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Clinical Insights, Risk Stratification, and Enhancing Outcomes
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CRUSADE. www.crusadeqi.com
Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines
CRUSADE: National quality improvement initiative
• 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
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CRUSADE: In-hospital mortality by age and acute treatment
Boden WE et al. Circulation. 2005;112:II-745.
*Aspirin, β-blockers, UFH/LMWH, GP IIb/IIIa inhibitors, clopidogrel <24 hours, PCI <48 hours N = 105,619 registry patients
3.13.55.2
6.7
8.7
10.4
17.6
0.611.8
2.73.5
10.7
6.5
0
2
4
6
8
10
12
14
16
18
20
0 1 2 3 4 5 6
Number of recommended therapies
Age >75 yrs
Age <75 yrs
%
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CRUSADE: Post-admission MI vs use of recommended therapies
Boden WE et al. Circulation. 2005;112:II-745.
Number of recommended therapies
%
2.22.52.6
2.93.4
4.2
6.7
1
2
3
4
5
6
0 1 2 3 4 5 6
7
Adjusted OR 0.91 (95% CI 0.88–0.95)
*Aspirin, β-blockers, UFH/LMWH, GP IIb/IIIa inhibitors, clopidogrel <24 hours, PCI <48 hours N = 105,619 registry patients
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CRUSADE: Impact of early aggressive management strategy on in-hospital mortality
No early invasive care (n = 9889)
Early invasive care (cardiac cath <48 h, n = 8037)
Bhatt DL et al. JAMA. 2004;292:2096-104.Adjusted for clinical differences and propensity score
88
72
26
74
94
7889
5151
0
20
40
60
80
100
Aspirin -Blocker Clopidogrel Heparin GP IIb/IIIa inhibitor
14
Acute medical therapy (<24 h)
3.72.5
0
2
4
6
8
In-hospital mortality 32%
P < 0.001
%
P < 0.001
%
N = 17,926 registry patients
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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
Alexander KP et al. JAMA. 2005;294:3108-16.NSTE ACS = non–ST-segment elevation acute coronary syndromes
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Alexander KP et al. JAMA. 2005;294:3108-16.
Major predictors of overdosing
Patients vulnerable to overdosing
Older age(≥65 years)
Female
Diabetes
CHF
Low bodyweight
Renalinsufficiency
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P < 0.001 for all treatment groups
Alexander KP et al. JAMA. 2005;294:3108-16.
60
50
40
30
20
10
0UFH LMWH GP IIb/IIIa inhibitors
<65 ≥75
Results: Excess dosing by age
70
Patient age (years)
Excessdose(%)
65–74
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Results: Antithrombotic therapy dose and major bleeding
Alexander KP et al. JAMA. 2005;294:3108-16.Data are for noncoronary bypass grafting and nontransfer population
35
30
25
20
15
10
5
0
Majorbleeding
(%)
2074 2063 2073 714
UFH
2327 3998 922 237
LMWH
5879 1955 178
GP IIb/IIIa inhibitors
Underdosed Recommended Mild excess Major excess
P < 0.001 P = 0.25 P < 0.001
N =
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Alexander KP et al. JAMA. 2005;294:3108-16.
Recommended dosing of antithrombotic agents
Drug Recommended dose Dosing adjustments
UFH Bolus 60–70 U/kg and infusion 12–15 U/kg per hr
Patients >60 yr may require 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 andinfusion 0.1 µg/kg per min
bolus and infusion by 50% to0.05 µg/kg per min if CrCl ≤30 mL/min
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Peterson ED et al. ACC. March 2005; Orlando, Fla.Data on file at: Duke Clinical Research Institute. Jan 2001–Dec 2004.
Median creatinineclearance(cc/min)
Age (years)
065–74 75–84 >84
20
40
60
80
<65
10
30
50
70
Creatinine clearance vs age
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Proper dosing of antithrombotic therapies is necessary to prevent bleeding complications in vulnerable patients
Alexander KP et al. JAMA. 2005:294:3108-16.
Clinical implications
• Early use of antithrombotic agents plays a key role in management of NSTE ACS, but dosing errors are common
• Altering dosing based on weight and renal function minimizes bleeding while preserving therapeutic benefit
• Dosing errors occur more often in elderly and others already vulnerable to bleeding
• Dosing errors predict an increased risk of major bleeding
• Patients receiving recommended doses of heparin and GP IIb/IIIa inhibitors alone or in combination have the lowest rates of bleeding
Clinical Insights, Risk Stratification, and Enhancing Outcomes
• Combination Therapy
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INTERACT: Study design
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
Evaluate safety and efficacy of GP IIb/IIIa inhibitors + enoxaparin vs UFHN = 746 with ischemic chest symptoms and ECG or CK-MB evidence of ACS
Prospective, randomized multicenter study
Primary safety outcome:96 h non–CABG-related major hemorrhage
Primary efficacy outcome:Recurrent ischemia detected by continuous ECG evaluation within 96 h
Eptifibatide 180 µg/kg bolus, then 2.0 µg/kg per min for 48 h
Goodman SG et al. Circulation. 2003;107:238-44.UFH = unfractionated heparin
INTegrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment
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Goodman SG et al. Circulation. 2003;107:238-44.
Heparin†Enoxaparin*
Patients (%)
Ischemia Bleeding (96 h)
P = 0.0002 P < 0.0001
P = 0.03P = 0.003
Major‡
380 366
Minor‡
n = 380 366
48–96 hInitial 48 h322 302n = 357 357
0
1
2
3
4
5
0
5
10
15
20
25
30
35
0
5
10
15
20
25
30
35
*Enoxaparin 1 mg/kg SC q 12 h for 48 h†UFH 70-U/kg bolus + 15-U/kg per h infusion for 48 hAll patients: Eptifibatide 180-g/kg bolus + 2-g/kg per min infusion ‡Non–CABG-related
INTERACT: LMWH/UFH plus GP IIb/IIIa inhibitor in UA/NSTEMI—Primary outcomes
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Effect on 30-day death/MI
Goodman SG et al. Circulation. 2003;107:238-44.
Proportionof patients
Days since randomization
Enoxaparin* + GP IIb/IIIa inhibitor
UFH† + GP IIb/IIIa inhibitor
P = 0.031
0 5 10 15 20 25 30
0
0.02
0.04
0.06
0.08
0.10
*Enoxaparin 1 mg/kg SC q 12 h for 48 h†UFH 70-U/kg bolus + 15-U/kg per h infusion for 48 hAll patients: Eptifibatide 180-g/kg bolus + 2-g/kg per min infusion
INTERACT: LMWH/UFH plus GP IIb/IIIa inhibition in UA/NSTEMI
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SYNERGY: Study design
Enoxaparin UFH
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
Primary outcome:Death or MI ≤30 days
Primary safety outcome:Major bleeding or stroke
GP IIb/IIIa inhibitor, aspirin, and clopidogrel
SYNERGY Trial Investigators. JAMA. 2004;292:45-54.
Superior Yield of the New Strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa Inhibitors
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Concomitant medications (%)
Aspirin 95.2 94.7Clopidogrel 62.5 63.3
GP IIb/IIIa inhibitor 56.5 58.2-Blocker 86.4 85.9
ACE inhibitor 63.8 62.2Statin 69.2 70.0
SYNERGY Trial Investigators. JAMA. 2004;292:45-54.
14.0%
Primary outcome (death or MI)
UFHEnoxaparin
14.5%
Proportion of
patientsHR 0.96(95% Cl 0.86–1.06)
0.1
0.2
10 20 30
Days from randomizationNo. at Risk
UFHEnoxaparin
49204936
44584508
43434375
43014338
42794313
42614300
35093550
0
Enoxn = 4993
UFHn = 4985
SYNERGY: Enoxaparin vs UFH with GP IIb/IIIa inhibition in ACS with early PCI
0
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PCI-CURE: Substudy design
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
Evaluate pre/post-PCI benefit of clopidogrel N = 2658 with NSTEMI
Double-blind, placebo-controlled, multicenter prespecified post-randomization analysis
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.
Percutaneous Coronary Intervention substudy of Clopidogrel in Unstable angina to prevent Recurrent ischemic Events
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Mehta SR et al. Lancet. 2001;358:527-33.
CV death, MI, or urgent target vessel revascularization
*Unadjusted
30% RRR*P = 0.03
0.08
0.06
0.04
0.02
00 5 10 15 20 25 30
Days of follow-up
Cumulative hazard rates
P = 0.03
Clopidogrel
Placebo
PCI-CURE: Reduction in primary outcome at 30 days
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ISAR-REACT: Study design
Clopidogrel 600 mg ≥2 h prior to PCIAspirin 325–500 mg
Evaluate abciximab + clopidogrel loading dose in PCIN = 2159 undergoing elective PCI
Double-blind, randomized, placebo-controlled multicenter study
Primary outcome:All-cause death, MI, urgent revascularization
Abciximab 0.25 mg/kg bolus, then0.125 µg/kg per min for 12 h
+ UFH 70 U/kg
Placebo+ UFH 140 U/kg
Follow-up: 1 month
Intracoronary Stenting and Antithrombotic Regimen–Rapid Early Action for Coronary Treatment
Kandzari DE et al. J Am Coll Cardiol. 2004;44:2133-6.
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Kandzari DE et al. J Am Coll Cardiol. 2004;44:2133-6.
All-cause death, MI, urgent revascularization
Death, MI, urgent
revascularization(%)
Time from randomization (days)
0 5 10 15 20 25 30
P = 0.79
0
2
4
6
8
10 <3 h
3–6 h
6–12 h
>12 h
Major bleeding (%)
1.6
0.5
0.4
1.1
ISAR-REACT: Timing of loading dose and primary outcome
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Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect
von Beckerath N et al. Circulation. 2005;112:2946-50.
120
ADP(5 µmol/L)-induced
aggregation(%)
80
100
60
40
20
0300 mg 600 mg 900 mg
P = 0.01 P = 0.59
P = 0.001
Maximal ADP-induced platelet aggregation after 4 hours
Clopidogrel (loading dose)
ISAR-CHOICE: No additional platelet effect with doses >600 mg
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ISAR-SWEET: Study design
Aspirin 500 mg and heparin
Evaluate abciximab + clopidogrel loading dose in PCIN = 701 with diabetes, undergoing elective PCI
Double-blind, randomized, placebo-controlled multicenter study
Primary outcome:All-cause death and MI at 1 year
Clopidogrel 600 mg ≥2 h prior to PCIAbciximab 0.25 mg/kg bolus, then
0.125 µg/kg per min for 12 hn = 351
Clopidogrel 600 mg ≥2 h prior to PCIPlacebon = 350
Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics
Mehilli J et al. Circulation. 2004;110:3627-35.TVR = target vessel revascularization
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Mehilli J et al. Circulation. 2004;110:3627-35.
All-cause death, MI
(%)
10
8
6
4
2
0
Time from randomization (months)
0 1 2 3 4 5 6 7 8 9 10 11 12
Abciximab
Placebo
RR 0.97(0.58–1.62)
P = 0.91
ISAR-SWEET: Neutral effect on primary outcome in diabetes
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Mehilli J et al. Circulation. 2004;110:3627-35.
Incidence(%)
Angiographicrestenosis
Target lesionrevascularization
Abciximab Placebo
40
30
20
10
0
P = 0.01
P = 0.03
ISAR-SWEET: Reduction in restenosis and target vessel revascularization in diabetes
28.9
37.8
23.2
30.4
RRR = 24%
RRR = 22%
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CLEAR PLATELETS: Study design
Clopidogrel 300 mg*
Compare effects of antiplatelet regimens on platelet reactivity and occurrence of myocardial necrosis
N = 120 undergoing elective stenting2 x 2 factorial study
Primary aim:Compare effects of four regimens
Clopidogrel 300 mg*
+ eptifibatide†
Clopidogrel 600 mg*
+ eptifibatide†
Secondary aim:Effect of treatment on platelet reactivity and postprocedural myocardial necrosis
Clopidogrel 600 mg*
Clopidogrel Loading with Eptifibatide to Arrest the Reactivity of PLATELETS
Gurbel PA et al. Circulation. 2005;111:1153-9.
*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
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§
Gurbel PA et al. Circulation. 2005;111:1153-9.*Response to adenosine diphosphate 5 mol/L
Platelet reactivity*Platelet inhibition*
†P ≤ 0.001 C or D vs A or B‡P = 0.001 A vs B
§P = 0.002 A vs BP < 0.001 C or D vs A or B
A B C D
Aggregation (%)
0
10
20
30
40
50
60
70
18–24 h3 h 8 h
Time (post-stenting)
Relative inhibition
(%)
A
B
CD
0
20
40
60
80
100
120
‡
†††
‡ ‡
Group
CLEAR PLATELETS: Platelet effects vs clopidogrel dose and GP IIb/IIIa inhibition
A: Clopidogrel 300 mg
B: Clopidogrel 600 mg
C: Clopidogrel 300 mg + eptifibatide
D: Clopidogrel 600 mg + eptifibatide
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Gurbel PA et al. Circulation. 2005;111:1153-9.
CK-MB release Troponin release
Clopidogrel 300 mg
Clopidogrel 600 mg
Clopidogrel 300 mg + eptifibatide
Clopidogrel 600 mg + eptifibatide
0CK-MB (>3x ULN)
10
20
Patients(%)
0
10
20
30
Troponin-I (> ULN)
*P < 0.05 vs clopidogrel 300 or 600 mg†P = 0.04 vs clopidogrel 300 mg‡P = 0.08 vs clopidogrel 600 mgULN = upper limit of normal
†
‡*
CLEAR PLATELETS: Effect of clopidogrel dose and GP IIb/IIIa inhibition on cardiac biomarkers
*
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Clopidogrel response variability: 300 mg vs 600 mg
Gurbel PA. J Am Coll Cardiol. 2005;45:1392-96.
N = 190
0369
1215182124273033
≤-30(-30,-20]
(-20,-10](-10,0]
(0,10](10,20]
(20,30](30,40]
(40,50](50,60]
(60,70]> 70
300 mg clopidogrel
Platelet aggregation (5 µM ADP-induced) at 24 hours
Patients(%)
Resistance 300 mg = 28% 600 mg clopidogrel
Nonresponsiveness
Resistance 600 mg = 8%
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Matetzky S et al. Circulation. 2004;109:3171-5.
120
100
80
60
40
20
0
ADP-induced platelet aggregation
Clopidogrel resistance
1 2 3 4 5 6
Days
4th Q
3rd Q2nd Q
%
1st Q
40
35
25
15
10
01st
n = 15
Recurrent CV events at 6 months
30
20
5
%
2ndn = 15
3rdn = 15
4thn = 15
Quartiles
40
6.7
0 0
P = 0.007
Clopidogrel resistance associated with increased CV risk
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REPLACE-2: Study design
Bivalirudin 0.75 mg/kg bolus, 1.75 mg/kg per h during PCI
Provisional GP IIb/IIIa inhibitor
Evaluate bivalirudin vs heparin + GP IIb/IIIa blockade post-PCIN = 6010 undergoing PCI
Randomized, double-blind multicenter study
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.
Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events
Heparin 65 U/kg bolusPlanned GP IIb/IIIa inhibitor
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0.2
Death MI Urgent revasc Major bleedComposite
2.4
1.21.4
7.0
6.2
0.4
9.210.0
10
8
6
4
2
0
Heparin + GP IIb/IIIa inhibitor(n = 3008)
Bivalirudin(n = 2994)
P = 0.32 P = 0.26 P = 0.23 P = 0.44 P < 0.001
Lincoff AM et al. JAMA. 2003;289:853-63.
4.1%
REPLACE-2: Death, MI, urgent revascularization, major bleeding
