Transcript Ultra-rapid management of oral anticoagulant therapy

Ultra-rapid management of
oral anticoagulant therapyrelated surgical intracranial
hemorrhage
Intensive Care Medicine (2007) 33:721-725
Zohra Daw, MD, FRCPC
Transfusion Medicine resident, University of Ottawa
TMR Journal Club
June13,2007
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Introduction
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OAC therapy increases the risk of major
hemorrhage by 2.4-8% per patient-year
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Rate of intracranial hemorrhage nearly
1% per patient-year and an estimated
60% mortality rate
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Traumatic VS OAC ICH
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The critical factor with ICH is the speed of treatment
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In traumatic subdural hematoma, mortality increases from <
30% to > 80% if surgical evacuation is delayed beyond 4 h
In OAC-related ICH, similar increase in mortality rate if
active treatment is not given before the patient becomes
unconscious
Bleeding persists during the first day in > 50% of
OAC-related ICH compared with 38% in non-OACrelated ICH
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Guidelines on oral anticoagulation: BJH 1998:101 (2), 374-387
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Guidelines on oral anticoagulation: BJH 2005:132,
277-85
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Recommendations for Managing Elevated INRs or Bleeding in
Patients Receiving VKAs*
Condition
Description
INR above therapeutic range but < 5.0; no significant
bleeding
Lower dose or omit dose, monitor more frequently, and resume at lower dose when
INR therapeutic; if only minimally above therapeutic range, no dose reduction
may be required (Grade 2C)
INR
5.0 but < 9.0; no significant bleeding
Omit next one or two doses, monitor more frequently and resume at lower dose when
INR in therapeutic range. Alternatively, omit dose and give vitamin K1 ( 5 mg
orally), particularly if at increased risk of bleeding. If more rapid reversal is
required because the patient requires urgent surgery, vitamin K1 (2 to 4 mg
orally) can be given with the expectation that a reduction of the INR will occur in
24 h. If the INR is still high, additional vitamin K1 (1 to 2 mg orally) can be given
(Grade 2C)
9.0; no significant bleeding
Hold warfarin therapy and give higher dose of vitamin K1 (5–10 mg orally) with the
expectation that the INR will be reduced substantially in 24–48 h. Monitor more
frequently and use additional vitamin K1 if necessary. Resume therapy at lower
dose when INR therapeutic (Grade 2C)
Serious bleeding at any elevation of INR
Hold warfarin therapy and give vitamin K1 (10 mg by slow IV infusion), supplemented
with fresh plasma or prothrombin complex concentrate, depending on the
urgency of the situation; recombinant factor VIIa may be considered as
alternative to prothrombin complex concentrate; vitamin K1 can be repeated
every 12 h (Grade 1C)
Life-threatening bleeding
Hold warfarin therapy and give prothrombin complex concentrate supplemented with
vitamin K1 (10 mg by slow IV infusion); recombinant factor VIIa may be
considered as alternative to prothrombin complex concentrate; repeat if
necessary, depending on INR (Grade 1C)
INR
Chest 126:204S–233S
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Objectives
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The Guidelines recommend the use of clotting factors PCC to
reverse OAC therapy in life-threatening hemorrhages
These guidelines appear to be poorly applied
 Two multicenter observational studies
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Management and prognostic features of intracerebral hemorrhage
during anticoagulant therapy: a Swedish multicenter study. Stroke
2001 Nov;32(11):2567-74
Sie P (2002) Prise en charge des surdosages en antivitamines K,
A propos d'une enquête observationnelle auprès de 70
établissements hospitaliers français. Urgence Pratique 54:3–5
reported:
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PCC was uncommonly used in major hemorrhages (<30%)
or was used with inadequate dosages
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Objectives
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The aim of the present study was to
evaluate the use of bolus infusion of PCC
and rapid management of patients with lifethreatening surgical OAC-related
intracranial hemorrhage.
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The Study
Question
 To evaluate the use PCC in life-threatening
surgical OAC-related ICH
Design
 Prospective observational study
Outcomes
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Short term: rapid anticoagulation reversal, speedy
surgery
Long term: Glasgow Outcome Scale (GOS) 6
months after the surgery
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Population
 Enrolment
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Neurosurgical ICU, university hospital (France)
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From May 2001 to January 2003
All patients >18years old admitted for OACrelated ICH & requiring urgent neurosurgery
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 Exclusion
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Patients with other hemostasis impairment or
platelet aggregation inhibitors treatment
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Intervention
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The PCC preparation (Kaskadil®, France):
20 IU/kg IV bolus (3min) of factor PCC & 5
mg of vit K was given through the NG tube
2 rapid (1min each) IV of PCC separated by
a 1-min interval (for intermediate blood
sampling)
The neurosurgical procedure was begun
immediately after the end of the 2nd infusion
without waiting for coagulation data.
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Intervention
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4 blood samples (on admission, immediately
after each bolus infusion 1min & 3min and
(6–12) h after AC reversal were collected to
measure PT, INR, factors (II, V, VII&X)
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Fibrinogen and platelet count were measured
at the time of admission and at least daily
during the ICU stay
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Results
Table 1: Individual demographic data
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Results
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The time between hospital admission
and normalization of coagulation was
110 ± 90 min
The time between hospital admission
and the start of the surgical procedure
was 193 ± 190 min
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Results
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Results
Table 2: Time profile of coagulation global indexes and factors on
admission and after reversal therapy
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Outcomes
 Primary outcome
 Coagulation is normalized immediately after
a bolus infusion of PCC
 Surgery can be started without delay
 Secondary outcome
 No clinical thrombotic events
 13 patients (73%) had good- moderate recovery
and only 4 patients (22%) had died during 6months period
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Conclusion
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A bolus infusion of PCC completely reverses
anticoagulation within 3 min.
Neurosurgery can be performed immediately
in OAC-related ICH.
This study shows that OAC–treated patients
can be managed as rapidly as non–
anticoagulated patients.
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Critical appraisal
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Are the results of the study valid?
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Small sample size
Single center
Prospective observational study
Included all varies types of ICH
Protocol violation( 5/18 (28%)didn’t receive vit. K)
Were the outcomes predefined? Yes
Was the follow-up long enough? Yes
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Critical appraisal
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Will the results help me in caring for my
patients?
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Can the results be applied to my patient care? No
Were all clinically important outcomes
considered? Probably ( short term didn’t look for
growth of hematoma)
Are the study conclusion benefits the treatment
costs? Yes
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Recombinant Activated Factor VII for
Acute Intracerebral Hemorrhage
NEJM 2005 Volume 352:777-785
Stephan A. Mayer, M.D., Nikolai C. Brun, M.D., Ph.D., Kamilla Begtrup, M.Sc., Joseph Broderick,
M.D., Stephen Davis, M.D., Michael N. Diringer, M.D., Brett E. Skolnick, Ph.D., Thorsten Steiner,
M.D., for the Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators
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Multicenter, double-blind study
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399 patients with spontaneous ICH (OAC excluded)
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Placebo (N= 96)
rFVIIa (N= 303) (108: 40 µg/Kg, 92: 80 µg/Kg, 103: 160
µg/Kg)
Primary outcome was the % change in the volume of
the ICH at 24 hr
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Recombinant Activated Factor VII for Acute
Intracerebral Hemorrhage NEJM 2005 Volume 352:777-785
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Increase in hematoma was
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Mortality at 90 days was
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29 % in the placebo group
16 % in the 40 µg/Kg group
14 % in the 80 µg/Kg group
11 % in the 103 µg/Kg group
29 % in the placebo group
18 % in the three rFVIIa groups combined (P=0.02)
Serious thromboembolic adverse events
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7 % rFVIIa group
2 % placebo group (P=0.12).
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Recombinant Activated Factor VII for Acute
Intracerebral Hemorrhage NEJM 2005 Volume 352:777-785
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Figure 1. Survival at 90 Days According to Study Group
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Recombinant Activated Factor VII for Acute
Intracerebral Hemorrhage NEJM 2005 Volume 352:777-785
Conclusions Treatment with rFVIIa within four hours
after the onset of intracerebral hemorrhage limits the
growth of the hematoma, reduces mortality, and
improves functional outcomes at 90 days, despite a
small increase in the frequency of thromboembolic
adverse events.
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Brown D. L., Morgenstern L. B.
N Engl J Med 2005; 352:828-830, Feb 24, 2005. Editorials
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The results of this trial are important but not clinically
directive
The exclusion criteria of the study were changed midway
through the trial because of concerns about safety
The highest dose of rFVIIa, 160 µg per kilogram, is
almost twice the amount given per dose to treat patients
with hemophilia
The treatment groups may not have been comparable in
terms of important factors known to be associated with
outcomes.
there was no adjustment for blood pressure in the
analysis of clinical outcomes in the trial
The lack of adjustment for the withdrawal of care
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Conclusion
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Further study of treating ICH with optimal
management of intracranial pressure,
surgical and medical treatments is warranted
Other trials of methods ( such as comparing
FVIIa/ PCC) to prevent rebleeding are
needed in the treatment of this common and
devastating disease
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Thank you
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