The management of cerebral hemorrhagic complications during anticoagulant therapy Maurizio Paciaroni Stroke Unit Division of Cardiovascular Medicine University of Perugia - Italy
Perugia Stroke Registry 2006-2014 (1 semester) 2218 strokes and TIAs 317 intracranial hemorrhages (14.3%) - 37 during warfarin (11.7%) - 2 during DAC In-hospital mortality: - 55/280 (19.6%) - 14/37 (38%) ICH during warfarin - 2/2 (100%) ICH during DAC 41%
ICH expansion in patients treated with warfarin and clinical outcome CHANT Investigators, Stroke 2009
Options for warfarin reversal Fresh Frozen Plasma Prothrombin Complex Concentrate Vitamin K Agents Doses Comments FFP 15 ml/kg Typically 4-6 units (200 ml) each are given or Prothrombin Complex 25-50 UI/kg Works faster than FFP but carries risk of DIC Concentrate and IV Vitamin K 10 mg Can take up to 24 h to normalise INR
Options for warfarin reversal Huttner et al, Stroke 2006: 37; 1465-1470
Prothrombin Complex Concentrate: potential advantages compared to Fresh Frozen Plasma faster correction of INR faster preparation rapid infusion (low volumes) - FFP 15ml/Kg - PCC ~ 2ml/Kg, bolus in 15 minutes low thrombotic risk ( 1%)
Prothrombin Complex Concentrate: thromboembolic risk
Prothrombin Complex Concentrate: practical use a. Suspend TAO and evaluate for INR b. Infuse Vit.K (5-10mg/100ml saline iv in 30 ) c. Infuse PCC in 15-20 - INR < 2 25 UI/Kg - 2 < INR < 4 35 UI/Kg - INR>4 50 UI/Kg d. Repeat INR after 20-30 min. e. Repeat the infusion of PCC if INR >1.4 Example: Patient 70Kg, INR 7 ------> infusion CCP 3500 UI = 7 bottles (140mL)
rfviia
Direct anticoagulants Apixaban Dabigatran Rivaroxaban Edoxaban
Intracranial Hemorrhage in AFib Patients During Anticoagulation With Warfarin or DOACs
Intracranial Hemorrhage in Atrial Fibrillation Patients During Anticoagulation With Warfarin or Dabigatran : The RE-LY Trial Mortality Dabigatran Dabigatran Warfarin 150 mg 110 mg All intracranial 36% (32/90) 35% (13/37) 41% (11/27) Intracerebral 41% (19/46) 64% (7/11) 64% (9/14) Hart RG et al, Stroke 2012
1 problem Quantify the effect of direct anticoagulants
Pharmacokinetic profile of DOCs: plasma concentration When was last dose administered? Tmax 2h 3h 3h
Quantifyng the anticoagulant effect of Direct Thrombin Inhibitors Van Ryn et al, Thromb Haemost 2010; 103: 1116-1127
Quantifyng the anticoagulant effect of Direct Thrombin Inhibitors Stangier J.. Presentation at Biomarkers Europe meeting, 5th November 2007, Vienna, Austria.
aptt Quantifyng the anticoagulant effect of Direct Thrombin Inhibitors Varies with different coagulometers Has different sensitivities for different reagents Often fails to reflect the amount of dabigatran administered High levels of aptt should be repeated or confirmed (es. TT, Hemoclot) Van Ryn et al, Thromb Haemost 2010; 103: 1116-1127
Quantifyng the anticoagulant effect of Direct Thrombin Inhibitors Van Ryn et al, Thromb Haemost 2010; 103: 1116-1127
aptt Quantifyng the anticoagulant effect of Direct Thrombin Inhibitors aptt normal (<1.5x): it is unlikely that an effect is present aptt 1.5-2: it is the expected anticoagulant effect (dabigatran 150 mg) aptt>80 sec (or 2-3 fold greater than the normal value): risk of overdose Van Ryn et al, Thromb Haemost 2010; 103: 1116-1127
Baglin, 2013
Quantifyng the anticoagulant effect of Direct Xa Inhibitors
Quantifyng the anticoagulant effect of Direct Xa Inhibitors Douxfils J et al, Thrombosis Research 2012: 130; 956-966
Suitable laboratory tests for rivaroxaban and clinical situations Chromogenic anti-factor Xa assay (with rivaroxaban calibrators) Acute renal failure Bleeding complications or thrombosis during treatment Emergency situations (if available in time): Prior to urgent surgery Life-threatening bleeding Stroke (if fibrinolytic treatment indicated) Acute percutaneous coronary intervention (if heparin bolus indicated) Overdose Suspected accumulation of drug Prothrombin time test (with rivaroxaban-sensitive reagent) Emergency situations when an anti- Factor Xa assay is not available Normal PT can indicate intact haemostatic function Samama et al. Thrombosis Journal 2013 11:11
Baglin, 2013
2 problem How to reverse the anticoagulant effect of direct anticoagulants
Dabigatran reversal agents In a rat tail model of template bleeding, adding apcc, lead to a significant reduction in the prolongation of bleeding time (BT) effects associated with high-dose dabigatran. No effect on aptt. In a rat tail model of template bleeding, adding rviia (0.1 or 0.5 mg/kg) significantly reduced BT and prolongation of aptt associated with high dose dabigatran. van Ryn J et al. Haematologica 2008; 93 (Suppl 1): 148.
Healthy volunteer study: immediate, complete, and sustained reversal of dabigatran anticoagulation End of idarucizumab injection (5 min infusion) 70 dtt (s) 65 60 55 50 45 Dabigatran + placebo Dabigatran plus: Placebo (n=9) 1 g idarucizumab (day 4) (n=9) 2 g idarucizumab (day 4) (n=9) 4 g idarucizumab (day 4) (n=8) Normal upper reference limit (n=86) Mean baseline (n=86) 40 35 30 2 0 2 4 6 8 10 12 24 36 48 60 72 Time after end of infusion (hours) Dabigatran Antidote Idarucizumab is currently in development and is not approved for use in any country. The information presented here is intended for medical education purposes only Normal upper reference limit refers to (mean+2sd) of 86 predose measurements from a total of 51 subjects Glund S et al. AHA 2013; abstract 17765
Study to evaluate reversal of the anticoagulant effects of dabigatran with idarucizumab in: Bleeding patients overt bleeding judged by the physician to require a reversal agent Surgical patients require an emergency surgery or procedure for a condition other than bleeding Started in April 2014, currently recruiting in >35 countries worldwide Idarucizumab is currently in development and is not approved for use in any country. The information presented here is intended for medical education purposes only NCT02104947: Available at http://www.clinicaltrials.gov/ct2/show/nct02104947; Accessed August 2014
Efficacy Endpoints: Primary: Maximum reversal of anticoagulation activity of dabigatran based on central lab measurements of dtt or ECT at any time point from the end of the first infusion up to 4 hours after the completion of the second infusion.
Dabigatran and renal function
Dabigatran and hemodialysis: reduction 60-69% in 4 hours
Rivaroxaban reversal effects No standard antidote available to reverse rivaroxaban effects Two molecules under clinical development: BAY1110262 (Bayer) PRT064445 (Portola Pharmaceuticals)
Rivaroxaban Use of procoagulant agents - PCC PT (protrombine time, in seconds) Post-Rivaroxan: Significant PT prolungation 15,8±1,3 vs 12,3±0,7 seconds compared to controls (p<0,001) Post-infusion PCC (4 factors): Complete normalisation 12,8±1,0 seconds (p<0,001) after 15 min for 24 h Eeremberg et al., Circulation 2011
Rivaroxaban Use of procoagulant agents - apcc " In vivo pre-clinical studies have demonstrated that activated Prothrombin Complex Concentrate, can reverse the effect of rivaroxaban Elisabeth Perzborn, Hanna Tinel: 20th International Congress on Thrombosis (ICT), 2008
Apixaban " Monitoring: No routine monitoring is required Anti factor Xa assay Linear relationship between apixaban plasma concentration and factor Xa inhibition No standardized assay Prothrombin time/inr " Reversal agent: No standard antidote investigational agent PRT064445: designed to reverse the actions factor Xa inhibitors. Prothrombin complex concentrates (theoretical) Recombinant factor VII (theoretical) Activated charcoal (preclinical study- reduced apixaban exposure)
1. Discontinue DOAC Summary 2. Administer active carbon: - within the first 2 h after the last intake of dabigatran or rivaroxaban - within 3 h for apixaban, 3. Administer a dose of 35 50 U/kg PCC iv. In the absence of effect, further administration of activated prothrombin complex concentrate (apcc) or recombinant coagulation factor VIIa (rfviia) should be considered 4. Lower blood pressure to below 140 mmhg Steiner et al. 2013 Clin Res Cardiol
irect Thrombin Inhibitors Direct Xa Inhibitors Tranexamic acid: 1gr iv + infusion 1 mg/kg/h
Clinical outcome 3 problem
FAST trial
FAST trial
CanPro Registry 141 cases of TAO related ICH treated with PCC 79.5% INR<1.5 within 1 h Mortality 42.3% Re-bleedings 45.5% Thromboembolic complications 3/141 (2%) within 7 days Dan Dowlasthaki et al Stroke 2012; 43: 1812-1817
Conclusions Warfarin To immediately reverse INR: prothrombin complex concentrates (PCC) are preferred over fresh frozen plasma (FFP). Vitamin K is needed to sustain any reversal following PCC or FFP. Data from randomised trials are not available
Direct anticoagulants Conclusions In the case of a major acute bleeding during DOAC, aptt and TT need to be measured for direct thrombin inhibitors, whereas PT and anti-xa level need to be measured for factor Xa inhibitors. Dialysis should be considered for thrombin inhibitors. PCC should be considered for reversing the anticoagulant effect of direct thrombin inhibitors (in the absence of effect: apcc or rfvii). PCC should be considered for reversing the anticoagulant effect of factor Xa inhibitors (in the absence of effect: apcc or rfvii). Specific antidotes for the DOACs need to be developed.