Emergency anticoagulant reversal B Vigué, DAR, CHU Bicêtre

1 to 2% of the population are prescribed VKA (Vitamin K Antagonist) - Annual incidence of hemorrhage is 4 to 13% [Hylek, Circulation, 2003] In France admissions per year in Emergency Department (ED) for bleeding under VKA (Sié 2002). In 2 month in a french universitary ED: 198 major bleedings, 34 for intracranial bleedings INR>5 : 150 to 450 cas in french county EDs Risk for intracranial haemorrhage: 1% per year

VKA decreases thrombotic risk - Cardiac Valves : Stroke : 4% / patient - year Aspirine : 2,2% / patient - year VKA : 1% / patient - year - Auricular Fibrillation Stroke around 4% / patient - year - Phlebitis and pulmonary embolism

Risk of VKA therapy VKA increases the risk for intracranial bleeding 7 to 10 fold Incidence : 0.3 to 1% per year Mortality: 60% VKA + intracranial haemorrhage expansion = 50% No VKA + intracranial haemorrhage expansion = 10% Risk factors for bleeding under VKA INR in over therapeutic zone (>4-5) HTA Starting treatment (first 3 month)

As soon as possible!!

FFP : fresh frozen plasma Risk of TRALI PCC (Prothrombin Complex Factor) : 4 factors superior to FFP No delay to normalize 60 ml of PCC = 2000 ml of FFP But factor VII 1/2 life = 5-6 hours Vitamin K : Delayed correction = 6 to 8 hours to be effective Which dose? Delayed correction No randomized trial

Thromb Haemost, 1997, United Kingdom 41 patients Retrospective study PCC : U IX / kg vs FFP (800ml) Vitamine K in all cases (1-5 mg IV) In 15 min : complete reversal for 28/29 patient with PCC and for 0/12 patients for PFC

60 ml PCC = 2000 ml of FFP

PCC superior to FFP for emergency reversal of VKA Needing of effective availability in all hospitals Administration «as soon as diagnostic confirmed»

Guidelines PCC(20-30 UI/kg) + Vitamin K (5-10 mg)

In France : management of INR in over therapeutic zone in cas of bleeding (n=198) Intravenous vitamine K alone = 44% Oral vitamine K alone = 5% Intravenous vitamin K = 41% PCC in association = 29% PCC alone = 7% FFP = 25% Under dosing of PCC (15 UI/kg instead of 20-30) Discrepancy between guidelines and reality (fear of thrombotic events, availability of product) Sié, 2002

PCCs are the most accurate solution to reverse anticoagulation Fact and hypothesis Intracranial bleeding under VKA : 50% mortality during the first month Stroke, 2001 Thromb Haemost, 1997 Delayed management could impair the prognosis “You wouldn't say that if you had seen a valve thrombosis”

To evaluate the rapidity of correction of INR after administration of PCC during the managment of neurosurgical bleeding Aim of the study

Methods Rapid intravenous administration (1 min) of two 2 doses of PCC (10 U/kg) Begining of surgical procedure immediately after Preparation of the operative room, installation of patient for craniotomy before any laboratory results or administration of PCC Laboratory study: PT and INR before infusions, between infusions, immediately after and 6 hours later Administration of oral vitamin K, 5 mg Inclusion criteria : patients under VKA admitted for intracranial bleeding requiring a neurosurgical procedure

Methods Emergency situation Be aware of pressure Come back to real risk Come back to the basics Create an emergency situation, a golden hour All are involved; emergency physicians, surgeons, anaesthesists, nurses Preparation of the operative room, installation of patient for craniotomy before any laboratory results or administration of PCC

Rapid intravenous administration (1 min) of two 2 doses of PCC (10 U/kg) Methods Dose of PCC: INR between 2 and 3,5 : administration of 10 to 20 UI/kg of factor IX to limit the thrombotic risk In INR in over therapeutic zone, 20 to 30 UI/kg of factro IX (25 UI/kg =1 ml /kg of factor IX) Administration: Rate of infusion slower than 4 ml/min : 68/4 = 17 mins !! Do not wait for laboratory control of reversal!

Laboratory study: PT and INR before infusions, between infusions, immediately after and 6 hours later Methods Do not wait for laboratory control of reversal! A race against time A place for bedside monitoring?

Methods Administration of oral vitamin K, 5 mg Oral vitamin K, efficiency to reverse anticoagulation in 6 to 12 hous (Br J of Haematology, 2001) Oral vitamin K, superior to sub-cutaneous vitamin K to reverse anticoagulation (Ann Intern Med, 2001) Oral vitamin K, equivalent to intravenous vitamin K to reverse anticooagulation (Ann Intern Med, 2003)

Results 18 patients included 12 subdural haematoma, 6 intracerbral haematoma No thrombotic complication Outcome : 13 patients with GOS 1 to 1, 4 patients died (23%)

SexeAge Reason for VKAGCSVolumeDose/kgGOS 1 F80FA146020,01 2 M73FA98022,52 3 M81FA96020,01 4 F71PHV66021,45 5 F71VTE66021,41 6 M62atherom108020,01 7 M82atherom67022,51 8 F54FA76025,02 9 M58PHV38020,05 10 F86AVC66030,02 11 F70FA86021,45 12 M56FA F73FA M58PHV F70FA M62VTE M78PHV F86VTE560225

admission1 min2 min6-12 h PT (%)20±962±1478±1566±17 PT (sec)40±2214±212±213±2 TCK (sec)53±1541±1040±1137±5 TT (sec)20±520±421±518±4 V (%)111±25107±25109±23111±25 II (%)33±2370±2094±2187±22 VII+X (%)15±1057±1578±1765±30 Results INR3,95±1,611,39±0,271,18±0,151,34±0,27

Results * * *

Progressive reinitiating of anticoagulation, No thrombotic event

Discussion 23% patients died (30 to 60 % in our litterature analysis) The gain of time improves the management of the urgent neurosurgery. No laboratory control are needed to begin the surgical procedure Think for vitamin K !!

Discussion Why PCC is not currrently used ?…

Conclusion (1/3) Ultra rapid reversal of anticoagulation without thrombotic events VKA reversal improves time to surgical procedure Outcome? Mortality?

Conclusion (2/3) There is no way to delay surgery Life-threatening events All urgent surgery (as peritonitis…) there is no way to delay the reversal of VKA Lost time +++ if life-threatening bleedings : intracranial and others Lost time +++ if major bleedings in EDs

Conclusion (3/3) Need of teaching program : fight against non scientific historic fears. Need of multicentric trials in France and Europen. Evaluate the acccuracy and the safety of PCC. Show PCC as an antidote As malignancy hyperthermia in anaesthesia care, organize the management of bleeding under VKA with standardized written procedure.

As soon as diagnosis confirmed

As soon as possible