“Challenging practice in non-ST segment elevation Acute

Coronary Syndromes (ACS)”

Professor Jennifer AdgeyRoyal Victoria Hospital, Belfast

26th January 2006

Conflicts of interest- Speaker symposia: Eli-Lilly, MSD, Sanofi-

Aventis, BMS, GSK

Chest pain in the A&E department

• Approximately 600,000 patients per annum attend A&E in the UK with chest pain

• 25% will have NSTE-ACS

J R Coll Physicians Edinb 2003;33:36-43

Epidemiology of Acute Coronary Syndromes

ST-segment elevation MI

Prevalence: 30%-42%

Non-ST-segment elevation ACS

Prevalence: 51%-63%

Death and non-fatal (re)-infarction at 6 months: 13%

Acute Coronary Syndromes: Mortality at 6 Months

Days from randomization

Savonitto et al. JAMA. 1999;281:707.

Mo

rta

lity

(%)

1800 20 40 60 80 100 1600

6

8

10

2

4

120 140

% Mortality at 6 Months

T-wave inversion3.4% (n=2,723)

ST-segment elevationand depression9.1% (n=1,769)

ST-segment depression8.9% (n=4,263)

ST-segment elevation6.8% (n=3,369)

Risk stratification, Risk of progression to death and MI

Elevated troponin levelsDiabetes Patients with recurrent ischaemiaRecurrent chest painDynamic ST-segment changes(ST-segment depression or transient ST-segment elevation)Haemodynamic instabilityMajor arrhythmias (VF, VT) Early post-infarction unstable angina

No elevation of troponin or otherNo elevation of troponin or other biochemical markersbiochemical markers

Negative troponin test recorded Negative troponin test recorded twicetwice

No recurrence of chest pain No recurrence of chest pain

within observational period within observational period

No ST-segment depressionNo ST-segment depressionNegative T waves, flat T waves, Negative T waves, flat T waves, normal ECGnormal ECG

High-risk patients Low-risk patients

Infusion of GP IIb-IIIa Inhibitor

Invasive strategy

Conservative strategy

Baseline treatment: heparin (LMWH or UFH), ASA, clopidogrel, beta-blockers, nitrates

Troponin + is associated with presence of Thrombus on Angioscopy

0

10

20

30

40

50

60

70

80

90

100

• Only 20% to 25% of thrombi seen on angioscopy (gold standard) is seen on angiography (i.e. angiography misses 4 out of 5 thrombi in Tn + pts)

Okamatsu et al, Circulation 2004; 109:465-470.

Tn - Tn -Tn + Tn +

9%18%

86%

34%

Angiogram Angioscope

% T

hro

mb

us

P=0.0001

P=0.41

Only 1 of 5 thrombi

detected

NSTE-ACS

Medical treatmentPCI with provisional

abciximab or eptifibatide

Conservative approach

Early non invasive stress testing

PCI with abciximab

or eptifibatide

PCI with eptifibatide or tirofiban

Silber S. et al. ESC PCI guidelines 2005

ESC PCI Guidelines for NSTE ACS

ASA, Clopidogrel, UFH, Betablockers, Nitrates, Statins (ACE)

Low risk

Without upstream GP IIb/IIIa RA

With upstream GP IIb/III RA

Invasive approach

High risk

Can the results of clinical trials be transferred to the real world? – NRMI 4

In-hospital mortality for patients treated with a glycoprotein (GP) IIb/IIIa inhibitor versus those not treated, by the National Registry of Myocardial Infarction non–ST-elevation myocardial infarction (NRMI-NSTEMI) risk score.

Early use

(N=15, 379)

No early use (N=45, 391)

Overall (N=60,770)

P

3.3% 9.6% 8% <0.0001

In-hospital mortality by early use of GPIIb/IIIa inhibitor

JACC 2003;42:45-53

JACC 2003;42:45-53

CRUSADE: Unadjusted Mortality According to Early* GP IIb-IIIa Inhibitor Use

∆ 41%P < 0.0001†

∆ 41%P < 0.0001†

2.7%

4.6%

0%

2%

4%

6%

8%

% In-hospital Mortality

No Early GP IIb-IIIa Inhibitor (n = 41,896)

Early GP IIb-IIIa Inhibitor (n = 24,168)

*Within 24 hours

†Risk-adjusted odds ratio:

0.96 (0.86, 1.07)

‡‡

Source: Duke Clinical Research Institute.

CRUSADE - Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines; GP = glycoprotein.

Are GPIIb/IIIa inhibitors really necessary when clopidogrel is available?

Eptifibatide provides additional platelet inhibition in Non-ST-Elevation MI patients already treated with aspirin and clopidogrel - PEACE

T1 – before clopidogrel administration

T2 – >2 hours after clopidogrel

T3 – during eptifibatide infusion following clopidogrel

JACC 2004;43:162-168

Months

Cum

ula

tive

eve

nt r

ate

(%)

14

12

10

8

6

4

2

0 2 4 6 8 10 12

placebo

INTEGRILIN 35% RRR p=0.001 (at 12 months)

12.4%

8.0% 3.9%

4.4%

NNT=23 (at 12 months)

ESPRIT: 1-Year Death or MI

(adapted from The ESPRIT Investigators study, 2000)

DEACON Study: Bivalirudin and Clopidogrel Alone Do Not Adequately Prevent

Platelet Aggregation

Am J Cardiol 2005;95:1453–1456

Bivalirudin + Clopidogrel

% Platelet Inhibition of TRAP-induced Aggregation

% Platelet Inhibition of ADP-induced Aggregation

- 20%

0%

20%

40%

60%

80%

Baseline 10 min 30 min 1 hr

100%

- 20%

0%

20%

40%

60%

80%

100%

Baseline 10 min 30 min 1 hr

Bivalirudin + Clopidogrel

INTEGRILIN + Heparin + Clopidogrel

INTEGRILIN + Heparin + Clopidogrel

Heparin + Clopidogrel Heparin +

Clopidogrel

When to start GPIIb/IIIa inhibitor therapy (upstream or downstream)?

Six month mortality in patients with and without new or recurrent MI during the first 72 hours after randomisation in the Platelet Glycoprotein

IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrelin Therapy (PURSUIT) trial.

0

2

4

6

8

10

12

14

16

18

20

1 2 3 4 5 6

MI within 72 h

No MI within 72h

Cu

mu

lati

ve m

ort

alit

y ra

te

Time in months

18.3%

5.5%

12.8% ↓ (p=0.001)

Clin Cardiol 2000;23 (suppV):V1-V12

Placebo and eptifibatide 180/2.0 combined

PURSUIT

• Patients receiving eptifibatide had significantly reduced incidence of MI at 72 hours (5.6% vs 6.9% with placebo p=0.009) as well as prior to PCI within 72 hours (1.8% vs 5.5% with placebo p=0.001)

Clin Cardiol 2000;23 (suppV):V1-V12

Incidence of death or MI at 30 days according to management strategy during the first 72 hours

Placebo (%)

Eptifibatide

(%)

P

Diagnostic CC<72 hours

North America

Worldwide

15.8

16.2

12.1

12.8

0.008

0.005

PCI <72 hours

North America

Worldwide

16.6

16.8

11.4

11.8

0.024

0.012

CABG <72 hours

North America

Worldwide

32.7

33.5

19.3

18.4

0.009

0.001

No PCI <72 hours

North America

Worldwide

14.5

15.6

11.8

14.6

0.035

0.226

PURSUIT

• The benefit of GpIIb/IIIa inhibitor (eptifibatide) is most marked if commenced within 6 hours of symptom onset

• Largest absolute reduction in death or MI at 30 days in those in whom eptifibatide was started within 6 hours of symptom onset (2.8%) compared to 2.3% AR reduction in patients treated between 6 and 12 hours and 1.4% AR reduction >12 hours

Clin Cardiol 2000;23 (suppV):V1-V12

Challenging practice in non-ST segment elevation Acute Coronary Syndromes (ACS)

• Identification of high risk patients admitted via the A&E department

• Early upstream administration of small molecule GPIIb/IIIa inhibitors (eptifibatide, tirofiban) are of benefit in patients receiving aspirin, clopidogrel, heparin and intervention (PCI)

• Long term follow up