How can venous thromboembolism risk be reduced when initiating Myfembree (relugolix, estradiol, norethindrone acetate)?

VTE Risk Reduction with Myfembree

The VTE risk associated with Myfembree (relugolix, estradiol, norethindrone acetate) can be reduced by avoiding use in patients with prior VTE history not on anticoagulation, screening for thrombophilia in high-risk patients, and considering transdermal estradiol alternatives when systemic estrogen is needed, as norethindrone acetate carries lower thrombotic risk than other progestins like medroxyprogesterone acetate. 1, 2, 3

Understanding Myfembree's Thrombotic Components

Myfembree contains three components with different VTE risk profiles:

• Oral estradiol: Increases VTE risk through first-pass hepatic metabolism, which elevates clotting factor production, increases factor VII activity, D-dimer, and prothrombin F1.2, while decreasing antithrombin III 4, 5
• Norethindrone acetate (progestin): Among progestins, norethindrone acetate has relatively lower thrombotic risk compared to medroxyprogesterone acetate (DMPA), which carries a 2.67-fold increased VTE risk (95% CI 1.29-5.53) 1, 2
• The combination of oral estrogen with progestin increases VTE risk more than estrogen alone, with combined therapy showing a 2.85-fold increased risk (95% CI 2.08-3.90) versus 1.31 (95% CI 0.78-2.21) for estrogen only 6

Contraindications and High-Risk Populations to Avoid

Myfembree should be avoided entirely in:

• Patients with history of DVT/PE not on therapeutic anticoagulation (Category 4 contraindication for combined hormonal therapy) 4, 5
• Patients with chronic coronary disease or previous stroke 1
• Patients with positive antiphospholipid antibodies 1
• Patients with cyanotic congenital heart disease, prior Fontan procedure, or pulmonary arterial hypertension 1
• Patients with inherited thrombophilias (Factor V Leiden, prothrombin G20210A mutation) who face markedly greater VTE risk with synthetic progestins 1, 7

Risk Stratification Before Initiating Myfembree

Screen for VTE risk factors using validated tools:

• The Padua VTE Risk Assessment Model identifies high-risk patients (score ≥4), which includes active cancer (3 points), previous VTE (3 points), known thrombophilia (3 points), obesity with BMI >30 (1 point), and age >70 years (1 point) 8
• Patients with two or more of the following risk factors have highest VTE risk: age ≥60 years, cancer, or prior VTE 8
• Obtain personal and family history of VTE, thrombophilia testing in patients with strong family history, and assess for obesity and immobilization risk 7, 6

Timing Considerations

The highest VTE risk occurs within the first year of oral estrogen-progestin therapy:

• VTE risk is elevated particularly in the first year of combined oral estrogen-progestin use and persists throughout treatment 5, 2
• Discontinue Myfembree at least 4-6 weeks before major surgery or during periods of prolonged immobilization 5
• Past users of oral estrogens have similar VTE risk to never users once discontinued, indicating risk resolves after stopping 2

Safer Hormonal Alternatives When Appropriate

If systemic hormone therapy is needed but VTE risk is elevated:

• Transdermal estradiol has significantly lower VTE risk than oral formulations, with an odds ratio of 0.9 (95% CI 0.4-2.1) versus 4.2 (95% CI 1.5-11.6) for oral estrogen, because it avoids first-pass hepatic metabolism 4, 9, 2
• Transdermal estradiol combined with progesterone (not synthetic progestins) appears safest, as micronized progesterone does not increase VTE risk while medroxyprogesterone acetate significantly does 2, 6
• For local genitourinary symptoms only, vaginal estrogen carries no systemic VTE risk (OR 0.69,95% CI 0.43-1.10) 4, 6

Prophylactic Anticoagulation Strategy

For patients requiring Myfembree who have elevated but not absolute contraindication to use:

• Consider prophylactic LMWH in patients with multiple VTE risk factors, particularly those with age >60 years, obesity, or prior VTE 8
• LMWH once daily is preferred over unfractionated heparin for convenience and lower heparin-induced thrombocytopenia risk 8
• Mechanical prophylaxis (intermittent pneumatic compression devices) alone is insufficient as monotherapy except when pharmacologic methods are contraindicated 8
• Combined pharmacologic and mechanical prophylaxis is appropriate for highest-risk patients with two or more risk factors (age ≥60, cancer, prior VTE) 8

Monitoring During Treatment

Patients on Myfembree should be monitored for:

• Signs of thrombosis including unilateral leg pain/swelling, chest pain, shortness of breath, or neurological symptoms 1
• Annual reassessment of VTE risk factors and bleeding risk if prophylactic anticoagulation is used 8
• Early ambulation and compression stockings for patients with additional immobilization risk 1

Common Pitfalls to Avoid

• Assuming all progestins carry equal thrombotic risk—norethindrone acetate in Myfembree has lower risk than medroxyprogesterone acetate, but still increases risk when combined with oral estrogen 2, 3
• Failing to recognize that oral estrogen route (as in Myfembree) carries substantially higher VTE risk than transdermal delivery 9, 2
• Overlooking that the combination of obesity with oral estrogen-progestin therapy synergistically increases VTE risk beyond either factor alone 7, 6
• Not discontinuing therapy before planned surgery or during prolonged immobilization periods 5