What is the mechanism by which Anastrozole (Arimidex) increases the risk of Deep Vein Thrombosis (DVT)?

Mechanism of Anastrozole-Induced Deep Vein Thrombosis

Unlike tamoxifen, which has a well-established mechanism for causing venous thromboembolism, anastrozole actually has a lower risk of deep vein thrombosis (DVT) compared to tamoxifen, though it still carries some thrombotic risk. 1

Comparative Risk Profile

Aromatase inhibitors like anastrozole have different side effect profiles compared to selective estrogen receptor modulators (SERMs) like tamoxifen:

• Tamoxifen: Higher risk of deep venous thrombosis, pulmonary emboli, and vaginal discharge 1
• Anastrozole: Higher risk of osteoporosis, fractures, joint stiffness, carpal tunnel syndrome, hypercholesterolemia, and stroke 1

Potential Mechanisms for Anastrozole-Related DVT

While anastrozole has a lower DVT risk than tamoxifen, several mechanisms may contribute to its thrombotic potential:

1. Estrogen Depletion Effects:

   • Anastrozole works by inhibiting the aromatase enzyme, dramatically reducing estrogen levels
   • Severe estrogen depletion may affect vascular endothelial function
   • Loss of estrogen's protective effects on the vascular system may promote endothelial dysfunction

2. Indirect Effects on Coagulation Factors:

   • Estrogen depletion may indirectly affect the balance of procoagulant and anticoagulant factors
   • May lead to relative hypercoagulability in some patients

3. Hypercholesterolemia:

   • Anastrozole is associated with hypercholesterolemia 1
   • Elevated cholesterol levels can contribute to endothelial damage and subsequent thrombosis

4. Inflammatory Pathway Activation:

   • Estrogen suppression may alter inflammatory pathways that influence thrombotic risk

Risk Stratification

The risk of DVT with anastrozole appears to be influenced by:

• Pre-existing Risk Factors: History of previous thrombosis, known thrombophilias, obesity, advanced age
• Treatment Duration: Risk may increase with longer exposure
• Concurrent Medications: Combination with other medications affecting coagulation

Clinical Implications

When considering anastrozole therapy:

• For postmenopausal women with a history of DVT or pulmonary embolism, anastrozole is generally a better choice than tamoxifen 1
• In women with osteoporosis, tamoxifen or raloxifene may be preferred over anastrozole 1
• Regular monitoring for signs and symptoms of thrombosis is recommended, especially in patients with additional risk factors

Comparative Evidence

The ATAC trial demonstrated that anastrozole was associated with significantly fewer venous thromboembolic events compared to tamoxifen (2.8% vs. 4.5%; P = .0004) 1, supporting that while anastrozole does carry some thrombotic risk, it is substantially lower than tamoxifen.

Similarly, the IBIS-II trial showed fewer deep vein thromboses with anastrozole compared to tamoxifen in women with DCIS 1.

In summary, while anastrozole has a lower risk of DVT compared to tamoxifen, the mechanism appears to be related to profound estrogen depletion affecting vascular function and coagulation pathways, rather than a direct effect on clotting factors.