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