new approaches to chronic anticoagulatio na

http://topworldofhealth.blogspot.com/2011/10/blood-clots-complication-information.html

Anticoagulation: The Art of BalanceAnticoagulation: The Art of Balance

Both efficacy and safety are important, imbalance in efficacy and safety may result in patient harm

Both efficacy and safety are important, imbalance in efficacy and safety may result in patient harm

1. Safety versus Efficacy2. Thrombosis = Clotting + Coagulation3. AntiThrombotics That Have Changed Clinical Practice

a) Anticoagulantsb) Antiplateletsc) Anticlotting

4. AntiCoagulantsa) Aspirinb) Warfarin

5. AntiPlateletsa) Clopidogrelb) Ticragrelorc) Bivalrudin

6. AntiClottinga) Dabigatranb) Apixibanc) Rivaroxaban

Dose (concentration) of Anticoagulant

Optimal Safety and EfficacyThrombosis

Bleeding

XI XIa

IX IXa

Xa

II IIa (Thrombin)

Fibrinogen Fibrin

VIIIa

Va

VIIa + TF VII

TF (Tissue Factor)

X

Extrinsic PathwayExtrinsic Pathway

Intrinsic PathwayIntrinsic Pathway

Intrinsic Intrinsic oror Extrinsic Extrinsic pathway activation pathway activation leads leads to thrombin formation via to thrombin formation via the final common the final common coagulation pathwaycoagulation pathway

Anticoagulants Low-molecular-weight heparin

Antiplatelet Drugs Thienopyridines Glycoprotein IIb/IIIa Inhibitors

Anticlotting Drugs

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Lewis BS, et al. Am Heart J. 2005;150:1177-1184. Lewis BS, et al. Am Heart J. 2005;150:1177-1184.

0.200.20

0.150.15

0.100.10

0.050.05

0.00.0

Cu

mu

lati

ve H

aza

rd R

ate

s D

eath

/ M

IC

um

ula

tive H

aza

rd R

ate

s D

eath

/ M

I

00 100100 200200 300300Days of Follow-upDays of Follow-up

<48 hrs after rand<48 hrs after rand

RR:0.53 (0.27-1.06)RR:0.53 (0.27-1.06)

Denotes medianTime to PCI

Denotes medianTime to PCI

0.200.20

0.150.15

0.100.10

0.050.05

0.00.0


PCI ≥ 48 hrs from rand and during initial hosp

PCI ≥ 48 hrs from rand and during initial hosp

RR:0.72 (0.51-1.01)RR:0.72 (0.51-1.01)

ASA + ClopidogrelASA + Clopidogrel

ASAASA

PCI after hospitaldischarge

PCI after hospitaldischarge

0.200.20

0.150.15

0.100.10

0.050.05

0.00.0


RR:0.70 (0.48-1.02)RR:0.70 (0.48-1.02)



ASAASA

ASAASA

Van Belle et al. Van Belle et al. Circulation.Circulation. 1998;97:26-33.1998;97:26-33.

% T

hro

mb

us

% T

hro

mb

us o

n

on

Angio

scopy

Angio

scopy

<< 8 Days 8 Days

(n=18)(n=18)

8 < &8 < &

<< 10 Days 10 Days

(n=10)(n=10)

> 15 Days> 15 Days

(n=14)(n=14)

10 < &10 < &

<< 15 Days 15 Days

(n=14)(n=14)

83%83%

70%70% 71%71%79%79%

0%0%

20%20%

40%40%

60%60%

80%80%

100%100%

Days after lysis or medical therapyDays after lysis or medical therapy

Angioscopic findings suggestive of plaque instability are extremely frequent (75% to 80% of the study population) as is the presence of clot even in the absence of clinical symptoms.

Only 16% of clot seen on angio

Angioscopic findings suggestive of plaque instability are extremely frequent (75% to 80% of the study population) as is the presence of clot even in the absence of clinical symptoms.

Only 16% of clot seen on angio

Rates of Recurrent MI

Rothberg et al. Ann. Int. Med. 2005;143:241-250Rothberg et al. Ann. Int. Med. 2005;143:241-250

999 Pts within 8 wks of UA or Acute MIRx : ASA 80 mg; Coumadin (INR 3-4); or Combination: ( INR 2-2.5)+ ASA 80

mg

999 Pts within 8 wks of UA or Acute MIRx : ASA 80 mg; Coumadin (INR 3-4); or Combination: ( INR 2-2.5)+ ASA 80

mg

Death

,MI,

CV

A

1 1 21 1 1

58

15

0

10

20

30

ASA Coumadin Combo

%

Major BleedTranfusionMinor Bleed

van Es et al Lancet 360:109,2002van Es et al Lancet 360:109,2002

Rate ofRate ofDiscontinuationDiscontinuation 10% 19% 20%

EfficacyEfficacy SafetySafetySafetySafety

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Effective Rapid onset and offset of action

Safe Predictable PK and PD Wide therapeutic window

Easy No need for monitoring Oral, preferably once daily Fixed doses Low propensity for food and drug

interactions

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TFPI (tifacogin)

FondaparinuxIdraparinux

RivaroxabanApixabanLY517717YM150DU-176bBetrixabanTAK 442

Dabigatran

ORAL PARENTERAL

DX-9065a

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

AT

APC (drotrecogin alfa)sTM (ART-123)

Adapted from Weitz & Bates, J Thromb Haemost 2007

TTP889

VIIa

Xa

IXa

XIa

XIIaTissue factor

Factor IIa(thrombin)

Dabigatran

II

×

StudyStudy Type of Type of surgerysurgery

ComparatorComparator Number of Number of patientspatients

Time to 1st Time to 1st administration administration of dabigatranof dabigatran

Treatment Treatment durationduration

RE-MODELRE-MODEL TKRTKR Enoxaparin Enoxaparin 40 mg od, starting 40 mg od, starting evening before evening before surgerysurgery

20102010 1–4 hours 1–4 hours post-surgerypost-surgery

6–10 days6–10 days

RE-MOBILIZERE-MOBILIZE TKRTKR Enoxaparin Enoxaparin 30 mg bid, starting 30 mg bid, starting 12–24 hours post-12–24 hours post-surgerysurgery



RE-NOVATERE-NOVATE THRTHR Enoxaparin Enoxaparin 40 mg od, starting 40 mg od, starting evening before evening before surgerysurgery



Dabigatran doses of 150 and 220 mg once daily (od) were investigated in all three studies

TKR: total knee replacement; THR: total hip replacement Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007

EnoxaparinEnoxaparin Dabigatran Dabigatran (150 mg)(150 mg)

Dabigatran Dabigatran (220 mg)(220 mg)

DVT, PE and all-cause mortality (%)DVT, PE and all-cause mortality (%)

RE-NOVATERE-NOVATE 6.76.7 8.6 8.6 pp<0.0001*<0.0001*

6.06.0pp<0.0001*<0.0001*

RE-MOBILIZERE-MOBILIZE 25.325.3 33.733.7pp=0.0009=0.0009††

31.131.1pp=0.02=0.02††

RE-MODELRE-MODEL 37.737.7 40.540.5pp=0.0005*=0.0005*

36.436.4pp=0.0345*=0.0345*

Major bleeding (%)Major bleeding (%)

RE-NOVATERE-NOVATE 1.61.6 1.31.3 2.02.0

RE-MOBILIZERE-MOBILIZE 1.41.4 0.60.6 0.60.6

RE-MODELRE-MODEL 1.31.3 1.31.3 1.51.5

*Non-inferior to enoxaparin; †inferior to enoxaparin Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007

VIIa

Xa

IXa

XIa

XIIaTissu

e factor

Fibrinogen Fibrin clot

Factor II(prothrombin)

RivaroxabanApixaban

YM150DU-176b LY517717Betrixaban

TAK 442

×

Oral, direct, selective factor Xa inhibitor

Produces concentration-dependent anticoagulation

No formation of reactive intermediates

No organ toxicity or LFT abnormalities in chronic toxicology studies

Low likelihood of drug interactions or QTc prolongation

Good oral bioavailability No food effect Balanced elimination (~25% renal) Half-life ~12 hrs

He et al., ASH, 2006, Lassen, et al ASH, 2006

N

N

NO

N O

NH2

O

O

Lassen et al. Blood 2006

10.68.6

6.8

26.6

15.6

0

5

10

15

20

25

30

Total VTE and All-Cause Total VTE and All-Cause Mortality (%)Mortality (%)

Total VTE and All-Cause Total VTE and All-Cause Mortality (%)Mortality (%) Major Bleeding (%)Major Bleeding (%)Major Bleeding (%)Major Bleeding (%)

Enoxaparin(30mg bid)

Apixaban od and bid (total daily doses 5-20mg) were Apixaban od and bid (total daily doses 5-20mg) were assessed relative to enoxaparin and warfarin, in 1,217 assessed relative to enoxaparin and warfarin, in 1,217 patientspatients

20mgApixaban Apixaban

(Total Daily Dose)(Total Daily Dose)

10mg5mg Warfarin (INR

1.8-3.0)

1.3 1.63.0

0 00

5

10

15

20

25

30

Enoxaparin(30mg bid)20mg

Apixaban Apixaban (Total Daily Dose)(Total Daily Dose)

10mg5mg Warfarin (INR

1.8-3.0)

Perc

en

t

Perc

en

t

Büller, Eur Heart J 2006

6.05.6

2.6

4.2

0

2

4

6

8

10

Composite of Symptomatic Composite of Symptomatic Recurrent VTE and Recurrent VTE and

Deterioration of Thrombotic Deterioration of Thrombotic Burden (%)Burden (%)

Composite of Symptomatic Composite of Symptomatic Recurrent VTE and Recurrent VTE and

Deterioration of Thrombotic Deterioration of Thrombotic Burden (%)Burden (%)

Major Bleeding (%)Major Bleeding (%)Major Bleeding (%)Major Bleeding (%)

Apixaban bid (5 and 10mg) and od (20mg) were assessed Apixaban bid (5 and 10mg) and od (20mg) were assessed relative to low molecular weight heparin (LMWH) or relative to low molecular weight heparin (LMWH) or fondaparinux followed by VKA, in 520 patientsfondaparinux followed by VKA, in 520 patients

20mg bid

Apixaban Apixaban

10mg bid

5mg bid

LMWH/ fondaparinux

+ VKA

0.80

0.80

0

2

4

6

8

10

20mg bid

Apixaban Apixaban

10mg bid

5mg bid

LMWH/ fondaparinux

+ VKA

Perc

en

t

Perc

en

t

Agent Disadvantages

Heparin • Parenteral administration• Risk of heparin-induced thrombocytopenia (HIT)• Narrow therapeutic window (low bioavailability, short

half-life)

Warfarin • Requires frequent monitoring due to:– Narrow therapeutic window– Unpredictable pharmacology – Multiple drug–drug and food–drug interactions– Increased risk of major and minor bleeds

LMWH • Parenteral administration• Risk of heparin-induced thrombocytopenia (HIT)

Indirect Xa Inhibitor(e.g. fondaparinux)

• Parenteral administration• Long half-life• Limitations related to special patient populations

Direct Thrombin Inhibitors

• Parenteral administration• Current applications limited to cardiovascular

management Albans S et al. Eur J Clin Invest 2005;35(Suppl 1):12-20.

Predictable pharmacology

High bioavailability Low risk of drug–drug

interactions Fixed dose No requirement for

monitoring

Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005

Rivaroxaban® – rivaroxaban

N NO

NH

O

SCl

O

O

O

Direct, specific, competitive Factor Xa inhibitor Inhibits free and fibrin-bound Factor Xa

activity, and prothrombinase activity

Does not directly inhibit thrombin, but inhibits thrombin generation via inhibition of Factor Xa activity

Does not affect agonist-induced platelet aggregation, and therefore has no direct effect on primary hemostasis

Does not require a cofactor No interaction with aspirin, enoxaparin,

digoxin, naproxen, ranitidine, or antacids

Perzborn et al., J Thromb Haemost 2005; ICT 2004; Depasse et al., ISTH 2005; Kubitza et al., J Clin Pharmacol 200; ASH 2005; Fareed et al., ISTH 2005

XI XIa

IX IXa

Xa

II IIa (Thrombin)

Fibrinogen Fibrin

VIIIa

Va

VIIa + TF VII

TF (Tissue Factor)

X

Extrinsic Extrinsic PathwayPathway

Intrinsic PathwayIntrinsic Pathway

If either Intrinsic If either Intrinsic oror Extrinsic Extrinsic pathway is activated, pathway is activated, Rivaroxaban blocks the final Rivaroxaban blocks the final common coagulation common coagulation pathway leading to thrombin pathway leading to thrombin formation by blocking Factor formation by blocking Factor XaXa

Two large, phase II studies of rivaroxaban for 3 mo for treatment and long term secondary VTE prevention:

› ODIXa-DVT : Rivaroxaban 10–30 mg bid and 40 mg od

› EINSTEIN DVT : Rivaroxaban 20–40 mg od

› LMWH followed by VKA comparator in both studies

Agnelli et al. Circulation 2007; Büller. Eur Heart J 2006

Oral rivaroxaban compared with subcutaneous enoxaparin for

extended thromboprophylaxis after total hip arthroplasty

Inci

dence

(%

)

Total VTETotal VTE

Major Major bleedingbleeding

Enoxaparin 40 mg once daily

Rivaroxaban 10 mg once daily

0

1

2

3

4

5

0.5% 0.3% 0.1% 0.3%

Symptomatic Symptomatic VTEVTE

RRR 70%

2.0% 0.2%

Major VTEMajor VTERRR 88%

1.1%3.7%

Extended thromboprophylaxis with rivaroxaban compared with short-term

thromboprophylaxis with LMWHafter total hip arthroplasty

Total VTE

Major bleeding

Major VTEMajor VTE

Inci

dence

(%

)

0

2

4

6

10

8

9.3%

RRR 78.9%

2.0%

5.1% 0.1% 0.1%

0.6%

RRR 87.8%RRR 80.1%

1.2% 0.2%


Enoxaparin 40 mg once daily

Rivaroxaban 10 mg once daily

Rivaroxaban – an oral, direct Factor Xa inhibitor – for the prevention of venous thromboembolism in total knee arthroplasty surgery

Total VTE

Major bleeding

20

Incid

en

ce (

%)

0

Major VTEMajor VTE5

10

15

NS

RRR 49%

RRR 62%


Rivaroxaban 10 mg od

Enoxaparin 40 mg od

RRR 65%

0.5% 0.6%

18.9%

9.6% 2.6% 1.0% 2.0% 0.7%

Time (hours)

% I

nh

ibit

ion

of

Facto

r X

a

0 2 4 6 8 10 12 14 16 18 20 22 24

0

10

20

30

40

50 Anti-Xa Activity

Rivaroxaban

Rivaroxaban

Rivaroxaban

Rivaroxaban

Rivaroxaban

Rivaroxaban

Placebo (n=25)

1.25 mg (n=8)

5 mg (n=6)

10 mg (n=8)

20 mg (n=7)

40 mg (n=8)

80 mg (n=6)

70

60

-10

Kubitza, et al. Clin Pharmacol Ther 2005;78(4):412-21.

► All once-daily dosage regimens demonstrated

Xa inhibition for out to 24 hours► These results provided foundation for

selection of once-daily dosing regimen for Phase III programs

Specific, competitive, direct FXa inhibitor

Inhibits free and clot-associated FXa activity, and prothrombinase activity

Inhibits thrombin generation via inhibition of FXa activity

◦ Prolongs time to thrombin generation

◦ Inhibits peak thrombin generation

◦ Reduces the total amount of thrombin generated

Does not require a cofactor

Perzborn et al. J Thromb Haemost 2005; ICT 2004; Depasse et al. ISTH 2005; Kubitza et al. Clin Pharmacol Ther 2005; Br J Clin Pharmacol, 2007; Graff et al. In press

Rivaroxaban (nM)0.01 0.1 1 10 100 1000

Inh

ibit

ion

of

Facto

r X

a a

cti

vit

y (

%)

0

20

40

60

80

100

Free FXaProthrombinase activityClot-associated FXa

• Dose peaks in 2.5–4 hrs, tDose peaks in 2.5–4 hrs, t1/21/2=5-9 hrs (11-13 hrs =5-9 hrs (11-13 hrs in elderly)in elderly)

• One doseOne dose will be selected for clinical use will be selected for clinical use

• No monitoringNo monitoring required given consistent dose required given consistent dose responseresponse

• Dual modes of excretionDual modes of excretion

•Renal (66%), no excess bleeding associated Renal (66%), no excess bleeding associated with CrClwith CrCl

•Fecal/biliary (28%)Fecal/biliary (28%)

• Minimal drug/drug interactions,Minimal drug/drug interactions, no major no major circulating metabolites, no drug accumulationcirculating metabolites, no drug accumulation

• Dose peaks in 2.5–4 hrs, tDose peaks in 2.5–4 hrs, t1/21/2=5-9 hrs (11-13 hrs =5-9 hrs (11-13 hrs in elderly)in elderly)

• One doseOne dose will be selected for clinical use will be selected for clinical use

• No monitoringNo monitoring required given consistent dose required given consistent dose responseresponse

• Dual modes of excretionDual modes of excretion

•Renal (66%), no excess bleeding associated Renal (66%), no excess bleeding associated with CrClwith CrCl

•Fecal/biliary (28%)Fecal/biliary (28%)

• Minimal drug/drug interactions,Minimal drug/drug interactions, no major no major circulating metabolites, no drug accumulationcirculating metabolites, no drug accumulation

Kubitza et al., Eur J Clin Pharmacol 2005; Eriksson et al., J Thromb Haemost 2006; Turpie et al., J Thromb Haemost 2005; Kubitza et al., ISTH 2005; Kubitza et al., ASH 2005; Kubitza et al., J Clin Pharmacol 2006

Rivaroxaban: Anti-Thrombotic Efficacy

0.30.3 1.01.0 3.03.000

2020

4040

6060

8080

100100

*

**

Rivaroxaban (mg/kg) p.o.Rivaroxaban (mg/kg) p.o.Rivaroxaban (mg/kg) p.o.Rivaroxaban (mg/kg) p.o.

Th

rom

bu

s r

ed

ucti

on

(%

)Th

rom

bu

s r

ed

ucti

on

(%

)Th

rom

bu

s r

ed

ucti

on

(%

)Th

rom

bu

s r

ed

ucti

on

(%

)

• Arterial thrombosis rabbit arteriovenous shunt model

• Rivaroxaban dose-dependently prevented arterial thrombosis

• Arterial thrombosis rabbit arteriovenous shunt model

• Rivaroxaban dose-dependently prevented arterial thrombosis

**PP<0.05 ; **<0.05 ; **PP<0.01<0.01**PP<0.05 ; **<0.05 ; **PP<0.01<0.01

Primary Total venous thromboembolism (VTE): any

deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality

Secondary Major VTE: proximal DVT, non-fatal PE, and

VTE-related death DVT: any, proximal, distal Symptomatic VTE

All endpoints were adjudicated centrally by independent, blinded committees

Rivaroxaban Safety: Bleeding TimeRivaroxaban Safety: Bleeding Time

Compound

X-fold prolongation of bleeding time at ED50

(control =1)

Rivaroxaban [po] 1.8

Enoxaparin [sc] 2.2

Ximelagatran [po] 3.7

Dabigatran [po] 4.9

Warfarin [po] > 6.3

Tail Transection Bleeding Time in RatsTail Transection Bleeding Time in Rats

Bleeding time comparable to enoxaparin

Lower compared to thrombin inhibitors or warfarin

Bleeding time comparable to enoxaparin

Lower compared to thrombin inhibitors or warfarin

Main Major bleeding starting after the first blinded

dose and ≤2 days after last dose◦ Bleeding that was fatal, into a critical organ or

required re-operation◦ Extra-surgical-site bleeding associated with a drop in

hemoglobin ≥2 g/dL or requiring transfusion of ≥2 units blood

Other Any bleeding on treatment* Non-major bleeding* Hemorrhagic wound complications* Cardiovascular adverse events Liver enzyme levels

All endpoints were adjudicated centrally by independent, blinded committees*Up to 2 days after last dose of study medication

Rivaroxaban: Bleeding Time with Combination Therapy

CompoundsX-fold prolongation

of bleeding time

Clopidogrel 1 mg/kg [po]

Aspirin 3 mg/kg [po] 2.1 +/- 0.3

Clopidogrel 1 mg/kg [po]

Aspirin 3 mg/kg [po]

+

Rivaroxaban 0.1 mg/kg [iv]

2.5 +/- 1

Similiar Bleeding Times

Tail Tail Transection Bleeding Time in RatsTransection Bleeding Time in RatsTail Tail Transection Bleeding Time in RatsTransection Bleeding Time in Rats

0 5 10 15 20 25 30 35 40 Enoxaparin40 mg

Total daily dose (mg) of Rivaroxaban

Incid

en

ce r

ate

%

0

10

20

30

DVT, PE, and all-cause mortalityMajor, post-operative bleeding

Eriksson et al., Circulation 2006

Liver function test (LFT) Rivaroxaban Enox

5 mg 10 mg 20 mg 30 mg 40 mg 40 mg

ALT > 3× ULN

%

5/119 4.2

6/1334.5

4/1333.0

7*/1295.4

5/1273.9

10/1407.1

Rivaroxaban was well tolerated, with similar incidence of AEs as enoxaparin

Rivaroxaban did not affect ECG parameters Rivaroxaban did not have any substance-specific effects

on laboratory parameters (except for clotting tests) LFT increases with BAY 59 7939 did not exceed the level

observed with enoxaparin› There was no dose-dependent increase in transaminase levels

*One patient had ALT >3× ULN and bilirubin >2× ULN (occurring before first intake of study drug)

VTE prevention in VTE prevention in hospitalized medically hospitalized medically ill patientsill patients

Secondary prevention Secondary prevention of acute coronary of acute coronary syndromessyndromes

Japanese Phase III study Japanese Phase III study Stroke prevention in Stroke prevention in atrial fibrillationatrial fibrillation

EINSTEIN-DVT EINSTEIN-DVT EINSTEIN-PEEINSTEIN-PE EINSTEIN-EXTEINSTEIN-EXT

ODIXa-DVTODIXa-DVT EINSTEIN-DVTEINSTEIN-DVT

VTE treatmentVTE treatment

RECORD1 RECORD1 RECORD2RECORD2 RECORD3RECORD3 RECORD4RECORD4

ODIXa-HIP1 ODIXa-HIP1 ODIXa-HIP2ODIXa-HIP2 ODIXa-KNEEODIXa-KNEE ODIXa-OD-HIPODIXa-OD-HIP

VTE prevention after VTE prevention after major orthopaedic major orthopaedic surgerysurgery

Phase III Phase III Phase IIPhase II

>42,000~8,000

RivaroxabaRivaroxabannRivaroxabaRivaroxabann

CM Gibson 2007CM Gibson 2007

SafetySafetySafetySafety

EfficacyEfficacyEfficacyEfficacy EaseEaseEaseEase

RivaroxabanRivaroxabanRivaroxabanRivaroxaban


Is a selective, reversible, active-site directed Factor Xa inhibitor that inhibits coagulation triggered by both the collagen (intrinsic) and tissue factor (extrinsic) pathways

Reduces thrombus formation in both venous and arterial thrombosis models

Has a bleeding risk comparable to Enoxaparin, and lower compared to thrombin inhibitors and Warfarin, in preclinical in vivo models


Reaches Peak (Cmax)) in 2.5–4 hours; half-life of 5–9 hours at steady state (little longer in older)

Dual modes of excretion: Renal (66%) & Faecal / biliary (28%)

No substantial accumulation after multiple dosing, few drug interactions

Dose dependent prolongation of prothrombin time


Target Enrollment Phase II-III 35,000 - 40,000

• Ongoing evaluation in acute and chronic settings for prevention and treatment

of multiple venous and arterial indications


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new approaches to chronic anticoagulatio na

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