How to manage a patient with fluctuating INR levels on warfarin therapy?

Management of Warfarin Hypersensitivity with Recurrent Supratherapeutic INR

This patient demonstrates warfarin hypersensitivity requiring permanent discontinuation of warfarin and transition to a direct oral anticoagulant (DOAC) such as dabigatran, rivaroxaban, or apixaban. 1

Critical Pattern Recognition

This case reveals a dangerous pattern of warfarin hypersensitivity:

• Initial excessive response: INR rose to 8.0 after only 4 days of 2mg daily dosing, indicating extreme warfarin sensitivity 1
• Rebound elevation after vitamin K: Despite appropriate IV vitamin K administration that initially corrected the INR to 2.4-3.7, a minimal restart dose of 0.5mg caused INR to spike to 5.9 within 24 hours 1
• Persistent elevation: INR remained elevated (2.0-3.3) for 8 days after the final 0.5mg dose and second vitamin K administration, demonstrating prolonged drug effect 2

This pattern indicates warfarin hypersensitivity requiring permanent discontinuation or extreme dose reduction with intensive monitoring. 1

Immediate Management Completed Appropriately

The acute management was handled correctly:

• First elevation (INR 8.0-9.1): IV vitamin K was appropriately administered for INR >9.0 2, 3
• Second elevation (INR 5.9): Oral vitamin K 5mg was correctly given for INR between 5.0-9.0 2, 3
• Monitoring frequency: INR checks were appropriately frequent during the acute phase 4

Recommended Next Steps

1. Discontinue Warfarin Permanently

• Do not attempt to restart warfarin in this patient given the demonstrated hypersensitivity pattern 1
• The rebound to INR 5.9 after only 0.5mg indicates this patient cannot be safely managed on warfarin even at extremely low doses 1

2. Transition to Direct Oral Anticoagulant

• Switch to a DOAC (dabigatran, rivaroxaban, or apixaban) as these agents have predictable dose-response relationships and do not require INR monitoring 1
• Wait until INR falls below 2.0 before initiating DOAC to avoid overlap-related bleeding risk 1
• Based on the current trajectory (INR 3.3 on Day 14), the INR should be rechecked in 2-3 days 3

3. Investigate Underlying Causes

• Screen for CYP2C9 and VKORC1 genetic variants that predict warfarin sensitivity 1, 4
• Review all medications for interactions, particularly antibiotics, NSAIDs, and aspirin that dramatically increase bleeding risk 1
• Assess for acetaminophen use, which is dose-dependently associated with elevated INR (>9100mg/week increases odds 10-fold) 5
• Evaluate for concurrent illness: diarrhea, decreased oral intake, or advanced malignancy increase risk of supratherapeutic INR 5

4. If Warfarin Must Be Continued (Rare Circumstances)

Only if DOACs are absolutely contraindicated:

• Target lower INR range of 2.0-2.5 to minimize bleeding risk 1
• Start with extremely low doses (0.5mg every other day or 0.25mg daily) 1, 4
• Monitor INR daily for the first 2 weeks after any dose adjustment 1
• Maintain consistent daily vitamin K intake through diet to avoid destabilizing INR 1

Common Pitfalls to Avoid

• Do not attempt "one more try" with warfarin at low doses—this patient has already demonstrated inability to tolerate even 0.5mg 1
• Do not start DOAC while INR >2.0—wait for adequate clearance to avoid additive anticoagulant effect 1
• Do not use subcutaneous vitamin K—response is unpredictable and sometimes delayed compared to oral or IV routes 2
• Do not use high-dose vitamin K (10mg)—this may cause warfarin resistance for up to a week if warfarin needs to be restarted 2

Monitoring After Transition

• No routine laboratory monitoring required with DOACs, which is a major advantage for this patient 1
• Renal function monitoring should be performed periodically as DOACs are renally cleared 1
• Counsel on medication adherence as DOACs have shorter half-lives than warfarin and missed doses have more immediate consequences 1