What is the recommended anticoagulation regimen for patients with pulmonary embolism?

Anticoagulation Regimen for Pulmonary Embolism

For most patients with acute pulmonary embolism, initiate treatment with low-molecular-weight heparin (LMWH) or fondaparinux subcutaneously, followed by transition to a direct oral anticoagulant (DOAC) such as rivaroxaban or apixaban, which are preferred over vitamin K antagonists for long-term therapy. 1, 2

Initial Anticoagulation (First 5-10 Days)

Hemodynamically Unstable (High-Risk) PE

• Initiate unfractionated heparin (UFH) intravenously without delay using a weight-adjusted bolus of 80 U/kg followed by continuous infusion at 18 U/kg/h 1, 2
• Adjust subsequent doses based on activated partial thromboplastin time (aPTT) to maintain 1.5-2.5 times control value 1
• UFH is preferred in high-risk patients because of its short half-life, ease of monitoring, and rapid reversibility with protamine 1
• Systemic thrombolytic therapy is recommended for patients presenting with cardiogenic shock or persistent hypotension 1, 2

Hemodynamically Stable (Non-High-Risk) PE

• LMWH or fondaparinux is the recommended initial treatment over UFH due to lower bleeding risk and no need for monitoring 1, 3
• Approved LMWH regimens include:
  • Enoxaparin 1.0 mg/kg subcutaneously every 12 hours, OR
  • Enoxaparin 1.5 mg/kg subcutaneously once daily 1
  • Tinzaparin 175 U/kg subcutaneously once daily 1
• Fondaparinux dosing (subcutaneous, once daily): 1
  • 5 mg for body weight <50 kg
  • 7.5 mg for body weight 50-100 kg
  • 10 mg for body weight >100 kg
• Anticoagulation should be initiated immediately in patients with high or intermediate clinical probability while awaiting diagnostic confirmation 1, 3

Special Circumstances Requiring UFH

UFH is recommended over LMWH/fondaparinux in: 1

• Severe renal impairment (creatinine clearance <30 mL/min)
• Severe obesity
• Patients being considered for primary reperfusion therapy

Transition to Oral Anticoagulation

Direct Oral Anticoagulants (DOACs) - Preferred

DOACs are recommended over vitamin K antagonists for all eligible patients 1, 2, 3

Rivaroxaban (Single-Drug Approach)

• 15 mg orally twice daily for 3 weeks, then 20 mg once daily 1
• No parenteral overlap required—can be started immediately 1
• Non-inferior to enoxaparin/warfarin in the EINSTEIN-PE trial 1
• Not recommended for hemodynamically unstable patients or those requiring thrombolysis 4

Apixaban

• Higher dose during first week, then maintenance dosing 2
• Effective alternative in cancer patients 3

Dabigatran

• Requires at least 5-10 days of parenteral anticoagulation before initiation 1
• Non-inferior to warfarin with fewer bleeding episodes in RE-COVER trials 1

Vitamin K Antagonists (VKAs) - Alternative

When DOACs are contraindicated or unavailable: 1

• Start warfarin on the same day as parenteral anticoagulation 1
• Initial dosing:
  • 10 mg daily in younger (<60 years), otherwise healthy outpatients
  • 5 mg daily in older patients or hospitalized patients 1
• Continue parenteral anticoagulation for at least 5 days AND until INR is 2.0-3.0 for two consecutive days 1
• Target INR: 2.5 (range 2.0-3.0) 1

DOAC Contraindications

DOACs are not recommended in: 2

• Severe renal insufficiency (CrCl <30 mL/min for rivaroxaban) 4
• Pregnancy and lactation
• Antiphospholipid syndrome (especially triple-positive patients)
• Prosthetic heart valves 4

Duration of Anticoagulation

Minimum 3 Months

All patients with PE require therapeutic anticoagulation for at least 3 months 3, 5

Discontinue After 3 Months

• First PE with transient/reversible major risk factor (e.g., surgery, trauma, immobilization) 2, 3, 5

Indefinite Anticoagulation

Recommended for: 2, 3

• Recurrent VTE not related to transient risk factors
• Active cancer (continue LMWH or DOAC as long as cancer is active)
• Antiphospholipid syndrome (use VKA, not DOAC) 2
• Idiopathic PE with intermediate recurrence risk (consider reduced-dose apixaban or rivaroxaban after 6 months) 3

Special Populations

Cancer Patients

• LMWH is preferred for initial and long-term treatment 1
• Dalteparin dosing: 200 IU/kg once daily for 1 month, then 150 IU/kg once daily for 5 months 1
• Apixaban, edoxaban, and rivaroxaban are effective alternatives to LMWH 3

Renal Impairment

• Avoid rivaroxaban if CrCl <15 mL/min; use with caution if CrCl 15-30 mL/min 4
• UFH is preferred in severe renal dysfunction (CrCl <30 mL/min) 1

Critical Pitfalls to Avoid

• Never delay anticoagulation while awaiting diagnostic confirmation in patients with high or intermediate clinical probability 1, 3
• Do not use rivaroxaban as initial therapy in hemodynamically unstable PE—UFH is required 4
• Do not stop parenteral anticoagulation before achieving therapeutic INR for 2 consecutive days when using VKAs 1
• Do not use DOACs in triple-positive antiphospholipid syndrome—associated with increased thrombotic events 4
• Avoid aggressive fluid resuscitation in high-risk PE—can worsen right ventricular failure 1