Do Vascular Endothelial Growth Factor (VEGF) inhibitors, such as bevacizumab (bevacizumab), increase the risk of stroke?

VEGF Inhibitors and Stroke Risk

VEGF inhibitors, particularly bevacizumab, increase the risk of stroke through multiple mechanisms including endothelial dysfunction, hypertension, and arterial thrombosis. 1

Mechanism of Stroke Risk with VEGF Inhibitors

VEGF inhibitors affect the vascular system in several ways that can lead to stroke:

1. Endothelial dysfunction:

   • VEGF is essential for maintaining normal endothelial cell function and vascular homeostasis
   • Blockade of VEGF pathway results in endothelial dysfunction 1
   • Decreased nitric oxide (NO) production when VEGF is inhibited 1

2. Hypertension development:

   • Decreased vasodilators (NO, prostacyclin) and increased vasoconstrictors (endothelin-1) 1
   • Hypertension occurs in 7-36% of patients on bevacizumab 1
   • Typically develops early in treatment (median 2.1 months) 1

3. Arterial thrombotic events:

   • VEGF inhibitors promote arterial thrombotic activity 1
   • Disturbances in endothelial regeneration 1
   • Procoagulant status and endothelial injury 1

Quantified Risk of Stroke and Arterial Thrombotic Events

The European Society of Cardiology position paper reports specific risks for arterial thrombotic events with VEGF inhibitors 1:

• Bevacizumab: 3.8% risk of arterial thrombosis
• Sorafenib: 1.7% risk
• Sunitinib: 1.4% risk

According to the American Heart Association, bevacizumab can induce stroke and transient ischemic attacks (TIAs) in approximately 3.8% of patients 1.

Risk Factors for Stroke with VEGF Inhibitors

Patients at highest risk for stroke while on VEGF inhibitors include 2:

• Age older than 65 years
• Previous thromboembolic events
• History of atherosclerotic disease
• Longer duration of VEGF inhibitor therapy

Management Considerations

1. Blood pressure monitoring and management:

   • Regular blood pressure monitoring is essential 3
   • Hypertension should be aggressively treated 1
   • Consider SPRINT blood pressure goals with pleiotropic vasoprotective agents 2

2. Risk assessment:

   • Evaluate pre-existing cardiovascular risk factors before initiating therapy 1
   • Cancer itself increases stroke risk (up to 6.3% 1-year incidence in some cancers) 1

3. Monitoring for symptoms:

   • Patients should be advised to immediately report signs of arterial thromboembolism 3
   • Particular vigilance during the first 6 months of treatment 1

Important Caveats

1. Risk varies by administration route:

   • Intravitreal bevacizumab for AMD showed mixed results:
     • One study found increased stroke risk during 2 years after first injection 4
     • Another study found no increased risk of stroke with repeated injections 5

2. Risk may vary by cancer type:

   • No increased risk observed in glioblastoma patients receiving bevacizumab 6

3. Timing of events:

   • Arterial thrombotic events can occur any time during treatment (median time 3 months) 1
   • Not dose-related but related to treatment duration 1, 2

Clinical Implications

The risk of stroke with VEGF inhibitors represents a significant clinical concern that requires careful patient selection, monitoring, and management. The benefits of cancer treatment must be weighed against the cardiovascular risks, particularly in patients with pre-existing risk factors for stroke or cardiovascular disease.

Healthcare providers should implement a comprehensive cardiovascular risk management strategy for patients receiving VEGF inhibitors, including blood pressure control, statin therapy when indicated, and possibly antiplatelet therapy in high-risk patients.