What are the causes and risk factors for recurrent unprovoked pulmonary embolism (PE)?

From the Guidelines

For recurrent unprovoked pulmonary embolism, indefinite anticoagulation therapy is strongly recommended. The preferred medications are direct oral anticoagulants (DOACs) such as apixaban (5 mg twice daily), rivaroxaban (20 mg once daily with food), edoxaban (60 mg once daily), or dabigatran (150 mg twice daily) 1. Alternatively, warfarin can be used with a target INR of 2.0-3.0, though it requires regular monitoring. Treatment should continue indefinitely unless there are significant bleeding complications or changes in risk factors.

Key Considerations

• Regular follow-up every 3-6 months is essential to assess for bleeding complications, medication adherence, and to reevaluate the risk-benefit ratio of continued therapy 1.
• Patients should be educated about symptoms of recurrent VTE and bleeding complications.
• The rationale for indefinite anticoagulation is that recurrent unprovoked pulmonary embolism indicates a persistent hypercoagulable state with a high risk of additional events (approximately 30-50% within 10 years if anticoagulation is stopped) 1.
• The benefits of preventing potentially fatal recurrent pulmonary embolism typically outweigh the bleeding risks associated with long-term anticoagulation in most patients.

Risk of Recurrence

• Patients with unprovoked VTE have a high risk of recurrence, with an annual risk of > 5% 1.
• The risk of recurrence is higher in patients with unprovoked VTE compared to those with provoked VTE 1.

Bleeding Risks

• Major bleeding events may occur in ∼1% to 3% of patients on anticoagulant therapy 1.
• The risk of bleeding should be carefully weighed against the benefits of anticoagulation in each patient.

From the FDA Drug Label

The AMPLIFY-EXT study enrolled patients with either an unprovoked DVT or PE at baseline (approximately 92%) or patients with a provoked baseline event and one additional risk factor for recurrence (approximately 8%) However, patients who had experienced multiple episodes of unprovoked DVT or PE were excluded from the AMPLIFY-EXT study. In the AMPLIFY-EXT study, both doses of apixaban were superior to placebo in the primary endpoint of symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE), or all-cause death Approximately 90% of patients enrolled in AMPLIFY had an unprovoked DVT or PE at baseline.

The apixaban is effective in reducing the risk of recurrent VTE in patients with unprovoked DVT or PE.

• The AMPLIFY study showed that apixaban was noninferior to enoxaparin/warfarin in reducing the risk of recurrent VTE.
• The AMPLIFY-EXT study showed that apixaban was superior to placebo in reducing the risk of recurrent VTE. However, the studies do not provide direct information on recurrent unprovoked pulmonary embolism specifically, as patients with multiple episodes of unprovoked DVT or PE were excluded from the AMPLIFY-EXT study 2.

From the Research

Recurrent Unprovoked Pulmonary Embolism

• The risk of recurrent venous thromboembolism is high when the initial episode was unprovoked or associated with persistent risk factors, such as cancer 3.
• A study found that apixaban is more effective than rivaroxaban in preventing recurrent venous thromboembolism and major bleeding events 4.
• The optimal duration of anticoagulant treatment following pulmonary embolism is determined by the risk of recurrent venous thromboembolism and the risk of anticoagulant-related bleeding 3.
• Extended anticoagulation with apixaban reduces the risk of recurrent venous thromboembolism without increasing the rate of major bleeding 5.

Treatment Options

• Direct oral anticoagulants, such as apixaban, edoxaban, rivaroxaban, or dabigatran, are noninferior to heparin combined with a vitamin K antagonist for treating pulmonary embolism and have a lower rate of bleeding 6.
• Apixaban is a simple, effective, and safe alternative to conventional acute or long-term treatment of venous thromboembolism 5.
• The use of apixaban compared to rivaroxaban is associated with a decreased risk of recurrent venous thromboembolism and major bleeding events 4.

Anticoagulation Duration

• The duration of anticoagulation may be modulated according to the presence or absence of certain additional risk factors, such as major thrombophilia, chronic pulmonary hypertension, or massive pulmonary embolism 3.
• If the risk of anticoagulant-related bleeding is high, the duration of anticoagulation should be shortened 3.
• Prescribing patterns of oral factor Xa inhibitor lead-in therapy duration are variable in patients receiving initial parenteral anticoagulation 7.