What are the first‑line anticoagulant options (low‑molecular‑weight heparin, unfractionated heparin, fondaparinux, direct oral anticoagulants, warfarin) and their dosing regimens for treating an acute pulmonary embolism?

Anticoagulants for Pulmonary Embolism

For hemodynamically stable patients with acute pulmonary embolism, direct oral anticoagulants (DOACs)—specifically rivaroxaban or apixaban—are the preferred first-line agents because they eliminate the need for parenteral bridging and demonstrate non-inferior efficacy with lower bleeding risk compared to traditional warfarin-based regimens. 1

Initial Anticoagulation Strategy

Hemodynamically Stable Patients (Low- or Intermediate-Risk PE)

Start anticoagulation immediately upon clinical suspicion—do not wait for imaging confirmation when clinical probability is high. 1

First-Line: Direct Oral Anticoagulants (DOACs/NOACs)

• Rivaroxaban is the most streamlined option: 15 mg orally twice daily for 21 days, then 20 mg once daily for the remainder of treatment—no parenteral lead-in required. 1, 2

• Apixaban is equally effective: 10 mg orally twice daily for 7 days, then 5 mg twice daily—no parenteral lead-in required. 1

• Edoxaban or dabigatran require at least 5 days of parenteral anticoagulation (LMWH or fondaparinux) before switching to the oral agent. 1, 3, 4

• DOACs are recommended over warfarin (Class I, Level A) due to comparable efficacy, significantly lower major bleeding rates (50% reduction with rivaroxaban), and elimination of INR monitoring. 1, 2

Second-Line: Low-Molecular-Weight Heparin (LMWH) or Fondaparinux Bridged to Warfarin

When DOACs are contraindicated or unavailable, use parenteral anticoagulation followed by warfarin:

• Enoxaparin 1 mg/kg subcutaneously every 12 hours or 1.5 mg/kg once daily. 1, 3

• Dalteparin 200 units/kg subcutaneously once daily (maximum 18,000 units). 1

• Tinzaparin 175 units/kg subcutaneously once daily. 1, 5

• Fondaparinux weight-based dosing: <50 kg = 5 mg, 50–100 kg = 7.5 mg, >100 kg = 10 mg subcutaneously once daily. 1

• LMWH and fondaparinux are preferred over unfractionated heparin (Class I, Level A) because they carry lower risk of major bleeding and heparin-induced thrombocytopenia, require no monitoring, and can be administered at home. 1

Warfarin bridging protocol:

• Start warfarin (approximately 5 mg daily) on day 1 simultaneously with parenteral anticoagulation. 3
• Continue parenteral anticoagulation for at least 5 full days regardless of INR. 1, 3
• Discontinue parenteral anticoagulation only after both conditions are met: (a) minimum 5 days completed, and (b) INR 2.0–3.0 on two consecutive days. 1, 3
• Target INR is 2.5 (range 2.0–3.0). 1

Hemodynamically Unstable Patients (High-Risk PE)

High-risk PE is defined by sustained hypotension (SBP <90 mmHg for >15 minutes), shock requiring vasopressors, or cardiac arrest. 1, 2

• Unfractionated heparin (UFH) is the only recommended initial anticoagulant in this setting (Class I, Level C). 1, 2

• Dosing: 80 units/kg IV bolus, then 18 units/kg/hour continuous infusion, adjusted to maintain aPTT 1.5–2.5 times control. 1, 2

• Systemic thrombolysis is first-line therapy (Class I, Level B): alteplase 100 mg IV over 90 minutes for stable patients, or 50 mg IV bolus during cardiac arrest. 1, 2

• After hemodynamic stabilization, transition to standard anticoagulation as for intermediate- or low-risk PE. 1

Absolute Contraindications to DOACs

Do not use DOACs in the following situations (Class III, Level C):

• Severe renal impairment (creatinine clearance <30 mL/min for rivaroxaban/apixaban; <25 mL/min for edoxaban). 1
• Pregnancy or breastfeeding. 1
• Antiphospholipid antibody syndrome. 1
• Mechanical heart valves. 2

In these patients, use LMWH/fondaparinux bridged to warfarin, or LMWH monotherapy (especially in pregnancy and cancer). 1

Duration of Anticoagulation

All patients require therapeutic anticoagulation for at least 3 months. 1, 6, 7

Clinical Scenario	Recommended Duration	Strength
Provoked PE (surgery, trauma, immobilization)	3 months, then stop	Class I, Level A [1,2]
First unprovoked PE	≥3 months; strongly consider indefinite therapy due to 10% annual recurrence risk	Class I, Level A [1,2]
Recurrent VTE (≥1 prior event)	Indefinite	Class I, Level A [1,2]
Active cancer	≥6 months with LMWH preferred over warfarin; continue while cancer is active	Class I, Level A [1,3]

• After 6 months of therapeutic anticoagulation in unprovoked PE, consider reduced-dose rivaroxaban (10 mg daily) or apixaban (2.5 mg twice daily) for extended prophylaxis to reduce bleeding risk. 6

Special Populations

Cancer-Associated PE

• LMWH monotherapy is superior to warfarin and should be continued for at least 6 months at 75–80% of initial dose (e.g., dalteparin 150 units/kg once daily after initial month at 200 units/kg). 1, 3
• Apixaban, edoxaban, and rivaroxaban are effective alternatives to LMWH in cancer patients. 6
• Continue anticoagulation indefinitely while cancer is active. 1, 3

Severe Renal Impairment (CrCl <30 mL/min)

• Avoid standard-dose LMWH due to accumulation and 2- to 3-fold increased bleeding risk. 1, 3
• Use UFH with aPTT monitoring, or reduce enoxaparin to 1 mg/kg once daily (instead of twice daily). 1, 3
• Fondaparinux is contraindicated if CrCl <20 mL/min. 3

Pregnancy

• Warfarin is teratogenic—never use during pregnancy. 1
• Use therapeutic-dose LMWH (e.g., enoxaparin 1 mg/kg every 12 hours) throughout pregnancy. 1
• Switch to UFH approaching delivery for easier reversal; discontinue or reduce dose 4–6 hours before expected delivery. 1
• Continue anticoagulation for 6 weeks postpartum or 3 months from diagnosis, whichever is longer. 1

Severe Obesity

• UFH is preferred over LMWH because weight-based LMWH dosing is less validated in patients >120 kg. 1

Inferior Vena Cava (IVC) Filters

Routine IVC filter placement is not recommended (Class III, Level A). 1, 2

Consider retrievable IVC filters only in:

• Absolute contraindication to anticoagulation (e.g., active major bleeding). 1, 2
• Recurrent PE despite therapeutic anticoagulation. 1, 2

Critical Pitfalls to Avoid

• Do not delay anticoagulation while awaiting imaging in high-probability patients—start treatment immediately. 1, 2, 4

• Do not stop LMWH before day 5 when bridging to warfarin, even if INR is therapeutic—this significantly increases recurrence risk. 3

• Do not stop LMWH until INR is 2.0–3.0 on two consecutive days—a single therapeutic INR is insufficient. 1, 3

• Do not use DOACs in severe renal impairment, pregnancy, or antiphospholipid syndrome—these are absolute contraindications. 1

• Do not give aggressive IV fluid boluses to hypotensive PE patients—this worsens right ventricular failure; use vasopressors (norepinephrine) instead. 1, 2

• Do not routinely thrombolyse intermediate-risk PE—reserve thrombolysis for hemodynamic deterioration. 1, 2

• Do not use warfarin as first-line in cancer patients—LMWH is superior. 1, 3

• Monitor platelet counts every 2–3 days from day 4 to day 14 when using heparin products to screen for heparin-induced thrombocytopenia. 3