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Clinical Insights,
Risk Stratification,
and Enhancing Outcomes
VBWG
CRUSADE: National quality improvement
initiative
Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes
with Early implementation of the ACC/AHA guidelines
• Academic collaboration among cardiology and
emergency medicine initiated in 2001
• Cross collaboration with ACC and AHA
• Multi-industry sponsor
• Goal: Improve adherence to ACC/AHA guidelines
for managing patients with ACS
CRUSADE. www.crusadeqi.com
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CRUSADE: In-hospital mortality by age and
acute treatment
20
18
Age >75 yrs
17.6
Age <75 yrs
16
14
%
12
10
8
10.7
8.7
6.7
6.5
6
4
2
0
10.4
5.2
3.5
0
2.7
3.5
1.8
1
2
3
4
5
Number of recommended therapies
*Aspirin, β-blockers, UFH/LMWH, GP IIb/IIIa
inhibitors, clopidogrel <24 hours, PCI <48 hours
N = 105,619 registry patients
3.1
1
0.6
6
Boden WE et al. Circulation. 2005;112:II-745.
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CRUSADE: Post-admission MI
vs use of recommended therapies
7
6.7
6
Adjusted OR 0.91
(95% CI 0.88–0.95)
5
4.2
%
4
3.4
2.9
3
2.6
2.5
2.2
2
1
0
1
2
3
4
5
Number of recommended therapies
*Aspirin, β-blockers, UFH/LMWH, GP IIb/IIIa
inhibitors, clopidogrel <24 hours, PCI <48 hours
N = 105,619 registry patients
6
Boden WE et al. Circulation. 2005;112:II-745.
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CRUSADE: Impact of early aggressive
management strategy on in-hospital mortality
N = 17,926 registry patients
Acute medical therapy (<24 h)
100
88
P < 0.001
94
80
72
In-hospital
mortality  32%
P < 0.001
89
78
74
8
60
51
51
%
40
% 4
26
14
20
0
6
Aspirin
-Blocker
Clopidogrel
No early invasive care
(n = 9889)
Heparin
3.7
2.5
2
GP IIb/IIIa
inhibitor
0
Early invasive care
(cardiac cath <48 h, n = 8037)
Adjusted for clinical differences and propensity score
Bhatt DL et al. JAMA. 2004;292:2096-104.
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CRUSADE: NSTE ACS dosing of
antithrombotics—Study overview
Objective:
Investigate association between dosing UFH, LMWH,
and GP IIb/IIIa inhibitors and major clinical outcomes
Design:
Prospective observational analysis
Population:
Registry patients with NSTE ACS receiving
antithrombotic agents
Primary outcome:
Relation between excessive dosing of UFH, LMWH,
and GP IIb/IIIa inhibitors and major bleeding,
in-hospital mortality, and length of stay
NSTE ACS = non–ST-segment elevation
acute coronary syndromes
Alexander KP et al. JAMA. 2005;294:3108-16.
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Major predictors of overdosing
Older age
(≥65 years)
Renal
insufficiency
Female
Patients
vulnerable to
overdosing
Low body
weight
Diabetes
CHF
Alexander KP et al. JAMA. 2005;294:3108-16.
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Results: Excess dosing by age
70
P < 0.001 for all treatment groups
60
50
Excess
dose
(%)
40
30
20
10
0
UFH
Patient age (years)
LMWH
<65
GP IIb/IIIa
inhibitors
65–74
≥75
Alexander KP et al. JAMA. 2005;294:3108-16.
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Results: Antithrombotic therapy dose
and major bleeding
35
30
25
Major
bleeding 20
(%)
P < 0.001
P = 0.25
P < 0.001
15
10
5
0
UFH
N=
2074
2063
2073
Underdosed
Data are for noncoronary bypass grafting
and nontransfer population
LMWH
714
2327
Recommended
3998
922
GP IIb/IIIa
inhibitors
237
Mild excess
5879
1955
178
Major excess
Alexander KP et al. JAMA. 2005;294:3108-16.
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Recommended dosing of antithrombotic agents
Drug
Recommended dose
Dosing adjustments
UFH
Bolus 60–70 U/kg and infusion Patients >60 yr may require
12–15 U/kg per hr
lower doses
LMWH:
Enoxaparin
1 mg/kg SC every 12 hr
 dose by 50% by increasing interval to
every 24 h if CrCl <30 mL/min
GP IIb/IIIa
inhibitor:
Eptifibatide
Bolus 180 µg/kg and
infusion 2 µg/kg per min
 infusion by 50% to 1 µg/kg per min
if CrCl ≤50 mL per min or serum
creatinine = 2–4 mg/dL
GP IIb/IIIa
inhibitor:
Tirofiban
Bolus 0.4 µg/kg and
infusion 0.1 µg/kg per min
 bolus and infusion by 50% to
0.05 µg/kg per min if CrCl
≤30 mL/min
Alexander KP et al. JAMA. 2005;294:3108-16.
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Creatinine clearance vs age
80
70
Median
creatinine
clearance
(cc/min)
60
50
40
30
20
10
0
<65
65–74
75–84
Age (years)
>84
Peterson ED et al. ACC. March 2005; Orlando, Fla.
Data on file at: Duke Clinical Research Institute. Jan 2001–Dec 2004.
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Clinical implications
• Early use of antithrombotic agents plays a key role in management
of NSTE ACS, but dosing errors are common
• Dosing errors occur more often in elderly and others already vulnerable
to bleeding
• Dosing errors predict an increased risk of major bleeding
• Altering dosing based on weight and renal function minimizes bleeding
while preserving therapeutic benefit
• Patients receiving recommended doses of heparin and GP IIb/IIIa
inhibitors alone or in combination have the lowest rates of bleeding
Proper dosing of antithrombotic therapies is necessary
to prevent bleeding complications in vulnerable patients
Alexander KP et al. JAMA. 2005:294:3108-16.
Clinical Insights,
Risk Stratification,
and Enhancing Outcomes
• Combination Therapy
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INTERACT: Study design
INTegrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome
Treatment
Evaluate safety and efficacy of GP IIb/IIIa inhibitors + enoxaparin vs UFH
N = 746 with ischemic chest symptoms and ECG or CK-MB evidence of ACS
Prospective, randomized multicenter study
Enoxaparin
1 mg/kg per 12 h for 48 h
UFH
70 U/kg IV bolus, then 15 U/kg per h for 48 h
Eptifibatide 180 µg/kg bolus, then 2.0 µg/kg per min for 48 h
Primary safety outcome:
96 h non–CABG-related major hemorrhage
Primary efficacy outcome:
Recurrent ischemia detected by continuous ECG evaluation within 96 h
UFH = unfractionated heparin
Goodman SG et al. Circulation. 2003;107:238-44.
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INTERACT: LMWH/UFH plus GP IIb/IIIa inhibitor
in UA/NSTEMI—Primary outcomes
Ischemia
Bleeding (96 h)
35
30
35
P = 0.0002
P < 0.0001
P = 0.003
30
5
4
25
25
Patients 20
(%)
15
20
3
15
2
10
10
5
5
0
Initial 48 h
n = 357 357
48–96 h
322 302
Enoxaparin*
0
P = 0.03
1
Minor‡
n = 380 366
0
Major‡
380 366
Heparin†
*Enoxaparin 1 mg/kg SC q 12 h for 48 h
†UFH 70-U/kg bolus + 15-U/kg per h infusion for 48 h
All patients: Eptifibatide 180-g/kg bolus + 2-g/kg per min infusion
‡Non–CABG-related
Goodman SG et al.
Circulation. 2003;107:238-44.
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INTERACT: LMWH/UFH plus GP IIb/IIIa inhibition
in UA/NSTEMI
Effect on 30-day death/MI
UFH† + GP IIb/IIIa inhibitor
0.10
0.08
Proportion
of patients
P = 0.031
0.06
0.04
Enoxaparin* + GP IIb/IIIa inhibitor
0.02
0
0
5
15
20
25
10
Days since randomization
*Enoxaparin 1 mg/kg SC q 12 h for 48 h
†UFH 70-U/kg bolus + 15-U/kg per h infusion for 48 h
All patients: Eptifibatide 180-g/kg bolus +
2-g/kg per min infusion
30
Goodman SG et al. Circulation. 2003;107:238-44.
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SYNERGY: Study design
Superior Yield of the New Strategy of Enoxaparin, Revascularization and
GlYcoprotein IIb/IIIa Inhibitors
Compare enoxaparin vs UFH and define role of enoxaparin
N = 10,027 high-risk NSTEMI patients managed with early PCI
Prospective, randomized, open-label, multicenter study
Enoxaparin
UFH
GP IIb/IIIa inhibitor, aspirin, and clopidogrel
Primary outcome:
Death or MI ≤30 days
Primary safety outcome:
Major bleeding or stroke
SYNERGY Trial Investigators. JAMA. 2004;292:45-54.
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SYNERGY: Enoxaparin vs UFH with
GP IIb/IIIa inhibition in ACS with early PCI
Primary outcome (death or MI)
0.2
UFH
Enoxaparin
14.5%
14.0%
Proportion
0.1
of
patients
HR 0.96
(95% Cl 0.86–1.06)
Concomitant medications (%)
Enox
UFH
Aspirin
Clopidogrel
GP IIb/IIIa inhibitor
-Blocker
ACE inhibitor
Statin
n = 4993
n = 4985
95.2
62.5
56.5
86.4
63.8
69.2
94.7
63.3
58.2
85.9
62.2
70.0
0
0
No. at Risk
UFH
Enoxaparin
10
20
30
Days from randomization
4920 4458 4343 4301 4279 4261 3509
4936 4508 4375 4338 4313 4300 3550
SYNERGY Trial Investigators. JAMA. 2004;292:45-54.
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PCI-CURE: Substudy design
Percutaneous Coronary Intervention substudy of Clopidogrel in Unstable angina to
prevent Recurrent ischemic Events
Evaluate pre/post-PCI benefit of clopidogrel
N = 2658 with NSTEMI
Double-blind, placebo-controlled, multicenter prespecified
post-randomization analysis
Clopidogrel 300 mg pre-PCI,
Open-label thienopyridine 2–4 wk,
Clopidogrel 3–12 mo
Placebo pre-PCI,
Open-label thienopyridine 2–4 wk,
Placebo 3–12 mo
Aspirin 75–325 mg (all patients)
Primary outcome:
CV death, MI, revascularization at 30 days
Follow-up: 1 month
Mehta SR et al. Lancet. 2001;358:527-33.
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PCI-CURE: Reduction in primary
outcome at 30 days
CV death, MI, or urgent target vessel revascularization
0.08
0.06
Cumulative
hazard rates
Placebo
30% RRR*
P = 0.03
0.04
Clopidogrel
0.02
P = 0.03
0
0
5
10
15
20
25
30
Days of follow-up
*Unadjusted
Mehta SR et al. Lancet. 2001;358:527-33.
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ISAR-REACT: Study design
Intracoronary Stenting and Antithrombotic Regimen–Rapid Early Action for
Coronary Treatment
Evaluate abciximab + clopidogrel loading dose in PCI
N = 2159 undergoing elective PCI
Double-blind, randomized, placebo-controlled multicenter study
Clopidogrel 600 mg ≥2 h prior to PCI
Aspirin 325–500 mg
Abciximab 0.25 mg/kg bolus, then
0.125 µg/kg per min for 12 h
+ UFH 70 U/kg
Placebo
+ UFH 140 U/kg
Primary outcome:
All-cause death, MI, urgent revascularization
Follow-up: 1 month
Kandzari DE et al. J Am Coll Cardiol. 2004;44:2133-6.
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ISAR-REACT: Timing of loading dose
and primary outcome
All-cause death, MI, urgent revascularization
Major
bleeding (%)
10
8
Death, MI,
urgent
revascularization
(%)
6
<3 h
1.6
3–6 h
0.5
6–12 h
0.4
>12 h
1.1
4
2
P = 0.79
0
0
5
10
15
20
25
Time from randomization (days)
30
Kandzari DE et al. J Am Coll Cardiol. 2004;44:2133-6.
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ISAR-CHOICE: No additional platelet
effect with doses >600 mg
Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral
Doses for Immediate Clopidogrel Effect
Maximal ADP-induced platelet
aggregation after 4 hours
120
P = 0.001
100
ADP
(5 µmol/L)-induced
aggregation
(%)
80
60
40
20
P = 0.01
P = 0.59
0
300 mg
600 mg
900 mg
Clopidogrel (loading dose)
von Beckerath N et al. Circulation. 2005;112:2946-50.
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ISAR-SWEET: Study design
Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to
Eliminate Elevated Thrombotic Risk in Diabetics
Evaluate abciximab + clopidogrel loading dose in PCI
N = 701 with diabetes, undergoing elective PCI
Double-blind, randomized, placebo-controlled multicenter study
Clopidogrel 600 mg ≥2 h prior to PCI
Abciximab 0.25 mg/kg bolus, then
0.125 µg/kg per min for 12 h
n = 351
Clopidogrel 600 mg ≥2 h prior to PCI
Placebo
n = 350
Aspirin 500 mg and heparin
Primary outcome:
All-cause death and MI at 1 year
TVR = target vessel revascularization
Mehilli J et al. Circulation. 2004;110:3627-35.
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ISAR-SWEET: Neutral effect
on primary outcome in diabetes
10
RR 0.97
(0.58–1.62)
P = 0.91
8
All-cause
death, MI
(%)
6
Abciximab
4
Placebo
2
0
0
1
2 3
4 5 6
7 8
9 10 11 12
Time from randomization (months)
Mehilli J et al. Circulation. 2004;110:3627-35.
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ISAR-SWEET: Reduction in restenosis and
target vessel revascularization in diabetes
RRR = 24%
P = 0.01
37.8
40
30
RRR = 22%
P = 0.03
30.4
28.9
23.2
Incidence
(%)
20
10
0
Angiographic
restenosis
Abciximab
Target lesion
revascularization
Placebo
Mehilli J et al. Circulation. 2004;110:3627-35.
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CLEAR PLATELETS: Study design
Clopidogrel Loading with Eptifibatide to Arrest the Reactivity of PLATELETS
Compare effects of antiplatelet regimens on platelet reactivity
and occurrence of myocardial necrosis
N = 120 undergoing elective stenting
2 x 2 factorial study
Clopidogrel
300 mg*
Clopidogrel
300 mg*
+ eptifibatide†
Clopidogrel
600 mg*
Clopidogrel
600 mg*
+ eptifibatide†
Primary aim:
Compare effects of four regimens
Secondary aim:
Effect of treatment on platelet reactivity
and postprocedural myocardial necrosis
*Loading dose immediately after stenting, then 75 mg/d
†Double bolus (180 g/kg) followed by infusion
(2 g/kg per min) for 18–24 hours postprocedure
Gurbel PA et al. Circulation. 2005;111:1153-9.
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CLEAR PLATELETS: Platelet effects vs
clopidogrel dose and GP IIb/IIIa inhibition
Platelet inhibition*
Platelet reactivity*
70
120
†
100
Relative 80
inhibition
60
(%)
60
†
†
D
C
‡
‡
‡
B
40
A
50
Aggregation 40
(%)
30
20

10
20
0
§
0
3h
8h
A
18–24 h
B
≤ 0.001 C or D vs A or B
‡P = 0.001 A vs B
*Response
A: Clopidogrel 300 mg
B: Clopidogrel 600 mg
C: Clopidogrel 300 mg + eptifibatide
D: Clopidogrel 600 mg + eptifibatide
to adenosine diphosphate 5 mol/L
D
Group
Time (post-stenting)
†P
C
§P
P
= 0.002 A vs B
< 0.001 C or D vs A or B
Gurbel PA et al. Circulation. 2005;111:1153-9.
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CLEAR PLATELETS: Effect of clopidogrel dose
and GP IIb/IIIa inhibition on cardiac biomarkers
20
Patients
(%)
CK-MB release
Troponin release
30
20
10
10
*
†
‡
*
0
0
CK-MB (>3x ULN)
*P < 0.05 vs clopidogrel 300 or 600 mg
†P = 0.04 vs clopidogrel 300 mg
‡P = 0.08 vs clopidogrel 600 mg
ULN = upper limit of normal
Troponin-I (> ULN)
Clopidogrel 300 mg
Clopidogrel 600 mg
Clopidogrel 300 mg + eptifibatide
Clopidogrel 600 mg + eptifibatide
Gurbel PA et al. Circulation. 2005;111:1153-9.
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Clopidogrel response variability:
300 mg vs 600 mg
N = 190
33
30
27
24
21
Patients
18
(%)
15
12
9
6
3
0
Resistance 600 mg = 8%
300 mg clopidogrel
Resistance 300 mg = 28%
600 mg clopidogrel
Nonresponsiveness
≤-30
(-20,-10]
(0,10]
(20,30]
(40,50]
(60,70]
(-30,-20]
(10,20]
(30,40]
(50,60]
> 70
(-10,0]
D Platelet aggregation (5 µM ADP-induced) at 24 hours
Gurbel PA. J Am Coll Cardiol. 2005;45:1392-96.
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Clopidogrel resistance associated with
increased CV risk
ADP-induced platelet aggregation
Recurrent CV events at 6 months
40
35
1st Q
30
25
2nd Q
20
3rd Q %
15
4th Q
10
5
0
Clopidogrel resistance
120
100
80
% 60
40
20
0
1
2
3
4
Days
5
6
40
P = 0.007
6.7
1st
n = 15
2nd
n = 15
0
0
3rd
n = 15
4th
n = 15
Quartiles
Matetzky S et al. Circulation. 2004;109:3171-5.
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REPLACE-2: Study design
Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events
Evaluate bivalirudin vs heparin + GP IIb/IIIa blockade post-PCI
N = 6010 undergoing PCI
Randomized, double-blind multicenter study
Bivalirudin 0.75 mg/kg bolus,
1.75 mg/kg per h during PCI
Provisional GP IIb/IIIa inhibitor
Heparin 65 U/kg bolus
Planned GP IIb/IIIa inhibitor
Primary outcome:
Death, MI, repeat revascularization, or in-hospital major bleeding
in ≤30 days
Secondary outcome:
Death, MI, repeat revascularization ≤30 days
Lincoff AM et al. JAMA. 2003;289:853-63.
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REPLACE-2: Death, MI, urgent revascularization,
major bleeding
P = 0.32
10
P = 0.26
P = 0.23
P = 0.44
P < 0.001
10.0
9.2
Heparin
+ GP IIb/IIIa inhibitor
(n = 3008)
8
7.0
6.2
6
Bivalirudin
(n = 2994)
%
4.1
4
2.4
2
1.4
1.2
0.4 0.2
0
Composite
Death
MI
Urgent revasc Major bleed
Lincoff AM et al. JAMA. 2003;289:853-63.