Warfarin therapy

Warfarin has a narrow therapeutic index, a half-life of several days and more than a hundred clinically relevant interactions. What determines whether the treatment is safe is not the starting dose but the system around the patient: that the weekly dose is adjusted in small steps, that every new prescription is assessed as a potential interaction, and that there is a ready-made plan for what happens when the INR runs away or the patient bleeds. In Sweden the treatment is usually managed from an anticoagulation clinic with dosing support, but whoever starts the drug is responsible for the first week.

Indications

• A mechanical valve prosthesis — warfarin is mandatory, and direct oral anticoagulants (DOACs) are contraindicated.
• Antiphospholipid syndrome, particularly triple-positive disease or after an arterial event, where DOACs have proved inferior.
• Atrial fibrillation with marked renal failure or on dialysis, where DOACs lack documentation or have only weak evidence.
• Venous thromboembolism when a DOAC cannot be used (interactions, cost, adherence, pregnancy after the first trimester under specialist care).
• Rheumatic mitral stenosis with atrial fibrillation.

In uncomplicated atrial fibrillation and in ordinary venous thromboembolism, a DOAC is the first choice in Sweden. Warfarin is started today because there is a reason to reject a DOAC, not as the standard option.

Contraindications

• Ongoing clinically significant bleeding.
• Pregnancy in the first trimester and close to delivery (embryopathy and fetal bleeding respectively).
• Marked liver failure with coagulopathy.
• Severe uncontrolled hypertension.
• Recent intracranial haemorrhage without a fresh assessment of benefit and risk.
• An inability to attend for sampling and follow-up — relative, but in practice decisive.

INR target ranges

Preparation and equipment

• INR, full blood count, creatinine with eGFR and liver function tests before starting.
• A complete medication list including over-the-counter drugs, herbal remedies and supplements.
• An assessment of bleeding risk and the risk of falls; anaemia and a known gastrointestinal source are investigated before starting.
• A referral or notification to the anticoagulation clinic, and a decision on who will dose during the first week.
• Written patient information: the Waran booklet (the Swedish warfarin patient record) or its equivalent, with a weekly dose schedule.
• With an acute indication: LMWH at treatment dose in parallel.

Procedure

Initiation with a loading dose

Used when a rapid effect is wanted and the patient is also receiving LMWH, for example in newly diagnosed venous thromboembolism.

1. Check the INR before the first dose. A raised baseline value suggests liver disease or vitamin K deficiency and must be investigated before treatment is started.
2. Give 7.5 mg (three 2.5 mg tablets) on day 1 and day 2. The doses are taken at the same time each day, usually in the evening so that a dose change can reach the patient the same day the result arrives.
3. Reduce to 5 mg (two tablets) on days 1 and 2 in patients over 75, with a weight below 60 kg, heart failure, hepatic impairment, malnutrition, concurrent amiodarone or known slow CYP2C9 metabolism.
4. Take the INR on day 3. The dose that day is determined by the value: below 1.5 means the full dose is continued, 1.5–2.0 a half to a full dose, 2.0–3.0 a half dose, and above 3.0 an omitted dose.
5. Take a new INR on day 5 and thereafter every two to three days until two consecutive values lie within the target range.
6. LMWH is given in parallel at treatment dose and is stopped only once the INR has been within the target range on two consecutive days and at least 5 days of overlap have been achieved. This is the step that is most often missed.

Initiation without a loading dose

Used in outpatient practice when there is no urgency, for example in atrial fibrillation without an acute thrombotic risk. The method produces fewer overshoots.

1. Start directly on an estimated maintenance dose, usually 2.5–5 mg daily (one to two tablets), lower in older and frailer patients.
2. The first INR is taken on day 4–5, then after a further week.
3. Expect the target range to be reached after 1–3 weeks. The full anticoagulant effect is not present until after 5–7 days, however high the INR may look earlier.

A rising INR during the first few days reflects the loss of factor VII, which has the shortest half-life, not that the patient is protected. Factor II is quantitatively the most important for thrombin generation and falls most slowly. There is therefore a window with a raised INR but a persisting thrombotic risk, and that is why overlap with LMWH is required in acute thrombosis.

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      {"t": 0, "faktor": "Factor VII (t½ 6 h)", "aktivitet": 100},
      {"t": 6, "faktor": "Factor VII (t½ 6 h)", "aktivitet": 50},
      {"t": 12, "faktor": "Factor VII (t½ 6 h)", "aktivitet": 25},
      {"t": 24, "faktor": "Factor VII (t½ 6 h)", "aktivitet": 6.3},
      {"t": 36, "faktor": "Factor VII (t½ 6 h)", "aktivitet": 1.6},
      {"t": 48, "faktor": "Factor VII (t½ 6 h)", "aktivitet": 0.4},
      {"t": 72, "faktor": "Factor VII (t½ 6 h)", "aktivitet": 0.02},
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      {"t": 6, "faktor": "Factor IX (t½ 24 h)", "aktivitet": 84},
      {"t": 12, "faktor": "Factor IX (t½ 24 h)", "aktivitet": 71},
      {"t": 24, "faktor": "Factor IX (t½ 24 h)", "aktivitet": 50},
      {"t": 36, "faktor": "Factor IX (t½ 24 h)", "aktivitet": 35},
      {"t": 48, "faktor": "Factor IX (t½ 24 h)", "aktivitet": 25},
      {"t": 72, "faktor": "Factor IX (t½ 24 h)", "aktivitet": 13},
      {"t": 0, "faktor": "Factor X (t½ 40 h)", "aktivitet": 100},
      {"t": 6, "faktor": "Factor X (t½ 40 h)", "aktivitet": 90},
      {"t": 12, "faktor": "Factor X (t½ 40 h)", "aktivitet": 81},
      {"t": 24, "faktor": "Factor X (t½ 40 h)", "aktivitet": 66},
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      {"t": 48, "faktor": "Factor X (t½ 40 h)", "aktivitet": 44},
      {"t": 72, "faktor": "Factor X (t½ 40 h)", "aktivitet": 29},
      {"t": 0, "faktor": "Factor II (t½ 60 h)", "aktivitet": 100},
      {"t": 6, "faktor": "Factor II (t½ 60 h)", "aktivitet": 93},
      {"t": 12, "faktor": "Factor II (t½ 60 h)", "aktivitet": 87},
      {"t": 24, "faktor": "Factor II (t½ 60 h)", "aktivitet": 76},
      {"t": 36, "faktor": "Factor II (t½ 60 h)", "aktivitet": 66},
      {"t": 48, "faktor": "Factor II (t½ 60 h)", "aktivitet": 57},
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The curves are calculated from the half-lives of the factors and show why the INR rises early while the protection lags behind: the INR is most sensitive to factor VII, which is almost gone within 24 hours, while factor II still retains around three quarters of its activity.

Dose adjustment during stable treatment

Always adjust the weekly dose, not individual daily doses, and change it in steps of 10–20 %. The effect of a change is not seen until after 5–7 days — the commonest reason for fluctuating values is that the dose is adjusted again before the previous change has taken effect.

Always look for a cause of an abnormal value before the dose is changed: a new course of antibiotics, a change of diet, alcohol, fever, diarrhoea, heart failure or missed doses explain most deviations and require no permanent change of dose.

Interactions and diet

• Antibiotics raise the INR almost without exception, partly through CYP inhibition (trimethoprim-sulfamethoxazole, metronidazole, ciprofloxacin, macrolides, fluconazole) and partly by wiping out the gut flora that produce vitamin K. Take an INR 3–5 days after the start of every course of antibiotics.
• Amiodarone increases the effect markedly and for a long time; reduce the weekly dose by about a third at the time of initiation and monitor closely for several weeks.
• NSAIDs, aspirin and SSRIs do not raise the INR but increase the bleeding risk through platelet function and the mucosa. The combination of an NSAID and warfarin should be avoided altogether.
• Interactions that lower the effect: carbamazepine, rifampicin, St John's wort and phenobarbital. The effect creeps in over 1–2 weeks.
• Diet: the problem is not the amount of vitamin K but the variation. The patient should eat vegetables as usual but evenly across the weeks — a sudden period of kale or broccoli, or conversely a week without vegetables during gastroenteritis, explains many unexpected values.
• Excessive alcohol raises the INR acutely; chronic heavy consumption can lower it.
• Cranberry juice and large doses of fish oil have been described as raising it.

Before surgery and dental procedures

flowchart TD
  A[A planned procedure during warfarin treatment] --> B{The bleeding risk of the procedure}
  B -- "Low: dental extraction, cataract surgery, skin surgery, gastroscopy without biopsy" --> C[Continue warfarin without interruption]
  C --> D[Check the INR within 24 hours; it must be below 3.0. Local haemostasis and topical tranexamic acid]
  B -- "Moderate to high: abdominal surgery, orthopaedics, neurosurgery, spinal anaesthesia" --> E[Stop warfarin for 3 to 5 days, longer with a low weekly dose]
  E --> F{A high thromboembolic risk}
  F -- "Yes: a mechanical mitral valve, an older valve model, thrombosis within the last 3 months, previous embolism during an interruption" --> G[Bridging with LMWH at treatment dose from 2 days after the last warfarin dose]
  F -- "No: atrial fibrillation without previous embolism, VTE older than 3 months" --> H[No bridging. Only prophylactic-dose LMWH postoperatively where needed]
  G --> I[The last LMWH dose no later than 24 hours before the procedure]
  H --> J[The INR is checked on the morning of surgery, target below 1.5]
  I --> J
  J --> K[Restart warfarin at the usual dose the evening after the procedure once haemostasis has been achieved]
  K --> L[LMWH is restarted no earlier than 6 to 24 hours postoperatively depending on the bleeding risk and continues until the INR is back in the target range]

For dental procedures the general rule is that warfarin is not stopped. The extraction of one to three teeth can be performed with a current INR below 3.0 taken within 24 hours. The socket is packed with a local haemostatic agent and sutured, and the patient bites on a swab moistened with tranexamic acid solution for 30–60 minutes. Stopping warfarin before a dental extraction carries a greater risk than the bleeding one is trying to avoid.

With a low weekly dose (below about 15 mg per week), 6–7 days without warfarin are often needed to reach an INR below 1.5, since these patients eliminate the drug slowly.

Reversal

flowchart TD
  A[A raised INR during warfarin treatment] --> B{Is the patient bleeding}
  B -- "No, only a high value" --> C{The INR level}
  C -- "3.0 to 3.9" --> C1[A half dose or omit for 1 day. Reduce the weekly dose]
  C -- "4.0 to 5.9" --> C2[Omit for 1 to 2 days. Phytomenadione 1 to 2 mg orally if the bleeding risk is increased]
  C -- "6.0 or higher" --> C3[Omit for at least 2 days. Phytomenadione 1 to 2 mg orally or intravenously. Repeat the sample after 2 to 4 days]
  B -- "Yes" --> D{The severity of the bleeding}
  D -- "Minor bleeding: epistaxis, haematuria, bruising, heavy menstruation" --> E[Local haemostasis. Omit for 1 to 2 days. With an INR above 4.0 also phytomenadione 1 to 2 mg orally or intravenously. Repeat the sample after 2 to 3 days]
  D -- "Serious bleeding: requiring transfusion, gastrointestinal, retroperitoneal, with haemodynamic compromise" --> F[Stop warfarin. Phytomenadione 10 mg IV. Prothrombin complex concentrate according to the INR and the weight. Treat the source of bleeding]
  D -- "Life-threatening bleeding: intracranial, spinal, uncontrolled" --> G[Reverse immediately. Phytomenadione 10 mg IV plus prothrombin complex concentrate. Do not wait for the CT when the suspicion is strong and the wait is long]
  F --> H[Check the INR 10 to 15 minutes after the dose. Target 1.5 or below. Give more if needed]
  G --> H
  H --> I[A further INR after 6 to 12 hours. The effect of the concentrate wears off before the vitamin K has taken effect]

The dose of prothrombin complex concentrate (Ocplex, Confidex) is determined by the baseline value:

Round up to the nearest whole pack (500 units) and give a further 500 units if the check value does not reach the target. If no concentrate is available, plasma 10–15 mL/kg is given, which is slower, imposes a large volume load and rarely brings the INR below 1.5.

Phytomenadione (Konakion Novum) must always be given together with the concentrate. The concentrate works within minutes but is exhausted within 6–8 hours; vitamin K needs 4–6 hours intravenously and 12–24 hours orally to take effect, but then lasts for several days. If only the concentrate is given, the coagulopathy returns during the night. Phytomenadione is given orally or slowly intravenously — never subcutaneously, where absorption is unpredictable.

Complications

• Bleeding, most often from mucosal surfaces, the gastrointestinal tract and the urinary tract. The risk is greatest during the first months of treatment.
• Intracranial haemorrhage — the feared and most lethal complication.
• Coumarin necrosis, typically on days 3–8 in patients with protein C or protein S deficiency, with painful skin necrosis over the breasts, thighs and buttocks. It is treated by stopping the drug, giving vitamin K and heparin.
• Calciphylaxis in patients on dialysis.
• Hair loss and skin rashes.
• Fetal harm after exposure in the first trimester.
• The patient remaining on warfarin with no continuing indication — the duration of treatment must be reviewed at every annual check.

Aftercare and follow-up

The INR is checked at least every four weeks during stable treatment, and more often with every change of medication, health status or diet. At every contact:

• Ask actively about bleeding symptoms, bruising, black stools and new drugs.
• Ask about dental treatment, planned procedures and travel.
• Assess the tendency to fall and the cognition in older patients — a patient who can no longer follow the dosing schedule needs a dosette box, help from home care services, or a change of treatment.
• Calculate the time in therapeutic range. A TTR below 60 % is in itself a reason to reconsider the choice of treatment, not to keep adjusting the dose.

The patient must have an up-to-date dosing schedule on paper, know to seek urgent care for headache after trauma or for black stools, and know that over-the-counter NSAIDs must not be used.

Common pitfalls

• LMWH stopped too early in newly diagnosed thrombosis, before 5 days of overlap and two values in the target range have been achieved.
• The INR interpreted as protection during the first few days. The value reflects factor VII, not factor II.
• The dose adjusted too often and by too much. Wait 5–7 days for the effect and change the weekly dose in steps of 10–20 %.
• A course of antibiotics without an INR check — the single commonest cause of acute overdose.
• Phytomenadione given subcutaneously, or only orally in serious bleeding; give it intravenously.
• Prothrombin complex concentrate without vitamin K — the coagulopathy returns within a few hours.
• Stopping warfarin before a dental extraction, which increases the thromboembolic risk without reducing any relevant bleeding.
• Bridging with LMWH in low-risk patients. Bridging increases the bleeding risk without reducing the number of emboli in patients with atrial fibrillation and no previous embolism.
• The patient discharged after reversal with no plan for when anticoagulation is to be resumed.