Acs – new biomarkers & role of newer anticoagulants

ACS – New biomarkers & Role of newer anticoagulants

ACS – New biomarkers & Role of newer anticoagulants

Dr. Arindam Pande,

Associate Consultant, Cardiology,

Apollo Gleneagles Hospital, Hospital

Dr. Arindam Pande,

Associate Consultant, Cardiology,

Apollo Gleneagles Hospital, Hospital

“A biomarker is a substance used as an indicator of a biologic state. It is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”--Wikipedia

“A biomarker is a substance used as an indicator of a biologic state. It is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”--Wikipedia

The perfect cardiac markerThe perfect cardiac marker

► Marker for myocardial necrosis, and also for cardiac ischemia

► Linear relationship between blood levels and extent of myocardial injury (and prognosis)

► 100% sensitive

► 100% specific

► Immediate increase (+ constant blood level for hours to days)

► Test kits : reliable, rapid, universally available and inexpensive

► Marker for myocardial necrosis, and also for cardiac ischemia

► Linear relationship between blood levels and extent of myocardial injury (and prognosis)

► 100% sensitive

► 100% specific

► Immediate increase (+ constant blood level for hours to days)

► Test kits : reliable, rapid, universally available and inexpensive

Copyright ©2005 American Association for Clinical ChemistryApple, F. S. et al. Clin Chem 2005;51:810-824

Biochemical profile in ACS patients: vascular inflammation to plaque rupture to ischemia to cell

death to myocardial dysfunction

Interdependence of Cardiac BiomarkersInterdependence of Cardiac Biomarkers

Coronary artery disease Risk factors (eg, cholesterol)

Coronary inflammation CRP, Lp-PLA2*, homocysteine, MPO

Plaque instability/disruption MPO, Lp(a), Lp-PLA2

Myocardial ischemia/necrosis Cardiac troponins, CK-MB, myoglobin

Ventricular overload BNP, Nt-proBNP

Pathophysiology Biochemical Markers

Adapted from Panteghini. Eur Heart J. 2004;25:1187-1196.* Lipoprotein associated phospholipase A 2

Progression of Biomarkers in ACSProgression of Biomarkers in ACS

ACS, acute coronary syndrome; UA, unstable angina; NSTEMI, non–ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction

Adapted from: Apple Clinical Chemistry March 2005

STEMIUA/NSTEMISTABLE CAD PLAQUE RUPTURE

MPOCRPIL-6

MPO ICAMsCD40LPAPP-A

MPOD-dimerIMAFABP

TnITnTMyoglobinCKMB

Inflammation has been linked to the development of vulnerable plaque and to plaque rupture

Stefan Blankenberg, MD; Renate Schnabel, MD; Edith Lubos, MD, et al., Myeloperoxidase Early Indicator of Acute Coronary Syndrome and Predictor of Future Cardiovascular Events 2005

TIME LINE OF MARKERS OF MYOCARDIAC DAMAGE & FUNCTION

TIME LINE OF MARKERS OF MYOCARDIAC DAMAGE & FUNCTION

1950 1960 1970 1980 1990 2000 2005

AST in AMI CK in

AMI

Electrophoresis for CK and LD

CK – MB

Myoglobin assay

RIA for ANP

CK-MB mass assay

cTnT assay

RIA for BNP and proANP

cTnl assay

RIA for proBNP

POCT for myoglobin CK-MB, cTnI

Immuno assay for proBNP

IMA

Genetic Markers

Timeline history of assay methods for markers of cardiac tissue damage and myocardial function.

AST: aspartate aminotransferase ANP: atrial natriuretic peptide

CK: creatine kinase BNP: brain natriuretic peptide

LD: lactate dehyydrogenase POCT: point-of-care testing

cTn: cardiac-specific troponin IMA: ischaemia-modified albumin

Time [years]

QUESTIONS ANSWERED BY CARDIAC MARKERS

QUESTIONS ANSWERED BY CARDIAC MARKERS

Rule in/out an acute MI Confirm an old MI (several days) Monitor the success of thrombolytic therapy Risk stratification of patients with unstable angina

pectoris

N.B. Risk stratification in apparently healthy persons is not done with cardiac markers, but by measurement and assessment of cardiac risk factors

Rule in/out an acute MI Confirm an old MI (several days) Monitor the success of thrombolytic therapy Risk stratification of patients with unstable angina

pectoris

N.B. Risk stratification in apparently healthy persons is not done with cardiac markers, but by measurement and assessment of cardiac risk factors

R. Hinzmann, 2002

BIOCHEMICAL MARKERS IN MYOCARDIAL ISCHAEMIA / NECROSIS

BIOCHEMICAL MARKERS IN MYOCARDIAL ISCHAEMIA / NECROSIS

IN: CK-MB (mass) c.Troponins (I or T) Myoglobin

IN: CK-MB (mass) c.Troponins (I or T) Myoglobin

OUT: AST activity LDH activity LDH isoenzymes CK-MB activity CK-Isoenzymes ?CK-Total

OUT: AST activity LDH activity LDH isoenzymes CK-MB activity CK-Isoenzymes ?CK-Total

NEW / FUTURE:NEW / FUTURE: Ischaemia Modified AlbuminIschaemia Modified Albumin Glycogen Phosphorylase BBGlycogen Phosphorylase BB Fatty Acid binding ProteinFatty Acid binding Protein Free fatty acidsFree fatty acids Fibrin peptide A & othersFibrin peptide A & others

““CARDIAC ENZYMES”CARDIAC ENZYMES”

are are

Obsolete!Obsolete!

““CARDIAC ENZYMES”CARDIAC ENZYMES”

are are

Obsolete!Obsolete!

The Future of Cardiac BiomarkersThe Future of Cardiac Biomarkers

Many experts are advocating the move towards a multimarker strategy for the purposes of diagnosis, prognosis, and treatment design

As the pathophysiology of ACS is heterogeneous, so must be the diagnostic strategies

Many experts are advocating the move towards a multimarker strategy for the purposes of diagnosis, prognosis, and treatment design

As the pathophysiology of ACS is heterogeneous, so must be the diagnostic strategies

Multiple Markers Are Needed for Diagnosis and Prognosis of ACS

Multiple Markers Are Needed for Diagnosis and Prognosis of ACS

No single ideal marker exists for ACS

Complicated diseases are not likely to be associated with single markers

Multiple markers define disease categories

Multi-marker panels can aid in differential diagnosis

No single ideal marker exists for ACS

Complicated diseases are not likely to be associated with single markers

Multiple markers define disease categories

Multi-marker panels can aid in differential diagnosis

04/08/23

C-Reactive ProteinC-Reactive Protein Elevated levels associated with increased risk

of recurrent events in ACS Multiple roles in cardiovascular disease have

been examined Screening for cardiovascular risk in otherwise

“healthy” men and women Predictive value of CRP levels for disease severity in

pre-existing CAD Prognostic value in ACS

Elevated levels associated with increased risk of recurrent events in ACS

Multiple roles in cardiovascular disease have been examined Screening for cardiovascular risk in otherwise

“healthy” men and women Predictive value of CRP levels for disease severity in

pre-existing CAD Prognostic value in ACS

BIOCHEMICAL MARKERS OF MYOCARDIAL FUNCTION

BIOCHEMICAL MARKERS OF MYOCARDIAL FUNCTION

CARDIAC NATRIURETIC PEPTIDES:(ANP, BNP & pro-peptide forms) Family of peptides secreted by cardiac atria (+ ventricles) with potent diuretic,

natriuretic & vascular smooth muscle relaxing activity increase with disease progression

Clinical usefulness (especially BNP/N-terminal pro-BNP) Detection of LV dysfunction Screening for heart disease Differential diagnosis of dyspnea Stratification of CCF patients Prognostic marker in acute coronary syndrome (increased risk of death at 10

months as concentration at 40 hours post-infarct increased and also increased risk for new or recurrent MI and postinfarct heart failure (OPUS-TIMI 16)

BNP levels in blood reflect neurohormonal activity, elevated levels associated with larger infarct size, increased probability of ventricular remodeling, lower ejection fraction, higher risk of heart failure, and increased mortality

BNP measurements also help determine the need for aggressive pharmacological and interventional therapies

CARDIAC NATRIURETIC PEPTIDES:(ANP, BNP & pro-peptide forms) Family of peptides secreted by cardiac atria (+ ventricles) with potent diuretic,

natriuretic & vascular smooth muscle relaxing activity increase with disease progression

Clinical usefulness (especially BNP/N-terminal pro-BNP) Detection of LV dysfunction Screening for heart disease Differential diagnosis of dyspnea Stratification of CCF patients Prognostic marker in acute coronary syndrome (increased risk of death at 10

months as concentration at 40 hours post-infarct increased and also increased risk for new or recurrent MI and postinfarct heart failure (OPUS-TIMI 16)

BNP levels in blood reflect neurohormonal activity, elevated levels associated with larger infarct size, increased probability of ventricular remodeling, lower ejection fraction, higher risk of heart failure, and increased mortality

BNP measurements also help determine the need for aggressive pharmacological and interventional therapies

MYOGLOBIN (Mb)MYOGLOBIN (Mb)

Peak at 6 – 9h Normal by 24 – 36h Currently earliest marker Useful for re-infarction diagnosis Like total CK it is by no means cardio-

specific Excellent NEGATIVE predictor of

myocardial injury 2 samples 2 – 4 hours apart with no rise in

levels virtually excludes AMI

Peak at 6 – 9h Normal by 24 – 36h Currently earliest marker Useful for re-infarction diagnosis Like total CK it is by no means cardio-

specific Excellent NEGATIVE predictor of

myocardial injury 2 samples 2 – 4 hours apart with no rise in

levels virtually excludes AMI

MyeloperoxidaseMyeloperoxidase Released by activated leukocytes at elevated levels in

vulnerable plaques Leads to oxidized LDL cholesterol which is phagocytosed by

macrophages producing foam cells Can cause endothelial denuding and superficial platelet

aggregation, vasoconstriction and endothelial dysfunction – elevated in coronary arteries remote from the culprit lesion

Predicts cardiac risk independently of other markers of inflammation

May be useful in triage of ACS (levels elevate in the 1st two hours)

Also identifies patients at increased risk of CV event in the 6 months following a negative troponin

NEJM 349: 1595-1604

Released by activated leukocytes at elevated levels in vulnerable plaques

Leads to oxidized LDL cholesterol which is phagocytosed by macrophages producing foam cells

Can cause endothelial denuding and superficial platelet aggregation, vasoconstriction and endothelial dysfunction – elevated in coronary arteries remote from the culprit lesion

Predicts cardiac risk independently of other markers of inflammation

May be useful in triage of ACS (levels elevate in the 1st two hours)

Also identifies patients at increased risk of CV event in the 6 months following a negative troponin

NEJM 349: 1595-1604

Glomerular Filtration RateGlomerular Filtration Rate Reduced GFR has been associated with:

Increased inflammatory factors Abnormal lipoprotein levels Elevated plasma homocysteine Anemia Arterial stiffness Endothelial dysfunction

Impaired renal function is independent of other standard risk factors such as Troponin elevation

Reduced GFR has been associated with: Increased inflammatory factors Abnormal lipoprotein levels Elevated plasma homocysteine Anemia Arterial stiffness Endothelial dysfunction

Impaired renal function is independent of other standard risk factors such as Troponin elevation

ISCHAEMIA-MODIFIED ALBUMIN (IMA)

ISCHAEMIA-MODIFIED ALBUMIN (IMA)

Serum albumin is altered by free radicals released from ischaemic tissue

Angioplasty studies show that albumin is modified within minutes of the onset of ischaemia.

IMA levels rise rapidly, remain elevated for 2-4 h + return to baseline within 6h

Clinically may detect reversible myocardial ischaemic damage Not specific (elevated in stroke, some neoplasms, hepatic cirrhosis,

end-stage renal disease) Thus potential value is as a negative predictor FDA approved as a rule-out marker in low risk ACS patients

(2003).

Serum albumin is altered by free radicals released from ischaemic tissue

Angioplasty studies show that albumin is modified within minutes of the onset of ischaemia.

IMA levels rise rapidly, remain elevated for 2-4 h + return to baseline within 6h

Clinically may detect reversible myocardial ischaemic damage Not specific (elevated in stroke, some neoplasms, hepatic cirrhosis,

end-stage renal disease) Thus potential value is as a negative predictor FDA approved as a rule-out marker in low risk ACS patients

(2003).

HEART-TYPE FATTY ACID BINDING PROTEIN (H-FABP)HEART-TYPE FATTY ACID

BINDING PROTEIN (H-FABP) Smaller molecule Diffuse through interstitial fluid more rapidly after cell death Become abnormal as early as 30 min after myocardial injury Low specificity for myocardial tissue Though 20 times more specific to cardiac muscle than myoglobin High false positivity Combination with troponin ↑diagnostic accuracy (Negative

predictive value of 98%) → could be used to identify those not suffering from MI at the early time point of 3-6 hours post chest pain onset

Also has prognostic value independent of troponin T, ECG and clinical examination

Smaller molecule Diffuse through interstitial fluid more rapidly after cell death Become abnormal as early as 30 min after myocardial injury Low specificity for myocardial tissue Though 20 times more specific to cardiac muscle than myoglobin High false positivity Combination with troponin ↑diagnostic accuracy (Negative

predictive value of 98%) → could be used to identify those not suffering from MI at the early time point of 3-6 hours post chest pain onset

Also has prognostic value independent of troponin T, ECG and clinical examination

Serum Amyloid A (SAA)Serum Amyloid A (SAA)

are family of apolipoproteins associated with HDL in plasma

secreted during the acute phase of inflammation increase within hours after inflammatory stimulus

(magnitude greater than that of CRP) elevated levels associated with ↑ risk for 14-day

mortality even among patients with negative assay for troponin T (TIMI 11A)

are family of apolipoproteins associated with HDL in plasma

secreted during the acute phase of inflammation increase within hours after inflammatory stimulus

(magnitude greater than that of CRP) elevated levels associated with ↑ risk for 14-day

mortality even among patients with negative assay for troponin T (TIMI 11A)

Glycogen phosphorylase isoenzyme BB (GPBB)

Glycogen phosphorylase isoenzyme BB (GPBB)

 elevated 1–3 hours after process of ischemia – one of the new early marker of ACS

 exists in heart and brain tissue, because of the blood–brain barrier GP-BB can be seen as heart muscle specific

during the process of ischemia, GP-BB is converted into a soluble form and is released into the blood

high sensitivity and specificity 

 elevated 1–3 hours after process of ischemia – one of the new early marker of ACS

 exists in heart and brain tissue, because of the blood–brain barrier GP-BB can be seen as heart muscle specific

during the process of ischemia, GP-BB is converted into a soluble form and is released into the blood

high sensitivity and specificity 

IL-6IL-6 IL-6 is a cytokine, a nonantibody protein and

intercellular mediator Plasma concentrations reflect the intensity

of plaque vulnerability to rupture and restenosis following percutaneous coronary intervention

Elevation of circulating IL-6 is a strong and independent marker of increased mortality in acute coronary events

IL-6 predicts future MIs in healthy men as well as total mortality in the elderly

IL-6 is a cytokine, a nonantibody protein and intercellular mediator

Plasma concentrations reflect the intensity of plaque vulnerability to rupture and restenosis following percutaneous coronary intervention

Elevation of circulating IL-6 is a strong and independent marker of increased mortality in acute coronary events

IL-6 predicts future MIs in healthy men as well as total mortality in the elderly

Plasma D-DimerPlasma D-Dimer Peptide end product of fibrin breakdown and reflects the

ongoing process of thrombus formation and dissolution ↑circulating levels of D-dimer associated with ↑

thrombotic complications in patients with MI Levels of D-dimer can predict acute MI, recurrent

coronary events, and peripheral atherothrombosis Because of its role early in ischemic

pathophysiology, D-dimer levels increase in acute coronary events before the elevation in levels of cardiac injury markers (including myoglobin)

Lack of specificity

Peptide end product of fibrin breakdown and reflects the ongoing process of thrombus formation and dissolution

↑circulating levels of D-dimer associated with ↑ thrombotic complications in patients with MI

Levels of D-dimer can predict acute MI, recurrent coronary events, and peripheral atherothrombosis

Because of its role early in ischemic pathophysiology, D-dimer levels increase in acute coronary events before the elevation in levels of cardiac injury markers (including myoglobin)

Lack of specificity

PREGNANCY-ASSOCIATED PLASMA PROTEIN (PAPP)

PREGNANCY-ASSOCIATED PLASMA PROTEIN (PAPP)

high molecular weight metalloproteinase originally identified in the serum of pregnant women before delivery

is abundant histologically in eroded and ruptured plaques but is not expressed in stable plaques

elevated in patients with both UA and acute MI, but levels are not influenced by sex, age, risk factors, or medications

elevated PAPP-A levels identify patients with UA even in the absence of elevation in cTn or hs-CRP levels

as a marker can detect plaque rupture before markers that indicate onset of MI and myocardial necrosis

high molecular weight metalloproteinase originally identified in the serum of pregnant women before delivery

is abundant histologically in eroded and ruptured plaques but is not expressed in stable plaques

elevated in patients with both UA and acute MI, but levels are not influenced by sex, age, risk factors, or medications

elevated PAPP-A levels identify patients with UA even in the absence of elevation in cTn or hs-CRP levels

as a marker can detect plaque rupture before markers that indicate onset of MI and myocardial necrosis

GLUCOSE / HbA1cGLUCOSE / HbA1c

Elevated admission value predict adverse outcome in both diabetic and nondiabetics

Synergistic relationship b/w hyperglycemia and inflammation

Risk associated with hyperglycemia amplified in patients with elevated CRP levels

Elevated admission value predict adverse outcome in both diabetic and nondiabetics

Synergistic relationship b/w hyperglycemia and inflammation

Risk associated with hyperglycemia amplified in patients with elevated CRP levels

THROMBUS PRECURSORS PROTEIN

THROMBUS PRECURSORS PROTEIN

Soluble fibrin polymer precursor to the formation of insoluble fibrin

Elevated levels significantly correlated with adverse clinical outcome

Soluble fibrin polymer precursor to the formation of insoluble fibrin

Elevated levels significantly correlated with adverse clinical outcome

WBC CountWBC Count

Simpler, universally available Nonspecific When elevated, have higher risk of

mortality and recurrent MI Association independent of CRP

Simpler, universally available Nonspecific When elevated, have higher risk of

mortality and recurrent MI Association independent of CRP

SUMMARYSUMMARY No single ideal marker exists for ACS “Cardiac Enzymes” are obsolete Measurement of hs-CRP, BNP/ NT-proBNP may be useful, in

addition to a cardiac troponin, for risk assessment in patients with a clinical syndrome consistent with ACS. The benefits of therapy based on this strategy remain uncertain

A multimarker strategy that includes measurement of two or more pathobiologically diverse biomarkers, in addition to a cardiac troponin, may aid in enhancing risk stratification in patients with a clinical syndrome consistent with ACS

Additional roles for cardiac markers in: Reperfusion monitoring, Infarct size/prognosis, Intra/post-operative MI (non-cardiac/cardiac surgery)

Development of multiple newer biomarkers of ACS targeting different pathophysiological aspect are very encouraging but they need to be validated in future studies to incorporate them in guidelines.

No single ideal marker exists for ACS “Cardiac Enzymes” are obsolete Measurement of hs-CRP, BNP/ NT-proBNP may be useful, in

addition to a cardiac troponin, for risk assessment in patients with a clinical syndrome consistent with ACS. The benefits of therapy based on this strategy remain uncertain

A multimarker strategy that includes measurement of two or more pathobiologically diverse biomarkers, in addition to a cardiac troponin, may aid in enhancing risk stratification in patients with a clinical syndrome consistent with ACS

Additional roles for cardiac markers in: Reperfusion monitoring, Infarct size/prognosis, Intra/post-operative MI (non-cardiac/cardiac surgery)

Development of multiple newer biomarkers of ACS targeting different pathophysiological aspect are very encouraging but they need to be validated in future studies to incorporate them in guidelines.

Newer anticoagulants in ACS

Newer anticoagulants in ACS

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

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

osp

ital

dea

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 PatientsBleeding 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

AnticoagulantsAnticoagulantsAnticoagulantsAnticoagulants

Unfractionated heparin (UFH) Enoxaparin Fondaparinux Bivalirudin

Unfractionated heparin (UFH) Enoxaparin Fondaparinux Bivalirudin

Mode of action of different antithrombins in coagulation cascadeMode of action of different antithrombins in coagulation cascade

Xa

II

IIa

Fondaparinox AT III

Indirect inhibition Direct inhibition

EnoxaparinAT III

UFHAT III

OtamixabanApixabanRivaroxaban

Bivalirudin

Dabigatran

X

X

X

X

X

XX

X

Limitations of heparin as a anticoagulant

Limitations of heparin as a anticoagulant

Non specific binding to plasma proteins and endothelial cells Release of platelet factor 4 and von Willibrand factor

from platelets during clotting Inability to inactivate fibrin bound thrombin Heparin induces platelet activation Forms heparin antibodies Dose-dependent half-life Need frequent monitoring of activated partial

thromboplastin time (aPTT) Ill-defined dose to achieve target ACT level in PCI

Non specific binding to plasma proteins and endothelial cells Release of platelet factor 4 and von Willibrand factor

from platelets during clotting Inability to inactivate fibrin bound thrombin Heparin induces platelet activation Forms heparin antibodies Dose-dependent half-life Need frequent monitoring of activated partial

thromboplastin time (aPTT) Ill-defined dose to achieve target ACT level in PCI

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

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

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 Reversed with recombinant factor

VIIa

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

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

Fon

dap

arin

ux

con

cen

trat

ion

(µ

g/m

L)

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

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

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

Study design of the OASIS-5 trial.21.

OASIS-5—conclusionOASIS-5—conclusion

Upstream therapy with fondaparinux compared with upstream enoxaparin substantially reduces major bleeding while maintaining efficacy, resulting in superior net clinical benefit.

Catheter thrombus was more common in patients receiving fondaparinux (0.9%) than enoxaparin alone (0.4%)

The use of standard UFH in place of fondaparinux at the time of PCI seems to prevent angiographic complications, including catheter thrombus, without compromising the benefits of upstream fondaparinux.

Upstream therapy with fondaparinux compared with upstream enoxaparin substantially reduces major bleeding while maintaining efficacy, resulting in superior net clinical benefit.

Catheter thrombus was more common in patients receiving fondaparinux (0.9%) than enoxaparin alone (0.4%)

The use of standard UFH in place of fondaparinux at the time of PCI seems to prevent angiographic complications, including catheter thrombus, without compromising the benefits of upstream fondaparinux.

12,000 Patients with STEMI < 12 h of symptom onsetInclusion: ST 2 mm prec leads or 1 mm limb leads

Exclusion: Contra-ind. for anticoagulant, INR>1.8, pregnancy, ICH<12 mo.

12,000 Patients with STEMI < 12 h of symptom onsetInclusion: ST 2 mm prec leads or 1 mm limb leads

Exclusion: Contra-ind. for anticoagulant, INR>1.8, pregnancy, ICH<12 mo.

UFH not indicatedUFH UFH notnot indicatedindicated

Study Design: Randomized, Double Study Design: Randomized, Double Blind, Double DummyBlind, Double Dummy

Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late)Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (egeg. late). late)

StratificationStratificationStratification

UFH indicatedUFH indicatedUFH indicated

Randomization Randomization

Fondaparinux2.5 mg Placebo

Fondaparinux2.5 mg UFH

OASISOASIS--6 Conclusions:6 Conclusions:

1. Fondaparinux significantly reduces mortality and re-MI in STEMI without increasing bleeding compared to placebo or UFH.

2. Benefits emerge at 9 days and are sustained to 180 days.

3. In primary PCI, there was no benefit with fondaparinux.

4. The benefits are marked in those receiving no reperfusion therapy and those receiving thrombolytics (21% RRR at 30 days), with lower severe bleeding.

5. Mortality is significantly reduced

Advantages of direct thrombin inhibitors

No nonspecific binding to plasma proteins

Not neutralized by platelet factor 4 (PF4)

Ability to inactivate free and bound thrombin

Inhibits thrombin-mediated platelet activation

No formation of heparin-PF4 complexes

Predictable anticoagulant response

Retains activity in presence of platelet-rich thrombi

Completely inhibits fluid-phase and fibrin-bound thrombin

No activation of clotting cascade or release of binding proteins

No heparin-induced thrombocytopenia

Courtesy of R Mehran, MD.

BIVALIRUDINBIVALIRUDIN

Direct, bivalent, synthetic, non competitive, reversible thrombin inhibitor

Bivalirudin is cleared by a combination of proteolytic cleavage and renal mechanisms

Bivalirudin has a half-life of about 25 minutes in patients with normal renal function, with prolongation seen in patients with moderate (34 min) or severe(57 min) renal impairment (creatinine clearance of 30 to 59 mL/min and less than 30 mL/min,respectively).

Coagulation times return to baseline approximately 1 hour following cessation of bivalirudin administration

Direct, bivalent, synthetic, non competitive, reversible thrombin inhibitor

Bivalirudin is cleared by a combination of proteolytic cleavage and renal mechanisms

Bivalirudin has a half-life of about 25 minutes in patients with normal renal function, with prolongation seen in patients with moderate (34 min) or severe(57 min) renal impairment (creatinine clearance of 30 to 59 mL/min and less than 30 mL/min,respectively).

Coagulation times return to baseline approximately 1 hour following cessation of bivalirudin administration

Bivalirudin Angioplasty Trial (BAT)Bivalirudin Angioplasty Trial (BAT) double-blind, controlled, randomized clinical study of

bivalirudin vs UFH in urgent PTCA in cases of unstable or post infract angina.

Concomittant treatment with Aspirin (300 to 325 mg) Randomized effectives 2059 / 2039 (studied vs. control) bivalirudin bolus dose of 1.0 mg per kilogram of body

weight, followed by a 4-hour infusion at a rate of 2.5 mg per kilogram per hour and a 14-to-20-hour infusion at a rate of 0.2 mg per kilogram per hour.

bolus dose of 175 units per kilogram followed by an 18-to-24-hour infusion at a rate of 15 units per kilogram per hour

Primary endpoint death, MI, abrupt clossure, rapide deterioration

double-blind, controlled, randomized clinical study of bivalirudin vs UFH in urgent PTCA in cases of unstable or post infract angina.

Concomittant treatment with Aspirin (300 to 325 mg) Randomized effectives 2059 / 2039 (studied vs. control) bivalirudin bolus dose of 1.0 mg per kilogram of body

weight, followed by a 4-hour infusion at a rate of 2.5 mg per kilogram per hour and a 14-to-20-hour infusion at a rate of 0.2 mg per kilogram per hour.

bolus dose of 175 units per kilogram followed by an 18-to-24-hour infusion at a rate of 15 units per kilogram per hour

Primary endpoint death, MI, abrupt clossure, rapide deterioration

Analysis and limitationsAnalysis and limitations

Bivalirudin reduced the combined primary end point (death, myocardial infarction (MI), and urgent revascularisation at 7 days) by 22% (p=0.039), whereas significant bleeding complications were lowered by 63% (3.5% vs 9.3%;p<0.001).

High UFH dose Done In 1990, no gp IIb/IIIa , clopidogrel , no

stents

Bivalirudin reduced the combined primary end point (death, myocardial infarction (MI), and urgent revascularisation at 7 days) by 22% (p=0.039), whereas significant bleeding complications were lowered by 63% (3.5% vs 9.3%;p<0.001).

High UFH dose Done In 1990, no gp IIb/IIIa , clopidogrel , no

stents

REPLACE 1REPLACE 1

Studied treatment bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/h infusion ,Control treatment heparin (70 U/kg initial bolus) adjusted to ACT of 200 to 300s procedure

Concomittant treatment aspirin;pretreatment with clopidogrel encouraged,and GPIIb/IIIa inhibitors at physician’s discretion

patients undergoing elective or urgent revascularization

Studied treatment bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/h infusion ,Control treatment heparin (70 U/kg initial bolus) adjusted to ACT of 200 to 300s procedure

Concomittant treatment aspirin;pretreatment with clopidogrel encouraged,and GPIIb/IIIa inhibitors at physician’s discretion

patients undergoing elective or urgent revascularization

AnalysisAnalysis

Bivalirudin reduced bleeding complications only without addition of Gp IIb/IIIa inhibitors (2.0% vs 0%; p<0.001),

No difference in bleeding was detected when Gp IIb/IIIa inhibitors were used (2.9% vs 2.9%).

Primary outcome data (a combination of death, MI, and urgent target vessel revascularization within 48 h) did not differ between study groups and were independent of the use or non-use of Gp IIb/IIIa inhibitors.

Bivalirudin reduced bleeding complications only without addition of Gp IIb/IIIa inhibitors (2.0% vs 0%; p<0.001),

No difference in bleeding was detected when Gp IIb/IIIa inhibitors were used (2.9% vs 2.9%).

Primary outcome data (a combination of death, MI, and urgent target vessel revascularization within 48 h) did not differ between study groups and were independent of the use or non-use of Gp IIb/IIIa inhibitors.

Replace 2 Replace 2 Studied treatment bivalirudin, with glycoprotein

IIb/IIIa (Gp IIb/IIIa) inhibition on a provisional basis for complications during PCI

Control treatment heparin plus planned Gp IIb/IIIa blockade

patients undergoing urgent or elective PCI Randomized effectives 2994 / 3008 (studied vs.

control) Design Parallel groups Blinding - double blind Follow-up duration 30 days Primary endpoint death, MI, urgent revascularization,

or in-hospital

Studied treatment bivalirudin, with glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition on a provisional basis for complications during PCI

Control treatment heparin plus planned Gp IIb/IIIa blockade

patients undergoing urgent or elective PCI Randomized effectives 2994 / 3008 (studied vs.

control) Design Parallel groups Blinding - double blind Follow-up duration 30 days Primary endpoint death, MI, urgent revascularization,

or in-hospital

AnalysisAnalysis

The primary composite net clinical end point (death, MI, urgent revascularization (UR), and major bleeding) was similar between treatment groups (10.0% vs 9.2%; p=0.324),

Bivalirudin was associated with reduced major (2.4% vs 4.1%)and minor (13.4% vs 25.7%) bleeding complications (p<0.001 for both).

The primary composite net clinical end point (death, MI, urgent revascularization (UR), and major bleeding) was similar between treatment groups (10.0% vs 9.2%; p=0.324),

Bivalirudin was associated with reduced major (2.4% vs 4.1%)and minor (13.4% vs 25.7%) bleeding complications (p<0.001 for both).

Moderate-high risk

ACS

ACUITYStudy Design – First Randomization

ACUITYStudy Design – First Randomization

Ang

iogr

aphy

with

in 7

2h

UFH orEnoxaparin

+ GP IIb/IIIa

Bivalirudin+ GP IIb/IIIa

BivalirudinAlone

R*

Medicalmanagement

PCI

CABG

Aspirin in all Clopidogrel dosing and timing per local

practice

ACUITY Design. Stone GW et al, AHJ 2004;148:764-75ACUITY Design. Stone GW et al, AHJ 2004;148:764-75

Moderate-high risk unstable angina or NSTEMI undergoing an invasive Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800)strategy (N = 13,800)

Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800)

Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800)

ACUITY Design. Stone GW et al. AHJ 2004;148:764–75ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

Moderate-high risk

ACS

Aspirin in allClopidogrel

dosing and timingper local practice

Aspirin in allClopidogrel

dosing and timingper local practice

BivalirudinAlone

Routine upstream GPI in all pts

GPI started in CCL for PCI only

R

R

Routine upstream GPI in all pts

GPI started in CCL for PCI only

UF

H, E

noxaparin,or B

ivalirudinU

FH

, Enoxaparin,

or Bivalirudin

Routine upstreamGPI in all pts

Deferred GPIfor PCI only

VS.VS.

Primary analysisPrimary analysis

Secondary

analysis

Secondary

analysis

Bivalirudin

UFH or Enoxaparin

AnalysisAnalysis

The combination of bivalirudin or UFH/enoxaparin with Gp IIb/IIIa inhibitors showed no significant benefit (‘non-inferiority’ p<0.0001) with respect to the composite ischaemic end point (death, MI, or UR: 7.7% vs 7.3%; =.39), major bleeding (5.3% vs 5.7%; p¼0.38), or the combined net clinical end point (11.8% vs 11.7%; p¼0.93), respectively.

In contrast, bivalirudin monotherapy significantly reduced major bleeding by 48% (3.0% vs 5.7%; p<0.001) without compromising efficacy

The combination of bivalirudin or UFH/enoxaparin with Gp IIb/IIIa inhibitors showed no significant benefit (‘non-inferiority’ p<0.0001) with respect to the composite ischaemic end point (death, MI, or UR: 7.7% vs 7.3%; =.39), major bleeding (5.3% vs 5.7%; p¼0.38), or the combined net clinical end point (11.8% vs 11.7%; p¼0.93), respectively.

In contrast, bivalirudin monotherapy significantly reduced major bleeding by 48% (3.0% vs 5.7%; p<0.001) without compromising efficacy

HORIZONS-AMI: Study designHarmonizing Outcomes with Revascularization and Stents in Acute Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial InfarctionMyocardial Infarction

UFH +GP IIb/IIIa inhibitor

n = 1802

Bivalirudinmonotherapy

n = 1800Randomized

30-day follow-up

ITT population

•• •• •• Withdrew Withdrew •• •• ••

•• •• •• Lost to followLost to follow--up up •• •• ••99

1515

1010

1313

N = 3602 with STEMI

Courtesy of R Mehran, MD; Mehran R et al. Am Heart J. 2008;156:44-56.ITT = intention to treat

n = 1778(98.7%)

n = 1802

n = 1777(98.7%)

n = 1800

R 1:1

ConclusionsConclusions In this large scale, prospective, randomized trial of

pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in:

A significant 16% reduction in the 1-year rate of composite net adverse clinical events

A significant 39% reduction in the 1-year rate of major bleeding

Significant 31% and 43% reductions in the 1-year rates of all-cause and cardiac mortality (absolute 1.4% and 1.7% reductions), with non significantly different rates of reinfarction, stent thrombosis, stroke and TVR at 1-year

In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in:

A significant 16% reduction in the 1-year rate of composite net adverse clinical events

A significant 39% reduction in the 1-year rate of major bleeding

Significant 31% and 43% reductions in the 1-year rates of all-cause and cardiac mortality (absolute 1.4% and 1.7% reductions), with non significantly different rates of reinfarction, stent thrombosis, stroke and TVR at 1-year

Mehran R, TCT 2008

Broad spectrum of experience with bivalirudin in clinical trials

Broad spectrum of experience with bivalirudin in clinical trials

27,735 patients undergoing invasive management of CAD27,735 patients undergoing invasive management of CAD

REPLACE-2(N=6,002)

CADPlanned PCI

BAT(N=4,312)

UA, NQWMIPlanned PTCA

ACUITY(N=13,819)

NSTE-ACSPCI <72h

HORIZONS(N=3,602)

STEMIEmergency PCI

Increasing risk of ischaemic complications

Lincoff et alJAMA, 2003

Bittl et alAHJ, 2001

Stone et alNEJM, 2006

Stone et alNEJM, 2007

RivaroxabanRivaroxaban

Oral ,direct factor Xa inhibitor High bioavailability Rapid onset of action 2.5 – 5 mg bd T ½ =7-11 hrs Metabolism= 2/3 hepatic , 1/3 renal

Oral ,direct factor Xa inhibitor High bioavailability Rapid onset of action 2.5 – 5 mg bd T ½ =7-11 hrs Metabolism= 2/3 hepatic , 1/3 renal

GOALS of ATLAS ACS TIMI 46GOALS of ATLAS ACS TIMI 46GOALS of ATLAS ACS TIMI 46GOALS of ATLAS ACS TIMI 46

Primary Goal - Safety:

• To identify tolerable doses of rivaroxaban in the treatment of ACS for evaluation in a large Phase III trial

Primary Goal - Safety:

• To identify tolerable doses of rivaroxaban in the treatment of ACS for evaluation in a large Phase III trial

Secondary Goal - Efficacy: • To explore efficacy of rivaroxaban at

tolerable doses

Conduct a robust phase II dose ranging trial

Gibson CM, AHA 2008

STUDY DESIGNSTUDY DESIGNSTUDY DESIGNSTUDY DESIGN

NO YES

Recent ACS PatientsRecent ACS PatientsStabilized 1-7 Days Post-Index EventStabilized 1-7 Days Post-Index Event

Treat for 6 Months Treat for 6 Months

MD Decision to Treat with ClopidogrelMD Decision to Treat with Clopidogrel

N = 3,491

Aspirin 75-100 mg

STRATUM 1ASA Alone

N=761

STRATUM 1ASA Alone

N=761

STRATUM 2ASA + Clop.

N=2,730

STRATUM 2ASA + Clop.

N=2,730

PLACEBON=253

5 mg (77)10 mg (98)20 mg (78)

RIVA QD N=254

5 mg (77)10 mg (99)20 mg (78)

RIVA BID N=254

2.5 mg (77)

5 mg (97)10 mg (80)

PLACEBON=907

5 mg (74)10 mg (428)15 mg (178)20 mg (227)

RIVA QDN=912

5 mg (78)10 mg (430)15 mg (178)20 mg (226)

RIVA BIDN=911

2.5 mg (76)5 mg (430)

7.5 mg (178)10 mg (227)

Gibson CM, AHA 2008

SUMMARY- SAFETYSUMMARY- SAFETYSUMMARY- SAFETYSUMMARY- SAFETY

• There was increased bleeding associated with higher There was increased bleeding associated with higher doses of rivaroxaban.doses of rivaroxaban.

• No evidence of drug induced liver injury

• Most bleeding was bleeding requiring medical attention, rather than TIMI major or TIMI minor bleeding

Gibson CM, AHA 2008

SUMMARY-EFFICACYSUMMARY-EFFICACYSUMMARY-EFFICACYSUMMARY-EFFICACY

22oo Endpoint Endpoint: : 31% RRR in the risk of death, MI, or stroke (HR 0.69, p=0.028)31% RRR in the risk of death, MI, or stroke (HR 0.69, p=0.028)

11oo Endpoint Endpoint: : 21% RRR (HR 0.79, p=0.10) in death, MI, stroke, or severe recurrent ischemia 21% RRR (HR 0.79, p=0.10) in death, MI, stroke, or severe recurrent ischemia requiring revascularization requiring revascularization

Gibson CM, AHA 2008

SELECTION OF DOSES FOR PHASE III

SELECTION OF DOSES FOR PHASE III

Based upon:1. Efficacy at lower doses of rivaroxaban2. Graded increase in bleeding at higher doses of rivaroxaban3. A trend for BID doses of rivaroxaban to be safer and more efficacious than QD

dosing of rivaroxaban in ACS

• Two low doses, 2.5 mg BID and 5 mg BID, have been selected for the Phase III trial

Based upon:1. Efficacy at lower doses of rivaroxaban2. Graded increase in bleeding at higher doses of rivaroxaban3. A trend for BID doses of rivaroxaban to be safer and more efficacious than QD

dosing of rivaroxaban in ACS

• Two low doses, 2.5 mg BID and 5 mg BID, have been selected for the Phase III trial

Gibson CM, AHA 2008

PHASE III DESIGNPHASE III DESIGNPHASE III DESIGNPHASE III DESIGNRecent ACS PatientsRecent ACS Patients(Event driven trial: (Event driven trial: 13,500 to16,000 pts)13,500 to16,000 pts)

Stabilized 1-7 Days Post-Index EventStabilized 1-7 Days Post-Index Event

Study is event driven---expected duration is 33 monthsStudy is event driven---expected duration is 33 months

PRIMARY EFFICACY ENDPOINT:PRIMARY EFFICACY ENDPOINT:CV Death, MI, StrokeCV Death, MI, Stroke

RIVAROXABAN

2.5 mg BID

RIVAROXABAN

2.5 mg BID

PLACEBO

PLACEBO

RIVAROXABAN

5.0 mg BID

RIVAROXABAN

5.0 mg BID

Stratified by Thienopyridine use

Gibson CM, AHA 2008

ApixabanApixaban Oral direct Xa inhibitor Dose = 5mg b.d T ½ = 8-15 hrs Metabolism and excretion = renal and

hepatic APPRAISE , APPRAISE 2 – dose releted

increase in bleeding and a trend to reduction in ischaemic events

Oral direct Xa inhibitor Dose = 5mg b.d T ½ = 8-15 hrs Metabolism and excretion = renal and

hepatic APPRAISE , APPRAISE 2 – dose releted

increase in bleeding and a trend to reduction in ischaemic events

OtamixabanOtamixaban I.V. , direct and selective Xa inhibitor Dose = 0.1- 0.4 mg/kg/hr T1/2 =30 mts Hepatic metabolism and excretion No dose adjutment in renal dysfunction SEPIA –PCI trial , SEPIA ACS 1 TIMI 42

trial

I.V. , direct and selective Xa inhibitor Dose = 0.1- 0.4 mg/kg/hr T1/2 =30 mts Hepatic metabolism and excretion No dose adjutment in renal dysfunction SEPIA –PCI trial , SEPIA ACS 1 TIMI 42

trial

DabigatranDabigatran Oral direct thrombin inhibitor Dose = 50-150 mg b.d T1/2 = 12- 17 hrs Renal excretion REDEEM trial

Oral direct thrombin inhibitor Dose = 50-150 mg b.d T1/2 = 12- 17 hrs Renal excretion REDEEM trial

PROTEASE-ACTIVATED RECEPTOR (PAR-1) ANTAGONIST

PROTEASE-ACTIVATED RECEPTOR (PAR-1) ANTAGONIST

Thrombin potently stimulates platelets by activating PAR-1

VORAPAXAR blocks this interaction Phase п trial in PCI patients revealed a trend

towards ↓ death/MI without ↑ bleeding Ongoing phase ш trial in patients with recent

ACS (TRACER)

Thrombin potently stimulates platelets by activating PAR-1

VORAPAXAR blocks this interaction Phase п trial in PCI patients revealed a trend

towards ↓ death/MI without ↑ bleeding Ongoing phase ш trial in patients with recent

ACS (TRACER)

Better Outcomes Observed with Newer Better Outcomes Observed with Newer Anticoagulants Anticoagulants

• • Recent improvements in Recent improvements in anticoagulant therapy have anticoagulant therapy have

dramatically reduced acute bleeding at the expense of a dramatically reduced acute bleeding at the expense of a

slightly lower, but insignificant, anti-ischemic efficacy, slightly lower, but insignificant, anti-ischemic efficacy,

particularly in PCI patients. particularly in PCI patients. This shift in the efficacy vs This shift in the efficacy vs

safety ratio translated into a mortality reduction at follow up.safety ratio translated into a mortality reduction at follow up.

• • Recent improvements in Recent improvements in anticoagulant therapy have anticoagulant therapy have

dramatically reduced acute bleeding at the expense of a dramatically reduced acute bleeding at the expense of a

slightly lower, but insignificant, anti-ischemic efficacy, slightly lower, but insignificant, anti-ischemic efficacy,

particularly in PCI patients. particularly in PCI patients. This shift in the efficacy vs This shift in the efficacy vs

safety ratio translated into a mortality reduction at follow up.safety ratio translated into a mortality reduction at follow up.

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

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

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

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

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

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

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

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 :ACC/AHA Guideline :Initial Conservative StrategyInitial Conservative Strategy

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

For UA/NSTEMI patients in whom an initial conservative strategy is selected, enoxaparin or fondaparinux is preferable to UFH as anticoagulant therapy, unless CABG is planned within 24 h. (Level of Evidence: B)

For UA/NSTEMI patients in whom an initial conservative strategy is selected, enoxaparin or fondaparinux is preferable to UFH as anticoagulant therapy, unless CABG is planned within 24 h. (Level of Evidence: B)

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

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

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

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

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

New Drugs

thank you thank you