Acs – new biomarkers & role of newer anticoagulants

ACS – New biomarkers & Role
of newer anticoagulants
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

The 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

Copyright ©2005 American Association for Clinical Chemistry
Apple, 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 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 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
MPO
CRP
IL-6
MPO
ICAM
sCD40L
PAPP-A
MPO
D-dimer
IMA
FABP
TnI
TnT
Myoglobin
CKMB
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
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
 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
IN:
 CK-MB (mass)
 c.Troponins (I or T)
 Myoglobin
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”
areare
Obsolete!Obsolete!

The 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

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

C-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

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

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

Myeloperoxidase
 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 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

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).

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

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)

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

IL-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

Plasma 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

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

GLUCOSE / 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

THROMBUS PRECURSORS
PROTEIN
 Soluble fibrin polymer precursor to the
formation of insoluble fibrin
 Elevated levels significantly correlated with
adverse clinical outcome

WBC Count
 Simpler, universally available
 Nonspecific
 When elevated, have higher risk of
mortality and recurrent MI
 Association independent of CRP

SUMMARY
 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.

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%
Death/MI
BleedingBleeding
1988
ASA
1992
ASA+
Heparin
1998
ASA+
Heparin+
Anti-
GPIIB/IIIA
2003
ASA+
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
Inhospitaldeath(%)
Inhospital major bleeding YesNo

Bleeding is Associated with an Increased Bleeding is Associated with an Increased
6-Month Mortality in UA/NSTEMI Patients6-Month Mortality in UA/NSTEMI Patients
Bleeding is Associated with an Increased Bleeding is Associated with an Increased
6-Month Mortality in UA/NSTEMI Patients6-Month Mortality in UA/NSTEMI Patients
Rao et al. Am J Cardiol 2005;96:1200-1206
N=26,452 ACS patients from GUSTO IIb, PURSUIT and PARAGON A & B
Unadjusted death rates Adjusted HR (95% CI)
No bleeding 5.2% (983/18,886) 1.0
Mild bleeding 6.3% (273/4358) 1.4 (1.2-1.6)
Moderate bleeding 9.9% (253/2566) 2.1 (1.8-2.4)
Severe bleeding 35.1% (107/305) 7.5 (6.1-9.3)
Hazard Ratio
GUSTO bleeding
-5 1 5 1510

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

Mode of action of different antithrombins in coagulation cascade
Xa
II
IIa
Fondaparinox

AT III
Indirect
inhibition Direct inhibition
Enoxaparin
AT III
UFH
AT III
Otamixaban
Apixaban
Rivaroxaban
Bivalirudin
Dabigatran
X
X
X
X
X
XX
X

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

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;340:1555–64
Wessler & 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
Xa
Va
PL
Ca2+
IIa
VIIIa
Ca2+
PL
IXa

Herbert et al. Cardiovasc Drug Rev 1997;15:1-26Herbert 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
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

IIaIIaIIII
FibrinogenFibrinogen Fibrin clotFibrin clot
ExtrinsicExtrinsic
pathwaypathway
IntrinsicIntrinsic
pathwaypathway
AT XaXaAT AT
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;267:12528-38
TurpieTurpie 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
Fondaparinux
concentration(µg/mL)
0 4 8 12 16 20 24 28 32 36
tmax = 1.7 hr
Cmax = 0.34 µg/mL
Cmax/2 = 25 min
t1/2 = 15–18 hr
Rapid onset of action with significant plasma levels
(Cmax/2) achieved within 25 min after s.c. injection
Fondaparinux: PharmacokineFondaparinux: Pharmacokinetictic
Profile with s.c. InjectionProfile with s.c. Injection
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.

12,000 Patients with STEMI < 12 h of symptom onset
Inclusion: 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 onset
Inclusion: ST ↑ ≥ 2 mm prec leads or ≥ 1 mm limb leads
Exclusion: Contra-ind. for anticoagulant, INR>1.8, pregnancy, ICH<12 mo.
UFH not indicatedUFHUFH notnot indicatedindicated
Study Design: Randomized, DoubleStudy 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
Fondaparinux
2.5 mg
Placebo
Fondaparinux
2.5 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.

BIVALIRUDIN
 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)
 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 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

REPLACE 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

Analysis
 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
 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

Analysis
 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
ACUITY
Study Design – First Randomization
Angiographywithin72h
UFH or
Enoxaparin
+ GP IIb/IIIa
Bivalirudin
+ GP IIb/IIIa
Bivalirudin
Alone
R*
Medical
management
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 invasiveModerate-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)
ACUITY Design. Stone GW et al. AHJ 2004;148:764–75
Moderate-
high risk
ACS
Aspirin in all
Clopidogrel
dosing and timing
per local practice
Bivalirudin
Alone
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
UFH,Enoxaparin,
orBivalirudin
Routine upstream
GPI in all pts
Deferred GPI
for PCI only
VS.
Primary analysis
Secondary
analysis
Bivalirudin
UFH or Enoxaparin

Analysis
 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

Conclusions
 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
27,735 patients undergoing invasive management of CAD
REPLACE-2
(N=6,002)
CAD
Planned PCI
BAT
(N=4,312)
UA, NQWMI
Planned PTCA
ACUITY
(N=13,819)
NSTE-ACS
PCI <72h
HORIZONS
(N=3,602)
STEMI
Emergency PCI
Increasing risk of ischaemic complications
Lincoff et al
JAMA, 2003
Bittl et al
AHJ, 2001
Stone et al
NEJM, 2006
Stone et al
NEJM, 2007

Rivaroxaban
 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 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 DESIGN
NO YES
Recent ACS PatientsRecent ACS Patients
Stabilized 1-7 Days Post-Index EventStabilized 1-7 Days Post-Index Event
Treat for 6 MonthsTreat for 6 Months
MD Decision to Treat with ClopidogrelMD Decision to Treat with Clopidogrel
N = 3,491
Aspirin 75-100 mg
STRATUM 1
ASA Alone
N=761
STRATUM 1
ASA Alone
N=761
STRATUM 2
ASA + Clop.
N=2,730
STRATUM 2
ASA + Clop.
N=2,730
PLACEBO
N=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)
PLACEBO
N=907
5 mg (74)
10 mg (428)
15 mg (178)
20 mg (227)
RIVA QD
N=912
5 mg (78)
10 mg (430)
15 mg (178)
20 mg (226)
RIVA BID
N=911
2.5 mg (76)
5 mg (430)
7.5 mg (178)
10 mg (227)
Gibson CM, AHA 2008

SUMMARY- SAFETYSUMMARY- SAFETY
• There was increased bleeding associated with higherThere 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-EFFICACY
22oo
EndpointEndpoint::
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
EndpointEndpoint::
21% RRR (HR 0.79, p=0.10) in death, MI, stroke, or severe recurrent ischemia21% RRR (HR 0.79, p=0.10) in death, MI, stroke, or severe recurrent ischemia
requiring revascularizationrequiring revascularization
Gibson CM, AHA 2008

SELECTION OF DOSES FOR
PHASE III
Based upon:
1. Efficacy at lower doses of rivaroxaban
2. Graded increase in bleeding at higher doses of rivaroxaban
3. 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 rivaroxaban
2. Graded increase in bleeding at higher doses of rivaroxaban
3. 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 DESIGN
Recent 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
PLACEBOPLACEBO RIVAROXABAN
5.0 mg BID
RIVAROXABAN
5.0 mg BID
Stratified by Thienopyridine use
Gibson CM, AHA 2008

Apixaban
 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

Otamixaban
 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

Dabigatran
 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
 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 NewerBetter Outcomes Observed with Newer
AnticoagulantsAnticoagulants
•• Recent improvements inRecent improvements in anticoagulant therapy haveanticoagulant therapy have
dramatically reduced acute bleeding at the expense of adramatically 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 vsThis 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
 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
*Limited data are available for the use of other low-molecular-weight heparins (LMWHs), e.g., dalteparin.
New
Drugs

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

Initial Invasive StrategyInitial Invasive Strategy
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
New
Drugs

Acs – new biomarkers & role of newer anticoagulants

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