1 Ultra-rapid management of oral anticoagulant therapy- related surgical intracranial hemorrhage Intensive Care Medicine (2007) 33: Zohra Daw, MD, FRCPC Transfusion Medicine resident, University of Ottawa TMR Journal Club June13,2007

2 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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4 Traumatic VS OAC ICH The critical factor with ICH is the speed of treatment  In traumatic subdural hematoma, mortality increases from 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

5 Guidelines on oral anticoagulation: BJH 1998:101 (2),

6 Guidelines on oral anticoagulation: BJH 2005:132,

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8 Table 6. Recommendations for Managing Elevated INRs or Bleeding in Patients Receiving VKAs * ConditionDescription 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

9 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): 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

10 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.

11 The Study Question To evaluate the use PCC in life-threatening surgical OAC-related ICH Design Prospective observational study Outcomes  Short term: rapid anticoagulation reversal, speedy surgery  Long term: Glasgow Outcome Scale (GOS) 6 months after the surgery

12 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

13 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 2 nd infusion without waiting for coagulation data.

14 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

15 Table 1: Individual demographic data Results

16 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

17 Results

18 Results Table 2: Time profile of coagulation global indexes and factors on admission and after reversal therapy

19 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

20 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.

21 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

22 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

23 Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage NEJM 2005 Volume 352: 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

24 Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage NEJM 2005 Volume 352: 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).

25 Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage NEJM 2005 Volume 352: Figure 1. Survival at 90 Days According to Study Group

26 Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage NEJM 2005 Volume 352: 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.

27 Brown D. L., Morgenstern L. B. N Engl J Med 2005; 352: , Feb 24, 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

28 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

29 Thank you