What is the most likely cause of this patient's stable International Normalized Ratio (INR) despite a recent doubling of their warfarin dose while taking rifampin for a nontuberculous mycobacterial infection?

Rifampin-Induced Enzyme Induction is the Most Likely Cause of Stable INR Despite Warfarin Dose Increase

The most likely cause of this patient's stable INR despite doubling of warfarin dose is induction of cytochrome P450 enzymes by rifampin (option E).

Mechanism of Interaction

• Rifampin is a well-known potent inducer of hepatic cytochrome P450 enzymes, particularly CYP2C9 and CYP3A4, which are responsible for metabolizing warfarin 1
• This enzyme induction significantly increases warfarin clearance, resulting in reduced anticoagulant effect and requiring higher doses to maintain therapeutic INR 2, 3
• The full induction of CYP450 enzymes typically takes 2-4 weeks after rifampin initiation and can persist for up to 2-4 weeks after discontinuation 1
• In this case, the patient's INR remains subtherapeutic (1.1) despite doubling the warfarin dose, consistent with rifampin's enzyme-inducing effect 3

Evidence Supporting Enzyme Induction

• The FDA drug label for rifampin explicitly states that it decreases warfarin exposure, requiring more frequent INR monitoring to establish and maintain the required anticoagulant dose 2
• Clinical studies demonstrate that patients on concurrent rifampin and warfarin therapy typically require a 50-100% increase in warfarin dosage to maintain therapeutic anticoagulation 3, 4
• A recent retrospective study found that 86.3% of patients using warfarin with rifampin experienced a significant drug-drug interaction with notable reduction in INR values 3
• Even with dose adjustments, approximately 31% of patients failed to reach target INR while on concurrent therapy 3

Why Other Options Are Less Likely

• Decreased protein binding (A): While some drug interactions with warfarin involve protein binding displacement, this typically causes a transient increase in INR, not a decrease 5, 6
• Eradication of gut flora (B): Some antibiotics can reduce vitamin K production by gut bacteria, which would increase INR rather than decrease it 1
• Increased alcohol intake (C): The patient's alcohol consumption (two beers daily) is stable and moderate; excessive alcohol would typically inhibit warfarin metabolism and increase INR 7
• Increased vegetable consumption (D): While high vitamin K intake from vegetables can antagonize warfarin, the patient only mentions trying to follow a "healthier diet" without specific details about increased vegetable consumption 1, 6

Clinical Management Recommendations

• Monitor INR more frequently during rifampin therapy and for 2-4 weeks after discontinuation 1, 5
• Expect to increase warfarin dose by approximately 50-100% to maintain therapeutic anticoagulation during rifampin therapy 3, 4
• Plan for warfarin dose reduction when rifampin is discontinued to prevent supratherapeutic INR and bleeding complications 1, 8
• Consider alternative antibiotics without significant CYP450 enzyme induction properties if appropriate for treating the nontuberculous mycobacterial infection 5

Important Considerations

• This patient has a mechanical aortic valve, making therapeutic anticoagulation particularly important to prevent thromboembolic complications 5
• The current INR of 1.1 is significantly below the recommended range (typically 2.5-3.5) for patients with mechanical heart valves 1
• The interaction between rifampin and warfarin is predictable but highly significant, requiring proactive management 1
• The time course of enzyme induction (2-4 weeks) explains why the patient's INR remains subtherapeutic despite the recent warfarin dose increase 1, 3