Excessive Warfarin Anticoagulation and Reversal Strategies in Asymptomatic Patients

1
Excessive Warfarin Anticoagulation and Reversal
Strategies in Asymptomatic Patients

• AIM Presentation
• Heather M. Powers, MD
• October 30, 2002

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Case Presentation

• 80 yo AA female with PMHx significant for HTN,
  DVT and PE on chronic anticoagulation therapy
  with warfarin. Pt presented to ortho service for
  repair of periprosthetic hip fracture.
• Medicine consult called for management of
  anticoagulation
• INR on presentation was 4.10

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Introduction

• Increases in INR w/o symptoms are common in pts
  on warfarin
• Increased INR inherently carries increased risk
  of bleeding complications but clinicians vary in
  their management of supratherapeutic INRs
• Most favor a passive approach by withholding
  warfarin
• Moderate incr. in INR rarely associated with
  serious bleeding in pts who are asymptomatic
• Risk and inconvenience of Vit K outweigh the
  benefits

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Warfarin - Pathophysiology

• Anticoagulant effect mediated by inhibition of
  vitamin K dependent ?-carboxylation of factors
  II, VII, IX, X
• Proteins become biologically inactive
• Effect of warfarin delayed until clotting factors
  are cleared from the circulation 36-72hrs
• Equilibrium reached in about 1 week

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Causes of excessive anticoagulation

• High dose warfarin
• Drug interactions
• Genetic polymorphisms- variations in pts
  response to warfarin
• Superimposed diseases (liver, malabsorption
  syndromes)
• Vitamin K deficiency
• Poor dietary intake (s/p chemo, surgery, etc.)
• TPN
• Prolonged course of ABX

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• Penning-van Beest et al performed study of 17,000
  outpts
• Factors associated with an INRgt6.0
• Diarrhea (RR 12.8)
• Decompensated heart failure (RR 3.0)
• Fever (RR 2.9)
• Impaired liver function (RR 2.8)
• Stable heart failure (1.6)

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Complications

• Risk of major bleeding related to degree of
  anticoagulation
• Palareti et al demonstrated evidence that an
  INRgt4.5 associated with significant risk of
  bleeding events
• The European Atrial Fibrillation Trial Study
  Group
• In pts w/ afib, risk of bleeding increases
  substantially at INRgt4.0

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The European Atrial Fibrillation Trial Study
Group
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Reversal Options

• Holding warfarin dose
• Holding dose Vit K
• Vit K
• Oral
• Subcutaneous
• Intraveneous
• FFP
• Prothrombin complex concentrate

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Hylek et al, Prospective study of the outcomes
of ambulatory patients with excessive warfarin
anticoagulation Arch Intern Med, 2000

• Hylek et al prospectively followed a group of
  patients on warfarin anticoagulation w/ INRgt6.0
  (114) vs. control group (268) with INR in the
  target range
• Warfarin held and no pts received Vit K
• 10 pts with INRgt6 had abnormal bleeding and 5 of
  these had major hemorrhage (4.4) during 14 day
  f/u (resulting in 2 deaths) compared with control
  group
• No pts had any thromboembolic events at F/U
• Only 33 of pts with INRgt6 had INRlt4 at 24hrs
• 45 of pts had INRgt4 at 48hrs

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• Concluded that outpatients with an INRgt6.0 have
  significant short term risk of major hemorrhage
• Holding warfarin doses alone may not be adequate
  therapy in this population of patients
• More studies needed to determine net benefit of
  Vit K treatment

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Crowther et al, Treatment of Warfarin-associated
coagulopathy with oral Vitamin K a randomised
controlled trial Lancet, 2000

• RCT of 1 mg oral Vit K vs. placebo in
  asymptomatic pts with INR 4.5-10.0
• Showed that tx with Vitamin K brought INR into
  target range more rapidly than withholding
  warfarin alone
• INR 1.8-3.2 on day after treatment seen in 56
  and 20 of pts in Vit K vs. Placebo respectively
• Did not lead to warfarin resistance
• 3mo. f/u found ? rate of bleeding in pts not
  receiving Vit K (4 vs. 17)

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Crowther et al, 2000
pts with INR gt 3.2
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Crowther et al Oral Vitamin K Lowers the INR
More Rapidly Than SQ Vitamin K in the Treatment
of Warfarin Associated Coagulopathy, 2002

• Design
• Randomized controlled trial
• Setting
• Two teaching hospitals in Canada and Italy
• Population
• Patients with an INR between 4.5 and 10.0
• Did not require immediate normalization of INR
• Current hemorrhage or at high risk for hemorrhage

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Crowther et al

• Methods
• Pts randomly assigned to receive 1mg of oral or
  SQ vitamin K
• INR testing mandated on the day following therapy
  but was optional thereafter
• Pts followed up at 1 month to determine if any
  bleeding or thromboembolic events had occurred

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Crowther et al

• Primary Outcome Measure
• INR on day after Vit K administration

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Crowther et al

• Results
• No patients excluded from the primary analysis
• 15/26 (58) of pts who received oral Vit K vs.
  only 6/25 (24) of pts receiving SQ Vit K had
  INRs of 1.8-3.2 on day after Vit K
  administration
• 2 pts actually had an ? INR on day after Vit K
• 3 patients had INR lt 1.8 in oral Vit K group

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Crowther et al

• Results (contd)
• During 1 mo. f/u no episodes of bleeding or
  thromboembolism in either subgroup
• Five pts died (all received oral Vit K) (p0.05)

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Crowther et al

• Conclusions
• Clinically important results since common
  practice not to treat patients with excessively
  increased INRs
• b/c pts considered low risk for bleeding
• overcorrection of INR and warfarin resistance
• Suggest that risk for hemorrhage is underestimated

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Conclusions

• Clinicians may be underestimating the risk of
  bleeding in patients with supratherapeutic INRs
• Oral Vit K is an appropriate option for reversal
  in pts with INR 4.5-10.0 and may be superior to
  SQ dosing
• More aggressive outpatient and inpatient
  treatment of supratherapeutic INRs
• Warfarin resistance is a myth???