What is the next step in management for an adult patient with a history of atrial fibrillation or previous venous thromboembolism, who has developed bilateral deep vein thrombosis (DVT) while on Eliquis (apixaban) and received a full dose of Lovenox (enoxaparin) yesterday?

Management of Bilateral DVT Despite Apixaban Therapy

Immediate Next Steps

This patient has experienced anticoagulant failure on apixaban and requires immediate investigation for underlying causes, continuation of therapeutic enoxaparin, and likely transition to long-term LMWH rather than returning to a DOAC. 1

Critical Initial Assessment

You must immediately evaluate for the following causes of breakthrough thrombosis:

• Drug-drug interactions affecting apixaban metabolism, particularly P-glycoprotein or CYP3A4 inducers (rifampin, phenytoin, carbamazepine, St. John's wort) that reduce apixaban levels 2, 3
• Medication non-adherence or incorrect dosing (verify the patient was taking 10 mg twice daily for days 1-7, then 5 mg twice daily) 2
• Underlying malignancy (cancer-associated thrombosis requires indefinite anticoagulation and may respond better to LMWH) 4, 1
• Antiphospholipid syndrome or other thrombophilia that may require alternative anticoagulation strategies 5
• Severe renal impairment (CrCl <25 mL/min reduces apixaban clearance unpredictably) 2

Anticoagulation Management

Continue Therapeutic Enoxaparin

Do not switch back to apixaban. For breakthrough VTE on a DOAC, guidelines recommend switching to low-molecular-weight heparin rather than another DOAC 1. Continue therapeutic-dose enoxaparin (1 mg/kg subcutaneously twice daily) until the underlying cause is identified and a long-term plan is established 6.

Long-Term Anticoagulation Strategy

• If malignancy is identified: Continue therapeutic LMWH indefinitely, as cancer-associated thrombosis requires extended anticoagulation and LMWH is superior to DOACs in this population 7, 4
• If drug interactions are identified: After eliminating the interacting medication, you may cautiously consider re-challenging with a different DOAC (rivaroxaban or dabigatran) after 2-4 weeks of therapeutic LMWH, though LMWH continuation is safer 1, 3
• If no cause is identified: This represents recurrent unprovoked VTE, which mandates indefinite anticoagulation with LMWH as the preferred agent given the failure on apixaban 4, 1

Duration of Therapy

This patient now has recurrent VTE (bilateral DVT while on anticoagulation constitutes treatment failure and recurrence), which requires extended anticoagulation without a scheduled stop date. 4 The American College of Chest Physicians strongly recommends indefinite anticoagulation for recurrent unprovoked VTE, even with moderate bleeding risk 4.

Antiplatelet Therapy Considerations

Stop all antiplatelet therapy immediately unless the patient has had recent PCI (<6 months), recent ACS (<12 months), or recent CABG (<1 year) 7, 8, 1. Combining aspirin with anticoagulation increases major bleeding risk (RR 1.26) without providing benefit for VTE treatment 8.

Mandatory Follow-Up

• Reassess bleeding risk annually using HAS-BLED score and adjust management accordingly 1
• Re-evaluate the underlying cause when clinically stable to determine if transition to an alternative anticoagulant is appropriate 1
• Monitor for post-thrombotic syndrome given the bilateral nature and extent of thrombosis 7

Critical Pitfalls to Avoid

• Do not simply increase the apixaban dose - this is not an FDA-approved strategy and the patient has already demonstrated treatment failure 2
• Do not use warfarin as the next step - switching from a failed DOAC to warfarin is not recommended; LMWH is preferred 1
• Do not consider reduced-dose anticoagulation - this patient needs full therapeutic anticoagulation indefinitely given recurrent VTE 4
• Do not delay workup for malignancy - cancer-associated thrombosis presenting as bilateral DVT on anticoagulation is a medical emergency requiring immediate investigation 4