What drug would increase the risk of hemorrhage in a patient on warfarin (anticoagulant) therapy?

Ketoconazole Increases Hemorrhage Risk in Warfarin-Treated Patients

Ketoconazole (Option A) is the correct answer—it significantly increases the risk of hemorrhage in patients on warfarin by inhibiting CYP2C9 and dramatically elevating warfarin plasma concentrations, requiring a 25-33% pre-emptive dose reduction. 1

Mechanism of Drug Interactions with Warfarin

CYP450 Inhibitors (Increase Bleeding Risk)

Ketoconazole is a strong CYP2C9 inhibitor that markedly increases warfarin exposure and anticoagulant effects, leading to dramatically elevated bleeding risk. 1 The mechanism involves:

• Inhibition of CYP2C9, the primary enzyme metabolizing warfarin's S-enantiomer, resulting in increased warfarin plasma concentrations and enhanced anticoagulant effects 1
• Very large increases in drug exposure caused by ketoconazole are likely to raise bleeding risk significantly 1
• Clinical evidence demonstrates that patients may require warfarin dose reductions exceeding 35-43% when high-dose ketoconazole is initiated 2

CYP450 Inducers (Decrease Bleeding Risk)

The other three options—griseofulvin, carbamazepine, and phenobarbitone—are enzyme inducers that accelerate warfarin metabolism and reduce its anticoagulant effect, thereby decreasing (not increasing) hemorrhage risk 1:

• These agents induce cytochrome P450 enzymes, requiring higher warfarin doses during treatment to maintain therapeutic anticoagulation 1
• The full effect of enzyme induction takes 2-4 weeks to develop and persists for 2-4 weeks after discontinuation 1
• Patients on these medications need increased warfarin dosing, not dose reductions, making hemorrhage less likely 1

Clinical Management of Ketoconazole-Warfarin Interaction

When ketoconazole must be initiated in a warfarin-treated patient:

• Consider a pre-emptive warfarin dose reduction of 25-33% at the time of ketoconazole initiation 1
• Monitor INR closely whenever ketoconazole is initiated, as all drug interactions affecting warfarin require careful INR monitoring 1
• The risk of major bleeding is significantly elevated when warfarin is combined with drugs that inhibit its metabolism 1
• Be prepared for dose reductions potentially exceeding 35%, as case reports demonstrate INR elevations requiring up to 43% warfarin dose reduction 2

Additional Hemorrhage Risk Factors

Concomitant medications that further increase bleeding risk include: 3, 4

• NSAIDs double the risk of bleeding versus warfarin alone through both pharmacokinetic interactions and direct antiplatelet effects 3
• Aspirin and antiplatelet agents impair platelet function and produce gastric erosions 3
• SSRIs more than double bleeding risk compared to warfarin alone 3

Patient-specific risk factors for hemorrhage include: 3

• Age ≥65 years (particularly >75 years, which increases major bleeding from 1.7% to 4.2% per year) 5
• History of gastrointestinal bleeding or stroke 3
• Renal insufficiency or anemia 3
• INR >3.0-3.5, which substantially increases intracranial hemorrhage risk 3

Critical Pitfall to Avoid

Do not confuse enzyme inhibitors with enzyme inducers. Ketoconazole inhibits warfarin metabolism (increasing bleeding risk), while griseofulvin, carbamazepine, and phenobarbitone induce warfarin metabolism (decreasing bleeding risk and potentially causing therapeutic failure). 1