What is the risk of thromboembolic events with megestrol (megestrol acetate) therapy?

Risk of Thromboembolic Events with Megestrol Acetate Therapy

Megestrol acetate carries a significant risk of thromboembolic events, with evidence showing increased rates of venous thromboembolism, particularly in patients with advanced cancer or other risk factors.

Thromboembolic Risk Profile

Megestrol acetate (MA) is a synthetic progestin commonly used as an appetite stimulant in patients with cancer-related anorexia and cachexia. However, its use comes with important safety concerns:

• The FDA drug label specifically lists thromboembolic phenomena including thrombophlebitis and pulmonary embolism as postmarketing adverse events associated with megestrol acetate 1

• According to the ESPEN guidelines on nutrition in cancer patients (2017), progestins including megestrol acetate may induce thromboembolism as a potential serious side effect 2

• A Cochrane review analyzing 35 trials with 3,963 patients concluded that megestrol acetate resulted in higher rates of thromboembolic phenomena compared to placebo 2

Risk Factors and Incidence

The risk of thromboembolic events appears to vary based on several factors:

• In nursing home residents, one retrospective review found that 32% of patients treated with megestrol acetate developed deep vein thrombosis, with most cases occurring after 50 days of treatment 3

• Cancer patients appear to be at particularly high risk, with one study showing 11.3% of advanced cancer patients on megestrol acetate and chemotherapy developing thrombosis 4

• Pancreatic cancer patients on megestrol may have an especially elevated risk 4

• Concomitant use of anticoagulants with megestrol requires careful monitoring, as there are reports of potential interactions that could increase bleeding risk 5

Mechanism of Action

The mechanism behind megestrol's thrombogenic effect is complex:

• While the drug label supports a prothrombotic mechanism, megestrol's pharmacology may also confer some anticoagulant properties in certain contexts 5

• The risk appears to be dose-related, with higher doses potentially carrying greater risk, though evidence comparing different dosages is limited 2

Clinical Recommendations

When considering megestrol acetate therapy:

1. Perform thrombotic risk assessment before initiating therapy

   • Evaluate for existing risk factors (cancer type, immobility, prior VTE history)
   • Consider alternative appetite stimulants in high-risk patients

2. Monitor for signs and symptoms of thromboembolism during treatment

   • Leg pain, swelling, warmth (DVT)
   • Dyspnea, chest pain, tachycardia (PE)
   • Increased vigilance after 50 days of treatment 3

3. Consider prophylactic anticoagulation in high-risk patients

   • Especially those with multiple risk factors or advanced cancer

4. Weigh benefits against risks

   • The ESPEN guidelines suggest considering progestins for appetite stimulation in anorectic cancer patients with advanced disease, but with awareness of the thromboembolism risk 2
   • Benefits may not outweigh risks in certain populations like nursing home residents 6

Special Populations

• Transgender medicine: Progestins like megestrol acetate are sometimes used in gender-affirming care but carry thromboembolism risk and are not recommended by the Endocrine Society due to concerns about thrombosis 2

• Elderly patients: Particularly vulnerable to both weight loss and thrombotic complications; megestrol is neither safe nor effective for malnourished nursing home residents 6

• Cancer patients: Risk of thrombosis may be compounded by the underlying malignancy and concurrent chemotherapy 4

In summary, while megestrol acetate can be effective for appetite stimulation, its use requires careful consideration of thromboembolic risk, particularly in patients with existing risk factors for thrombosis.