anticoagulants in acs

Anticoagulants in ACSAnticoagulants in ACS

Surachet Loetthiraphan,Surachet Loetthiraphan,

Preventive Medicine Department,Preventive Medicine Department,

SWU.SWU.

Topic outlinedTopic outlined

Focus on new anticoagulantsFocus on new anticoagulants

Antithrombotics in UA/NSTEMI Patients in the Last Two Decades: Increased Efficacy

at the Price of Increased Bleeding

16-20% 12-15% 8-12% 6-10% 4-8%Dea

th /

MI

BleedingBleeding

1988ASA

1992ASA+

Heparin

1998 ASA+

Heparin+Anti-

GPIIB/IIIA

2003ASA+

LMWH +Clopidogrel +Intervention

With permission from Christopher Cannon

< 1988

Major Bleeding is Associated with an Increased Major Bleeding is Associated with an Increased Risk of Hospital Death in ACS PatientsRisk of Hospital Death in ACS Patients

Moscucci et al. Eur Heart J 2003;24:1815-23

GRACE Registry in 24,045 ACS patients

*After adjustment for comorbidities, clinical presentation, and hospital therapies**p<0.001 for differences in unadjusted death rates

OR (95% CI) 1.64 (1.18 to 2.28)*

0

Overall ACS UA NSTEMI STEMI

10

20

30

40

**

** **

**

5.1

18.6

3.0

16.1

5.3

15.3

7.0

22.8

Inh

os

pit

al d

ea

th (

%)

Inhospital major bleeding Yes

No

Bleeding is Associated with an Increased Bleeding is Associated with an Increased 6-Month Mortality in UA/NSTEMI Patients6-Month Mortality in UA/NSTEMI Patients

Rao et al. Am J Cardiol 2005;96:1200-1206

N=26,452 ACS patients from GUSTO IIb, PURSUIT and PARAGON A & B

Unadjusted death rates Adjusted HR (95% CI)

No bleeding 5.2% (983/18,886) 1.0

Mild bleeding 6.3% (273/4358) 1.4 (1.2-1.6)

Moderate bleeding 9.9% (253/2566) 2.1 (1.8-2.4)

Severe bleeding 35.1% (107/305) 7.5 (6.1-9.3)

Hazard Ratio

GUSTO bleeding

-5 1 5 1510

MortalityMortality

Major BleedingMajor Bleeding

TransfusionTransfusionHypotensionHypotension Cessation of Cessation of ASA/ClopidogrelASA/Clopidogrel

IschemiaIschemia Stent ThrombosisStent Thrombosis InflammationInflammation

Bhatt DL et al. In Braunwald: Harrison’s Online 2005.

Potential mechanism for Morbidity/Mortality Potential mechanism for Morbidity/Mortality associated with bleedingassociated with bleeding

AnticoagulantsAnticoagulants

Unfractionated heparin (UFH)Unfractionated heparin (UFH)Enoxaparin Enoxaparin Fondaparinux Fondaparinux Bivalirudin Bivalirudin

Coagulation cascadeCoagulation cascade

Site of Anticoagulant ActionSite of Anticoagulant ActionTissue factorTissue factor

Plasma clottingcascade

Plasma clottingcascade

ProthrombinProthrombin

ThrombinThrombin

FibrinogenFibrinogen FibrinFibrin

ThrombusThrombus

Platelet aggregationPlatelet aggregation

Platelet activationPlatelet activation

CollagenCollagen

Thromboxane A2Thromboxane A2

ADPADP

ATAT

ATAT

Aspirin

ClopidogrelPrasugrelCangrelor

EptifibatideAbciximabTirofiban

Bivalirudin

FactorXa

FactorXa

Heparin Enoxaparin

Fibrinolytics

Fondaparinux

ATAT

Sites of action for anticoagulantsSites of action for anticoagulants

Factor XaFactor Xa Factor IIa (thrombin)Factor IIa (thrombin)

FondaparinuxFondaparinuxFondaparinuxFondaparinux

EnoxaparinEnoxaparinEnoxaparinEnoxaparin

UnfractionatedUnfractionatedHeparinHeparin

UnfractionatedUnfractionatedHeparinHeparin BivalirudinBivalirudinBivalirudinBivalirudin

Unfractionated Heparin (UFH)Unfractionated Heparin (UFH)

Heterogeneous mixture of polysaccharide chains Heterogeneous mixture of polysaccharide chains Molecular weight 3,000-30,000 DaltonsMolecular weight 3,000-30,000 Daltons Narrow therapeutic window, required monitoring of Narrow therapeutic window, required monitoring of

aPTT, optimal target level of 50-75 secaPTT, optimal target level of 50-75 sec Rebound reactivation of coagulation processRebound reactivation of coagulation process Dose: initial bolus of 60-70 IU/kg with a maximum of

5000 IU, followed by an infusion of 12-15 IU/kg/h, to a maximum of 1000 IU/h

Weitz J, et al. N Engl J Med 1997

Unfractionated Heparin (UFH)Unfractionated Heparin (UFH)

Unfractionated heparin in ACS (N = 1353)Unfractionated heparin in ACS (N = 1353)

Oler et al. JAMA 1996;276:811-6

Limitations of UFHLimitations of UFH

Biological limitationsBiological limitations Heparin induced thrombocytopenia (HIT)Heparin induced thrombocytopenia (HIT) Heparin induced osteoporosisHeparin induced osteoporosis

Pharmacokinetic limitationsPharmacokinetic limitations Variable anticoagulant response (binding to plasma Variable anticoagulant response (binding to plasma

proteins, endothelial cells and macrophage)proteins, endothelial cells and macrophage) Inability to penetrate clot bound thrombinInability to penetrate clot bound thrombin Stimulate platelet aggregationStimulate platelet aggregation Inhibited by platelet factor 4Inhibited by platelet factor 4 Need frequent monitoring of activated partial Need frequent monitoring of activated partial

thromboplastin time (aPTT)thromboplastin time (aPTT)

Advantages of UFHAdvantages of UFH

Rapid and complete neutralized by Rapid and complete neutralized by protamineprotamine1 mg of protamine neutralize 100 units of UFH1 mg of protamine neutralize 100 units of UFHADR: hypotension and bradycardiaADR: hypotension and bradycardia

Non-renal clearanceNon-renal clearanceEffective in modulating contact activation Effective in modulating contact activation

pathwaypathway

Low-Molecular-Weight Heparin Low-Molecular-Weight Heparin (LMWH)(LMWH)

Heparin derived compound by Heparin derived compound by depolymerization with molecular weight depolymerization with molecular weight ranging from 2,000-10,000 Daltonsranging from 2,000-10,000 Daltons

Relatively more inhibition of FXa than Relatively more inhibition of FXa than FIIaFIIa

Ratios of anti-factor Xa:IIa from 1.9-12Ratios of anti-factor Xa:IIa from 1.9-12Dose: 1 mg/kg SC q 12 hrsDose: 1 mg/kg SC q 12 hrs

EnoxaparinEnoxaparin

Weitz J, et al. N Engl J Med 1997

LMWHLMWH More predictable anticoagulant responseMore predictable anticoagulant response Better bioavailabilityBetter bioavailability Less platelet activationLess platelet activation Not neutralized by platelet factor 4Not neutralized by platelet factor 4 Longer half lifeLonger half life Lower risk of HITLower risk of HIT Dose independent clearance mechanismDose independent clearance mechanism Predominantly renal route clearancePredominantly renal route clearance Monitoring of anti-Xa activity is not necessary Monitoring of anti-Xa activity is not necessary

except in renal failure and obesity patientexcept in renal failure and obesity patient

Risk of bleedingRisk of bleeding

Dose-relatedDose-relatedHigher ageHigher ageFemaleFemaleLower body weightLower body weightReduced renal functionReduced renal function Interventional proceduresInterventional procedures

ENOXENOX Bolus 30 mg IVBolus 30 mg IV1.0 mg / kg Q12h1.0 mg / kg Q12h

Pt. with UA/NQMI Pt. with UA/NQMI << 24 h 24 h

Primary Endpoint:

UFH UFH >> 3 days 3 daysBolus 70 U / kgBolus 70 U / kg

INF 15 U / kg / hINF 15 U / kg / h

Major BleedingSerious AEs

ASAASA

aPTT 1.5-2.5 x aPTT 1.5-2.5 x controlcontrol

Hosp DC Hosp DC (or 8 days)(or 8 days)

TIMI 11BProtocol Design

Death, MI, Urgent Revascularization

Acute Phase Protocol

Antman et al, Circulation 1999 Oct 12;100(15):1593-601

22

44

66

88

1010

1212

1414

1616

1818

2020

00 22 44 66 88 1010 1212 1414

P=0.029RRR 15 %

UFUFHHENOENOXX

16.7 %16.7 %

14.2 %14.2 %%

Days

14.5 %14.5 %

12.4 %12.4 %

P=0.048RRR 15 %

TIMI 11BPrimary Results

Death/MI/Urgent Revascularization at 14 Days

E. Antman for The TIMI 11B Investigators Circulation 1999.

JACC 2000;36:693

Peterson JL: JAMA 2004; 292:89-96

Factor Xa Factor Xa A Key Step in Coagulation PathwayA Key Step in Coagulation Pathway

Rosenberg & Aird. N Engl J Med 1999;340:1555–64Wessler & Yin. Thromb Diath Haemorrh 1974;32:71–8

Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin (IIa)

Intrinsic pathway Extrinsic pathway

1

50

Xa X

II

FibrinFibrinogen

Clot

XaVa

PLCa2+

IIa

VIIIa

Ca2+

PL

IXa

Herbert et al. Cardiovasc Drug Rev 1997;15:1-26 Herbert et al. Cardiovasc Drug Rev 1997;15:1-26 van Boeckel et al. van Boeckel et al. Angew Chem [Int Ed Engl] 1993;32: 1671-90Angew Chem [Int Ed Engl] 1993;32: 1671-90

Single chemical entity No risk of pathogen contamination Highly selective for its target Once-daily administration Rapid onset (Cmax/2=25 min)

FondaparinuxFondaparinux A Synthetic Inhibitor of Factor XaA Synthetic Inhibitor of Factor Xa

No liver metabolism No protein binding (other than AT) No reported cases of HIT No dose adjustment necessary

in the elderly

IIa IIa IIII

FibrinogenFibrinogen Fibrin clotFibrin clot

Extrinsic Extrinsic pathwaypathway

IntrinsicIntrinsicpathwaypathway

AT XaXaAT AT

Fondaparinux Fondaparinux

XaXa

Antithrombin

Fondaparinux (AT-Dependent):Fondaparinux (AT-Dependent):MechanismMechanism of Action of Action

Olson et al. J Biol Chem 1992;267:12528-38Turpie Turpie et al. Net al. N EnEngl J Med 2001;344gl J Med 2001;344:619:619-25-25

THROMBIN

Recycled

Time (hour)Time (hour)

0.05

0.10

0.15

0.20

0.25

0.30

0.35

Fo

nd

apar

inu

x co

nce

ntr

atio

n (

µg

/mL

)

0 4 8 12 16 20 24 28 32 36

tmax = 1.7 hr

Cmax = 0.34 µg/mL

Cmax/2 = 25 min

t1/2 = 15–18 hr

Rapid onset of action with significant plasma levels (Cmax/2) achieved within 25 min after s.c. injection

Fondaparinux: PharmacokineFondaparinux: Pharmacokinetictic Profile with s.c. InjectionProfile with s.c. Injection

Donat et al. Clin Pharmacokinet 2002;41(suppl):1-9

FondaparinuxFondaparinux

Excellent bioavailabilityExcellent bioavailabilityPlasma half life 17 hrs.Plasma half life 17 hrs.Excreted unchanged in urineExcreted unchanged in urineNot caused HITNot caused HITReversed with recombinant factor VIIaReversed with recombinant factor VIIa

OASIS 5: An International, Multicenter, OASIS 5: An International, Multicenter, Randomized, Double-Blind, Double-Dummy Trial Randomized, Double-Blind, Double-Dummy Trial

in 41 Countriesin 41 Countries

20,078 patients with UA/NSTEMI20,078 patients with UA/NSTEMI20,078 patients with UA/NSTEMI20,078 patients with UA/NSTEMI

Fondaparinux2.5 mg s.c. od up to 8 days

Aspirin, Clopidogrel, anti-GPIIb/IIIa, planned Cath/PCI as per local practice

Randomization

Enoxaparin1 mg/kg s.c. bid for 2-8 days

1 mg/kg s.c. od if ClCr<30mL/min

1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e102. OASIS 5 Investigators. N Engl J Med 1464-76

Vital status ascertained in 20,066 (99.9%) Lost to follow-up at day 9: fondaparinux: n=7 and enoxaparin: n=5

Study Objectives and OutcomesStudy Objectives and Outcomes

Outcomes (centrally adjudicated)Primary efficacy: 1st occurrence of the composite of death, MI, or refractory

ischemia (RI) up to day 9

Primary safety: Major bleeding up to day 9

Risk benefit: Death, MI, refractory ischemia, major bleeds up to day 9

Secondary: Above & each component separately at days 30 and 180

ObjectivesPrimary efficacy objective: To demonstrate non-inferiority of fondaparinux

compared with enoxaparin

Primary safety objective: To determine whether fondaparinux was superior to enoxaparin in preventing major bleeding

ObjectivesPrimary efficacy objective: To demonstrate non-inferiority of fondaparinux

compared with enoxaparin

Primary safety objective: To determine whether fondaparinux was superior to enoxaparin in preventing major bleeding

1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e102. OASIS 5 Investigators. N Engl J Med 2006;354:1464-76

Fondaparinux Was Non-Inferior to Enoxaparin Fondaparinux Was Non-Inferior to Enoxaparin at Day 9 (Primary Efficacy: death/MI/RI)at Day 9 (Primary Efficacy: death/MI/RI)

Fondaparinux: 5.8% (579 events)Enoxaparin: 5.7% (573 events)

Time to event death/MI/RI up to day 9

Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0.04

0.05

0.06

0 1 2 3 4 5 6 7 8 9

Enoxaparin

Fondaparinux

HR: 1.01 95% CI: 0.90-1.13p=0.007 for non-inferiority

Fondaparinux Significantly Reduced Fondaparinux Significantly Reduced Mortality Mortality vs.vs. Enoxaparin up to Day 30 Enoxaparin up to Day 30


Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0 3 6 9 12 15 18 21 24 27 30

HR: 0.83 95% CI: 0.71-0.97p=0.02

Enoxaparin

Fondaparinux

0.04

The Fondaparinux-Associated Reduction The Fondaparinux-Associated Reduction in Mortality Was Maintained up to 6 Monthsin Mortality Was Maintained up to 6 Months


Days

Cu

mu

lati

ve H

azar

d

0.0

0.02

0.04

0.06

0 20 40 60 80 100 120 140 160 180

HR: 0.8995% CI: 0.80-1.00 p=0.05

Enoxaparin

Fondaparinux

0.08

Fondaparinux Reduced the Rate of the Fondaparinux Reduced the Rate of the Composite of Death, MI or Stroke up to 6 MonthsComposite of Death, MI or Stroke up to 6 Months


0.0

Days0 20 40 60 80 100 120 140 160 180

Cu

mu

lati

ve H

azar

d

HR: 0.8995% CI: 0.82-0.97 p=0.007

Enoxaparin

Fondaparinux

0.02

0.04

0.06

0.08

0.10

0.12

0.14


Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0.04

0 1 2 3 4 5 6 7 8 9

HR: 0.52 95% CI: 0.44-0.61 p<0.001

Enoxaparin

Fondaparinux

Fondaparinux Patients Experienced Half the Rate Fondaparinux Patients Experienced Half the Rate of Major Bleeding Than Enoxaparin Patients at of Major Bleeding Than Enoxaparin Patients at

Day 9 (Primary Safety)Day 9 (Primary Safety)

The Reduction in Major Bleeding with The Reduction in Major Bleeding with Fondaparinux Was Consistent in Almost All Fondaparinux Was Consistent in Almost All

CategoriesCategoriesMajor bleeding Major bleeding at day 9at day 9

EnoxaparinEnoxaparinN (%)N (%)

FondaparinuxFondaparinuxN (%)N (%)

P P valuevalue

No. RandomizedNo. Randomized 10,02110,021 10,05710,057

Total Major BleedsTotal Major Bleeds 412 (4.1%)412 (4.1%) 212 (2.1%)212 (2.1%) <0.001<0.001

IntracranialIntracranial 7 (0.1)7 (0.1) 7 (0.1)7 (0.1) NSNS

Requiring surgeryRequiring surgery 77 (0.8)77 (0.8) 41 (0.4)41 (0.4) <0.001<0.001

RetroperitonealRetroperitoneal 37 (0.4)37 (0.4) 9 (0.1)9 (0.1) <0.001<0.001

Requiring transfusionRequiring transfusion 287 (2.8)287 (2.8) 164 (1.6)164 (1.6) <0.001<0.001

Associated with death Associated with death at study endat study end

79 (0.8)79 (0.8) 38 (0.4)38 (0.4) <0.001<0.001

OASIS 5 Investigators. N Engl J Med 2006;354:1464-76

Multiple Types of Bleeding Were Reduced Multiple Types of Bleeding Were Reduced in the Fondaparinux Group at Day 9in the Fondaparinux Group at Day 9

OutcomeOutcome EnoxaparinEnoxaparin(%)(%)

FondaparinuxFondaparinux(%)(%)

P valueP value

No. RandomizedNo. Randomized 10,02110,021 10,05710,057

Total bleedsTotal bleeds 7.37.3 3.33.3 <0.001*<0.001*

Major bleedsMajor bleeds 4.14.1 2.22.2 <0.001**<0.001**

TIMI major+fatal bleedsTIMI major+fatal bleeds 1.31.3 0.70.7 <0.001***<0.001***

Fatal bleedsFatal bleeds 0.20.2 0.10.1 0.0050.005

Minor bleedsMinor bleeds 3.23.2 1.11.1 <0.001<0.001

*HR (95% CI): 0.44 (0.39-0.50);**n=7 with fondaparinux vs. 22 with enoxaparin;***HR (95% CI): 0.55 (0.41-0.74)


The Reduction in Major Bleeding at Day 9 with The Reduction in Major Bleeding at Day 9 with Fondaparinux Was Consistent in All SubgroupsFondaparinux Was Consistent in All Subgroups


Characteristics N Enoxaparin Fondaparinux

% %

Age≥ 65 yr 12,261 5.5 2.7< 65 yr 7814 2.1 1.4 0.11

SexMale 12,379 3.3 2.0Female 7699 5.5 2.5 0.07

CreatinineAt or above median* 11,124 4.7 2.4Less than median* 8871 3.4 1.9 0.71

Heparin at randomizationYes 3566 5.0 3.0No 16,512 4.0 2.0 0.35

Revascularization in 9 daysYes 7372 6.0 4.2No 12,706 3.0 1.0 < 0.001

Catheterization laboratory in centerYes 14,028 5.0 2.6No 6050 2.3 1.2 0.88

1.0 1.40.2

Fondaparinux better Enoxaparin better

0.4 0.6 0.8 1.2*The median value for creatinine was 88 µmol/L (1.04 mg/dL)

Interaction p value

The Fondaparinux-Associated Reduction The Fondaparinux-Associated Reduction in Major Bleeding Appeared Early and in Major Bleeding Appeared Early and

was Maintained Through Day 30was Maintained Through Day 30


Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0.04

0.05

0 3 6 9 12 15 18 21 24 27 30

HR: 0.62 95% CI: 0.54-0.72p<0.001

Enoxaparin

Fondaparinux

The Fondaparinux-Associated Reduction in The Fondaparinux-Associated Reduction in Major Bleeding Was Maintained up to 6 MonthsMajor Bleeding Was Maintained up to 6 Months

Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0.04

0.05

0.06

0 20 40 60 80 100 120 140 160 180

HR: 0.7295% CI: 0.64-0.82p<0.001

Enoxaparin

Fondaparinux


Patients Who Bled by Day 9 Experienced an Patients Who Bled by Day 9 Experienced an

Increased Mortality at Day 30 and 6 MonthsIncreased Mortality at Day 30 and 6 Months

Budaj et al. JACC 2006;abstract 972-224

Adjusted HR (95% CI) at day 30: 5.06 (4.59-5.62; p<0.05); at day 180: 3.16 (2.92-3.44; p<0.05)

0.00

0.05

0.10

0.15

0.20

0 30 60 90 120 150 180

Major Bleed 9 days

No Major Bleed 9 days

Mo

rta

lity

cu

mu

lati

ve

Ha

zard

Days

Patients Who Bled by Day 9 Experienced an Patients Who Bled by Day 9 Experienced an Increased Risk of MI at Day 30 and 6 MonthsIncreased Risk of MI at Day 30 and 6 Months



0 30 60 90 120 150 180

Days

0.00

MI c

um

ula

tiv

e H

aza

rd

0.05

0.10

0.15

Major Bleed 9 days


Patients Who Bled by Day 9 Experienced an Patients Who Bled by Day 9 Experienced an Increased Risk of Stroke at Day 30 and 6 MonthsIncreased Risk of Stroke at Day 30 and 6 Months



0 30 60 90 120 150 180

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Str

ok

e c

um

ula

tiv

e H

aza

rd

Days

Major Bleed 9 days



Fondaparinux Showed a Significant Net Clinical Fondaparinux Showed a Significant Net Clinical Benefit (Death/MI/RI/Major Bleeding) up to 6 Benefit (Death/MI/RI/Major Bleeding) up to 6

MonthsMonths

Days

Cu

mu

lati

ve H

azar

d

0.0

0.05

0.10

0.15

0 20 40 60 80 100 120 140 160 180

Enoxaparin

Fondaparinux

HR: 0.8695% CI: 0.81-0.93p<0.001

0.20

Events at Day 9 in Patients with PCI in the First Events at Day 9 in Patients with PCI in the First 8 Days Comparable to Overall Study Results8 Days Comparable to Overall Study Results


p<0.001

1.2

5.0 5.1

8.6

1.2

5.1

2.3

9.3

0

2

4

6

8

10

12

Death MI Major bleed Death/MI/RI

Eve

nt

Rat

e (%

)Clinical Events at Day 9

Enoxaparin (n=3104) Fondaparinux (n=3135)

EventsEventsEnoxaparin (%)Enoxaparin (%)

n=3104n=3104

Fondaparinux Fondaparinux (%)(%)

n= 3135n= 3135HR (95% CI)HR (95% CI)

Any complicationAny complication11 8.68.6 9.59.5 1.11 (0.94-1.29)1.11 (0.94-1.29)

Coronary Coronary complicationcomplication22

5.25.2 6.06.0 1.16 (0.94-1.42)1.16 (0.94-1.42)

Catheter-related Catheter-related thrombus with no thrombus with no clinical complicationclinical complication

0.10.1 0.30.3 2.99 (0.81-2.99 (0.81-11.04) 11.04)

All catheter-related All catheter-related thrombithrombi

0.40.4 0.90.9 3.59 (1.64-3.59 (1.64-7.84)7.84)33

PCI-Related ComplicationsPCI-Related Complications

1Includes death, MI or stroke at 48 hours, plus the events listed in the table2Abrupt closure, new thrombus with reduced flow, dissection, no reflow3p=0.001


Clinical ImplicationsClinical Implications

THE OASIS 5 TRIAL CLEARLY DEMONSTRATES THAT FONDAPARINUX SHOULD BE THE PREFERRED ANTICOAGULANT FOR TREATMENT OF ACS.

Direct Thrombin InhibitorsDirect Thrombin Inhibitors

Weitz JI, et al. Circulation 2002; 105: 1004-11.

• Bivalent direct thrombin inhibitor

• High specificity and potency

• Lack of dependence on antithrombin-III

• Effect on clot-bound & free thrombin

• No platelet activation

• No inhibition by PF4 and others

• t½ of 25 min

• Predominant renal clearance

• No antidote

(Gly)4

Bivalirudin PharmacologyBivalirudin Pharmacology

Gly-Pro-Arg-Pro (active site binding region)

C-terminal dodecapeptide(exosite 1-binding region)

Direct Thrombin InhibitorsDirect Thrombin Inhibitors

Eikelboom JW, et al. J Am Coll Cardiol 2003; 41: 70S-78.

Moderateand highrisk ACS

(n=13,819)

ACUITYACUITY

An

gio

gra

ph

y w

ith

in 7

2h

Aspirin in allClopidogrel

dosing and timingper local practice

Aspirin in allClopidogrel

dosing and timingper local practice

UFH/Enox+ GP IIb/IIIa(n=4,603)

Bivalirudin+ GP IIb/IIIa(n=4,604)

BivalirudinAlone

(n=4,612)

R*

*Stratified by pre-angiography thienopyridine use or administration*Stratified by pre-angiography thienopyridine use or administration

Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)

Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)

Medicalmanagement

PCI

CABG

56%

11%

33%

11.7%11.8% 1.01 (0.90-1.12)<0.001

0.93

0 1 2

Risk ratio±95% CI

Risk ratio±95% CI

Primaryendpoint

Primary Endpoint Measures (ITT) – 30 DaysPrimary Endpoint Measures (ITT) – 30 Days

UFH/Enoxaparin + GPI vs. Bivalirudin + GPIUFH/Enoxaparin + GPI vs. Bivalirudin + GPI

Net clinical outcome

Ischemic composite

Major bleeding

Bivalirudin + IIb/IIIa betterBivalirudin + IIb/IIIa better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better

Bival+ IIb/IIIa

UFH/Enox+ IIb/IIIa

RR (95% CI)p value(non inferior)

(superior)

7.3%7.7% 1.07 (0.92-1.23)0.0150.39

5.7%5.3% 0.93 (0.78-1.10)<0.001

0.38Up

per

bo

un

dar

y n

on

-in

feri

ori

ty

Stone GW et al. NEJM 2006;355:2203-16

0 1 2

Primary Endpoint Measures (ITT) – 30 DaysPrimary Endpoint Measures (ITT) – 30 Days

Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better

Risk ratio±95% CI

Risk ratio±95% CI

Primaryendpoint

Bivalalone

UFH/Enox+ IIb/IIIa

RR (95% CI)

Net clinical outcome

Ischemic composite

Major bleeding

Up

per

bo

un

dar

y n

on

-in

feri

ori

ty

11.7%10.1% 0.86 (0.77-0.97)<0.0010.015

7.3%7.8% 1.08 (0.93-1.24)0.010.32

5.7%3.0% 0.53 (0.43-0.65)<0.001<0.001

p value(non inferior)

(superior)

UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone

Stone GW et al. NEJM 2006;355:2203-16

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

5

15

25

Isch

emic

Co

mp

osi

te (

%)

Days from Randomization

10

20 UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

EstimateP

(log rank)

30 day

7.4%0.367.8%0.347.9%

—

EstimateP

(log rank)

16.3%0.3816.5%0.3116.4%

1 year

—

p=0.55

Bivalirudin alone vs. Hep+GPIHR [95% CI] = 1.05 (0.95-1.17)

Bivalirudin+GPI vs. Hep+GPIHR [95% CI] = 1.05 (0.94-1.16)

Ischemic Composite EndpointIschemic Composite Endpoint(Death, MI, unplanned revascularization for ischemia)(Death, MI, unplanned revascularization for ischemia)

UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone

Mo

rtal

ity

(%)

Days from Randomization

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

5

15

30

10

25

20

1 yearEstimate

Major Bleed only (without MI) (N=551) 12.5%28.9%Both MI and Major Bleed (N=94)

3.4%No MI or Major Bleed (N=12,557)MI only (without Major Bleed) (N=611) 8.6%

Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year

28.9%

12.5%

8.6%

3.4%

ConclusionsConclusions• In patients with moderate and high risk ACS

undergoing an early invasive strategy with the use of GP IIb/IIIa inhibitors

• Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin

• Compared to either UFH/enoxaparin with GP IIb/IIIa inhibitors or bivalirudin with GP IIb/IIIa inhibitors

• A bivalirudin alone strategy results in marked reduction of bleeding at 30 days, and similar rates of mortality and composite ischemia at 1-year

• The results of this study further establish the important relationship between iatrogenic bleeding complications and subsequent mortality in patients with ACS

Bleeding conceptsBleeding concepts

Bleeding carries high risk of death, MI and Bleeding carries high risk of death, MI and strokestroke

Rate of major bleeding is as high as the rate of Rate of major bleeding is as high as the rate of death at the acute phase of ACSdeath at the acute phase of ACS

Prevention of bleeding is equally as important as Prevention of bleeding is equally as important as prevention of ischemic events and results in a prevention of ischemic events and results in a significant risk reduction of death, MI and strokesignificant risk reduction of death, MI and stroke

Risk stratification for bleeding should be part of Risk stratification for bleeding should be part of the decision making processthe decision making process

Anticoagulant optionsAnticoagulant options

Unfractionated heparinUnfractionated heparin Advantages - Advantages -

Measurable, Reversible, Measurable, Reversible, ExperienceExperience

Disadvantages - Platelet Disadvantages - Platelet activation, HIT(TS), activation, HIT(TS), Unreliable degree of Unreliable degree of antithrombin activityantithrombin activity

LMWHLMWH Advantages - More Advantages - More

reliable anticoagulationreliable anticoagulation Disadvantages - Not Disadvantages - Not

measurable, Platelet measurable, Platelet activation, Some degree activation, Some degree of discomfort during PCIof discomfort during PCI

FondaparinuxFondaparinux Advantages - Similar Advantages - Similar

efficacy to LMWH with efficacy to LMWH with less bleedingless bleeding

Disadvantages - Not Disadvantages - Not demonstrated to be safe demonstrated to be safe during PCI, Not easily during PCI, Not easily reversiblereversible

BivalirudinBivalirudin Advantages - Less Advantages - Less

bleeding, Measurable, bleeding, Measurable, Short tShort t1/21/2

Disadvantages - Not more Disadvantages - Not more efficacious than UFH, efficacious than UFH, Trends toward slightly Trends toward slightly more ischemic eventsmore ischemic events

ESC Guideline 2007ESC Guideline 2007

In an non-urgent situation:In an non-urgent situation:FondaparinuxFondaparinux is recommended on the basis of is recommended on the basis of

the most favourable efficacy/safety profile (I-A)the most favourable efficacy/safety profile (I-A)Enoxaparin with a less favourable efficacy/safety Enoxaparin with a less favourable efficacy/safety

profile than fondaparinux should be used only if profile than fondaparinux should be used only if the bleeding risk is low (IIa-B)the bleeding risk is low (IIa-B)

In an urgent invasive strategy:In an urgent invasive strategy:UFH (I-C), enoxaparin (IIa-B), or bivalirudin (I-B) UFH (I-C), enoxaparin (IIa-B), or bivalirudin (I-B)

should be immediately startedshould be immediately started

ACC/AHA Guideline 2007:ACC/AHA Guideline 2007:Initial Conservative StrategyInitial Conservative Strategy

For patients in whom a For patients in whom a conservative strategy is selected, conservative strategy is selected, regimens using either enoxaparin or regimens using either enoxaparin or UFH UFH (Level of Evidence: A) (Level of Evidence: A) or or fondaparinux fondaparinux (Level (Level of Evidence: B) of Evidence: B) have established efficacyhave established efficacy

In patients in whom a conservative In patients in whom a conservative strategy is selected and who have an strategy is selected and who have an increased risk of bleeding, increased risk of bleeding, fondaparinux is preferablefondaparinux is preferable

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII


*Limited data are available for the use of other low-molecular-weight heparins (LMWHs), e.g., dalteparin.

New Drugs

ACC/AHA Guideline 2007: ACC/AHA Guideline 2007: Initial Invasive StrategyInitial Invasive Strategy

For patients in whom an For patients in whom an invasive strategy is selected, invasive strategy is selected, regimens with established regimens with established efficacy at a efficacy at a Level of Evidence: Level of Evidence: A A include enoxaparin and include enoxaparin and unfractionated heparin (UFH) unfractionated heparin (UFH) and those with established and those with established efficacy at a efficacy at a Level of Evidence: Level of Evidence: B B include bivalirudin and include bivalirudin and fondaparinux fondaparinux



New Drugs

anticoagulants in acs

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