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Ultra-rapid management of oral anticoagulant therapy-related surgical intracranial hemorrhage Intensive Care Medicine (2007) 33:721-725

Zohra Daw, MD, FRCPCTransfusion Medicine resident, University of OttawaTMR Journal ClubJune13,2007

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Introduction

OAC therapy increases the risk of major hemorrhage by 2.4-8% per patient-year

Rate of intracranial hemorrhage nearly 1% per patient-year and an estimated 60% mortality rate

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Traumatic VS OAC ICH

The critical factor with ICH is the speed of treatment 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-OAC-related 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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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)

INR   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)

Recommendations for Managing Elevated INRs or Bleeding in Patients Receiving VKAs*

Chest 126:204S–233S

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Objectives 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 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: PCC was uncommonly used in major hemorrhages (<30%) or was used with inadequate dosages

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Objectives

The aim of the present study was to evaluate the use of bolus infusion of PCC and rapid management of patients with life-threatening surgical OAC-related intracranial hemorrhage.

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The Study

Question To evaluate the use PCC in life-threatening

surgical OAC-related ICHDesign Prospective observational study Outcomes

Short term: rapid anticoagulation reversal, speedy surgery

Long term: Glasgow Outcome Scale (GOS) 6 months after the surgery

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Population

Enrolment Neurosurgical ICU, university hospital (France) From May 2001 to January 2003 All patients >18years old admitted for OAC-

related ICH & requiring urgent neurosurgery

Exclusion Patients with other hemostasis impairment or

platelet aggregation inhibitors treatment

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Intervention

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

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)

Fibrinogen and platelet count were measured

at the time of admission and at least daily during the ICU stay

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Table 1: Individual demographic data

Results

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Results

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 6-months period

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Conclusion

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

Are the results of the study valid? 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

Will the results help me in caring for my patients? 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 HemorrhageNEJM 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

Multicenter, double-blind study 399 patients with spontaneous ICH (OAC excluded)

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

Increase in hematoma was 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

Mortality at 90 days was 29 % in the placebo group 18 % in the three rFVIIa groups combined (P=0.02)

Serious thromboembolic adverse events 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

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 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

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