Can a patient with a history of clotting disorder use raloxifene (Selective Estrogen Receptor Modulator)?

Raloxifene is Contraindicated in Patients with a History of Clotting Disorders

Patients with a documented history of venous thromboembolism (VTE), including deep vein thrombosis, pulmonary embolism, or retinal vein thrombosis, should permanently discontinue or never initiate raloxifene therapy. 1, 2

Absolute Contraindications

Raloxifene is explicitly contraindicated in the following clotting-related conditions:

• Active or past history of venous thromboembolism (deep vein thrombosis, pulmonary embolism, retinal vein thrombosis) 2
• Women with documented thromboembolic disease must permanently discontinue raloxifene 1
• History of stroke or transient ischemic attack (TIA) - the risk-benefit balance strongly disfavors use 1, 2

Mechanism of Increased Thrombotic Risk

Raloxifene increases the risk of venous thromboembolism by approximately 2-fold compared to placebo (RR 2.1; 95% CI 1.2-3.8), with an excess event rate of 1.8 per 1,000 woman-years. 3 The greatest risk occurs during the first 4 months of treatment, with risk remaining elevated for approximately the first 2 years. 2, 3

• In the RUTH trial, raloxifene increased VTE likelihood by 44% (HR 1.44; 95% CI 1.06-1.95) 1, 4
• The number needed to harm is 170 patients treated over 3.3 years to cause one VTE event 3

Additional High-Risk Scenarios

Beyond documented clotting disorders, raloxifene should be avoided in:

• Prolonged immobilization: Discontinue at least 72 hours prior to elective surgery or anticipated prolonged bed rest; resume only after full ambulation 2
• Congestive heart failure - increases baseline thrombotic risk 2
• Active malignancy - compounds VTE risk 2
• Superficial thrombophlebitis - even this less serious condition warrants caution 2

Stroke-Related Mortality Risk

In women with underlying coronary heart disease or cardiovascular risk factors, raloxifene increases the risk of fatal stroke by 49% (HR 1.49; 95% CI 1.00-2.24). 1, 2 This finding from the RUTH trial demonstrates that women with vascular disease should not receive raloxifene. 1

Risk factors that should prompt avoidance include:

• Prior stroke or TIA 1, 2
• Atrial fibrillation 1, 2
• Uncontrolled hypertension 1
• Cigarette smoking 1, 2

Important Clinical Caveat: Factor V Leiden

Interestingly, women with Factor V Leiden or prothrombin G20210A mutations receiving raloxifene in clinical trials were NOT at increased risk of VTE compared to women without these mutations. 1 However, this does not change the contraindication for documented prior VTE, and prospective screening for these mutations is not recommended. 1

Antiplatelet Therapy Does Not Mitigate Risk

Concomitant use of aspirin or other antiplatelet agents (clopidogrel, ticlopidine, dipyridamole) does NOT reduce the VTE risk associated with raloxifene. 4 In the RUTH trial, no difference in VTE risk was observed between women using raloxifene alone versus those using raloxifene with antiplatelet agents (interaction p=0.88). 4

Guideline Consensus Across Indications

The 2023 American College of Rheumatology guidelines for glucocorticoid-induced osteoporosis conditionally recommend against raloxifene due to harms of VTE and fatal stroke, except in patients intolerant of other agents. 1 This recommendation applies to both adults ≥40 years and <40 years at any fracture risk level. 1

Patient Education Requirements

If raloxifene were ever considered despite these warnings (which it should not be in patients with clotting history), patients must be educated about:

• Symptoms of deep vein thrombosis (leg pain, swelling, warmth, redness) 1
• Symptoms of pulmonary embolism (sudden chest pain, shortness of breath, coughing blood) 1
• The need to move periodically during prolonged travel 2
• Instructions to contact physicians immediately if symptoms develop 1