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NEW ORAL ANTICOAGULANTS�(TARGET SPECIFIC ANTICOAGULANTS)

BY

MOHAMED ISMAEIL, MD

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DISCLAIMER

Today’s speaker did not receive financial support from nor have any commercial relationship with any drug or equipment product manufacturers or vendors that may be mentioned or displayed in the course of the presentation.

There is NO mention of off label use of equipment or medications mentioned in this presentation.

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OBJECTIVES

1- Physiology of hemostasis and coagulation

2-Pharmacological aspects of new oral anticoagulants

3- Impact of the new oral anticoagulants on anesthesia practice

4-Management of complications related to the new oral anticoagulants

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WHY PATIENTS USE OR WILL USE ANTICOAGULANTS?

Mechanical heart valves.

Cardiac arrhythmias.

Prophylaxis for deep venous thrombosis (DVT), pulmonary embolism and other thromboembolic events which are commonly associated with surgical procedures.

Treatment of acute thromboembolic events

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CONSEQUENCES OF THROMBUS

consequences

angina

Myocardial infaction

stroke

Deep venous thrombosis

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HEMOSTASIS

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HEMOSTASIS

HEME= BLOOD

STASIS= TO HALT

PROCESS OF RETAINING BLOOD WITHIN THE VASCULAR SYSTEM

REPAIRS INJURY TO BLOOD VESSELS

STOPS OR PREVENTS BLOOD LOSS

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COMPONENTS OF HEMOSTASIS

Vascular System

Controls rate of blood flow

Platelet System

Interaction of vasculature and platelets form a temporary plug

Coagulation System

Forms a stable insoluble plug (i.e) fibrin forming

Fibrinolytic System

Fibrin lysing

Coagulation Inhibition System

Natural inhibitors
Control fibrin formation and fibrin lysis

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HEMOSTASIS

Vessel Injury

Platelet

Activation

Platelet

aggregation

Blood Vessel

Constriction

Coagulation

Activation

Stable Hemostatic Plug

Fibrin clot

Reduced

Blood flow

Tissue Factor

Primary hemostatic plug

Neural

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Steps in Hemostasis

A. Vasoconstriction

B. Primary hemostasis (Platelet plug formation)

C. Secondary hemostasis (Fibrin clot formation)

D. Clot Retraction

E. Clot Dissolution

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A. VASOCONSTRICTION

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B. Primary Hemostasis: Platelets

latelet

adhesion

vWF

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C. Secondary Hemostasis: The Clotting Mechanism

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COAGULATION

Coagulation is a complex process by which blood forms clots.

Coagulation begins almost instantly after an injury to the blood vessel has damaged the endothelium (lining of the vessel).

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COAGULATION

A highly regulated cascade of reactions that form a variety of products involved in hemostasis

Participants include:
– Enzymatic coagulation factors
– Non-enzymatic co-factors

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ENZYMATIC COAGULATION FACTORS

Proenzymes: Plasma proteins that circulate in inactive form; produced mainly in hepatocytes

Upon activation, they gain the suffix “a”; Prekallikrein is an exception, the activated form is called kallikrein

Production of some proenzyme factors is vitamin-K dependent – Factors II, VII, IX, X

These factors bind Ca+2 to allow critical interactions with phospholipid membranes

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Factor Common Name

Number

I Fibrinogen

II Prothrombin

III Tissue Factor

IV Ca2+

Va Proaccelerin

VII Proconvertin

VIII Antihemophilic Factor

IX Christmas Factor

X Stuart Factor

XI Plasma thromboplastin antecedent

XII Hageman factor

XIII Fibrin Stabilizing Factor

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COAGULATION FACTORS

FACTORS	PLASMA t ½ (hrs)
Fibrinogen (I)	72-120
Prothrombin (II)	60-70
V	12-16
VII	3-6
VIII	8-12
IX	18-24
X	30-40

FACTORS	PLASMA t ½ (hrs)
XI	52
XII	60
Protein C	6
Protein S (total)	42
Tissue factor	--
Thrombomodulin	--
antithrombin	72

Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

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SECONDARY HEMOSTASIS�THE COAGULATION CASCADE

The coagulation cascade of secondary hemostasis has two pathways:

The contact activation pathway (formerly known as the intrinsic pathway)
The tissue factor pathway (formerly known as the extrinsic pathway)
That lead to fibrin formation.

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CLOTTING CASCADE

AJHP 2004;61:S7.

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THE NEW MODEL OF COAGULATION

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Initiation phase

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Amplification phase

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Propagation phase

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ANTICOAGULANTS

Although tissue breakdown and platelets destruction are normal events in the absence of trauma, intravascular clotting does not usually occur because:

the amounts of procoagulants released are very small
natural anticoagulants are present (Antithrombin III, Heparin, Antithromboplastin, Protein C and S)

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NATURAL ANTICOAGULANTS

Antithrombin III – inhibits factor X and thrombin

Heparin from basophils and mast cells potentiates effects of antithrombin III (together they inhibit IX, X, XI, XII and thrombin)

Antithromboplastin –inhibits tissue factor (tissue thromboplastins)

Protein C and S – activated by thrombin; degrade factor Va and VIIIa

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ATIII

Clotting Factors

Tissue factor

PAI-1

Antiplasmin

TFPI

Protein C

Protein S

Procoagulant

Anticoagulant

Fibrinolytic System

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ANTICOAGULANTS

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DEVELOPMENTAL HISTORY �CURRENT FDA APPROVED ANTICOAGULANTS

1930s

Heparin

1950s

1990s

2002

1970s

Warfarin

LMWHs

Factor Xa inhibitor

DTIs

Argatroban

Bivalirudin

Lepirudin

Fondaparinux

Enoxaparin

Dalteparin

Tinzaparin

1980s

2010-12

DTI and

Factor Xa

inhibitors

Dabigatran

Rivaroxaban

Apixaban

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Blood Vessel Injury

IX

IXa

XI

XIa

X

Xa

XII

XIIa

Tissue Injury

Tissue Factor

VIIa

VII

X

Prothrombin

Thrombin

Fibrinogen

Fibrin monomer

Fibrin polymer

XIII

First generation Anticoagulants

Factors affected

By Heparin

Vit. K dependent Factors

Affected by Oral Anticoagulants

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SECOND AND EMERGING THERAPIES

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New anticoagulant drugs

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DISADVANTAGE OF FIRST GENERATIONS ANTICOAGULANTS

Narrow therapeutic index
Need for frequent monitoring
Slow onset and offset of action
Route of administration
Large inter-individual dosing differences
Drug-Drug and drug-food interactions
Genetic polymorphisms

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COMPLICATIONS OF FIRST GENERATION ANTICOAGULANTS

Bleeding

New Thrombosis

Heparin-induced thrombocytopenia

Osteoporosis

Warfarin skin necrosis

Warfarin embryopathy

Slow onset of action

Needs regular monitoring

Interaction with food

Interacts with medications

Difficult titration-regular dose adjustments

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THE IDEAL ORAL ANTICOAGULANT

Require no remote monitoring

Have little interaction with food or other drugs

Broad therapeutic window

Offer a good safety profile with regard to bleeding risk

Have similar efficacy to warfarin in reducing thromboembolic events

Reach therapeutic levels within several hours

Oral and/or IV administration

Ability to inhibit free and clot bound thrombin

Availability of an antidote

Easily reversible

Affordable (acceptable cost-benefit ratio)

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NEW TERMINOLOGY

DOACs – Direct oral anticoagulants
NOACs – New oral anticoagulants
TSOACs – Target specific oral anticoagulants

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BACKGROUND

TSOACs work further down the clotting cascade
There are currently three FDA-approved TSOACs:

Dabigatran (Pradaxa): a direct thrombin inhibitor
Rivaroxaban (Xarelto): a factor Xa inhibitor
Apixaban (Eliquis): a factor Xa inhibitor

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TSOACS VS. WARFARIN

Multiple large randomized controlled trials have been performed comparing TSOACs with warfarin

TSOACs are at least as effective as warfarin in patients with atrial fibrillation and venous thromboembolism
TSOACs have similar, if not lower, rates of serious hemorrhagic complications (e.g., intracranial hemorrhage, gastrointestinal bleeding)

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DIRECT THROMBIN INHIBITION

VIIa

Xa

IXa

XIa

XIIa

Tissue factor

Factor IIa�(thrombin)

Dabigatran

II

×

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DABIGATRAN

Oral direct thrombin inhibitor (DTI)
Rapidly converted from dabigatran etexilate to dabigatran (hydrolysed by esterases in the stomach to active drug)
Needs acidic environment for best absorption
Binds clot-bound and free thrombin with high affinity and specificity
Predictable anticoagulant effect
Low plasma protein binding
No liver toxicity based on available clinical data

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DABIGATRAN

Absorption

Bioavailability ~6%
Requires acidic environment

Onset is immediate with peak activity at 2-3 hrs
Plasma t ½ 12-17 hours
Excreted renally (80%); eliminated in bile
Reduced renal function results in up to a six-fold increase in plasma concentration and a prolonged half-life
In cases of end-stage renal disease, elimination half-life doubled from 14 to 28 h.
In healthy elderly subjects, concentrations are 40–60% higher than in younger subjects, which is primarily a reflection of reduced renal function.

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DABIGATRAN

No significant food-drug interaction

Not metabolized by P450 Isoenzymes

Few drug-drug interactions (amiodarone, quinidine, verapamil )

dose once daily

Approved for

Non valvular Afib
DVT and PE

No monitoring is required

NOT for use in patients with artificial valves

Approved in Europe and Canada for orthopedic prophylaxis

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DABIGATRAN ETEXILATE CLINICAL TRIALS

TRIAL	PATIENT POPULATION	DOSING	COMPARATOR	OUTCOME	RESULTS
VTE PREVENTION
RE-NOVATE	THR	150 or 220mg qday (28-35 days)	Enox 40mg qday	VTE + all cause mortality	Non-inferior
RE-MODEL	TKR	150 or 220mg qday (6-10 days)	Enox 40mg qday		Non-inferior
RE-MOBILIZE	TKR	150 or 220mg qday (12-15 days)	Enox 30mg bid		Failed to achieve noninferiority
STROKE PREVENTION
RE-LY	AFIB	110 or 150mg bid	Warfarin (INR 2-3)	Stroke or systemic embolism	150mg (superior) 110mg (non-inferior)

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DABIGATRAN SAFETY

Trial	Patient population	Dosing	Comparator	Outcome		Results
VTE PREVENTION
RE-NOVATE	THR	150 or 220mg qday (28-35 days)	Enox 40mg qday	Major Bleeding	2.0% (220mg) 1.3% (150mg) vs. 1.6%
RE-MODEL	TKR	150 or 220mg qday (6-10 days)	Enox 40mg qday		1.5% (220mg) 1.3% (150mg) vs. 1.3%
RE-MOBILIZE	TKR	150 or 220mg qday (12-15 days)	Enox 30mg bid		0.6% (220mg) 0.6% (150mg) vs. 1.4%
STROKE PREVENTION
RE-LY	AFIB	110 or 150mg bid	Warfarin (INR 2-3)	Major Bleeding	3.11% (150mg) 2.71%(110mg)* vs. 3.36%

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DIRECT FACTOR XA INHIBITION

VIIa

Xa

IXa

XIa

XIIa

Tissue factor

Fibrinogen

Fibrin clot

Factor II�(prothrombin)

Rivaroxaban

Apixaban

Edoxaban

×

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RIVAROXABAN

Direct factor-Xa inhibitor
Inhibits free factor-Xa as well as prothrombinase-bound and clot bound factor-Xa
Circulates primarily bound to albumin (95%)
80-100% oral bioavailability
Peak activity at 2-4 hours
Hepatic metabolism with renal and fecal excretion
Avoid with CrCl <15 ml/min; caution when CrCl 15-30ml/min
No food and few drug interactions

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RIVAROXABAN

Elimination

1/3 unchanged in urine
1/3 inactive metabolites excreted in urine
1/3 inactive metabolites fecal
T ½

5-9 hrs (young patients)
11-13 hrs (elderly)

Metabolism

CYP 3A4, 2J2, CYP independent mechanism

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RIVAROXABAN CLINICAL TRIALS

TRIAL	PATIENT	DOSING	COMPARATOR	OUTCOME	RESULTS
RECORD 1	THR	10mg qday (31-39 days)	Enox 40mg qday	Composite VTE and all cause mortality	Riva 1.1% Enox 3.7% p<0.001 (sup)
RECORD 2	THR	10mg qday (31-39 days)	Enox 40mg qday (10-14 days)		Riva 2% Enox 9.3% p<0.001 (sup)
RECORD 3	TKR	10mg qday (10-14 days)	Enox 40mg qday		Riva 9.6% Enox 18.9% p=0.012 (sup)
RECORD 4	TKR	10mg qday (10-14 days)	Enox 30mg bid		Riva 6.9% Enox 10.1% p<0.001 (sup)

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RIVAROXABAN SAFETY

Thromb Haemost 2010: 103:572-585

TRIAL	PATIENT	DOSING	COMPARATOR	OUTCOME	RESULTS
RECORD 1	THR	10mg qday (31-39 days)	Enox 40mg qday	Major Bleeding	Riva 0.3% Enox 0.1% p=0.18
RECORD 2	THR	10mg qday (31-39 days)	Enox 40mg qday (10-14 days)		Riva 0.1% Enox 0.1% p=1.00
RECORD 3	TKR	10mg qday (10-14 days)	Enox 40mg qday		Riva 0.6% Enox 0.5% p=0.79
RECORD 4	TKR	10mg qday (10-14 days)	Enox 30mg bid		Riva 0.7% Enox 0.3% p=0.31

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APIXABAN

Direct factor-Xa inhibitor
Inhibits free factor Xa as well as clot bound Xa and activated prothrombinase bound Xa
Peak activity at 3 hours
T ½ - 8 to 11 hours
Non-renal metabolism with renal (25-30%) and fecal (65%) excretion
Reduce dosing with ketoconazole, itraconazole, ritonair, clarithromycin

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APIXABAN CLINICAL TRIALS

Thromb Haemost 2010: 103:572-585

Trial	Patients	Dosing	Comparator	Outcome	Results
ADVANCE-1	TKR	2.5mg BID (10-14 days)	Enox 30mg bid	Total VTE + all cause mortality	API 9.0% Enox 8.8% Non-Inferiority not met
				Bleeding	API 5.3% Enox 6.6%
ADVANCE-2	TKR	2.5mg BID (10-14 days)	Enox 40mg qday	Total VTE + all cause mortality	Api 15.1% Enox 24.4% p=0.001
				Bleeding	Api 3.5% Enox 4.8% p=0.09

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TSOAS

Thromb Haemost 2010: 103:572-585

J Thromb Thrombolysis 2013;36:133-140.

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NEW ANTICOAGULANTS

Benefits

Efficacy similar in to present therapy in many clinical settings
Large trials support relative safety compared to VKA
Wide therapeutic window

Problems

Inability to accurately monitor the agents
NO antidotes
Short t ½ may leave patients unprotected with missed doses
No clear indication of patients that may benefit most from the new therapies

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MONITORING

Requires understanding of the available coagulation tests

Should not be done “routinely” but limited to clinical situations a specific goal in mind

Urgent pre-op assessment
Active bleeding assessment

Presently – do not quantitatively assess the degree of anticoagulation but can make a qualitative assessment

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MONITORING

Dabigatran Do not have reliable laboratory monitoring

PT is insensitive to dabigatran

INR rarely exceeds 1.2

aPTT is more sensitive with less variability
Very high dabigatran levels are underestimated by aPTT values

van Ryn et al. Thromb Haemost 2010;103:1116-1127.

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MONITORING

van Ryn et al. Thromb Haemost 2010;103:1116-1127.

For DTIs - ECT is the best lab monitor – not widely available/not FDA approved

Chromogenic anti-factor II – FDA approved but not for monitoring DTIs

Thrombin time is too sensitive

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MONITORING

Limited data a best are available for rivaroxaban and apixaban for monitoring or reversal

Rivaroxaban and Apixaban influences

prothrombin time (PT) > aPTT

Rivaroxaban and apixaban should be able to be monitored by chromogenic Anti-Xa assays

Standards have not been set/reported

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MONITORING GUIDELINES

J Thromb Thrombolysis 2013;36:187-194.

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CLINICAL SITUATION RELATED TO NEW ORAL ANTICOAGULANTS

Time to discontinue and start the NOAs

Bleeding Issues and its management

Regional anesthesia, what we do

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PRE-PROCEDURE INTERRUPTION OF THE NOAS

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PRE-PROCEDURAL INTERRUPTION

J Thromb Thrombolysis 2013;36:212-222.

Levy JH, Key NS, Azran MS. Novel oral anticoagulants: implications in the perioperative setting. Anesthesiology 2010;113:726-45.

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PRE-PROCEDURAL INTERRUPTION

Cleve Clin J Med 2013;80:443-451.

Hall R, Mazer CD. Antiplatelet drugs: a review of their pharmacology and management in the perioperative period. Anesth Analg 2011;112:292-318.

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Bridging algorithm for vitamin K antagonists and new oral anticoagulants.

Gallego P et al. Circulation 2012;126:1573-1576

Editorial, Circulation, September 2012 vol. 126 no. 13 1573-1576

Bridging algorithm for vitamin K antagonists and new oral anticoagulants.

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'New' direct oral anticoagulants in the perioperative setting.

Breuer, Georg; Weiss, Dominik; Ringwald, Juergen

Current Opinion in Anaesthesiology. 27(4):409-419, August 2014.

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'New' direct oral anticoagulants in the perioperative setting.

Breuer, Georg; Weiss, Dominik; Ringwald, Juergen .Current Opinion in Anaesthesiology. 27(4):409-419, August 2014.

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PRE-OP MANAGEMENT�(EUROPEAN EXPERIENCE)

If surgery cannot be delayed, there is an increased risk of bleeding in patients receiving anticoagulants.

Risk of bleeding should be weighed against the urgency of intervention.

Discontinue drugs minimum 1 to 2 days (CrCl ≥ 50 mL/min)

Patients with the highest risk of bleeding hold for 2-4 days

major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required

CrCl< 50 mL/min hold 2 to 5 days before elective invasive or surgical procedures

van Ryn et al. Thromb Haemost 2010;103:1116-1127.

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BRIDGING OR NO BRIDGING

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BRIDGING DECISION

Does AC need interrupted?

Is bridging required (risk assessment)?

Anticoagulation Intensity

(risk/bleeding assessment)
“full” or “therapeutic”

(e.g., Enoxaparin 1 mg/kg BID or UFH gtt)

“prophylactic”

(e.g., Enoxaparin 40 mg/day or SQ UFH)

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RISK STRATIFICATION FOR BLEEDING

High bleeding-risk surgeries/procedures include:

Urologic surgery/procedures: TURP, bladder resection or tumor ablation, nephrectomy or kidney biopsy (untreated tissue damage after TURP and endogenous urokinase release)
Pacemaker or ICD implantation (separation of infraclavicular fascia and no suturing of unopposed tissues may lead to hematoma)
Colonic polyp resection, especially >1-2 cm sessile polyps (bleeding occurs at transected stalk after hemostatic plug release)
Vascular organ surgery: thyroid, liver, spleen
Bowel resection (bleeding may occur at anastomosis site)
Major surgery tissue injury: cancer surgery, joint arthroplasty, recoinvolving considerable nstructive plastic surgery
Cardiac, intracranial or spinal surgery (small bleeds can have serious clinical consequences)

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SUGGESTED RISK STRATIFICATION: MECHANICAL HEART VALVES

High Risk

Any mitral valve prosthesis
Older (caged-ball or tilting disc) aortic valve prosthesis
Recent (within 6 months) stroke or TIA

Moderate Risk

Bileaflet aortic valve and at least one of:
Atrial fibrillation, prior stroke or transient ischemic attack, hypertension, diabetes, congestive heart failure, age >75 years

Low Risk

Bileaflet aortic valve without atrial fibrillation and no other risk factors for stroke

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SUGGESTED RISK STRATIFICATION: ATRIAL FIBRILLATION

High Risk

CHADS score = 5
Recent (within 3 months) stroke or TIA
Rheumatic valvular heart disease

Moderate Risk

CHADS score = 3-4

Low Risk

CHADS score = 0-2 and no prior stroke or TIA

N.B. Individual patient characteristics (eg, prior embolic stroke or perioperative stroke/TIA) may override suggested risk stratification

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SUGGESTED RISK STRATIFICATION: VENOUS THROMBOEMBOLISM

High Risk

Recent VTE (<3 months ago)
Severe thrombophilia (eg, antiphospholipid antibodies)

Moderate Risk

VTE within the past 3-12 months
Nonsevere thrombophilia (eg, heterozygous factor V mutation)
Recurrent VTE
Active cancer (treated within 6 months or palliative)

Low Risk

Prior VTE >12 months ago and no other risk factors

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BRIDGING PROTOCOL

Arch Cardiovasc Dis 2011;104:669-676.

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BLEEDING

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MANAGING BLEEDING

Hold the drug

Local hemostatic measures

Supportive PRBC/PLT transfusions

Initiate a hematology consult early

Institutional protocols are recommended

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MANAGING BLEEDING

Maintain adequate diuresis given renal elimination

With overdose – when given within 1-2 hours of ingestion activated charcoal can adsorb dabigatran (in vitro data)

Protamine sulfate and vitamin K should not be expected to affect the anticoagulant activity

Specific reversal agents (“antidotes”) not yet available

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MANAGING BLEEDING

Dabigatran can be dialyzed with removal of about 60% of drug over 2-3 hrs.

Rivaroxaban is not expected to be dialyzable (high plasma protein binding).

Consider transfusion of fresh frozen plasma, platelets or red blood cells for supportive management

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FRESH FROZEN PLASMA

There are no studies evaluating the efficacy and safety of fresh frozen plasma (FFP) for reversal of NOACs.

In a recent case report, administration of FFP in conjunction with recombinant activated factor VII (rVIIa) was ineffective at restoring hemostasis in a patient with dabigatran-associated epidural hematoma and spinal cord compression following traumatic injury .

FFP reduced the volume of intracerebral hemorrhage in mice receiving high-dose dabigatran, without an effect on mortality.

High-dose FFP only partially reversed the prolonged PT induced by edoxaban in a rat model.

FFP administration is associated with increased risk of circulatory overload, transfusion-related acute lung injury, allergic reactions and infection.

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DILUTION IS INEVITABLE WHEN GIVING�BLOOD COMPONENTS

80

Whole blood 500 mL

(Hct 38%–50%; PLTs 150K–400K; Plasma coagulation activity 100%)

1 U PRBC

(335 mL, Hct 55%)

1 U Plasma

(275 mL, coagulation activity 80%)

1 U PLTs

(50 mL, 5.5 x 10¹⁰PLTs

150 mL anticoagulant added; centrifuged

Patient Receives 650 mL fluid:

Hct 29%, PLTs 88K, 65% coagulation activity

Adapted from Dutton RP. Pharmacotherapy. 2007;27(9 pt 2):85S–92S.

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MANAGING BLEEDING

Some evidence supports use of activated prothrombin complex concentrates (FEIBA) for rivaroxaban, recombinant factor VIIa (Novoseven) for dabigatran or concentrates of coagulation factors II, IX, or X (PCC) but data are limited.

4-factor PCC recently approved in the US.

Best data available for the DTIs

Always concerns about the “potentially” prothrombotic state created with bypassing agents.

Xa recombinant reversing agent is under investigation. Phase II data was encouraging

Phase III in development

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REGIONAL ANESTHESIA

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TSOACS AND NEURAXIAL ANESTHESIA

Recent guidelines from the American Society of Regional Anesthesia and Pain Medicine recommend that TSOACs be stopped for 2–4 days (depending on which of the 3 was used) prior to initiation of neuraxial anesthesia

These guidelines recommend against use of a TSOAC while a catheter is in place if possible, or to delay removal of a catheter until the anticoagulant effect is minimal

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Last application of a NOAC before neuraxial anesthesia

'New' direct oral anticoagulants in the perioperative setting. Breuer, Georg; Weiss, Dominik; Ringwald, Juergen. Current Opinion in Anaesthesiology. 27(4):409-419, August 2014.

Baron TH, Kamath PS, McBane RD. Management of antithrombotic therapy in patients undergoing invasive procedures. N Engl J Med 2013;368:2113-24.

Connolly G, Spyropoulos AC. Practical issues, limitations, and periprocedural management of the NOAC's. J Thromb Thrombolysis 2013;36:212-22.

Liew A, Douketis J. Perioperative management of patients who are receiving a novel oral anticoagulant. Intern Emerg Med 2013;8:477-84.

Gogarten W, Vandermeulen E, Van Aken H, Kozek S, Llau JV, Samama CM; European Society of Anaesthesiology. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol 2010;27:999-1015.

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Recommendations for neuroaxial anesthesia if NOAs administered for venous thromboembolic prophylaxis

	Dabigatran	Rivaroxaban	Apixaban
Time between epidural anesthetic technique and next anticoagulant dose	2-4 h	4-6 h	6h
Time before last anticoagulant dose and epidural catheter removal	NR	22-26h	26-30h
Time between removal of epidural catheter and next anticoagulant dose	6h	4-6h	4-6h

'New' direct oral anticoagulants in the perioperative setting. Breuer, Georg; Weiss, Dominik; Ringwald, Juergen. Current Opinion in Anaesthesiology. 27(4):409-419, August 2014.

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REGIONAL ANESTHESIA

Anesthesiology 2013;118:1466-1474.

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