoms of disease progression (transformation to myelofibrosis or acute leukemia) regularly. 3

Common Pitfalls to Avoid

• Do not accept hematocrit targets of 45-50%: The CYTO-PV trial definitively showed increased thrombotic risk at these levels. 3
• Do not use phlebotomy alone in high-risk patients: Phlebotomy does not prevent aspirin-responsive microcirculatory disturbances because thrombocythemia persists. 7
• Avoid inadequate fluid replacement during phlebotomy: This can precipitate hypotension, particularly in elderly patients with cardiovascular disease. 3
• Do not use chlorambucil or ³²P in younger patients: These agents carry significantly increased leukemia risk. 3
• Do not delay cytoreductive therapy in high-risk patients: The combination of phlebotomy, aspirin, and hydroxyurea is superior to phlebotomy and aspirin alone for preventing recurrent thrombotic events. 1, 3, 4

Special Consideration: Recurrent Stroke Despite Optimal Therapy

• If the patient experiences recurrent ischemic stroke while on low-dose aspirin 100 mg daily, adding warfarin to aspirin may be considered to further reduce cerebral ischemic events, although this combination substantially increases bleeding risk. 2
• Alternative antiplatelet options include clopidogrel 75 mg daily or aspirin combined with extended-release dipyridamole (25 mg/200 mg twice daily). 2