Pharmacology of Anticoagulants - IJN College PowerPoint - 01_Pharmacology … · Pharmacology of Anticoagulants Kong Ming Chai Senior Principal Clinical Pharmacist. 2. 3 Fondaparinux,

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Pharmacology of Anticoagulants

Kong Ming Chai

Senior Principal Clinical Pharmacist

2

3

Fondaparinux,

Rivaroxan,

Dabigatran,

4Antithrombotic drugs – Anticoagulants, Antiplatelets, Fibrinolytic

5Antithrombotic drugs – Anticoagulants, Antiplatelets, Fibrinolytic

6

FibrinolyticsFibrinolytics

Antithrombotic drugs – Anticoagulants, Antiplatelets, Fibrinolytic

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FibrinolyticsFibrinolytics

Antithrombotic drugs Antithrombotic drugs –– Anticoagulants, Antiplatelets, Anticoagulants, Antiplatelets,

FibrinolyticFibrinolytic

8

Approaches to Antithrombotic Approaches to Antithrombotic TherapyTherapy

Platelet Adherence Platelet Adherence

AggregationAggregationPlatelet InhibitorsPlatelet Inhibitors

Vascular InjuryVascular Injury Risk Factor ReductionRisk Factor Reduction

Coagulation Activation

Thrombin Generation Fibrin Formation

AnticoagulantsAnticoagulants

Plasmin Generation Plasmin Generation

FibrinolysisFibrinolysisThrombolyticsThrombolytics

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Anticoagulants

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Vitamin Kantagonists

• Warfarin

Anticoagulant drugs

• Unfractionated Heparin (UFH)

• Low molecular weight heparin (LMWH)

• Synthetic

pentasaccharides

(fondaparinux, idraparinux)

HeparinsDirect thrombin

inhibitors

• Hirudin

• Recombinant

- Hirudin

- Bivalirudin

• Synthetic

- Argatroban

- Melagatran

- Dabigatran

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AnticoagulantsnHeparin

nLow Molecular Weight Heparins (LMWH)

nIndiret Anti-Xa inhibitor - Fondaparinux

nWarfarin

nDirect Thrombin Inhibitor

u - Lepirudin

u - Dabigatran (new)

nDirect Xa inhibitor

u - Rivaroxaban (new)

12

Anticoagulants – historical development

1916 1924 1936 1940 1950s 20061970s 1976 1980s 1990s 2001

Oral

Injection

Spoiled Spoiled sweet cloversweet clover

DicoumarolDicoumaroldiscovereddiscovered

WarfarinWarfarinclinical useclinical use

Warfarin / Vitamin KWarfarin / Vitamin Kmechanismmechanism

High / low doseHigh / low doseWarfarin / INRWarfarin / INR

WarfarinWarfarinclinical trialsclinical trials

HeparinHeparindiscovereddiscovered

HeparinHeparinclinical useclinical use

Continous heparinContinous heparininfusion/infusion/

aPTTaPTT

LMWHLMWHdiscovereddiscovered

LMWHLMWHclinical trialsclinical trials

PentasaccharidePentasaccharideclinical trialsclinical trials

XimelagatranXimelagatran

clinical trialsclinical trials

DabigatranDabigatran

RivaroxabanRivaroxaban

ApixabanApixaban

AZD0837AZD0837

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History of Heparin, LMWH, Fondaparinux

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1912 Doyon: Homogenate from dog liver

1916 McLean: Extract from the liver which strongly inhibits coagulation

1918 Howell: named the agent - Heparin

1933 Purification of heparin from various organs by Charles and Scott

1937 Chemical characterisation of heparin by Jorpes and Best

1970 Depolymerisation: LMWH (optimal molecular weight not defined)

1980 Clinical trials with LMWH

1981 Choay: Synthesis of the pentasaccharide sequence

2001 Pentasaccharide clinical trials

Heparins - history

William H. Howell

OO OOOO OOOO

HNHN--COCHCOCH33

OOOO

OO

HNHN--SOSO33--

OO

HNHN--SOSO33--

HH22CC--OO--SOSO33--HH22CC--OO--SOSO

33-- HH22CC--OO--SOSO

33--

COOCOO--

COOCOO--

OHOHOHOHOHOHOHOH

OHOH

OSOOSO33--

OSOOSO33--

OO

15

Heparin is a polymer composed of heterogenous polysaccharide units

16

Unfractionated heparinUnfractionated heparin

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Low molecular weight heparinLow molecular weight heparin

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FondaparinuxFondaparinux

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Heparin - MOA

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Heparins Heparins –– mechanism of actionmechanism of action

All heparins inhibit the coagulation process by enhancing the activity of the endogenous inhibitor, antithrombin by 1000 x.

21Heparins Heparins –– mechanism of actionmechanism of action

The binding of antithrombin to the pentasaccharide sequence in heparin…

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The binding of antithrombin to the pentasaccharide sequence in heparin… ……induces a conformational change in antithrombin,…


The binding of antithrombin to the pentasaccharide sequence in heparin , induces a conformational change in antithrombin, thereby increasing the affinity for thrombin by 1000x.

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The binding of antithrombin to the pentasaccharide sequence in heparin , induces a conformational change in antithrombin, thereby increasing the affinity for thrombin. Unfractionated heparin binds to both antithrombin and thrombin to form a ternary complex…


The binding of antithrombin to the pentasaccharide sequence in heparin , induces a conformational change in antithrombin, thereby increasing the affinity for thrombin. Unfractionated heparin binds to both antithrombin and thrombin to form a ternary complex… …and then dissociates, leaving the enzyme irreversibly bound to its inhibitor.


The binding of antithrombin to the pentasaccharide sequence in heparin , induces a conformational change in

antithrombin, thereby increasing the affinity for thrombin. Unfractionated heparin binds to both antithrombin and

thrombin to form a ternary complex… …and then dissociates, leaving the enzyme irreversibly bound to its inhibitor.

Once dissociated, heparin is free …





Once dissociated, heparin is free … …to bind to another antithrombin molecule…





Once dissociated, heparin is free … …to bind to another antithrombin molecule… …and subsequently…

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Once dissociated, heparin is free to bind to another antithrombin molecule and subsequently inhibit more thrombin.




thrombin to form a ternary complex… …and then dissociates, leaving the enzyme irreversibly bound to its

inhibitor. Once dissociated, heparin is free to bind to another antithrombin molecule and subsequently inhibit

more thrombin. In addition to thrombin, the heparin-antithrombin complex also inhibits factor Xa. This interaction, however, does not involve binding between heparin and factor Xa.

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LMWH - MOA

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LMWH LMWH –– mechanism of actionmechanism of action

Low molecular weight heparins (LMWHs) are obtained from heparin via chemical or enzymatical degradation. This procedure results in some heparin chains cleaving at the site where thrombin binds.

Thus, LMWHs have a reduced capacity to inhibit thrombin, but the anti-factor Xa activity remains intact as this factor does not need the thrombin binding site.

LMWHs are therefore sometimes characterised with an anti-factor Xa to anti-factor IIa ratio, e.g. 4:1, which means that the anti-factor Xa activity is 4 times higher than the anti-factor IIa activity.

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Heparin, LMWH - MOA

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Thrombin Inactivation: Heparin

Pentasaccharidesequence

Heparin / ATIII / IIaTernary complex accelerates inactivation of IIa by ATIII

LMW Heparin / ATIIINo acceleration of inactivation of IIa by ATIII without ternary complex

IIa

ATIII

IIa

ATIII


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Factor Xa Inactivation: LMWH/Heparin

Heparin / ATIIITernary complex not necessary to accelerate inactivation of Xa by ATIII

XaXaATIII

LMW Heparin / ATIIITernary complex not necessary to accelerate inactivation of Xa by ATIII


XaXa ATIII

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Site of ActionHeparin,LMWH,Fondaparinux

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HeparinHeparinPentasaccharidePentasaccharide

ThrombinThrombin

ATAT

Heparin and the coagulation cascade

ProthrombinProthrombin ThrombinThrombin

AntithrombinAntithrombin

Tenase complexTenase complex

FIXaFIXaFVIIIaFVIIIa

FXaFXa

FXFX

Prothrombinase complexProthrombinase complex

FXaFXaFVaFVa

The antithrombin/heparin complexThe antithrombin/heparin complex

is a poor inhibitor of fibrinis a poor inhibitor of fibrin--bound bound

thrombinthrombin

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FXaFXa

PentasaccharidePentasaccharideLMWHLMWH

ATAT

Low molecular weight heparin

and the coagulation cascade

The antithrombin/LMWH complexThe antithrombin/LMWH complex


thrombinthrombin





FXaFXa

FXFX


FXaFXaFVaFVa

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FXaFXa

ATAT

Fondaparinux and the coagulation cascade





FXaFXa

FXFX


FXaFXaFVaFVa

The antithrombin/LMWH complexThe antithrombin/LMWH complex


thrombinthrombin

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Heparin

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Unfractionated heparin - pharmacokinetics

n Administered by continous i/v or s/c injection

n The clearance involves a rapid, saturable mechanism and a slower, unsaturable mechanism.

n A renal pathway is primarily responsible for the slow, unsaturable component

n Once in the blood stream, UFH binds to plasma proteins, endothelial cells and macrophages (accounts for the rapid, saturable phase of heparin clearance)

n The complex kinetics explains the non-linear relationship between dose and plasma half-life and the variable anticoagulant effect

n The apparent biological half-life of heparin increases with increasing doses

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Unfractionated heparin – major use

n Treatment of thromboembolic diseases, mainly as induction of vitamin K antagonists

n Prevention of postoperative VTE

n Prevention of thrombosis after MI

n Prevention of coagulation during extracorporal circulation e.g. during renal dialysis or cardiac surgery

n Treatment of disseminated intravascular coagulation (DIC)

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Heparin—Clinical Applications

n Prophylaxis and treatment of

u Venous thrombosis and its extension

u Pulmonary Embolism

u Peripheral arterial embolism

n Prevention of post-op DVT/PE

n Atrial fibrillation with embolization

n Diagnosis and treatment of DIC

n Prevention of clotting in surgery

n Anticoagulant in blood transfusions and dialysis

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Unfractionated heparin – major drawbacksn Inconvenience of administration by injection and the need for

regular monitoring, which delays hospital discharge and therefore increases the demand on hospital resources

n Risk of heparin-induced thrombocytopenia (HIT) u – need to monitor platelet level 2-3x/week, ?

u platelet<50x10^9, 50% drop from baseline

n A relatively high risk of bleeding compared to more recently developed alternatives .

u - monitor HB 2-3x/week for sign and symptoms of bleeding

n Sometimes associated with osteoporosis in chronic use

n The drawbacks above are reduced with LMWH and

UFH has now largely been replaced by LMWH for prevention and treatment of thrombosis

45Heparin dosing: body-weight based dosing of IV heparin

n Heparin 25,000 U in 250 ml normal saline --� 100 u /ml

n Initial Dosing: Loading at 80U/kg

n Maintenance infusion at 18U/kg/hr (APTT in 6 hrs)

n Subsequent dose adjustmentsAPTT (S) Dose change Additional

Action Next APTT

<35 +4U/kg/hr Rebolus 80U/kg 6 hrs

35-45 +2u/kg/hr Rebolus with 40U/kg

6 hrs

46-70 0 0 6 hrs

71-90 -2 U/kg/hr 0 6hrs

>90 -3 U/kg/hr Stop infusion 1 hr

6hrs

During the first 24 hrs, repeat APTT every 6 hrs. Thereafter obtain APTT once every am

unless it is outside the therapeutic range.

Ref: Hyers TM. Handbook of Antithrombotic Therapy. 4

th Edition

46Heparin dosing: body-weight based dosing of IV heparin

47

Heparin dosing: body-weight based dosing of IV heparin

48

LMWH

49LMWH – pharmacokinetics

n Typically administered by subcutaneous injection

n More predictable dose-response relationship, a 2-4 times

longer plasma half-life, and improved bioavailability after

subcutaneous administration compared to UFH, due to

reduced binding to plasma proteins, macrophages and endothelial cells

n Clearance is mostly via a renal pathway, thus the half-life can be prolonged in patients with renal failure

n Regular coagulation monitoring is not required.

n However, in certain situations (if needed) anti-factor Xa

activity is measured, as LMWH has less effect on the activated partial thromboplastin time (aPTT)

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LMWH – major use

n Treatment of VTE

n Prevention of postoperative VTE and prolonged prophylaxis of VTE after elective hip surgery

n Prevention of VTE in patients with acute medical diseases

n Acute coronary syndrome (ACS) –

u Ischemic complications of unstable angina and non-Q wave MI

n Prevention of coagulation during extracorporal circulation during renal dialysis

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LMWH dosingn Available preparations in SGH: Enoxaparin, Tinzaparin

n Usual dose for enoxaparin, tinzaparin:

n DVT prophylaxis:

u Enoxaparin : 20 mg or 40 mg daily, 30mg BD, obese 0.5mg/kg/day

u Tinzaparin : 75u/kg/day

n Treatment for VTE:

u Enoxaparin1mg/kg/dose Q12hr (normal renal function)

u Tinzaparin 175 u/kg/day (normal renal function)

n Impaired Renal Function (CrCL < 30ml/min)

� Start with half the usual dose

� Monitor therapy using anti-Xa level

� Peak Anti-Xa: drawn 3 hours after 3rd injection, aim at 0.5 -0.8

� Trough Anti-Xa, aim < 0.5, prevent accumulation

52LMWH – advantages over unfractionated heparin

n Effective subcutaneous administration

n No need for regular coagulation monitoring due to more predictable dose-response relationship

n Improved bioavailability

n Longer plasma half life – allows for once-daily dosing

n Reduced risk of toxic effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis

n LMWH has largely replaced UFH as a front-line therapy

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LMWH – major drawbacksn Can only be administered by injection

n Risk of thrombocytopenia, while lower than with UFH, is still a concern due to the severity of this condition

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Biological Consequences of Reduced Binding of LMWH to Proteins and Cells

Binding Target Biological Effects Clinical Consequences

Thrombin Reduced anti-IIa to Unknownanti-Xa ratio

Proteins More predictable Monitoring of anticoagulantanticoagulant response effect unnecessary

Macrophages Cleared through renal Longer plasma half-life;mechanism once daily subcutaneous

treatment effective

Platelets Reduced incidence of Reduced incidence ofheparin-dependent heparin-inducedantibody thrombocytopenia

Osteoblasts Reduced activation of Lower incidence ofosteoclasts osteopenia

Hirsh J. et al; Eighth ACCP Consensus Conference oAntithrombotic Therapy. Chest 2008;133: 141-15

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Heparin/LMWH Methods of administration

n Heparin

u IV, SQ

u IV Bolus dose + continuous infusion

u IV Bolus + SC Q12h

u aPTT monitoring every 4-6 hourly

n LMWH

u SQ

u Fixed – prophylactic:

� 20mg om, 30mg BD, 40mg om,

� 0.5 mg/kg/day (obese)

u Treatment dose weight-adjusted dosing 1mg/kg Q12h

u Anti-Xa (recommended for obese, ESRF, aged, cancer)

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CAUTION

LOOK LIKE

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Different dosage forms of Clexane®

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Different dosage forms of Clexane®

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CAUTION

LOOK LIKE

60

Dosage form for Innohep®

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� LMWH

� Bleeding

� Thrombocytopenia

� Less osteoporosis

� Less hypersensitivity ie lesser incidence of HIT

Heparin/LMWH—Adverse Effects

� Heparin

� Bleeding

� Thrombocytopenia

� Osteoporosis

� Hypersensitivity

� Heparin Induced Thrombocytopenia (HIT)

62

Adapted from the black box warning of LMWH

LMWH—Special Precautions

When neuroaxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to beanticoagulated with LMWHs for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.

Risk of these events is increased by the use of indwelling epidural catheters or concomitant use of NSAIDs, platelet inhibitors, or other anticoagulants.

Patients should be frequently monitored for signs and symptoms of neurological impairment.

63

Monitoring parametersn Lab: Hb, Plt, Cr, APTT/PT, Anti-Xa level

n Bleeding symptoms – hematuria, melena, bruises, bleeding from surgical sites, pain at injection sites

n Watch out for s&s of HIT?

u -Platelet<50x10^9, >50% decline from baseline

n Perioperative management:

n D/C heparin about 6 hours and LMWH about 12-24 hours before operation

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Antidote: Protamine

n Heparin/LMWH antagonist (antidote)

n Indications:

u Hemorrhage due to heparin overdose

u Increased risk of hemorrhage is present

u Reverse effects of excess heparin following cardiopulmonary bypass procedures

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n 1 mg of protamine: 100u of heparin, max of 50 mg of protamine

n 1mg of protamine: 1 mg (1mg=100iu of Anti-Xa Enoxaparin) of enoxaparin

n 1 mg of protamine to 100 anti-Xa units of tinzaparin

n Effects of protamine on LMWH less than heparin i.e. no complete neutralization of anti-factor Xa activity (max: ~ 60-70%).

n Do not exceed 50mg protamine within 10 min

n Risk of anaphylactoid-like symptoms if given too rapidly

Protamine dosing & administration

66

Protamine: Contraindications and Precautions

Contraindications

n 1) Hypersensitivity to protamine products

Precautions

n 1) Too-rapid administration may cause severe hypotensive and

anaphylactoid reactions

2) Hypersensitivity to fish

3) Infertile or vasectomized men

4) Previous exposure to protamine

5) Heparin rebound or bleeding has been reported in cardiac

surgery patients despite adequate neutralization of heparin with

protamine

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Fondaparinux

68

Fondaparinux – Indirect Xa inhibitor

n Binds to antithrombin III (ATIII) potentiating inactivation of factor Xa.

n At least as effective as LMWH or UFH

n Synthetic source (not porcine / bovine)

69

Fondaparinux – pharmacokinetics

n After subcutaneous injection, peak plasma concentrations are achieved after approximately 2 hr

n Long plasma half-life 17-21 hr, which allows a once-daily regimen

n Exclusively eliminated by the kidneys

n Regular coagulation monitoring is not required.

However, in certain situations if needed, anti-factor Xa

activity is measured, as fondaparinux has less effect on the activated partial thromobplastin time (aPTT)

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Fondaparinux – major use

n DVT prophylaxis in orthopaedic surgery

� Prevention of venous thromboembolism (VTE) after major orthopaedic surgery such as hip and knee replacement or hip fracture repair

n Treatment of acute DVT with or without PE

n Treatment of ACS

n Prophylaxis against VTE in general medical and surgical patients

71

Fondaparinux – major drawbacks

n Fondaparinux, like all heparins also carries the disadvantage of only being available in an injectable formulation

n Fondaparinux has a long plasma half-life and this, taken together with the increased risk of bleeding seen in some studies, raises concerns

72

Fondaparinux - Adverse Effects

n Bleeding

n Major bleeding rates <1% up to 1.3%

n No antidote to reverse effects

n Thrombocytopenia (peri-operative) – 3%

n Severe thrombocytopenia (platelets < 50k) - <0.2%

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Fondaparinux Injection (Arixtra(R) )

n Not to be used in patient with severe renal impairment of <30ml/min

n Laboratory monitoring: Platelet count

n No monitoring for anticoagulant effects

n Does not affect aPTT, PT or ACT assays

74

Fondaparinux - Dosing

n Prophylaxis after hip or knee surgery

u 2.5mg sc once daily

u Start 6-8 hours after surgery

n Treatment of acute DVT and/or PE

u <50kg : 5 mg sc od (once daily)

u 50-100kg : 7.5 mg sc od

u >100kg : 10 mg sc od

n Overlap with warfarin till INR therapeutic

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Use of Fondaparinux (off label)

n In vitro studies demonstrated a lack of cross-reactivity between fondaparinux and HIT antibodies

n Use of fondaparinux in HIT/HITTS is limited to abstract form with few details of the patients studied

n STEMI / NSTEMI

Bradner J, Hallisey RK, Kuter DJ. Foandaparinux in the treatmentBradner J, Hallisey RK, Kuter DJ. Foandaparinux in the treatment od HIT (abstract). Blood 2004;104(11):abstract 1775.od HIT (abstract). Blood 2004;104(11):abstract 1775.

Boshkov LK, Kirby A, Heuschkel M. Pharmacokinetics of fondanapriBoshkov LK, Kirby A, Heuschkel M. Pharmacokinetics of fondanaprinux by antinux by anti--xa levels and clinical response to anticoagulation in a 4xa levels and clinical response to anticoagulation in a 4--mth old congenital cardiac patient with HIT and established venomth old congenital cardiac patient with HIT and established venous thrombosis transitioned from argatroban us thrombosis transitioned from argatroban

to fondaparinux (abstract). Blood 2004; 104(11): abstract 4072.to fondaparinux (abstract). Blood 2004; 104(11): abstract 4072.

Kuo KHM, Kovacs MJ. Successful treatment of HIT with fondaparinuKuo KHM, Kovacs MJ. Successful treatment of HIT with fondaparinux (abstract). Blood 2004; 102(11): abstract 1147. x (abstract). Blood 2004; 102(11): abstract 1147.

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Heparin vsLMWH vsFondaparinux

77

78

Anticoagulants

nHeparin


nAnti-Xa inhibitor - Fondaparinux

nWarfarinnNew Drugs

u - Rivaroxaban

u - Dabigatran

79

The warfarin story

80

WARFarinWARFarin

Wisconsin Alumni Research FoundationWisconsin Alumni Research Foundation

81

草木樨草木樨草木樨草木樨(sweet clover)

82

83

84

1962 : Standardization of prothrombin time (PT)

1984 : INR established.

19851985---- Target INR ranges, optimal rangesTarget INR ranges, optimal ranges

1995 :

1999 : Revised ISI range 0.9 – 1.7.

Recombinant thromboplastin low ISI

between 0.9 to 1.2.

Laboratory Testing for monitoring of warfarin

85

Warfarin—Mechanism of Action

Vitamin K

Warfarin

Synthesis of Dysfunctional Coagulation

Factors, reduction by 30% to 50%.

VIIVII

IXIX

XX

IIII

Vitamin K Utilization Reduced

Protein C

Protein S

86

Ansel et al; Pharmacology and Management of the Vitamin K AntagoAnsel et al; Pharmacology and Management of the Vitamin K Antagonists: ACCP Guidelines 8nists: ACCP Guidelines 8thth Ed; Ed; Chest 2008;133;160Chest 2008;133;160--198198

t1/2 – 45ht1/2 – 29h

CYP 2C19

CYP 2C8

CYP 2C18

87Elimination Half-Lives of Vit K-Dependent Proteins

Protein Half Life

Factor VII 4 - 6 hours

Factor IX 24 hours

Factor X 48–72 hours

Factor II 60 hours

Protein C 8 hours

Protein S 30 hours

Warfarin 40 hours (range 20-60 h)

88

44--6 h6 h

8 h8 h

24 h24 h

30 h30 h

2020--60 h60 h

4848--72 h72 h

0.2

89Initiation : Loading dose vs Maintenance dose

90

Warfarin—Indications

n Prophylaxis and/or treatment of:

u Venous thrombosis and its extension

u Pulmonary embolism

n Thromboembolic complications associated with AF and/or cardiac valve replacement

n Reduce risk of death, recurrent MI, and

thromboembolic events such as stroke or systemic embolization after MI

91

Warfarin—Contraindications

n Risk of hemorrhage is greater than benefits of therapyu Hemorrhagic tendencies or blood dyscrasias

u Traumatic surgery with large open areas, recent or contemplated surgery of CNS or eye

u Bleeding tendencies with active ulceration or overt bleedingu Spinal puncture and procedures with potential for uncontrollable

bleeding

n Pregnancy

n Senility, alcoholism, psychosis or other lack of patient cooperation

n Inadequate laboratory facilities

92

Warfarin—Adverse Effects

n Fatal or non-fatal hemorrhage from any tissue or organ

n Necrosis of skin and other tissues

n Other adverse reactions reported less frequently include:

u Systemic cholesterol microembolization

u Alopecia

u Purple toes syndrome, urticaria, dermatitis including bullous eruptions

93

Dosing Considerations

n Initial

u 2–5mg per day

u Dosage adjustments based on PT/INR determinations

u Large loading dose may increase the incidence of hemorrhagic complications

n Maintenance

u 2–10 mg daily

u Individual dose and interval should be gauged by the patient’s PT/INR response

n Duration of therapy

u Individualized

94

Hylek EM, Singer DE. Ann Int Med 1994;120:897-902Hylek EM, et al. N Engl J Med 1996;335:540-546

u PTR above 2.0 (INR of 3.7 to 4.3) increases the risk of bleeding

u The estimated odds ratio of subdural hemorrhage increased 7.6 fold as the PTR increased from 2.0 to 2.5

1.61.61.41.400 1.81.8 22 2.32.3 2.72.7

Prothrombin Time RatioProthrombin Time Ratio

00

22

44

66

88

1010

18.218.211.211.2

Od

ds

Rat

io f

or

ICH

Optimal Intensity for Warfarin Therapy

INRINR Odds RatioOdds Ratio

2.02.0 1.01.0

1.71.7 2.02.0

1.51.5 3.33.3

1.31.3 6.06.0

1.01.0 1.51.5 3.03.0 4.04.0 7.07.0

11

33

55

1010

1515

INRINR2.02.0

Od

ds

Rat

io f

or

Str

oke

u INR Odds Ratio for thromboembolic stroke

95

Intensity of Anticoagulation (INR) Intensity of Anticoagulation (INR)

Clin

ical

Eve

nts

Clin

ical

Eve

nts

TherapeuticTherapeutic

WindowWindow

Hemor

rhag

ic

Hemor

rhag

ic

Thromboem

bolic

Thromboem

bolic

96

IndicationIndication INRINR

Venous thromboembolismVenous thromboembolism 2.02.0––3.03.0

(including pulmonary embolism)(including pulmonary embolism)

Thromboembolic complications associated with:Thromboembolic complications associated with:

Atrial fibrillationAtrial fibrillation 2.02.0––3.03.0

Bioprosthetic heart valvesBioprosthetic heart valves 2.02.0––3.03.0

Mechanical heart valvesMechanical heart valves 2.52.5––3.53.5

PostPost--myocardial infarctionmyocardial infarction 2.52.5––3.53.5

Note: an INR of greater than 4.0 appears to provide no additionaNote: an INR of greater than 4.0 appears to provide no additional therapeutic benefit in most l therapeutic benefit in most

patients and is associated with a higher risk of bleeding.patients and is associated with a higher risk of bleeding.

Recommended Therapeutic Range for Oral Anticoagulant Therapy

97Conversion from Heparin/LMWH to Warfarinn May begin concomitantly with heparin therapy or may be delayed 3–6 days

n Check baseline FBC, aPTT, PT / INR

n Patients receiving both heparin & warfarin should have blood drawn for PT/INR determination at least:

u 5 hours after last IV heparin bolus, or

u 4 hours after cessation of continuous IV infusion of heparin, or

u 24 hours after last subcutaneous heparin injection

n Time to peak anticoagulant effect with warfarin may be delayed 72–96 hours

n When PT/INR reaches desired therapeutic range for 2 consecutive days, then discontinue heparin. (need to overlap heparin and warfarin for at least 5 days)

n Check for CBC for platelet and HB for any sign and symptoms of HIT or bleeding.

98

Anticoagulants

nHeparin


nAnti-Xa inhibitor - Fondaparinux

nWarfarin

nDTI

nNew Drugs

u - Dabigatran

u - Rivaroxaban

99

Direct Thrombin Inhibitor

(DTI)

100

Direct Thrombin Inhibitors

101


Hirudin

ArgatrobanArgatroban

BivalirudinBivalirudin

ExositeExosite

HeparinHeparin--BindingBindingDomainDomain

ActiveActive

SiteSiteIIaIIa

IIaIIa IIaIIa

IIaIIa

Adapted from Verstraete M, Zoldelyi P, Willerson J. Cardiovascular Thrombosis-Thrombocardiology aThromboneurology, Verstraete M, Fuster V, Topol E, eds. Philadelphia: Lippincott-Raven, 19

102


n Provide predictable inhibition of thrombin independent of other cofactors

n Inhibit thrombin in the fluid phase and clot-bound thrombin

n Lack of direct effects on platelet function

n Monitored by aPTT

n No antidote available

103

Direct Thrombin InhibitorsLepirudin (Recombinant Hirudin)

n Indication—anticoagulation in patients with heparin-

induced thrombocytopenia (HIT) and associated

thromboembolic disease in order to prevent further thromboembolic complications

n Adverse effects—hemorrhagic events, fever, abnormal liver function, pneumonia, sepsis

n Dosing—intravenous, weight based

n Monitored with an aPTT in range of 1.5–2.5

104DTI – Dabigatran –(new drugs)

n Route of Administration : Oral

n Absorption and Clearance :

n Rapid Absorption, bioavailability 6.5%; initially slow postoperatively.

n Peak plasma levels within 0.5-2 hours, delayed 2 hours by food.

n Half-life elimination is 11 hours, elderly lengthen to 14-17 hours.

n Metabolized by liver, and excreted in urine (85%, primarily as unchanged drug) and feces (6% of total dose).

n Mechanism of Action : Dabigatran Etexilate (pro-drug)

u Prodrug lacking anticoagulant activity that is converted in vivo to the active

dabigatran, a specific, reversible, direct thrombin inhibitor that inhibits both free and fibrin-bound thrombin.

u Inhibits coagulation by preventing thrombin-mediated effects, including

cleavage of fibrinogen to fibrin monomers, activation of factors V, VIII, XI and XIII, and inhibition of thrombin-induced platelet aggregation.

105DTI – Dabigatran –(new drugs)

n Labeled Indications : Postoperative thromboprophylaxis in

patients who have undergone total hip or knee replacement procedures

n Unlabeled/InvestigationalInvestigational: Prevention of stroke

and systemic embolism in patients with nonvalvular atrial fibrillation

n Adverse effects— Bleeding (8% to 14%; major: ≤2%), dyspepsia (11%)

n Dosing – Oral

n Postoperative thromboprophylaxis: Knee replacement:

u Initial: 110 mg given 1-4 hours after completion of surgery and establishment of hemostasis OR

u 220 mg as one dose in postoperative patients in whom therapy is not initiated on day of surgery regardless of reason;

u maintenance: 220 mg once daily (total duration of therapy: 10 days)

106Direct Thrombin Inhibitors - Dabigatrann Hip replacement:

u Initial: 110 mg given 1-4 hours after completion of surgery and establishment of hemostasis OR

u 220 mg as one dose in postoperative patients in whom therapy is not initiated on day of surgery regardless of reason;

u maintenance: 220 mg once daily (total duration of therapy: 28-35 days)

n GeriatricPostoperative thromboprophylaxis:

Patients >75 years: Dosage reduction to 150 mg/day is suggested by the manufacturer.

107Direct Thrombin Inhibitors - Dabigatrann Dosing: Renal Impairment

u Moderate renal impairment (Clcr 30-50 mL/minute):

u Initial: 75 mg given 1-4 hours after completion of surgery and establishment of hemostasis;

u maintenance: 150 mg/day.

u Severe renal impairment (Clcr < 30 mL/minute): contraindicated.

n Dosing: Hepatic Impairment

u Mild hepatic impairment: no specific recommendations.

u Moderate-to-severe hepatic impairment:

u Use not recommended.


108

Anti-Xa

109Rivaroxaban – Direct Xa inhibitorn Absorption and Clearance

n Absorption is rapid and nearly complete.

n Bioavailability: ~100%.

n Peak plasma level in 2-4 hrs.

n Metabolize via hepatic CYP 3A4, CYP 3A5, CYP 2J2.

n Elimination half-life:

u 5-9 hrs (young individual),

u 11-13 (elderly).

u Urine (33% unchanged, 33% inactive metabolites);

u feces (33% inactive metabolites)

110Rivaroxaban – Direct Xa inhibitorn Indication : Postoperative thromboprophylaxis in patients who

have undergone elective total hip or knee replacement procedures

n Dosing:

n Postoperative thromboprophylaxis: Oral:

n Knee replacement: 10 mg once daily; initial dose should be

administered within 6-10 hours after completion of surgery

and establishment of hemostasis (total duration of therapy: 14 days)

n Hip replacement: 10 mg once daily; initial dose should be

administered within 6-10 hours after completion of surgery

and establishment of hemostasis (total duration of therapy: 35 days)

111Rivaroxaban – Direct Xa inhibitorn Dosing:

n Hepatic Impairment

u Mild hepatic impairment: no dosing recommendations

u Significant hepatic impairment : contraindicated.

n Dosing: Renal Impairment

u Moderate renal impairment (Clcr 30-49 mL/minute):

� Use with caution; no specific dosage adjustments are specified in approved labeling.

u Severe renal impairment (Clcr <30 mL/minute): not recommended.


112

Comparison

Warfarin,

Dabigatran,

Rivaroxaban

113

Warfarin Dabigatran Rivaroxaban

Onset of Effect

Onset : 24 hours

Peak : 72 - 96 hours Peak : within 2 hrs. Peak : 2-4 hours

Duration of Action

2 – 5 days

Half-life 40 hour, (20-60 hours)

highly variable among

Individuals

11 hours; Elderly 14-17 hours

Young: 5-9 hours; Elderly: 11-13 hours

Protein Binding 99% Albumin Protein binding: 34% to 35% 92% to 95% albumin

Absorption 100% Bioavailability: ~6.5% 100%

Distribution 0.14 liter/kg, It does not

appear to distribute into milk.

Distribution: Vd: 60-70 L Vdss: ~50 L

Metabolism Stereoselectively

metabolized by CYP-450

(major route) and reductases

to inactive metabolites.

The CYP2C9 isoenzyme is

likely to be the principal

CYP-450 isoenzyme.

Hepatic; dabigatran etexilate is rapidly and completely hydrolyzed

to dabigatran (active form) by plasma and hepatic esterases;

dabigatran undergoes hepatic glucuronidation to active

acylglucuronide isomers, 20% Dabigatran Glucuronide

Hepatic via CYP3A4, CYP3A5, and

CYP2J2

Substrate of P-Glycoprotein

Elimination Excreted in bile as inactive

metabolites, are reabsorbed

and excreted in urine.

Up to 92% of the orally

administered dose is

recovered in urine.

Urine (85%, primarily as unchanged drug); Renal elimination represents major pathway [~ 80%]

Feces (6% of total dose)

Biliary elimination [~20%]

Urine (33% as unchanged drug; 33% as inactive

metabolites);

feces (33% as

inactive metabolites)

1. Efficacy : Comparison of PK profile

114Monitoring Parameters

Warfarin (2) Dabigatran (5) Rivaroxaban(4)

Monit-oring

Para-Meters

Prothrombin

Time / INR,

CBC with differential,

Activated partial

thromboplastin time

(aPTT) (values >2.5 x control may indicate Over-anticoagulation),

Renal function

CBC with differential,

thrombin time (TT),

ecarin clotting test (ECT)

if available,

Therapy should not be initiated until hemostasis has been established.

Prothrombin time (PT),

Hepatic function;

Renal function,

CBC with differential

Note: In major clinical trials, monitoring of aPTT, PT/INR, or antifactor Xa levels did not occur. However, certain patient populations (eg, renal insufficiency, hepatic impairment, low body weight, extreme obesity) may require monitoring of the PT time which correlates well with rivaroxaban concentrations (Abrams, 2009; Kubitza, 2005).

Test Interactions : Prolongs activated partial thromboplastin

time (aPTT), HepTest®, and Russell viper

venom time

115

Clinical

ConditionsWarfarin Dabigatran Rivaroxaban

Arterial

thrombo-

Embolism

Post-

Procedural

Vessel

Thrombosis

Postoperative

Thrombo-

prophylaxis

(initial prophylaxis with

Heparin/LMWH +

Warfarin)

Postoperative

Thrombo-

prophylaxis

in patients who have undergone total

hip or knee replacement procedures

(Renovate, Remodel, Remobilize for

post-op prophylaxis) - completed and

Approved

Postoperative

Thrombo-

prophylaxis

in patients who have

undergone total hip or knee

replacement procedures

Atrial

Fibrillation

Prophylaxis Unlabeled/

Investigational:Prevention of stroke and systemic

embolism in patients with nonvalvular

atrial fibrillation

RELY trial - completed

-increase risk of MI

-warfarin TTR 64%

ROCKET AF study trial

1. Efficacy Indications for Anticoagulation

116

Clinical Conditions


Venous

thrombo-embolism

DVT / PE Treament Treatment - pending for approval

(RECOVER, RECOVER II - for acute DVT)

EINSTEIN

-DVT, PE, EXT

Venous

thrombo-embolism

DVT / PE Prophylaxis Prophylaxis - pending for approval

(REMEDY, RESONATE trial for secondary prevention of VTE-ongoing)

MAGELLAN

Arterial

thrombo-embolism

Acute

coronary syndromes

Prophylaxis REDEEM trial – ongoing ATLAS ACS TIMI 46

1. Efficacy : Indications for Anticoagulation

117

Clinical Conditions Warfarin Dabigatran Rivaroxaban

Venous

thrombo-

Embolism

Cerebral vein

thrombosisProphylaxis NIL NIL

Hypercoagulable

stateeg protein C deficiency,

Protein S Deficiency,

AntiThrombin III deficiency,

SLE,

ACA+,

Antiphospholipid Syndrome

Prophylaxis NIL NIL

Arterial

thrombo-embolism

Prosthetic heart

valves –

Mechanical &

Bioprosthethic

Prophylaxis NIL NIL

Cardiomyopathy Prophylaxis NIL NIL

Peripheral Arterial thrombosis

Prophylaxis NIL NIL

Intra-cardiac thrombus Prophylaxis NIL NIL



Special Population


Pregnancy contraindicated in women who are or may become pregnant because the drug passes

through the placental barrier and may cause fatal hemorrhage to the fetus in utero. Furthermore, there have been

reports of birth malformations in children born to mothers who have been treated with warfarin during pregnancy.

Adverse events were observed in some animal reproductive studies.

There are no adequate and well-

controlled studies in pregnant women. Dabigatran etexilate should be used in pregnant women only if clinical benefit outweighs risks of therapy.

contraindicated in pregnancy

1st trimester

aXTo stop warfarin before 6 wk of pregnancy. Risk of teratogenicity is highest between 6th to 12th week. Restart with warfarin afterthat, if required, or alternative Heparin or LMWH.

r r

2nd trimester a r r

3rd trimester

aXstop Warfarin at last 2 weeks of pregnancy to prevent hemorragein baby. Change over to Heparin. Restart Warfarin postpartum.

r r

Breast Feeding a r r

Breast Feeding

Breast-feeding precautions: Warfarin is excreted in breast-milk in an inactive form, and prothrombin times

of nursing infants have not been affected.

Monitoring hypoprothrombinemic effects in the infant is advisable.

Studies have shown no risk to the nursing infant: monitor for signs of hypoprothrombinemia.

Excretion in breast milk unknown / not recommended

contraindicated.


Special Population


Geriatric

aprecaution for risk of

bleeding

Dosing: GeriatricPostoperative thromboprophylaxis:

Patients >75 years: Oral: Refer to adult dosing. Dosage reduction to 150 mg/day is suggested by the manufacturer. Note: Therapy should not be initiated until hemostasis has been established.

Not recommended

Moderate

Renal Impairment a

precaution for risk of bleeding

Dosing: Renal ImpairmentModerate renal impairment (Clcr 30-50 mL/minute):

Initial: 75 mg given 1-4 hours after completion of surgery and establishment of hemostasis; maintenance: 150 mg/day.

Dosing: Renal ImpairmentModerate renal impairment (Clcr 30-49 mL/minute): Use with caution;

no specific dosage adjustments are specified in approved labeling.

Severe

Renal Impairment


bleeding

Dosing: Renal ImpairmentSevere renal impairment (Clcr < 30 mL/minute): Use is contraindicated.

Dosing: Renal ImpairmentSevere renal impairment (Clcr <30 mL/minute): Use not recommended.

Mild

Hepatic Impairment a

precaution for risk of bleeding

Dosing: Hepatic ImpairmentMild hepatic impairment: Manufacturer provides no specific recommendations.

Dosing: Hepatic Impairment

Mild hepatic impairment: Manufacturer provides no specific dosing recommendations in approved labeling.

Limited data indicates pharmacokinetics and pharmacodynamic response were similar to healthy subjects.

Moderate-to-Severe

Hepatic Impairment


bleeding


Moderate-to-severe hepatic impairment: Use not recommended.


Significant hepatic impairment (including Child-Pugh classes B and C): Use is contraindicated.

120

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