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warfarin

warfarin

Pharmacology

  • also called coumadin
  • 100% bioavailability given orally as the sodium salt;
  • 99% bound to plasma proteins
  • small Vd (the albumin space = 0.14L/kg)
  • long half-life 20-60hrs (mean 36hrs) & lack of excretion of unchanged drug
  • drug interactions with other highly bound drugs
  • duration of action 2-5 days (see above under mechanism of action).
  • although warfarin crosses placenta, active warfarin is NOT found in breast milk.
  • usually commence Rx with small daily doses of 5mg rather than the large loading doses formerly used.
  • Initial adjustment of dosing according to target INR usually takes about 1wk & maintenance dose is usually 5-7mg/day.
  • NB. warfarin crosses the placenta & can cause serious birth defects characterised by abnormal bone formation.
  • drugs that do NOT significantly effect INR include:
    • ethanol, phenothiazines, benzodiazepines, paracetamol, narcotics, indomethacin & most antibiotics.
  • genetic variation in vitamin K and warfarin metabolism results in sub-groups of patients such as:
    • effect of polymorphisms in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1):
      • maintenance dose of warfarin differed significantly among the 3 combinations of 2 haplotype groups (low-dose haplotype group (A) or a high-dose haplotype group (B)): low-dose (A/A), intermediate-dose (A/B), and high-dose (B/B) 1)

contra-indications

  • severe active bleeding
  • increased risk of severe bleeding:
    • severe uncontrolled hypertension
    • recent GI or genitourinary bleeding
    • active peptic ulceration
    • severe thrombocytopenia
    • poor compliance
  • PH intracerebral haemorrhage
  • high falls risk and non-valvular AF with CHADS2 score of 0 or 1

indications

  • cardiac valve replacement
  • valvular heart disease with stroke risk
  • stroke (CVA) risk with non-valvular AF and CHADS2 score of 1 or more
    • NB. whilst increasing age increases risk of bleeding on warfarin, risk of stroke (CVA) also increases and benefit of antiplatelets decreases and is of little benefit in those aged over 77yrs, hence age is thought not to be a C/I to warfarin per se as relative benefit is still there.

Clinical usage

  • pts should be usually be antocoagulated first with heparin or enoxaparin to avoid warfarin-induced thrombosis and skin necrosis due to decreased synthesis of Protein C, and also to ensure immediate therapeutic anticoagulation, although patients with chronic AF or heart valve can be started on warfarin alone.
    • Risk is higher if starting at 10mg (0.01-1% pts) instead of 5mg and in females (85% of reported cases);
  • heparin should be continued for at least 4 days & not be discontinued until INR is > 2.0 for 2 consecutive days

target therapeutic INR ranges:

  • if mechanical prosthetic heart valve target INR is 2.5-3.5, for all other conditions, target INR is 2.0-3.0

loading doses of warfarin:

  • derived from Gedge et al Age Ageing 2000; 29:31-34 (ie. WH guideline)
  • initial loading dose on 1st 2 days should usually be 5mg (not 10mg which increases chance of over-shoot and warfarin-induced thrombosis, consider 2-4mg loading doses in frail, elderly, poorly nourished at risk patients)
  • daily INR initially
  • day 1: if INR < 1.4 and not an at risk patient, then 5mg, otherwise consider 2-4mg
  • day 2: if INR < 1.8 then repeat day 1 load dose; if INR 1.8-2.0 then 1mg; if INR > 2.0 then nil
  • day 3: if INR < 2.0 then 5mg; if INR 2.0-2.5 then 4mg; if INR 2.6-2.9 then 3mg; if INR 3.0-3.2 then 2mg; if INR 3.3-3.5 then 1mg;
  • day 4:
    • if INR < 1.4 then 10mg; if INR 1.4-1.5 then 7mg; if INR 1.6-1.7 then 6mg; if INR 1.8-1.9 then 5mg;
    • if INR < 2.0-2.3 then 4mg; if INR 2.4-3.0 then 3mg; if INR 3.1-3.2 then 2mg; if INR 3.3-3.5 then 1mg; if INR > 3.5 then nil.
  • subsequent maintenance doses empirically according to regular INRs

therapy duration:

  • prosthetic heart valves ⇒ lifelong
  • venous thromboembolism:
    • anti-cardiolipin Abs ⇒ lifelong
    • PE with non-transient risk factor ⇒ 12mths
    • PE with transient risk factor ⇒ 6mths
    • DVT with non-transient risk factor ⇒ 6mths
    • DVT with transient risk factor ⇒ 3mths
  • chronic AF ⇒ lifelong until risks outweigh the benefits

Adverse effects

  • bleeding - see below
  • warfarin-induced skin necrosis
    • an uncommon side effect that occurs primarily in pts with protein C or S deficiency
    • due to thrombotic occlusion of small vessels
    • usually occurs 3-8 days after warfarin Rx initiated & probably results from the rapid decrease in protein C that precedes the reduction in prothrombin, factors IX & X
    • minimise risk by:
      • start warfarin Rx without a loading dose in pts with protein C or S deficiency
      • continue heparin Rx until INR is therapeutic for 2 consecutive days

Risk factors for bleeding & excessive anticoagulation:

  • intensity of therapy
    • each unit rise in INR raises risk of bleeding 3.5-fold
    • levels > 4.5 in particular are associated with bleeding complications (6x risk cw < 4.5) and should be treated
  • instability of therapeutic control:
    • poor pt compliance
    • taking new medication known to potentiate warfarin
    • change in vitamin K intake
  • concomitant antiplatelet Rx, aspirin or NSAID
  • prolonged duration of Rx or newly initiated Rx
  • inappropriate anticoagulation
  • PH bleeding (especially GIT bleeding, stroke)
  • age > 75yrs
  • hypertension
  • serious comorbidities:
    • renal insufficiency; anaemia; advanced malignancy; 
    • recent diarrhoeal illness or decreased intake;
    • CCF; AMI; CVA; AF; liver disease;
warfarin.txt · Last modified: 2015/03/17 07:58 by gary1