Antiplatelet Interventions in Acute Coronary Syndromes

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Contents

I. Acute Coronary Syndromes: Tailoring Treatment to Level of Risk

II. Thrombus Susceptibility and the Vulnerable Plaque: Relationship Between Inflammation and Thrombosis

III. ACC/AHA UA/NSTEMI Guidelines: Role of GP IIb/IIIa Inhibitors

IV. Clinical Trials of GP IIb/IIIa Inhibition

V. Clinical Insights, Risk Stratification, and Enhancing Outcomes

VI. GP IIb/IIIa Inhibition in STEMI: Growing Clinical Trial Evidence

Acute Coronary Syndromes: Tailoring Treatment to Level of Risk

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US hospital discharges: Unstable angina/NSTEMI and STEMI

AHA. Heart Disease and Stroke Statistics–2005 Update.

STEMI = ST-elevation myocardial infarction (MI), or Q-wave MINSTEMI = non–ST-elevation MI, or non–Q-wave MI

1.67 million hospital discharges

STEMI

1.17 million discharges per year

500,000 discharges per year

Acute coronary syndromes

UA/NSTEMI

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Braunwald E et al. J Am Coll Cardiol. 2002;40:1366-74.

ACC/AHA 2002 UA/NSTEMI guidelines: High-risk indicators for early invasive strategy

• Recurrent angina/ischemia on treatment

• Elevated troponin levels

• New ST-segment depression

• Recurrent angina/ischemia with CHF symptoms, S3 gallop, pulmonary edema, worsening rales, new or worsening mitral regurgitation

• High-risk noninvasive test results

• Depressed LV function (EF <40%)

• Sustained ventricular tachycardia

• PCI within 6 months

• Prior CABG

Class I (Level of evidence: A)

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Odds ratio (95% CI)0.1 0.2 0.5 1 2 5 10

Favors routineinvasive

Favors selectiveinvasive

OR 1.60, P = 0.007

OR 0.76, P = 0.01

Mortality during hospitalization

Mortality after dischargeTIMI 3B 3.32.8VANQWISH 11.713.4MATE 6.910.0FRISC II 3.01.2TACTICS 2.81.9VINO 9.41.6RITA 3 7.35.2

Subtotal 1.11.8

TIMI 3B 1.92.2VANQWISH 1.34.5MATE 3.30.9FRISC II 0.91.1TACTICS 0.71.4VINO 4.51.6RITA 3 0.71.6

Subtotal 3.8 4.9

Cons (%)Inv (%)

Invasive Rx in ACS: Early and late mortality

Mehta SR et al. JAMA. 2005;293:2908-17.

7 trials, N = 9212

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Mehta SR et al. JAMA. 2005;293:2908-17.

7 trials, N = 9212

*TIMI 3B, VANQWISH, MATE†FRISC II, TACTICS, VINO, RITA 3‡Data by troponin status available only in FRISC II, TACTICS, RITA 3

Invasive management of UA/NSTEMI meta-analysis: Subgroups

Trial Routine (%) Selective (%) Odds ratio

Favorsroutine

invasive

Favorsselective invasive P

<0.001

0.0010.42

0.010.40

0.92After 1999† 12.49.4 0.73

Positive troponin‡ 10.0 14.0 0.69

Negative troponin 6.7 7.4 0.89

Marker positive 14.7 17.4 0.82

Marker negative 7.7 8.5 0.90

Before 1999* 19.3 19.6 0.99

0.001Overall 12.2 14.4 0.82

Odds ratio (95% Cl)0.5 1.0 2.0

Death or MI at follow-up

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RITA 3: Benefit of routine invasive strategy mainly in high-risk patients

Death or MI at 5 yrs

Risk score quartile* Event rate (%) OR (95% CI)

Invasive(n = 895)

Conservative(n = 915)

1st Q (1.71) 6.6 6.1 0.96 (0.44–2.10)

2nd Q (>1.71–2.20) 12.8 12.2 1.10 (0.62–1.95)

3rd Q (>2.20–2.83) 16.0 19.0 0.80 (0.49–1.30)

4th Q, lower (>2.83–3.28) 31.3 35.4 0.76 (0.44–1.35)

4th Q, upper (>3.28) 29.2 48.5 0.44 (0.25–0.76)

Fox KAA et al. Lancet. 2005;366:914-20.

Randomized Intervention Trial of unstable Angina

*Based on age, diabetes, prior MI, smoking, ST, pulse, grade 3/4 angina, sex, left bundle branch block, transient ST

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Clayton TC et al. Eur Heart J. 2004;25:1641-50.

HR 0.61(95% CI 0.44–0.85)

HR 1.09(95% CI 0.70–1.71)

20

0

12

16

8

4

0 1 32Time (years)

Invasive

Men

Conservative

Invasive

545 491 354 189 350 316 228 125

Conservative 583 507 356 194 332 305 230 119

20

0

12

16

8

4

0 1 32Time (years)

Women

Invasive

Conservative

Deathor MI(%)

No. patients

RITA 3: Greater benefit of early invasive strategy in men vs women with ACS

n = 682 women, 1128 men with UA/NSTEMI

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Death or MI(%)

Lagerqvist B et al. J Am Coll Cardiol. 2001;38:41-8.

Time (days)

20

16

12

8

4

00

4

8

12

20

0 60 120 180 240 300 360

n = 749 women, 1708 men with UA/NSTEMI

Time (days)

Fragmin and fast Revascularization during InStability in Coronary artery disease

16

0 60 120 180 240 300 360

Men Women

Invasive (n = 348)

Noninvasive (n = 401)Invasive (n = 874)

Noninvasive (n = 834)

P < 0.001ns

15.8%

9.6%

12.4%

10.5%

FRISC II: Men with ACS show greater benefit from early invasive strategy than women

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Multiples of the upper

reference limit

Days after onset of acute MI

50

20

10

5

2

1

0 1 2 3 4 5 6 7 8

Antman EM. N Engl J Med. 2002;346:2079-82.

Upperreference

limit

Cardiac troponin after“classic” acute MI

CK-MB after acute MI

Cardiac troponin after“microinfarction”

Release of cardiac troponins and CK-MB in acute MI

0

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Roe MT et al. Arch Intern Med. 2005;165:1870-6.Reference limit: maximum troponin ratio 0–1x upper limit of normal

Maximum troponin ratio

7

6

5

4

3

2

1

00 1 2 3 4 5 6 7 8 9 10

In-hospital mortality

(%)

CRUSADE: N = 23,298

In-hospital mortality higher with any degree of troponin elevation in NSTEMI patients

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*Family history of CAD, hypertension, elevated cholesterol, diabetes, current smoker†Creatine-kinase MB and/or cardiac troponins Antman EM et al. JAMA. 2000;284:835-42.

TIMI risk score for UA/NSTEMI

• Age ≥65 years

• ≥3 CAD risk factors*

• Significant coronary stenosis

• ST-segment deviation

• Severe angina (≥2 anginal events in last 24 hours)

• Daily use of aspirin in prior 7 days

• Elevated serum cardiac markers†

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Antman EM et al. JAMA. 2000;284:835-42.n = 1957 ACS patients

Risk factors (n)

0

45

35

25

15

5

0/1 2 3 4 5 6/7

Death/MI/severe ischemia

at 14 days (%)

4.78.3

13.2

19.9

26.2

40.9

TIMI risk score in UA/NSTEMI

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OPUS-TIMI 16

Sabatine MS et al. Circulation. 2002;105:1760-3.

TACTICS-TIMI 18

1

1.8

3.5

6

12.1

5.7

13

1 2 301 2 30

14

10

6

2

BNP = B-type natriuretic peptideCRP = C-reactive protein

6

4

2

0

30-day mortality relative

risk

Elevated cardiac biomarkers (n) Elevated cardiac biomarkers (n)

P = 0.014 P < 0.001

67 150 155 78 504 717 324 90

0

Multimarker strategy: Identifying high-risk patients by troponin I, CRP, and BNP

n =

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Hemodynamic stress

Giugliano RP et al. J Am Coll Cardiol. 2005;46:906-19.

Troponin +++ ++ +++BNP +++ ++ 0Renal dysfunction ++ + +Glucose metabolism + 0 +CRP ++ ++ ++

Blood glucose

Myocyte necrosis

Acceleratedatherosclerosis

Vasculardamage

Inflammation

hs-CRP, CD40L

Troponin

BNP, NT-proBNP

CrClMicroalbuminuria

A1C

BiomarkerIndependent

predictor of riskUseful in

multimarker strategyTherapeuticimplication

Multimarker approach in ACS