Is It Just Me or Is Every *#%& Trauma Patient on a Blood Thinner??? Rapid Reversal of Anticoagulation

Is It Just Me or Is Every *#%& Trauma Patient on a Blood Thinner???

Rapid Reversal of Anticoagulation

Disclosures• I have no financial disclosures or conflicts.

• I will be discussing the use of medications in non-approved and off-label use in this presentation

• All medication doses mentioned should be confirmed by practitioners prior to use should they decide to use them.

Morbidity and Mortality Weekly Report Recommendations and Reports / Vol. 61 / No. 1 January 13, 2012 Guidelines for Field Triage of Injured Patients Recommendations of the National Expert Panel on Field Triage, 2011 Anticoagulation and Bleeding Disorders: Patients with Head Injury Are at High Risk for Rapid Deterioration: Criterion Modified

The Panel modified this criterion to highlight the potential for rapid deterioration in anticoagulated patients with head injuries. Anticoagulation use has been associated with an increased risk for intracranial hemorrhage following head injury and longer hospital stays

FDA News ReleaseFDA approves anti-clotting drug SavaysaDrug approved to treat atrial fibrillation, deep vein thrombosis, and pulmonary embolismFor Immediate ReleaseJanuary 8, 2015

NOT Such A GREAT LEAP FORWARD IN THE

MANAGEMENT OF ATRIAL FIBRILLATION

Epidemiology of AnticoagulationA Fib

• Atrial Fibrillation(AF) incidence increases with age and increases stroke risk X 5 – Responsible for 20% of strokes

• 59% have major functional disability

– ~3 million currently affected (8% age 80 and above)– 2050 estimated to be >50 million people with AF– 4.5% annually will have a stroke

• 1.5% below age 60, 23% over 80

• Worldwide sales of anticoagulants are expected to double from 2011-2018

• CDC

Epidemiology of anticoagulationDVT

• 60-100K deaths/yr from PE/DVT• 10-30% die within first month following Dx• Sudden death first symptom in 25% of PE• 50% with DVT will have long term Sx• 1/3 with DVT will recur within 10 years• 5-8% of the population have have an

inherited thrombophilia• CDC

Hans Tapper, and Heiko Herwald Blood 2000;96:2329-2337

©2000 by American Society of Hematology

Common Oral Anticoagulants and Antiplatelet Drugs

• Vitamin K inhibitor– Warfarin (Coumadin)

• Direct thrombin inhibitor– Dabigatran (PRADAXA)

• Direct factor Xa inhibitors– Rivaroxiban (XARELTO)– Apixaban (ELIQUIS)– Edoxaban (SAVAYASA)



• Direct thrombin inhibitor– dabigatran (PRADAXA)


Novel Oral AnticoagulantsNOACs

Target-SpecificOral AnticoagulantsTSOACs

Coagulation CascadeOral Inhibitors





• Cyclooxgenase inhibitor– ASA

• Trifusal (DISGREN)

• ADP receptor inhibitors– Clopidogrel (PLAVIX)

• Parasugrel (EFFIENT)• Ticagrelor (BRILINTA)

– Tilopidine (TICLID)

• PAR-1 inhibitors– Vorapaxar (ZONTIVITY)





• Cyclooxgenase inhibitor– ASA

• Trifusal (DISGREN)

• ADP receptor inhibitors– Clopidogrel (PLAVIX)

• Parasugrel (EFFIENT)• Ticagrelor (BRILINTA)

– Tilopidine (TICLID)

• PAR-1 inhibitors– Vorapaxar (ZONTIVITY)

Platelet Activation

Why would you ever need to reverse therapeutic anticoagulation?

Reversal of AnticoagulationLIFE THREATENING OR SERIOUS BLEEDING

• Actually reverse – Warfarin only

• Remove the drug– Bind in GI tract– dialysis (dabigatran only)

• Slow fibrinolysis• Increase Factor levels to overcome block

– May get clot where you don’t want it!

Reversal of Anticoagulation

• Rapid restoration of normal coagulation– Decreased blood loss– Ability to manage injuries non-operatively– Critical volume compartments

• Problems with reversal– Direct effects

• Volume overload with blood products

– Indirect effects• Native disease requiring anticoagulation

Reversal of AnticoagulationOnly if the risk of reversal < the benefit!

Other reasons to bleed (uremia, cirrhosis…)?How much and where is the bleeding?

Is the bleeding active?Is it in a critical area?Is there an available mechanical intervention?

What medication(s) are they taking?Why are they taking it?When did they last take it?

Any recent physiologic changes (renal dysfunction)?How thin has the blood thinner made them?

Can I figure this out?

Antiplatelet agents

• ASA– Irreversible platelet effect– 4 days expected– > risk of surgical bleeding X 1-5 fold– Doesn’t increase severity of most bleeding

• 10% of acute cardiac events preceded by ASA withdrawal before surgery

– Bleeding time, PFA, TEG with platelet assay• Not sure what it means

– We usually treat for TBI pt with DDAVP• Platelet transfusion as necessary

Antiplatelet agents

• Clopidagrel (plavix)– P2Y12 inhibitor (ADP inhibition on assays)– 5-7 days of inhibition

• Generally enough around to inhibit new platelets– Need more transfused platelets as a result

– DDAVP shortens bleeding time– Generally do treat plavix patients with significant

injury

Warfarin (Coumadin)

• Oldest and best studied agent

Vitamin K

Warfarin (Coumadin)• Oldest and best studied agent• Inhibits your ability to recycle Vitamin K

– Depletion limits production of Factors• II, VII, IX, & X

• Extrinsic Pathway• Testing with PT/INR• Daily dose• Frequent testing• Multiple confounding factors

– A salad a day will not keep the doctor away

Narrow therapeutic window

Warfarin (Coumadin)

Factors II, VII, IX & X

Death and Disability from Warfarin-AssociatedIntracranial and Extracranial Hemorrhages

Margaret C. Fang, MD, MPH,a Alan S. Go, MD,a,b,c Yuchiao Chang, PhD,d Elaine M. Hylek, MD, MPH,eLori E. Henault, MPH,e Nancy G. Jensvold, MPH,c Daniel E. Singer, MDd

[Am J Med], ISSN: 1555-7162, 2007 Aug; Vol. 120 (8), pp. 700-5

• 13,559 pts non-valvular AF on warfarin– 72 intracranial & 98 major extracranial bleeds– 76% with ICH had severe disability or died– 3% with major extracranial bleed died

• 88% of deaths in 30 days were ICH– Intracerebral 60%– Subdural 27%

• Intra-cranial hemorrhage caused 90% of deaths from warfarin associated bleeding

• Increased fall risk Medicare pt = increased TBI risk– Warfarin probably preferred given reversibility– 13.7/100 year stroke rate

Warfarin Reversal• ONLY antithrombotic with an “antidote”

– Vitamin K will fully reverse• 5-10 mg slow IVP

– NOT FOR 12-24 HOURS• Time to manufacture the enzymes• Will make later resumption of warfarin difficult

• Vitamin K given for any reversal effort– ½ life of other agents< that of warfarin– Vitamin K gives sustained reversal

• In critical bleeding, Vitamin K alone is worthless– Must give other more immediate agents– Never the less, give it!

• We can measure and follow the reversal (PT/INR)

Warfarin Reversal Options:Along with VK FFP

• Contains Factors II, VII, IX and X• FFP Advantages

– Has all 4 factors– Widely available– Familiar product– Relatively inexpensive

• Disadvantage– Time to thaw, check compatibility and infuse– Need 8 or more units to reverse (1.5-2 liters, acutely)

• 15 ml/kg starting dose

Warfarin Reversal Options:Along with V K PCC

• Unactivated Prothrombin Complex Concentrate– 3 Factor PCC (Profilnine and Bebulin)

• II, IX and X (minimal VII)• Need to give FFP (~2 units) for VII replacement• rFVIIa not recommended

– 4 Factor PCC (Kcentra)• All 4 factors

• Disadvantages– Cost– Availability– Thrombosis

• No good data on outcomes 3 vs 4 factor• Per kg X INR or one time dose dose

NOACs

• Can’t pronounce them• Can’t keep up with them• Can’t afford them• Can’t reverse them• Can’t measure them

– Abnormal/ prolonged aPTT, PT, TT – Consistent with continuing effect– Unfortunately, normal doesn’t mean there is no effect– Lab results or trends don’t really prove reversal– Manage the patient!

NOACsDabigatran

NOACsDabigatran

• Approved in US 2010– AF and DVT/PE

• Not for valves

– No lab monitoring or dose manipulation• PT calibrated for warfarin so meaningless• aPTT may be qualatative

– ½ life 12-17 hour with normal renal function– NO REVERSAL AGENTS

NOACsDabigatran… and Bleeding

• Activated charcoal if with a few hours of last dose• Dialysis can remove active drug (up to ½ of circulating

drug)***• FFP

– Does not work.– May still be needed as competent therapy during massive

transfusion• PCCs may help

– Risk of thrombosis – critical bleeding– aPCC (factor VII inhibitor activity bypassing agent)FEIBA

• VII already in active form


• Don’t forget the other side of the equation…Fibrinolysis

• Tranexamic acid (TXA)– Well studied in military and cardiac surgery– 10-20 mg/kg bolus; 10 mg/kg IV q 6-8 hours

• Renal excretion

• ε-aminocaproic acid– 2 gm IV q 6h (up to 1 gm/hr can be given)


• DDAVP – 0.3 mcg/kg IVPB once

• Releases von Willibrand’s Factor from endothelial cells• Binds to F VIII and improves platelet adhesion

– Takes time to remanufacture– Watch for hyponatremia


• STOP THE BLEEDING MECHANICALLY IF POSSIBLE!– Tourniquet– Pelvic binder– Direct pressure– Topical hemostatics– Embolization– Suture– Operate

NOACsFactor Xa “-bans” …and Bleeding

NOACsFactor Xa “-bans”

• Rapid onset of effect• ½ life 7-12 hours• Renal excretion but protein bound

– Can not dialyze off• No monitoring or dose adjustments

– Interaction with cytochrome P450• No food interactions• aPTT may be affected in a dose-dependent manner

– Different assays and different reagents give variable results

NOACsFactor Xa “-bans”… AND BLEEDING

• Activated charcoal if with a few hours of last dose• Dialysis DOES NOT HELP***• FFP

– Does not work.– May still be needed as competent therapy during massive

transfusion• PCCs may help

– Risk of thrombosis – critical bleeding– aPCC (factor VII inhibitor activity bypassing agent)FEIBA

• VII already in active form

NOACsFactor Xa “-bans”… AND BLEEDING

• Don’t forget the other side of the equation…Fibrinolysis

• Tranexamic acid (TXA)– Well studied in military and cardiac surgery– 10-20 mg/kg bolus; 10 mg/kg IV q 6-8 hours

• Renal excretion

• ε-aminocaproic acid– 2 gm IV q 6h (up to 1 gm/hr can be given)


• STOP THE BLEEDING MECHANICALLY IF POSSIBLE!– Tourniquet– Pelvic binder– Direct pressure– Topical hemostatics– Embolization– Suture– Operate


• DDAVP – 0.3 mcg/kg IVPB once

• Releases von Willibrand’s Factor from endothelial cells• Binds to F VIII and improves platelet adhesion

– Takes time to remanufacture– Watch for hyponatremia

Multi-tasking

Dabigatran-associated subdural hemorrhage: using thromboelastography (TEG®) to guide decision-making

Ron Neyens1, Nicole Bohm2 , Madelyne Cearley1, Charles Andrews3 and Julio Chalela3

Journal of Thrombosis and Thrombolysis A Journal for Translation, Application and Therapeutics in Thrombosis and Vascular Science, Published online: 11 May 2013

• Pradaxa presents uncertainties – Lack of an assay to quantify degree of anticoagulation– Absence of a proven antidote

• aPTT, PT slightly elevated. TT >50 sec• FEIBA given X 2 for TT still >50 sec

– TEG with Nl R, Nl K, Nl α angle and Nl MA– Uneventful evacuation

• Identified adequate polymerization of fibrin– In vitro

http://link.springer.com/article/10.1007/s11239-013-0933-9/fulltext.html

Monitoring of dabigatran anticoagulation and its reversal in vitro by thrombelastographySasha Solbeck, Martin A.S. Meyer, Pär.I. Johansson, Anna Sina P. Meyer

International Journal of CardiologyVolume 176, Issue 3, 20 October 2014, Pages 794–799

• dabigatran changed all TEG parameters for both CK and CKH in a hypocoagulable direction corresponding to increased R time and reduced angle, A5, A10, MA, and MRTG; all p < 0.05

Abstract W P58 : Thromboelastography Can Detect the Anticoagulant Effect of Factor Xa Inhibitors in Patients Who Might Be Eligible for Tissue Plasminogen Activator Treatment for Acute Ischemic Stroke

Ritvij Bowry, Stuart Fraser, et. al International Stroke Conference Poster Abstracts

• Higher R values were seen from baseline to 18 hours, lower, G, MA, and alpha angle values were present for 4 hours

NOACsGood news

The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis

Chatree Chai-Adisaksopha, Mark Crowther, Tetsuya Isayama, and Wendy Lim

October 9, 2014; Blood: 124

• Meta-analysis of 12 anticoagulation RCTs with >100,000 patients

• Warfarin had a low incidence of fatal and intracranial bleeding (0.52% and 1.08%).

• TSOACs risk of major bleeding (RR0.72), fatal bleeding (RR 0.53) and intracranial bleeding (RR 0.43) is significantly less– Consistent with previous systematic reviews

• Postulates that warfarin causes greater thrombin suppression in the brain

Efficacy and Safety of the New Oral Anticoagulants Dabigatran, Rivaroxaban, Apixaban, and Edoxaban in the Treatment and Secondary Prevention of Venous Thromboembolism: A Systematic Review and Meta-analysis of Phase III Trials

S. K. Kakkos, G. I. Kirkilesis, I. A. Tsolakis European Journal of Vascular and Endovascular Surgery 48 (5), November 2014, pp565–575

• 10 RCTs, 3800 patients• Fatal bleeding 0.09% vs 0.18%• Increase in relevant non-major bleeding but not

major bleeding– 4.3% vs 1.8%

• Compared to VKAs, NOAs are not only effective in treating VTE but also safer in terms of bleeding, thereby conferring clinical benefit. Their safety and efficacy was confirmed further in secondary prevention trials.

Perspective

Effect of four factor prothrombin complex concentrate on in-hospital mortality in patients with an intracranial hemorrhage on oral

anticoagulation

Poster #: 9-284

Baylor University Medical Center; Dallas, TX

Sarah Harrison, PharmD; Kelsey Kohman, PharmD, BCPS; Jennifer Roth, PharmD, BCPS; Shreya Goyal; John Garrett, MD

Baylor Healthcare System Reversal Guideline

INR < 1.4 INR ≥ 1.4

INR 1.4-3.9 INR 4.0-5.9

INR ≥ 6.0

Both within normal range

YesNo or

Unknown

Intracranial Hemorrhage with Current Oral Anticoagulant

Therapy

Vitamin K Antagonists:

Warfarin

Measure PT/INR

Reversal Not

Indicated

4F-PCC 25

units/kg

4F-PCC 35

units/kg

4F-PCC 50

units/kg

Reversal Not

Indicated

Did patient take medication

within past 24 hours?

Direct Thrombin Inhibitors: Dabigatran

Factor Xa Inhibitors:

Rivaroxaban, Apixaban

Administer: 4F-PCC and Vitamin

K 10 mg IV

Either aPTT or PT > normal

Measure aPTT/PT

Did patient take medication

within past 2 hours?

Administer Activated

Charcoal 1g/kg PO

Consider Hemodialysis

with Dabigatran

Yes

No

Final Jeopardy for Anticoagulation

• Increasing use in the population– Generally poorly educated about complications– Be suspicious

• NOACs generally “safer” than warfarin– Fewer spontaneous ICH and other bleeding– Easier to take

• No labs or monitoring

– Shorter half life• Supportive care usually works• No “antidote” yet


• Risk of reversal should not be worse than risk of bleeding… A threat to life.– Where possible, stop the bleeding mechanically– When not, attack the bleeding aggressively and

appropriately• Warfarin

– Vitamin K is required but does not reverse NOW– FFP works but takes time and volume– PCC (now 4 factor) is expensive

• But it works!• Fast!


• NOACs will become increasingly common– Abnormal coagulation labs mean something

• Normal studies in a bleeding patient mean ??• TEG MAY give an indication of actual disruption in physiologic

clotting

– PCC and aPCC seem to help in critical situations– Reducing fibrinolysis is generally safe (TXA, e-ACA)– Increasing platelet adhesion may decrease blood loss

(DDAVP)– Reduce drug levels with activated charcoal – Reduce dabigatran with dialysis


• Antiplatelet agents– DDAVP to increase vWB factor– Transfuse platelets as needed

• Likely need more than you think?

– Platelet function studies may or may not predict degree of bleeding.

Documents

Is It Just Me or Is Every *#%& Trauma Patient on a Blood Thinner??? Rapid Reversal of Anticoagulation