This document discusses biomarkers for acute coronary syndrome (ACS) and the role of newer anticoagulants. It summarizes that no single biomarker exists for ACS and that a multimarker approach is better. It describes several traditional and newer biomarkers for various pathophysiological aspects of ACS including inflammation, plaque rupture, ischemia, and myocardial injury. It also notes that while anticoagulation therapy for ACS has increased in efficacy over time, it has also increased bleeding risks. Newer anticoagulants may provide an opportunity to further reduce thrombotic risks while maintaining an acceptable bleeding profile.
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Acs – new biomarkers & role of newer anticoagulants
1. ACS – New biomarkers & Role
of newer anticoagulants
Dr. Arindam Pande,
Associate Consultant, Cardiology,
Apollo Gleneagles Hospital, Hospital
2. “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
3. 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
6. 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
7. 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
8. 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]
9. 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
10. 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
12. 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
13. 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
15. 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
16. 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
17. 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
18. 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
19. 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
20. 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).
21. 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
22. 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)
23. 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
24. 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
25. 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
26. 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
27. 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
32. 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.
34. 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
39. 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
41. 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
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
42. IIaIIaIIII
FibrinogenFibrinogen Fibrin clotFibrin clot
ExtrinsicExtrinsic
pathwaypathway
IntrinsicIntrinsic
pathwaypathway
AT XaXaAT AT
FondaparinuxFondaparinux
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
43. 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
45. 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.
46.
47. 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
48. 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
49. 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.
50. 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
51. 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
52. 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
53. 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
54. 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.
55. 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
56. 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).
57. 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)
58. 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
59. 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
60.
61. 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
62. 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
63.
64.
65. 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
66. 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
68. 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
69. 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
70. 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
71. 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
72. 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
73. 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
75. 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)
76. 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.
77. 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
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
78. 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)
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
79. ACC/AHA Guideline :ACC/AHA Guideline :
Initial Invasive StrategyInitial Invasive Strategy
ACC/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
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
Inflammatory cytokines: interleukin-6 (IL-6), IL-8, etc.
Cellular adhesion molecules: integrins, selectins, NCAM (neural cell adhesion molecule), VCAM (vascular cellular adhesion molecule), etc.
Acute-phase reactants: C-reactive protein (CRP)
Plaque destabilization and rupture biomarkers: Myeloperoxidase (MPO) and possibly matrix metalloproteinase-9 (MMP-9), although it is not well defined.
Biomarkers of ischemia: ischemia modified albumin (IMA)
Biomarkers of myocardial stretch: BNP
The theories behind the development of coronary artery disease (CAD) have revealed a strong component of inflammation. This is where MPO can be useful, as predictive of CAD and also in the acute phase as an early marker of plaque rupture. The necrosis markers are only seen hours after the damage has been done. Ideally we want to identify patients before this occurs.
There are many markers of inflammation but few have been truly shown to be of use in ACS
Hypochlorous acid-(chemical) an oxyacid of chlorine containing monovalent chlorine that acts as an oxidizing or reducing agent
Lymphocytes-identify foreign substances and produce antibodies and cells that specifically target them
Neutrophils-made in bone marrow and move from blood vessels into infected tissue to attack bacteria.
Leukopenia-low WBC count
Leukocytosis-high WBC count
Atherogenic-capacity to accelerate the process of atherogenesis (formation of lipid deposits in arteries)
Monocytes- one of three types of WBCs, monocytes are precursors to macrophages.
Macrophage-type of WBC that ingests foreign material. Important in the immune response to foreign invaders. Blood monocytes migrate into tissue and then differentiate into macrophages.
Foam cells-lipid laden macrophages originating from monocytes or from smooth muscle cells.
Oxidize- To combine with oxygen, or subject to the action of oxygen, or of an oxidizing agent.
Risk significantly increased with increasing MPO level. The risk elevated quickly for 72 hr outcome, and then appears to stabilize over 6 months.
The difference in the tertiles was significant as indicated on the graph. This data includes the 547 pts in the placebo arm of the CAPTURE trial.
An association between the occurrence of bleeding complications and increased mortality was evidenced in the GRACE Registry.
Hazard ratios were adjusted for age, gender, body weight, site of randomization, diabetes mellitus, smoking status, peripheral vascular disease, chest pain duration, Killip’s class, MI at enrollment, heart rate, prerandomization medications, systolic blood pressure, and treatment assignment (active vs. control).
As bleeding severity increased, the adjusted hazard for 6-month death increased.
The start of coagulation is triggered by the tissue factor/factor VIIa complex (TF/VIIa), which activates factor IX and factor X. Activated factor IX (IXa) propagates coagulation by activating factor X in a reaction that utilizes activated factor VIII (VIIIa) as a cofactor. Activated factor X (Xa), with activated factor V (Va) as a cofactor, converts prothrombin (II) to thrombin (IIa). Thrombin then converts fibrinogen to fibrin.
In healthy volunteers, recombinant factor VIIa (rFVIIa) was capable of normalizing coagulation times and thrombin generation during fondaparinux treatment. The duration of this effect ranged from 2 to 6 hours after rFVIIa injection. These results suggest that rFVIIa may be useful to reverse the anticoagulant effect of fondaparinux in case of serious bleeding complications or need for acute surgery during treatment with fondaparinux.
Bijsterveld et al. Circulation 2002;106:2550-4.
Each molecule of fondaparinux binds to one molecule of antithrombin at a specific site and with very high affinity. The binding is rapid, non-covalent and reversible. It induces a critical conformational change in antithrombin, exposing a loop containing an arginine residue that binds factor Xa. This exposure greatly increases the affinity of antithrombin for factor Xa, potentiating the natural inhibitory effect of antithrombin against factor Xa (about 300 times).
Once antithrombin binds to factor Xa (a covalent binding), a further conformational change releases fondaparinux unchanged from its binding site. Thus, once fondaparinux is released, it can catalyze the binding of further antithrombin molecules to factor Xa.
Following s.c. administration, fondaparinux is completely and rapidly absorbed, the absolute bioavailability being 100%.
Following a single s.c. injection of 2.5 mg of fondaparinux to young healthy subjects, peak plasma concentrations (mean Cmax=0.34 mg/L) are obtained 1.7 hours post-dosing. Plasma concentrations of half the mean Cmax (Cmax/2) are reached within 25 minutes of dosing.
The rapid rise in plasma levels is followed by a slow decline such that substantial plasma concentrations of the compound are maintained following dosing.
The long half-life of fondaparinux (about 17 hours) is independent of the dose and allows once-daily dosing.
Study design of the OASIS-5 trial.21
Lo stesso tipo di relazione tra il minore rischio emorragico di una terapia antitrombotica e un miglior outcome è stato suggerito dallo studio OASIS 5, che ha confrontato l’ antagonista selettivo del fattore X attivato, fondaparinux, ed enoxaparina in oltre 20.000 pazienti con NSTEACS. L’ endpoint primario dello studio era l’ incidenza di morte+MI+ischemia refrattaria a 9 giorni, simile nei due gruppi di trattamento.
Nel gruppo tratato con fondaparinux, tuttavia, l’ incidenza di sanguinamento maggiore a 9 giorni è risultato dimezzato rispetto al gruppo enoxaparina
There was an increase in guiding catheter thrombosis with fondaparinux.