Warfarin (Guidelines)

• Bleeding disorders
  • Acquired bleeding disorders, such as: liver failure, renal failure, antiplatelet drugs (NSAIDs, aspirin, clopidogrel, prasugrel, ticagrelor)
  • Inherited bleeding disorders, such as: haemophilia, von Willebrand disease
  • And other clotting deficiencies
• Risk of bleeding:
  • Eg: cerebral bleed, cerebral infarct in last 2 weeks, active peptic ulcer disease, GI or genito-urinary bleed in last 6 months
• Thrombocytopenia
• Non-compliance/ inability to understand therapy
• Pregnancy
• Chronic alcoholism
• Risk of fits or falls
• Severe hypertension
  • Eg: systolic greater than 160mmHg or diastolic greater than 100mmHg

Adapted from Pisters R et al. HAS-BLED. Chest. 2010:138:1093-1100

• Counsel patient on warfarin usage; refer to checklist in section 17.2 of SIGN 129
• Measure PT, APTT, Clauss fibrinogen, INR, U&Es, LFTs and FBC.
• Fill in In-patient Oral Anticoagulant Prescription Chart.
• Patients receiving an anti-platelet agent as primary prophylaxis for cardiovascular disease, eg, patients with myloproliferative neoplasms, on developing an indication for warfarin should stop their anti-platelet agent.
• Patients with peripheral artery disease or previous ischaemic stroke on antiplatelet therapy should stop this agent if warfarin is commenced.
• Patients on aspirin or clopidogrel as secondary prophylaxis with stable ischaemic heart disease (often defined as more than 12 months following acute myocardial infarction) should stop their antiplatelet agent while being treated with warfarin.
• Patients on a single antiplatelet agent less than 12 months following an acute coronary syndrome (ACS), who require to start warfarin therapy should continue aspirin therapy until 12 months post-ACS, unless they are regarded as having a high bleeding risk.
• Patients on aspirin and clopidogrel/prasugrel/ticagrelor (DAPT) following an ACS or stent placement, who develop an indication for warfarin, should be carefully assessed for bleeding risk and discussed with their cardiologist, with a view to introducing warfarin and minimising the duration of triple therapy.

This slow initiation schedule of prophylactic and therapeutic warfarin therapy is intended for use where the need for rapid induction is not necessary, ie in the majority of patients.

Slow initiation of warfarin is less likely to lead to bleeding problems and is preferable.

• Determine and record in the medical notes (and on the In-patient Oral Anticoagulant Prescription Chart if in-patient):
  • Therapeutic indication
  • Target INR (see below)
  • And duration of treatment 
• Obtain pre-treatment INR.
  
  • NB: INRs are inaccurate if the patient is receiving standard heparin and the APTT ratio is >3·0.
  • Low molecular weight heparin (LMWH) does not affect the INR.
• For Venous thromboembolism (VTE) patients:
  
  • Continue LMWH for at least 5 days and until the INR is above the lower limit of the desired therapeutic range for 24 hours, ie 2 INRs 24 hours apart.
  • Stop the LMWH immediately if INR is greater than the upper limit of the desired therapeutic range.

Commence warfarin 2mg daily

• Check INR on days 3 and 7. (For those with: liver failure eg LFTs ≥1·5 times ULN, receiving drugs which interact with warfarin, or weighing less than 50kg a smaller starting dose may be appropriate. Discuss with Haematology before initiating therapy.)
  • If INR >4·0: omit for at least 2 days, measuring INR on the first day dose is omitted.
    Once INR is <3·0: recommence at 1mg daily. Check INR again after 3 days.
  • If INR 3·0 to 4·0: reduce 2mg dose to 1·5mg (a 1·5mg dose to 1mg, and a 1mg dose to 0·5mg). Check INR again after 3 days.
  • If INR <3·0: continue on current dose until next planned check (day 7 or day 14).
• Recheck INR after 2 weeks of anticoagulation and predict maintenance dose as follows:

•  Check INR weekly for 6 to 8 weeks. Warfarin dose is only changed when:
  • INR >4·0, but <5·0: omit for 2 days and recommence daily dose at 20% less than previous dose. Recheck after 3 days.
  • INR >3·5 to 4·0: reduce daily dose by 20%. Recheck after 3 days.
  • INR 3·0 to 3·5: reduce daily dose by 10%. Recheck after 3 days.
  • INR <1·5 for 2 consecutive weeks: then increase daily dose by 25%. Recheck after 1 week.
  • if INR is not stable by week 6: 10% daily dose adjustments can be made weekly.

Adapted from Fennerty et al, BMJ 1988; 297: 1285-8.
Adapted from Br.J.Clin.Pham.1998; 46: 159.

Rapid initiation of oral anticoagulation is potentially hazardous. If required in patients with newly-diagnosed venous thromboembolism discuss this with a Consultant Haematologist before initiating warfarin treatment. The Haematologist will give dosing guidance based on individual patient factors. The initial dosing regimen will vary between patients depending on whether there is increased sensitivity to warfarin, eg aged over 65, low body weight, parenteral feeding, heart failure, liver failure, prolonged baseline prothrombin time or receiving other drugs known to potentiate oral anticoagulants.

• Determine and record in medical notes and on the In-patient Oral Anticoagulant Prescription Chart:
  • Therapeutic indication
  • Target INR (see below)
  • And duration of treatment 
• Obtain pre-treatment INR.
  • NB: INRs are inaccurate if the patient is receiving standard heparin and the APTT ratio is >3·0.
  • LMWH does not affect the INR.
• Check INR and prescribe warfarin daily as per dose plan agreed with the Haematologist.
• Continue LMWH for at least 5 days and until the INR is above the lower limit of the desired therapeutic range for 24 hours, ie 2 INRs 24 hours apart.
• Stop the LMWH immediately if INR is greater than the upper limit of the desired therapeutic range.

On discharge:

• Complete IDL, including the Anticoagulant Therapy section.
• Phone GP regarding INR monitoring.
• All patients should receive verbal and written information. The nurse discharging the patient must ensure that the patient has an up-to-date completed booklet.
  • Oral Anticoagulant Therapy booklets can be obtained from Pharmacy.
  • GPs may order booklets from the Supplies Department, Raigmore Hospital (code WMZ 045).

When completing the IDL for in-patients continuing or starting warfarin therapy, a warning box appears: ‘A tab has been created for completion’. This Anticoagulant Therapy section must be completed prior to sending the IDL to pharmacy. When the IDL has been completed the Anticoagulant Therapy letter created within it should be e-mailed to whoever is responsible for the ongoing management of the patient’s anticoagulation. This information also appears on all copies of the patient’s discharge letter and is emailed to GPs.

Because of the long half-life of oral anticoagulant drugs the full effect of a dose change is not seen for 3 to 4 days in many patients. For those on weekly dosing regimens it will be longer.

Most dose changes should be subtle (ie, 10 to 20% of the current average daily dose at a time). The change may well represent less than 0·5mg in patients who only require small doses of warfarin or acenocoumarol and thus an alternate day or weekly dosing regimen may be required to deliver such a change.

There is a wide range of drug and dietary interactions with coumarins which should be carefully considered, refer to BNF. Where antibiotics are required, it should be noted that many antibiotics interact with coumarins and ideally the INR should be rechecked three days after starting a course of antibiotics, regardless of the length of the antibiotic course.

This is a guide. Patients may require higher or lower levels of anticoagulation depending upon their individual risk factors for bleeding or thrombosis.

Indications for oral anticoagulation, target INR and grade of recommendations

For advice on bridging therapy refer to: TAM: Warfarin, DOACs and antiplatelets in adults undergoing surgery or invasive procedures.

Life-threatening bleeding (eg intracranial or major gastro-intestinal bleed)

1. Stop warfarin.
2. Intravenous phytomenadione (vitamin K₁) by slow intravenous injection 10mg, repeated if necessary 12 hours later.
3. Prothrombin complex concentrate (Beriplex^®). The dose will depend on the current INR and the targeted INR. In the following table approximate doses (mL/kg body weight of the reconstituted product) required for normalisation of INR (≤1·2 within 1 hour) at different initial INR levels are given.
   

   Initial INR	2·0 to 3·9	4·0 to 6·0	>6·0
   Approximate intravenous dose* (units Factor IX/kg body weight)	25	35	50

   *The maximum single dose should not exceed 5000 units Factor IX, given at a maximum rate of 200 units/min, ie 8 mL/min of the 25 units/mL reconstituted solution.
   • The correction of the INR persists for approximately 6 to 8 hours. However, the effects of phytomenadione (vitamin K₁) if administered simultaneously, are usually achieved within 4 to 6 hours. Thus, repeated treatment with Beriplex^® is not usually required when phytomenadione (vitamin K₁) has been administered.
4. If Beriplex^® is unavailable or unsuitable, consider fresh frozen plasma (15mL/kg body weight – approximately 1 litre for adult). Beriplex^® and fresh frozen plasma are accessible from the Blood Transfusion Service after discussing with on-call Haematologist.

Less severe bleeding (eg haematuria, epistaxis)

• INR >8·0: Minor bleeding
  
  • Stop warfarin
  • Give phytomenadione (vitamin K₁) 1 to 5mg by slow intravenous injection
  • Repeat dose of phytomenadione (vitamin K₁) if INR still too high after 24 hours
  • Restart warfarin at 15 to 20% less than previous maintenance dose when INR <5·0, and bleeding has stopped.
• INR 2·0 to 8·0: Minor bleeding
  • Stop warfarin
  • Give phytomenadione (vitamin K₁) 1 to 3mg by slow intravenous injection
  • Restart warfarin at 10 to 15% less than previous maintenance dose when INR <5·0 (if target INR range is between 3·0 and 4·0), and when INR <4·0 (if target INR range is between 2·0 and 3·0) and bleeding has stopped.
• Unexpected bleeding at therapeutic levels:
  • Always investigate possibility of underlying cause, eg unsuspected renal or gastro-intestinal tract pathology, and haemorrhagic stroke.
  • Also drug interactions, patient unwell, diet change etc.

Discuss with Haematology if more advice required.

High INR but no bleeding

• INR >8·0: No bleeding
  • Stop warfarin
  • Give phytomenadione (vitamin K₁) 1 to 3mg by mouth using the intravenous preparation orally [off-label]
  • Repeat dose of phytomenadione (vitamin K₁), if INR still too high after 24 hours
  • Restart warfarin at a 15 to 20% less than previous maintenance dose when INR <5·0.
• INR 5·0 to 8·0: No bleeding
  • Withhold 1 or 2 doses of warfarin
  • And restart warfarin at 10 to 15% less than previous maintenance dose when INR <5·0 (if target INR range is between 3·0 and 4·0), or when INR <4·0 (if target INR range is between 2·0 and 3·0).
• Unexpected high INR
  • Always investigate possibility of underlying cause, eg unsuspected renal or gastro-intestinal tract pathology and haemorrhagic stroke.
  • Also drug interactions, patient unwell, diet change etc.

Discuss with Haematology if more advice required.

Surgical or invasive procedures

• Seek specialist advice before proceeding. Also see advice on bridging therapy: TAM: Warfarin, DOACs and antiplatelets in adults undergoing surgery or invasive procedures.

Adapted from:

• Scottish Intercollegiate Guidelines Network (SIGN) (2013) SIGN Publication No. 129, Antithrombotics: Indications and management. SIGN, Edinburgh.
• Guidelines on oral anticoagulation with warfarin – fourth edition, British Committee on Standards in Haematology (2011)
• British Medical Association, Royal Pharmaceutical Society of Great Britain (2012) British National Formulary, 66^th edn.

See TAM guidance: Major haemorrhage and emergency invasic procedures in patients on DOACs.