Clinical Insights, Risk Stratification, and Enhancing Outcomes

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