What is the absolute risk of Venous Thromboembolism (VTE) in patients taking Aromatase Inhibitors (AIs), such as anastrozole, letrozole, or exemestane, without comparison to other agents?

Absolute Risk of VTE with Aromatase Inhibitors

Aromatase inhibitors (AIs) have a low absolute risk of venous thromboembolism (VTE) and do not appear to increase VTE risk compared to the general cancer population, with evidence suggesting they may actually reduce VTE risk compared to other hormonal therapies like tamoxifen. 1, 2

Mechanism and Risk Profile

Mechanism

Aromatase inhibitors work by blocking the enzyme aromatase, which converts androgens to estrogens. Unlike tamoxifen (a selective estrogen receptor modulator), AIs:

• Do not appear to impact hemostasis parameters 1
• Do not increase coagulation factors or reduce anticoagulant proteins
• Do not demonstrate prothrombotic effects in laboratory studies 1

Absolute Risk Data

The absolute risk of VTE with aromatase inhibitors is relatively low:

• In breast cancer patients on AIs, the crude rate is approximately 4.6 per 1000 person-years for DVT and 2.8 per 1000 person-years for PE 2
• This is significantly lower than the VTE risk associated with tamoxifen (AI use was associated with at least 41% lower VTE risk compared to tamoxifen) 2
• In the MAP.3 trial evaluating exemestane, the incidence of VTE was 11 cases in the exemestane group versus 7 cases in the placebo group, which was not statistically significant 3

Risk Factors for VTE in Cancer Patients

When assessing VTE risk in patients taking AIs, consider these additional risk factors 3:

1. Cancer-related factors:

   • Primary site of cancer (very high risk: stomach, pancreas; high risk: lung, lymphoma, gynecological)
   • Advanced/metastatic disease
   • Initial period after cancer diagnosis

2. Patient-related factors:

   • Age >60 years
   • Previous history of VTE
   • Immobility
   • Obesity (BMI ≥35 kg/m²)
   • Comorbidities (infections, renal disease, etc.)

3. Treatment-related factors:

   • Concurrent chemotherapy (especially platinum-based)
   • Central venous catheter use
   • Major surgery

Comparative VTE Risk Among Different AIs

While the overall VTE risk is low with all AIs, there may be subtle differences between agents:

• The ranking of CV risk (including thrombotic events) in descending order appears to be: letrozole, exemestane, and anastrozole 4
• However, these differences are not clinically significant enough to drive treatment decisions based on VTE risk alone 5, 6

Clinical Implications

1. Risk assessment:

   • Use established risk models like the Khorana score to assess baseline VTE risk in cancer patients 3
   • Consider patient-specific factors that may increase risk

2. Monitoring:

   • No systematic screening for VTE is recommended in asymptomatic patients on AIs 3
   • Detection should be based on clinical symptoms

3. Prophylaxis considerations:

   • Routine thromboprophylaxis is not recommended for patients on AIs alone 3
   • Consider prophylaxis only for high-risk patients with multiple risk factors

Important Caveats

• The FDA label for anastrozole specifically notes a lower incidence of venous thromboembolic events compared to tamoxifen 7
• Most studies focus on comparative risk (AIs vs. tamoxifen) rather than absolute risk
• VTE risk may be influenced by concurrent treatments and cancer stage
• Individual patient factors remain important in determining overall VTE risk

In summary, aromatase inhibitors do not appear to significantly increase VTE risk through any direct mechanism and may actually be protective compared to other hormonal therapies like tamoxifen. The absolute risk remains low in the absence of other significant risk factors.