Warfarin, a urinary tract infection and a supra-therapeutic INR in a patient with a mechanical valve
A 71-year-old woman with a mechanical mitral valve and atrial fibrillation takes warfarin 5 mg daily. Her INR has been stable between 2.4 and 3.0 for eight months. Long-term medicines are amiodarone 200 mg daily, omeprazole 20 mg daily and bisoprolol 5 mg daily. Her eGFR is 52 mL/min/1.73 m2 and her weight is 58 kg. Five days ago she was prescribed trimethoprim-sulfamethoxazole double-strength twice daily for seven days for dysuria (urine culture: E. coli), and a single 150 mg dose of fluconazole for vaginal candidiasis. She now reports bleeding gums when brushing, and has two small buccal ecchymoses. INR today is 7.8; haemoglobin has fallen from 12.3 to 10.9 g/dL. She is haemodynamically stable, has no melaena, no haematuria and no neurological symptoms.
1. Explain the pharmacological basis of the INR rise, naming every contributing interaction in this regimen.
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Three drugs are acting on the same pathway. (1) Trimethoprim is a potent inhibitor of CYP2C9, the principal enzyme clearing S-warfarin, and sulfamethoxazole additionally displaces warfarin from albumin and can inhibit CYP2C9; the combination typically raises INR within 3-5 days, exactly the timing seen here. (2) Fluconazole, even as a single 150 mg dose, is a strong CYP2C9 and CYP3A4 inhibitor; a single dose is enough because the enzyme blockade outlasts the drug's own exposure. (3) Amiodarone is a long-standing CYP2C9 and CYP3A4 inhibitor with a half-life of several weeks; the patient's maintenance warfarin requirement may already be partly set by it, but it also means any new inhibitor is added to an already inhibited baseline, and changes in amiodarone status would alter INR for months.
Omeprazole contributes little directly (it inhibits CYP2C19) but can reduce vitamin K absorption and add to the bleeding risk with warfarin. The quantitative effect is not additive but multiplicative: two CYP2C9 inhibitors plus protein-binding displacement can easily double the INR. The haemoglobin fall is disproportionate to visible blood loss and warrants a stool occult blood and a repeat full blood count, since retroperitoneal or gastrointestinal bleeding must be excluded.
2. Give your immediate management plan with specific doses, and state what you would recheck and when.
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She has minor bleeding with a markedly elevated INR, so the correct action is not simply to stop warfarin. Stop warfarin and give vitamin K1 2.5-5 mg orally (intravenous only if she deteriorates or bleeding becomes major, because IV vitamin K risks anaphylactoid reactions and over-correction with valve thrombosis). Oral vitamin K has a slower onset, so if there were major bleeding you would add a four-factor prothrombin complex concentrate rather than fresh frozen plasma, weight-adjusted, and involve cardiology immediately.
Do not give FFP here: she is not haemodynamically compromised, the INR is the marker rather than the disease, and volume load is undesirable.
Recheck INR at 12-24 h and daily thereafter; the expected fall after 2.5 mg oral vitamin K is 1-2 INR units in 24 h. Transfuse only if haemoglobin falls further or she becomes symptomatic. Once the INR is below 4 and bleeding has stopped, restart warfarin at a reduced dose (for example 3-4 mg) because the amiodarone interaction limits her capacity to metabolise it, and re-titrate with INR every 3-4 days. Antiplatelet therapy should not be added. Document the interaction prominently in her record and give her a written anticoagulant alert card.
3. The infection still needs treatment. How would you choose the antibiotic and adjust long-term anticoagulation strategy?
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Select an agent with minimal cytochrome interaction and predictable renal clearance. Nitrofurantoin 100 mg twice daily for five days has essentially no CYP interaction; her eGFR of 52 mL/min is above the usual 30 mL/min cutoff but efficacy falls with renal impairment, so monitor for failure. Fosfomycin trometamol 3 g as a single dose is an alternative with no relevant interaction. Avoid ciprofloxacin and other fluoroquinolones (CYP1A2 inhibition plus QT and tendon risk in a patient on amiodarone), and avoid further azoles.
For long-term strategy: a mechanical mitral valve mandates a vitamin K antagonist, so switching to a DOAC is contraindicated. The right answer is therefore a planned 'sick-day' interaction plan rather than a drug switch: for any new antibiotic, increase INR monitoring to twice weekly for the duration plus one week, pre-emptively reduce the warfarin dose by 15-20% when a known CYP2C9 inhibitor is unavoidable, and give the patient a clear instruction to report bleeding immediately. Record the amiodarone interaction permanently. If INR control remains labile because of polypharmacy, a pharmacist-led anticoagulation clinic with a self-monitoring option should be considered, and the omeprazole should be reviewed for deprescribing if there is no ongoing indication.