A high INR after a common prescribing cascade
A 71-year-old man with atrial fibrillation, hypertension and COPD has taken warfarin for eight years with stable INRs between 2.2 and 3.0. He is on day 10 of a 14-day course of fluconazole 100 mg daily for oesophageal candidiasis. He attends with three days of painless visible haematuria and gums that bleed when he brushes his teeth. He is alert, blood pressure 128/74 mmHg, pulse 88 and irregular with no postural drop, no melaena and a soft, non-tender abdomen. Haemoglobin is 116 g/L (baseline 138), platelets 190 ×10⁹/L, creatinine 96 µmol/L, INR 8.6. His other medicines are amlodipine, salbutamol and tiotropium inhalers, and he takes no NSAIDs or aspirin. He has had no recent surgery, head injury or fall.
1. Classify the severity of his bleeding and give your immediate management with explicit drugs, doses and routes. What would you avoid?
Read the worked answer
This is clinically relevant non-major bleeding with a markedly elevated INR: he is haemodynamically stable but has a 22 g/L haemoglobin fall.
Immediate management.
- Stop warfarin.
- Vitamin K 1–2 mg by slow intravenous injection (not intramuscular, which risks a haematoma; oral is inadequate when there is active bleeding). Expect the INR to fall within 6–12 hours; recheck at 6–8 hours.
- Consider prothrombin complex concentrate (e.g. 25–50 units/kg by factor IX content, according to local protocol) if the bleeding continues or worsens, or if he becomes unstable. If PCC is unavailable and there is major bleeding, fresh frozen plasma is the fallback.
- Resuscitate with fluids as needed, send a crossmatch, catheterise for bladder irrigation if clots cause retention, and investigate the haematuria (urinalysis and culture, ultrasound) once bleeding is controlled.
Avoid: intramuscular injections, further NSAIDs or antiplatelets, and platelet transfusion (count is normal). Avoid FFP as first-line reversal when PCC is available - it is a large volume and takes longer to work. Do not reverse and then leave him unprotected long-term without a written plan.
2. Explain the drug interaction and set out a day-by-day plan for the next week, including what to do about the remaining fluconazole.
Read the worked answer
Mechanism. Fluconazole is a potent inhibitor of CYP2C9 (and a moderate inhibitor of CYP3A4). S-warfarin, the more potent enantiomer, is cleared almost entirely by CYP2C9, so inhibition leads to warfarin accumulation and a rising INR within 3–5 days; because fluconazole's half-life is around 30 hours, the effect persists for several days after it is stopped. This is a well-recognised, predictable interaction rather than an idiosyncratic reaction.
Plan.
- Day 0: stop warfarin; give IV vitamin K; daily INR.
- Fluconazole: he has oesophageal candidiasis requiring systemic therapy. Options are to complete the remaining four days while warfarin is held and INR is monitored daily, or (if he deteriorates or needs a simpler course) switch to a topical or non-azole agent after discussion with microbiology. Do not stop the antifungal without treating the candidiasis - untreated oesophagitis is a greater immediate risk.
- Days 2–5: when the INR has fallen below 3 and bleeding has stopped, restart warfarin at a reduced dose (typically 50–75% of his previous maintenance dose) and check the INR every 1–2 days, adjusting to the trend rather than a single value.
- Day 7: once he is stable on two consecutive in-range INRs, revert to his usual monitoring interval; recheck haemoglobin and renal function.
Document the interaction in the notes and on his anticoagulant card, and write to the prescriber.
3. For his longer-term anticoagulation, what would you recommend and how would you counsel him to prevent a recurrence?
Read the worked answer
Agent choice. A DOAC is preferable to warfarin for long-term stroke prevention in non-valvular AF: fewer major bleeds, particularly intracranial haemorrhage, no INR monitoring, and a wider therapeutic margin. His creatinine is 96 µmol/L with a Cockcroft–Gault clearance of roughly 55–60 mL/min, so apixaban 5 mg twice daily (or an alternative at full dose) is appropriate. Confirm his weight and creatinine before dosing. Residual cautions: DOACs are still affected by strong CYP3A4/P-gp inhibitors and inducers, and he will need renal function checked at least annually (more often as he ages).
Counselling.
- Carry an anticoagulant alert card; tell every prescriber, dentist and pharmacist that he is anticoagulated.
- Never take aspirin, NSAIDs or over-the-counter 'cold cures' without checking; avoid St John's wort and high-dose fish oil.
- If a new medicine is started, especially an azole, macrolide or antiepileptic, ask specifically about interaction.
- Know the warning signs - black stools, red or brown urine, unusual bruising, prolonged nosebleeds, any head injury needing immediate assessment.
- If he remains on warfarin by preference, arrange INR checks within 3–5 days of starting any new drug and use a self-monitoring record book.
Arrange a review with repeat FBC and renal function in 4 weeks, then annually, and refer for investigation of the haematuria if it recurs.