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Daniel I. Simon, M.D.Daniel I. Simon, M.D.Chief, Division of Cardiovascular MedicineChief, Division of Cardiovascular Medicine
Director, Heart & Vascular InstituteDirector, Heart & Vascular InstituteUniversity Hospitals Case Medical CenterUniversity Hospitals Case Medical Center
Herman K. Hellerstein Professor of MedicineHerman K. Hellerstein Professor of MedicineCase Western Reserve University School of MedicineCase Western Reserve University School of Medicine
Anti-Thrombotic Therapy in ACS: Update for 2008
Disclosures-Drug
• Accumetrics– Research Grant
• Eli Lilly– Consultant– Speaker honoraria
• Medicines Company– Steering Committee– Speaker bureau
• Millennium– Consultant
• Sanofi-Aventis– Consultant– Speaker honoraria
• Schering-Plough– Scientific Advisory Board– Speaker honoraria– Research grant
Disclosures-DeviceDisclosures-Device
• Boston Scientific/Guidant– TAXUS V DSMB– Speaker honoraria– Live-case transmission support
• Cordis/J&J– Consulting– Speaker honoraria– Fellowship research support– FDA panel team
• Medtronic– Consulting
CaseCase• 44 yo women with 2 days of intermittent 44 yo women with 2 days of intermittent
CP occurring with minimal exertion and at CP occurring with minimal exertion and at rest.rest.
• CRF: HTN, smokerCRF: HTN, smoker• Med: ACEI, thiazide diuretic, ASAMed: ACEI, thiazide diuretic, ASA• PE: WNLPE: WNL• Labs: CPK 54, cTnI 0.13Labs: CPK 54, cTnI 0.13• EKGEKG
Management IssuesManagement Issues
• UFH, LMWH, fondaparinux, or bivalirudinUFH, LMWH, fondaparinux, or bivalirudin
• ClopidogrelClopidogrel– 300 or 600 mg load300 or 600 mg load– DurationDuration
• Invasive or conservative strategyInvasive or conservative strategy
• If invasive, cath <6h or tomorrowIf invasive, cath <6h or tomorrow
• GP IIb/IIIa inhibitor upstream or in cath labGP IIb/IIIa inhibitor upstream or in cath lab
Link Between Overall ACC/AHA Guidelines Adherence and Mortality
Link Between Overall ACC/AHA Guidelines Adherence and Mortality
Peterson et al, ACC 2004Peterson et al, ACC 2004
5.95
5.16 4.97
4.16
5.074.63
4.17
6.33
0
1
2
3
4
5
6
7
<=25% 25 - 50% 50 - 75% >=75%
Hospital Composite Quality Quartiles
% I
n-H
osp
Mo
rtal
ity
Adjusted Unadjusted
5.95
5.16 4.97
4.16
5.074.63
4.17
6.33
0
1
2
3
4
5
6
7
<=25% 25 - 50% 50 - 75% >=75%
Hospital Composite Quality Quartiles
% I
n-H
osp
Mo
rtal
ity
Adjusted Unadjusted
Every 10% Every 10% in guidelines adherence in guidelines adherence 11% 11% in in mortalitymortality
PTCA/stentPTCA/stent
Fatal thrombus
Plaque Rupture:A common substrate for acute coronary syndromes
- Michael Davies- Earling Falk- Paris Constantinides
Clinical
Presentation
% Patients
ACC/NCDR
N=210,158
UFH
+
IIb/IIIa Inhibitor
Bivalirudin UFH
+
clopidogrel
STEMI 13.1% RAPPORT
ISAR-2
ADMIRAL
CADILLAC
HORIZONS
NSTEMI 15.4% CAPTURE
PRISM/PRISM-PLUS
PURSUIT
PARAGON A/B
ACUITY ISAR-REACT 2
Non-inferiority
rejected
USA 35.6% CAPTURE
PRISM/PRISM-PLUS
PURSUIT
PARAGON A/B
ACUITY ISAR-REACT 2
Non-inferiority
rejected
Elective PCI
Low-risk ACS
33.9% EPILOG
EPISTENT
ESPRIT
REPLACE-2 ISAR-REACT
64%
Anti-Thrombotic Strategies in PCI
USA/Non-ST Elevation ACSUSA/Non-ST Elevation ACS
Generally caused by partially occlusive,
platelet-rich thrombus
Unobstructedlumen
thrombus
Results from cross-linking of fibrinogen by platelet GP IIb-
IIIa receptors at sites of plaque rupture
platelet
fibrinogen
Rupturedplaque
GP IIb-IIIa
Artery wall
AspiriAspirinn++
IV heparin/LMWH*IV heparin/LMWH*++
IV platelet IV platelet GP IIb/IIIa GP IIb/IIIa AntagonistAntagonist
++clopidogrelclopidogrel
AspirinAspirin++
SQ LMWH*SQ LMWH*oror
IV heparinIV heparin++
clopidigrelclopidigrel
Possible Possible ACSACS
Likely/Definite Likely/Definite ACSACS
Definite ACSDefinite ACSWith Cath and PCIWith Cath and PCI
AspirinAspirin
Braunwald et al. Braunwald et al. J Am Coll Cardiol.J Am Coll Cardiol. 2000;36:970-1062 2000;36:970-1062
Class I Recommendations for Antithrombotic Therapy
*Class IIa: Enoxaparin preferred over UFH
UA/NSTEMI GUIDELINES – March 15 2002UA/NSTEMI GUIDELINES – March 15 2002
Prior CABGHigh-risk findings on noninvasive stress testing
PCI within 6 monthsRecurrent angina/ischemia with CHF, S3, PE, rales, etc.
Sustained VTST-segment depression
Hemodynamic instabilityElevated TnT or Tnl
Ejection fraction <.40Recurrent angina/ischemia
Class IAn early invasive strategy in patients with UA/NSTEMI and any of the following high-risk indicators (Level of Evidence: A)
Braunwald et al. J Am Coll Cardiol. 2002;40:1366-1374.
ACC/AHA Guidelines for UA/NSTEMI:Early Invasive Strategy
Invasive vs. Conservative Strategy for UA/NSTEMI – All Studies
TIMI IIIBTIMI IIIB
Conservative Invasive
VANQWISHVANQWISHMATEMATE
FRISC IIFRISC II
TACTICS-TIMI 18
TACTICS-TIMI 18
VINOVINO
RITA-3RITA-3
# Pts: 1140 1674 7018
TRUCS TRUCS
ISAR-COOL ISAR-COOL
ICTUSICTUS
Bavry AA, et al. J Am Coll Cardiol 2006;48:1319–1325. Reprinted with permission from Elsevier. CI = confidence interval; RR = relative risk.
Relative Risk of All-Cause Mortality for Early Invasive Therapy Compared With Conservative
Therapy at a Mean Follow-Up of 2 y
0%
2%
4%
6%
8%
10%
PCIPCI
N=2754N=2754PP=0.001=0.001
N=12,296N=12,296PP=0.001=0.001
+24 h +48 h +72 h +24 h +48 h
Boersma et al. Circulation. 1999;100:2045
4.3%4.3%
2.9%2.9%
8.0%8.0%
4.9%4.9%
Dea
th o
r M
ID
eath
or
MI
Medical RxMedical Rx Post PCIPost PCI
Control
GP IIb/IIIa inhibitor
0
GP IIb-IIIa Inhibition:Beneficial pre- and post-PCI
Meta-analysis CAPTURE, PURSUIT, PRISM-PLUS
ESPRIT Sub-study:Procedural risk vs. clinical risk
Tcheng & Simon. 2008
ADP Receptor Blockers:ADP Receptor Blockers:CURE, PCI-CURE, CREDO,CURE, PCI-CURE, CREDO,ISAR-REACT, ISAR-COOL,ISAR-REACT, ISAR-COOL,
ISAR-REACT 2, CHARISMA,ISAR-REACT 2, CHARISMA,TRITONTRITON
Different Mechanisms of ActionDifferent Mechanisms of Action Oral Antiplatelet AgentsOral Antiplatelet Agents
CollagenThrombin
TXA2
Aspirin
ADPADP
(FibrinogenReceptor)
clopidogrel bisulfate
TXA2
ADP
Dipyridamole
Phosphodiesterase
ADP
Gp IIb/IIIa Activation
COXCOX
ticlopidine HCl
ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.Schafer AI. Am J Med. 1996;101:199–209.
Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events
Aspirin 75-325mg
Aspirin 75-325mg
Plac
ebo
Clopid
ogrel
300m
g
load
ing d
ose
Patients withNon-ST elevation
Acute Coronary
Syndrome
R
1 3 6 9 12 Months
The CURE Trial InvestigatorsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
3 months double-blind treatment 12 months3 months double-blind treatment 12 months
Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.*
(6259 patients)
Placebo + ASA 75-325 mg q.d.*(6303 patients)
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Cu
mu
lati
ve H
azar
d R
ate
Clopidogrel Clopidogrel + ASA*+ ASA*
33 66 99
Placebo Placebo + ASA*+ ASA*
Months of Follow-UpMonths of Follow-Up
11.4%11.4%
9.3%9.3%
20% RRR20% RRRPP < 0.001 < 0.001
N = 12,562N = 12,562
00 1212
* In combination with standard therapy
The CURE Trial InvestigatorsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Primary End Point: MI/Stroke/CV Death
0.150.15
0.100.10
0.050.05
0.00.0
0 100100 200200 300300 400400Days of follow-upDays of follow-up
12.6%12.6%
8.8%8.8%
31% RRR31% RRRP P = 0.002= 0.002N = 2658N = 2658
ClopidogrelClopidogrel+ ASA*+ ASA*
PlaceboPlacebo+ ASA*+ ASA*
Cu
mu
lati
ve H
azar
d R
ate
Composite of CV death or MI from randomization to end of follow-up
Overall Long-Term ResultsPCI-CURE
Mehta et al. Lancet 2001;358:527-33
Sabatine MS, et al. JAMA 2006
Optimal Timing?
Steinhubl et al. J Am Coll Cardiol 2006;47:939-43
Hours After Randomization
Within 24 hrs of Randomization
Cumulative Hazard Rates
0.0
0.005
0.010
0.015
0.020
0.025
0 2 4 6 8 10 12 14 16 18 20 22 24
p=0.003
Placebo+ ASA
Clopidogrel+ ASA
34%34%Relative RiskRelative Risk
ReductionReduction
MI/Stroke/CV MI/Stroke/CV Death/Severe IschemiaDeath/Severe Ischemia
Yusuf et al. for the CURE Trial Investigators. Yusuf et al. for the CURE Trial Investigators. CirculationCirculation. 2003;107:966. 2003;107:966
Major/Life-Threatening Bleeds Major/Life-Threatening Bleeds within 7 days of CABG Surgerywithin 7 days of CABG Surgery
PlaceboPlacebo ClopidClopid RRRR pp
Stopped Stopped << 5 days 5 days prior to CABGprior to CABG
N = 476N = 476 N = 436N = 436
Pts with Maj/LT BldPts with Maj/LT Bld TIMI MajorTIMI Major
6.3%6.3%2.7%2.7%
9.6%9.6%2.5%2.5%
1.531.530.920.92
0.060.06NSNS
Stopped > 5 days Stopped > 5 days prior to CABGprior to CABG
N = 454N = 454 N = 456N = 456
Pts with Maj/LT Bld Pts with Maj/LT Bld TIMI MajorTIMI Major
5.3%5.3%2.4%2.4%
4.4%4.4%1.8%1.8%
0.830.830.720.72
0.530.53NSNS
Yusuf et al. for the CURE investigators. NEJM. 2001;345:494-502Fox et al. Circulation. 2004;110:1202-08
7.57.2
9.1
7.9
5.96.5
0
2
4
6
8
10
(%)
All <= 5 days >5 days
Clopidogrel
Placebo
Major Bleeding In ThoseUndergoing CABG
All P=NS
n=67 n=69 n=33 n=38 n=34 n=31
Time from d/c of study med to CABG
TARGET: TARGET: Clopidogrel pre-treatmentClopidogrel pre-treatment
Chan et al. J Amer Coll Cardiol 2003; 42:1196
Clopidogrel pre-treatment: RR = 0.61 (0.44-0.84) P=0.003
ISAR-COOL:“cooling” off strategyISAR-COOL:“cooling” off strategyEarly <6h vs. cool-off 3-5d Early <6h vs. cool-off 3-5d
Neumann et al. JAMA 2003;290:1593-9
ASA 100 mg BIDClopidogrel 600 mg load, 75 mg BIDIV heparin 60U/kgTirofiban 10 g/kg, 0.1 g/kg/min
ISAR-CHOICE:300 vs. 600 vs. 900 mg ISAR-CHOICE:300 vs. 600 vs. 900 mg
Von Beckerath et al. Circulation 2005:112:2946-2950
Clopidogrel Non-responsiveness
0
5
10
15
20
25
30
35
%
300 mg 600 mg
P<0.002
28
8
32
8
Gurbel et al. J Amer Coll Cardiol 2005
ADP 5 ADP 20
P<0.002
% Non-responders at 24h
ARMYDA-2:Clopidogrel 300 vs. 600 mg ARMYDA-2:Clopidogrel 300 vs. 600 mg
Patti et al. Circulation 2005:111:2099-2106
Cuisset et al. J Amer Coll Cardiol 2006;48:1339-45
Clopidogrel 300 mg (n=146) or clopidogrel 600 mg (n=146), Clopidogrel 300 mg (n=146) or clopidogrel 600 mg (n=146), platelet reactivity (ADP 10 platelet reactivity (ADP 10 M) and clinical outcomesM) and clinical outcomes
Clopidogrel and Platelet Reactivity
High post-High post-treatment treatment platelet platelet reactivity reactivity (HPPR) > 70%(HPPR) > 70%
25% 300 mg25% 300 mg15% 600 mg15% 600 mgP=0.03P=0.03
CV Event-freeCV Event-freeSurvivalSurvivalHPPR: RR 13.8HPPR: RR 13.8P<0.0001P<0.0001
ISAR-REACT 2 Trial: Study DesignISAR-REACT 2 Trial: Study DesignISAR-REACT 2 Trial: Study DesignISAR-REACT 2 Trial: Study Design
Primary Endpoint: Composite of death, MI, and urgent target vessel Primary Endpoint: Composite of death, MI, and urgent target vessel revascularization (TVR) due to myocardial ischemia within 30 daysrevascularization (TVR) due to myocardial ischemia within 30 days
Secondary Endpoint: In-hospital major and minor bleedingSecondary Endpoint: In-hospital major and minor bleeding
Primary Endpoint: Composite of death, MI, and urgent target vessel Primary Endpoint: Composite of death, MI, and urgent target vessel revascularization (TVR) due to myocardial ischemia within 30 daysrevascularization (TVR) due to myocardial ischemia within 30 days
Secondary Endpoint: In-hospital major and minor bleedingSecondary Endpoint: In-hospital major and minor bleeding
2022 patients with an episode of angina within the preceding 48 hours and an elevated troponin T level or new ST-segment depression of ≥0.1 mV or
transient (<20 minutes) ST-segment elevation of ≥0.1 mV or new or presumed new bundle-branch block; significant angiographic lesions in a native
coronary vessel or venous bypass graft amenable to and requiring a PCI Placebo Controlled. Randomized. Blinded.
24% female, mean age 66 years, mean follow-up 30 days
2022 patients with an episode of angina within the preceding 48 hours and an elevated troponin T level or new ST-segment depression of ≥0.1 mV or
transient (<20 minutes) ST-segment elevation of ≥0.1 mV or new or presumed new bundle-branch block; significant angiographic lesions in a native
coronary vessel or venous bypass graft amenable to and requiring a PCI Placebo Controlled. Randomized. Blinded.
24% female, mean age 66 years, mean follow-up 30 days
Abciximab(usual bolus or infusion dose)
n=1012
Abciximab(usual bolus or infusion dose)
n=1012
Placebon=1010
Placebon=1010
Pre-treatment with high dose (600mg) clopidogrel at least 2h pre-procedurePre-treatment with high dose (600mg) clopidogrel at least 2h pre-procedure
Kastrati et al. JAMA 2006;295:1531-8Kastrati et al. JAMA 2006;295:1531-8
ISAR-REACT 2: Primary EndpointISAR-REACT 2: Primary EndpointISAR-REACT 2: Primary EndpointISAR-REACT 2: Primary Endpoint
• The primary The primary composite composite endpoint occurred endpoint occurred less frequently in less frequently in the abciximab the abciximab group compared to group compared to placebo (8.9% vs placebo (8.9% vs 11.9%; relative risk 11.9%; relative risk [RR] 0.75 p=0.03)[RR] 0.75 p=0.03)
8.9%
11.9%
0%
5%
10%
15%
Abciximab Placebo
8.9%
11.9%
0%
5%
10%
15%
Abciximab Placebo
Composite of death, MI, or urgent TVR due to Myocardial Ischemia within 30 days (%)
p=0.03
Kastrati et al. JAMA 2006;295:1531-8Kastrati et al. JAMA 2006;295:1531-8
Study Design
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
PRASUGREL60 mg LD/ 10 mg MD
CLOPIDOGREL300 mg LD/ 75 mg MD
1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch
CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic
Median duration of therapy - 12 months
N= 13,600
Healthy VolunteerHealthy VolunteerCrossover StudyCrossover Study
-20-20
00
2020
4040
6060
8080
100100
IPA
at
24 h
ou
rs (
%)
IPA
at
24 h
ou
rs (
%)
Response to Response to Prasugrel 60 mgPrasugrel 60 mg
Response to Response to Clopidogrel 300 mgClopidogrel 300 mg
Clopidogrel ResponderClopidogrel Responder
Clopidogrel Non-responderClopidogrel Non-responder
Inte
rpat
ien
tIn
terp
atie
nt
Var
iab
ility
Var
iab
ility
Interp
atient
Interp
atient
Variab
ilityV
ariability
From Brandt JT AHJ 153: 66e9,2007
N=66
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)P=0.0004
Prasugrel
Clopidogrel
HR 0.80P=0.0003
HR 0.77P=0.0001
Days
Pri
ma
ry E
nd
po
int
(%)
12.1(781)
9.9 (643)
Primary EndpointPrimary EndpointCV Death,MI,StrokeCV Death,MI,Stroke
NNT= 46
ITT= 13,608ITT= 13,608 LTFU = 14 (0.1%)LTFU = 14 (0.1%)
Stent ThrombosisStent Thrombosis(ARC Definite + Probable)(ARC Definite + Probable)
0
1
2
3
0 30 60 90 180 270 360 450
HR 0.48P <0.0001
Prasugrel
Clopidogrel2.4
(142)
NNT= 77
1.1 (68)
Days
En
dp
oin
t (%
)
Any Stent at Index PCIAny Stent at Index PCI N= 12,844 N= 12,844
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)P=0.0004
Prasugrel
Clopidogrel
Days
En
dp
oin
t (%
)
12.1
9.9
HR 1.32(1.03-1.68)
P=0.03
Prasugrel
Clopidogrel1.82.4
138 events
35 events
Balance of Balance of Efficacy and SafetyEfficacy and Safety
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 46
NNH = 167
1.8
0.9 0.9
0.10.3
2.4
1.41.1
0.4 0.3
0
2
4
TIMI MajorBleeds
LifeThreatening
Nonfatal Fatal ICH
Bleeding EventsBleeding EventsSafety CohortSafety Cohort
(N=13,457)(N=13,457)
% E
ven
ts%
Eve
nts
ARD 0.6%ARD 0.6%HR 1.32HR 1.32P=0.03P=0.03
NNH=167 NNH=167
ClopidogrelClopidogrel
PrasugrelPrasugrel
ARD 0.5%ARD 0.5%HR 1.52HR 1.52P=0.01P=0.01
ARD 0.2%ARD 0.2%P=0.23P=0.23
ARD 0%ARD 0%P=0.74P=0.74
ARD 0.3%ARD 0.3%P=0.002P=0.002
ICH in Pts w ICH in Pts w Prior Stroke/TIA Prior Stroke/TIA
(N=518)(N=518)
Clop 0 (0) %Clop 0 (0) % Pras 6 (2.3)%Pras 6 (2.3)% (P=0.02) (P=0.02)
Net Clinical BenefitNet Clinical BenefitDeath, MI, Stroke, Death, MI, Stroke,
Major Bleed (non CABG)Major Bleed (non CABG)
0
5
10
15
0 30 60 90 180 270 360 450Days
En
dp
oin
t (%
)
HR 0.87P=0.004
13.9
12.2
Prasugrel
ClopidogrelITT= 13,608ITT= 13,608
-23
6
-25
-20
-15
-10
-5
0
5
10
Events per 1000 ptsEvents per 1000 pts
MIMI Major BleedMajor Bleed(non CABG)(non CABG)
++All CauseAll CauseMortalityMortality
Clop 3.2%Clop 3.2%Pras 3.0 %Pras 3.0 %
P=0.64P=0.64
Diabetic SubgroupDiabetic Subgroup
0
2
4
6
8
10
12
14
16
18
0 30 60 90 180 270 360 450
HR 0.70P<0.001
Days
En
dp
oin
t (%
)
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 21
N=3146N=3146
17.0
12.2
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel 2.6
2.5
Net Clinical BenefitNet Clinical BenefitBleeding Risk SubgroupsBleeding Risk Subgroups
OVERALL
>=60 kg
< 60 kg
< 75
>=75
No
Yes
0.5 1 2
Prior Stroke / TIA
Age
Wgt
Risk (%)
+ 37
-16
-1
-16
+3
-14
-13
Prasugrel Better Clopidogrel BetterHR
Pint = 0.006
Pint = 0.18
Pint = 0.36
Post-hoc analysisPost-hoc analysis
Bleeding Risk SubgroupsBleeding Risk SubgroupsTherapeutic ConsiderationsTherapeutic Considerations
Significant Net Clinical Benefit
with Prasugrel80%
MD MD 10 mg10 mg
Reduced MD
Guided by PK
Age > 75 or
Wt < 60 kg
16%
Avo
id
Prasu
grel
Prio
r
CV
A/T
IA4%4%
Anti-platelet Therapy in ACSAnti-platelet Therapy in ACS
0
1 08
Placebo APTC CURE TRITON-TIMI 38
Single Antiplatelet Rx
Dual Antiplatelet Rx
Higher IPA
ASAASA +
Clopidogrel ASA + Prasugrel
- 22%
- 20%
- 19%
+ 60% + 38% + 32%
Reduction in
IschemicEvents
Increase in
Major Bleeds
IIaS
C
Direct antithrombin
LMWH
ATXa
ATXa
Pentasaccharide
= saccharide unit.Konkle BA, Schafer AI. In: Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald’s Heart Disease. 7th ed. Vol 2. Philadelphia: Elsevier Saunders; 2005:2067-2092.
ATIIa
Hep
UFH
Lots of Anticoagulant Choices
Study DesignAt least 2 of 3 required:At least 2 of 3 required:
• Age Age 60 60
• ST ST (transient) or (transient) or • (+) CK-MB or Troponin(+) CK-MB or Troponin
Enoxaparin IV Heparin
Primary endpoint: Death or MI at 30 days
High-RiskHigh-RiskACS PatientsACS Patients
RandomizeRandomize(n = 10,000)(n = 10,000)
Early invasive strategyOther therapy per AHA/ACC Guidelines
(ASA, -blocker, ACE, clopidogrel, GP IIb/IIIa)
60 U/kg 60 U/kg 12 U/kg/hr 12 U/kg/hr (aPTT 50-70 sec)(aPTT 50-70 sec)1 mg/kg SC Q12H1 mg/kg SC Q12H
JAMA 2004;292:45-54
SYNERGY: Primary End Point
0 5 10 15 20 25 300.8
0.85
0.9
0.95
1.0
Free
dom
from
Dea
th /
MI
Days from Randomization
UFHEnoxaparin
HR 0.96 (0.87-1.06)
30-Day Death/MI30-Day Death/MI
0.80.8 11 1.21.2
Hazard Ratio (95% CI)
Enoxaparin
Better
UFH
Better
Mahaffey et al, for the SYNERGY Investigators. JAMA. 2004;292:45-54.Adapted from www.clinicaltrialresults.org.
Hazard Ratio (95% CI)
Enox UFHBetter Better
0.60.6 11 22
Hazard Ratio (95% CI)
Enox UFHBetter Better
0.60.6 11 22
Prior Antithrombin Therapy: Efficacy and Safety
Enox UFH (%) (%)Enox UFH (%) (%)
30-DAY DEATH / MI
30-DAY DEATH / MI
BLEEDINGGUSTO Severe
TIMI Major
BLEEDINGGUSTO Severe
TIMI MajorEnox UFH (%) (%)Enox UFH (%) (%)
2.9 2.42.9 2.4Total(n = 9978)
14.0 14.514.0 14.59.1 7.69.1 7.6
3.1 1.83.1 1.8No Prior Rx(n = 2440)
12.6 14.812.6 14.89.7 6.99.7 6.9
3.1 2.23.1 2.2ConsistentTherapy(n = 6138)
13.3 15.913.3 15.99.3 7.99.3 7.9
Patients with NSTE ACS, Chest discomfort < 24 hours2 of 3: Age>60, ST Segment Δ, cardiac markers
Patients with NSTE ACS, Chest discomfort < 24 hoursPatients with NSTE ACS, Chest discomfort < 24 hours2 of 3: Age>60, ST Segment 2 of 3: Age>60, ST Segment ΔΔ, , cardiac markerscardiac markers
Fondaparinux2.5 mg sc once daily
FondaparinuxFondaparinux2.5 mg sc once daily2.5 mg sc once daily
Study Design: Randomized, Double Blind
ASA, Clop, GP IIb/IIIa, planned Cath/PCI as per
local practice
ASA, Clop, GP ASA, Clop, GP IIb/IIIaIIb/IIIa, , planned planned CathCath/PCI as per /PCI as per
local practicelocal practice
RandomizeRandomize
Enoxaparin1 mg/kg sc twice daily
EnoxaparinEnoxaparin1 mg/kg sc twice daily1 mg/kg sc twice daily
Primary: Efficacy: Death, MI, refractory ischemia at 9 days Safety: Major bleeding at 9 daysRisk benefit: Death, MI, refractory ischemia, major bleeds 9 days
Secondary: Above & each component separately at day 30 & 6 monthsHypothesis: First test non-inferiority, then test superiority
Primary:Primary: EfficacyEfficacy:: Death, MI, refractory ischemiaDeath, MI, refractory ischemia at 9 days at 9 days SafetySafety:: Major bleeding at 9 daysMajor bleeding at 9 daysRisk benefitRisk benefit:: Death, MI, refractory ischemia, major bleeds 9 daysDeath, MI, refractory ischemia, major bleeds 9 days
SecondarySecondary:: Above & each component Above & each component separatelyseparately at day 30 & 6 monthsat day 30 & 6 monthsHypothesisHypothesis:: First test nonFirst test non--inferiority, then test superiorityinferiority, then test superiority
Outcomes
PCI< 6 hPCI< 6 h,, No additional UFHNo additional UFHPCI >6 hPCI >6 h,, IV UFHIV UFHWith With IIb/IIIaIIb/IIIa 65 U/kg65 U/kgWithout Without IIb/IIIaIIb/IIIa 100 U/kg100 U/kg
PCI <6 hPCI <6 h:: IV Fonda 2.5 mgIV Fonda 2.5 mgwithout without IIb/IIIaIIb/IIIa, 0 with , 0 with IIb/IIIaIIb/IIIaPCI> 6 hPCI> 6 h:: IV Fonda 2.5 mg withIV Fonda 2.5 mg withand 5.0 mg without and 5.0 mg without IIb/IIIaIIb/IIIa
ExcludeAge < 21Any contra-ind to EnoxHem stroke< 12 mo.Creat> 3 mg/dL/265 umol/L
N=20,000
Death/MI/RI: Day 9
Days
Cum
ulat
ive
Haz
ard
0.0
0.01
0.02
0.03
0.04
0.05
0.06
0 1 2 3 4 5 6 7 8 9
Enoxaparin
Fondaparinux
HR 1.01 95% CI 0.90-1.13
Major Bleeding: 9 Days
Days
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0.04
0 1 2 3 4 5 6 7 8 9
HR 0.53 95% CI 0.45-0.62
P<<0.00001
Enoxaparin
Fondaparinux
Mortality: Day 30
Days
Cu
mu
lati
ve H
aza
rd0.
00.
010.
020.
03
0 3 6 9 12 15 18 21 24 27 30
HR 0.83 HR 0.83 95% CI 0.7195% CI 0.71--0.970.97
P=0.022P=0.022
Enoxaparin
Fondaparinux
OASIS-6 Trial: PCI Substudy at 30 Days
There was no difference in the primary endpoint for patients who were managed with primary PCI (6.1% vs 5.1%, P=.19)
Guiding catheter thrombosis in the primary PCI cohort occurred more often with fondaparinux compared with control (n=22 vs n=0, P <.001)
6.1%
5.1%
0%
2%
4%
6%
8%
Fondaparinux Control
Primary Endpoint of Death or MI in PCI Cohort (%)P =.19
Yusuf S, et al. JAMA. 2006;295:1519-1530.Adapted with permission from www.clinicaltrialresults.org
What about direct thrombin inhibitors in ACS and PCI?
Moderate-to high-
riskACS
ACUITY Study Design:First Randomization
An
gio
gra
ph
y w
ith
in 7
2 h
Aspirin in all,Clopidogrel dosing
and timingper local practice
UFH or enox+ GP IIb/IIIa
n=4603
Bivalirudin+ GP IIb/IIIa
n=4604
Bivalirudinalone
n=4,612
R*
Moderate- to high-risk patients with UA or NSTEMIundergoing an invasive strategy (N = 13,819)
Medicalmanagement
PCI
CABG
Stone et al. N Engl J Med 2006
*Stratified by pre-angiography thienopyridine use or administration.
Moderate-to high-risk ACS
ACUITY Study Design: Second Randomization
Moderate- to high-risk patients with unstable anginaor NSTEMI undergoing an invasive strategy (N = 13,819)
Aspirin in all,Clopidogrel
dosing and timingper local practice
Bivalirudinalone N=4612
UFH or EnoxaparinRoutine upstream GPI in all pts (2294)
GPI started in CCL for PCI only (2309)
R
Bivalirudin
R
Routine upstream GPI in all pts (2311)
GPI started in CCL for PCI only (2293)
UF
H, E
no
xaparin
,o
r Bivaliru
din
Routine upstreamGPI in all pts
n=4603
Deferred GPIfor PCI only
N=4604
vsvs
Primary analysis
Secondary
analysis
Stone et al. N Engl J Med 2006
0 1 2
ACUITY: Primary End Point Measures*
Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better
Risk ratio±95% CI
Risk ratio±95% CI
Primaryend point
Bivalalone
UFH/Enox+ IIb/IIIa
RR (95% CI)
Net clinical outcome
Ischemic composite
Major bleeding
Up
per
bo
un
dar
y n
on
-in
feri
ori
ty
11.7%10.1% 0.86 (0.77-0.97)<.001.015
7.3%7.8% 1.08 (0.93-1.24).02.32
5.7%3.0% 0.53 (0.43-0.65)<.001<.001
P value(noninferior)
(superior)
UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin alone
*ITT population.
UFH = unfractionated heparin
Stone et al. N Engl J Med 2006
LBCT March 29, 08
ISAR ISAR REACT 3REACT 3
2,289 Pts
30-day Follow-up
2,281 Pts
UFHBivalirudin
PCI
4,570 Patients
Study Population
LBCT March 29, 08
ISAR ISAR REACT 3REACT 3
Days after randomization
Cumulative incidence (%)
0
2
4
6
8
10
0 5 10 15 20 25 30
Primary (Quadruple) EndpointDeath, MI, UTVR, Major Bleeding
8.3%8.7%
RR=0.94 [95% CI, 0.77-1.15], P=0.57
Bivalirudin
UFH
LBCT March 29, 08
ISAR ISAR REACT 3REACT 3
Cumulative incidence (%)
0
2
4
6
8
10
0 5 10 15 20 25 30
Days after randomization
Secondary (Triple) EndpointDeath, MI, UTVR
5.0%5.9%
RR=1.16 [95% CI, 0.91-1.49], P=0.23
Bivalirudin
UFH
LBCT March 29, 08
ISAR ISAR REACT 3REACT 3
3.1
6.8
1.3
4.6
9.9
1.8
0
2
4
6
8
10
12
Major bleeding Minor bleeding Transfusion
Incidence (%)
P=0.008
Bleeding Events
P=0.0001 P=0.15
BivalirudinUFH
LBCT March 29, 08
ISAR ISAR REACT 3REACT 3 Conclusion
In biomarker negative patients with stable and unstable angina undergoing PCI pretreated with
clopidogrel 600 mg for >2 hours, bivalirudin does not improve “net clinical benefit”
– the quadruple endpoint – at 30 days compared to UFH,
although it significantly reduces bleeding
Major Bleeding Associated With Increased Ischemic Events and Mortality
9.3
3.0
24.2
5.4
17.1
0.8
7.85.5
0
5
10
15
20
25
30
Compositeischemia
Death MI (all)
Major bleeding (n=462) No major bleeding (n=7,327)
P<.001 for all
30-d
ay e
ven
ts (
%)
Data on file. The Medicines Company, Parsippany, NJ.
Unplanned revascularization
Mauri et al. ACC 2008
Mauri et al. ACC 2008
Mauri et al. ACC 2008
Algorithm for Patients with UA/NSTEMI Managed by an Initial Invasive Strategy
Proceed to Diagnostic Angiography
ASA (Class I, LOE: A)Clopidogrel if ASA intolerant (Class I,
LOE: A)
Diagnosis of UA/NSTEMI is Likely or Definite
Invasive StrategyInit ACT (Class I, LOE: A)
Acceptable options: enoxaparin or UFH (Class I, LOE: A) bivalirudin or fondaparinux (Class I, LOE: B)
Select Management StrategyProceed with an
Initial Conservative
Strategy
Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 7. ACT = anticoagulation therapy; LOE = level of evidence.
A
B
B1
B2
Prior to AngiographyInit at least one (Class I, LOE: A) or
both (Class IIa, LOE: B) of the following:
ClopidogrelIV GP IIb/IIIa inhibitor
Factors favoring admin of both clopidogrel and GP IIb/IIIa inhibitor include:
Delay to AngiographyHigh Risk Features
Early recurrent ischemic discomfort
Init clopidogrel (Class I, LOE: A) Consider adding IV eptifibatide or tirofiban (Class
IIb, LOE: B)
Conservative StrategyInit ACT (Class I, LOE: A):
Acceptable options: enoxaparin or UFH (Class I, LOE: A) or fondaparinux (Class I, LOE: B), but
enoxaparin or fondaparinux are preferable (Class IIa, LOE: B)
Select Management Strategy
ASA (Class I, LOE: A)Clopidogrel if ASA intolerant (Class I, LOE: A)
Diagnosis of UA/NSTEMI is Likely or Definite
Algorithm for Patients with UA/NSTEMI Managed by an Initial Conservative Strategy
Proceed with Invasive Strategy
(Continued)Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 8. ACT = anticoagulation therapy; LOE = level of evidence.
C2
C1
A
CaseCase
• 44 yo women with 2 days of intermittent 44 yo women with 2 days of intermittent CP occurring with minimal exertion and at CP occurring with minimal exertion and at rest.rest.
• CRF: HTN, smokerCRF: HTN, smoker• Med: ACEI, thiazide diuretic, ASAMed: ACEI, thiazide diuretic, ASA• PE: WNLPE: WNL• Labs: CPK 54, cTnI 0.13Labs: CPK 54, cTnI 0.13• EKGEKG
4.78.3
13.219.9
26.2
40.9
0
10
20
30
40
50
0/1 2 3 4 5 6/7
D/M
I/U
rg R
evas
c (%
)
Number of Risk Factors% Popl’n: 4.3 17.3 32.0 29.3 13.0 3.4
Antman et al JAMA 2000
TIMI Risk Score For UA/NSTEMI• Age Age >> 65 y 65 y• >> 3 CAD Risk Factors 3 CAD Risk Factors• Prior Stenosis > 50 % Prior Stenosis > 50 % • ST deviationST deviation• >> 2 Anginal events 2 Anginal events << 24 h 24 h• ASA in last 7 daysASA in last 7 days• Elev Cardiac MarkersElev Cardiac Markers
Management IssuesManagement Issues
• UFH, LMWH, fondaparinux, or bivalirudinUFH, LMWH, fondaparinux, or bivalirudin
• ClopidogrelClopidogrel– 300 or 600 mg load300 or 600 mg load– DurationDuration
• Invasive or conservative strategyInvasive or conservative strategy
• If invasive, cath <6h or tomorrowIf invasive, cath <6h or tomorrow
• GP IIb/IIIa inhibitor upstream or in cath labGP IIb/IIIa inhibitor upstream or in cath lab
Ostial Ostial LADLAD
Ostial LADOstial LAD
ClopidogrelClopidogrel600 mg (ER)600 mg (ER)
UFHUFHEptifibatideEptifibatide
andandCypherCypher3.5 x 133.5 x 13
(cath lab)(cath lab)
Post-dilPost-dil4.04.0
16 atm16 atm
FinalFinal
FinalFinal