Does erythropoietin (EPO) increase the risk of stroke in patients, particularly those with pre-existing conditions such as hypertension, diabetes, or a history of vascular disease?

Erythropoietin and Stroke Risk

Yes, erythropoietin (EPO) significantly increases stroke risk, particularly in patients with chronic kidney disease where it nearly doubles the risk (92% relative increase), and should be used with extreme caution while targeting conservative hemoglobin goals of 100-120 g/L. 1

Evidence from Chronic Kidney Disease Populations

The most compelling evidence comes from patients with chronic kidney disease, where the stroke risk is unequivocally elevated:

• A clinical trial in chronic kidney disease demonstrated a 92% increase in relative risk of stroke with darbepoetin alfa, with absolute risk rising from 2.6% to 5.0%. 1

• This increased risk occurs when targeting higher hemoglobin levels, which is why current guidelines specifically recommend hemoglobin targets between 100-120 g/L, not higher. 2, 3

• The TREAT study confirmed this doubling of stroke risk with higher hemoglobin targets achieved through erythropoietin-stimulating agents. 2

Thrombogenic Mechanisms

EPO carries inherent thrombogenic potential that operates independently of hemoglobin levels:

• Erythropoietin has thrombogenic potential independent of hemoglobin levels, meaning stroke risk exists even when hemoglobin is not excessively elevated. 1

• Early trials targeting high hematocrit (42 ± 3%) showed increased vascular events (both arterial and venous). 1

• Four meta-analyses reported 48-69% increases in relative risk of thrombotic events with ESA use, with absolute venous thromboembolism risk of 7.5% versus 4.9% in controls. 1

High-Risk Patient Populations

Certain patients face particularly elevated stroke risk with EPO:

Patients with pre-existing thrombosis risk factors are at higher risk and require careful evaluation before EPO initiation, including those with: 1

• History of thromboembolism
• Hypertension (uncontrolled blood pressure must be addressed first)
• Diabetes
• Hypercoagulability or heritable mutations
• Recent surgery or prolonged immobilization
• Concurrent use of steroids or hormonal agents

Acute Stroke Treatment Context

The American Heart Association/American Stroke Association explicitly recommends against using erythropoietin for acute ischemic stroke treatment due to increased mortality risk without demonstrated clinical benefit. 2

• Preliminary data from a pivotal trial showed EPO treatment increased mortality in acute stroke patients. 2

• While a small pilot trial showed nonsignificant reduction in death and dependency, this was not confirmed in larger studies. 2

• Considerable experimental and clinical research is required before EPO can be recommended for acute stroke treatment. 2

Hemodialysis-Specific Considerations

In hemodialysis patients, the stroke risk picture is more nuanced:

• A 2021 retrospective cohort study of 12,948 hemodialysis patients found no increased overall stroke risk with EPO use (adjusted HR 1.03,95% CI 0.92-1.15). 4

• However, earlier observational data from 1996 showed increased stroke incidence in the post-EPO period (odds ratio 1.22,95% CI 1.06-1.41). 5

• The American Journal of Kidney Diseases notes that targeting higher hemoglobin levels with EPO actually doubles stroke risk, making conservative hemoglobin targets of 100-120 g/L essential. 3

Critical Management Principles

When EPO must be used, implement these risk-reduction strategies: 1

1. Control blood pressure before initiating EPO therapy and monitor regularly throughout treatment - hypertension is both a risk factor for stroke and can be exacerbated by EPO. 1

2. Target hemoglobin levels below 12 g/dL - risks of shortened survival and tumor progression have not been excluded even at these conservative targets. 1

3. Monitor hemoglobin levels closely to decrease risk of hypertension and seizures (seizures have been reported in chronic renal failure patients receiving EPO). 1

4. Avoid EPO in cancer patients outside the active chemotherapy treatment period (defined as anemia after chemotherapy initiation through approximately 6 weeks post-completion). 1

Common Pitfalls to Avoid

• Never target hemoglobin levels ≥12 g/dL - this substantially increases vascular event risk including stroke. 1

• Do not assume stroke risk is eliminated by achieving "normal" hemoglobin - the thrombogenic potential exists independent of hemoglobin levels. 1

• Do not use EPO for acute stroke treatment - this increases mortality without proven benefit. 2

• Do not initiate EPO without first controlling hypertension - uncontrolled blood pressure amplifies stroke risk. 1