1. “Challenging practice in non-ST segment elevation Acute Coronary Syndromes (ACS)” Professor Jennifer Adgey Royal Victoria Hospital, Belfast 26th January Conflicts of interest- Speaker symposia: Eli-Lilly, MSD, Sanofi-Aventis, BMS, GSK

2. 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

3. Epidemiology of Acute Coronary Syndromes
ST-segment elevation MI
Prevalence: 30%-42%
Non-ST-segment elevation ACS
Prevalence: 51%-63%
Epidemiology of Acute Coronary Syndromes
Results from recent European and worldwide registries in patients with acute coronary syndromes (ACS) indicate that non-ST-segment elevation (NSTE) ACS are much more prevalent (51%-63%) than ST-segment elevation myocardial infarction (MI) (30%-42%) and that the rate of death or non-fatal (re)-infarction at 6 months in patients with ACS is high (13%).
23F B5C8- E684F324AF3A/0/ESC_ACS_Guidelines_slideset.pdf
Accessed 7 October, 2004.
Death and non-fatal (re)-infarction at 6 months: 13%

4. Acute Coronary Syndromes: Mortality at 6 Months
ST-segment elevation and depression 9.1% (n=1,769) 10
% Mortality at 6 Months
ST-segment depression 8.9% (n=4,263) 8
ST-segment elevation 6.8% (n=3,369) 6
Mortality (%) 4
T-wave inversion 3.4% (n=2,723) 2
Acute Coronary Syndromes: Mortality at 6 Months
Patients with non–ST-segment elevation (NSTE) acute coronary syndromes (ACS) require rapid initiation of aggressive antithrombotic therapy to reduce the high risk of acute and long-term morbidity and mortality. In the Global Use of Strategies to Open Occluded Arteries (GUSTO) IIb trial, patients with NSTE ACS who had ST-segment depression and were treated with aspirin and an antithrombin agent (either unfractionated heparin or direct thrombin inhibitor hirudin) had 30% higher mortality at 6 months (8.9%) than did patients with ST-segment elevation myocardial infarction treated with aspirin, an antithrombin, and fibrinolytics (6.8%). In addition, 6-month mortality rate in patients with both ST-segment elevation and depression (9.1%) was very similar to the rate observed in patients with ST-segment depression alone (8.9%).
Savonitto et al. JAMA. 1999;281:707. 20 40 60 80
100
120
140
160
180
Days from randomization
Savonitto et al. JAMA. 1999;281:707.

5. Infusion of GP IIb-IIIa Inhibitor
Risk stratification, Risk of progression
to death and MI
Baseline treatment: heparin (LMWH or UFH), ASA, clopidogrel, beta-blockers, nitrates
High-risk patients
Low-risk patients
Elevated troponin levels
Diabetes
Patients with recurrent ischaemia
Recurrent chest pain
Dynamic ST-segment changes
(ST-segment depression or transient ST-segment elevation)
Haemodynamic instability
Major arrhythmias (VF, VT)
Early post-infarction unstable angina
No elevation of troponin or other
biochemical markers
Negative troponin test recorded twice
No recurrence of chest pain
within observational period
No ST-segment depression Negative T waves, flat T waves, normal ECG
ESC Guidelines for NSTE ACS: Patients at High Risk for Progression to Death or MI
According to the European Society of Cardiology (ESC) guidelines for management of patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS), each of the following characteristics: recurrent ischaemia (demonstrated as recurrent chest pain or dynamic ST-segment changes [in particular ST-segment depression or transient ST-segment elevation]), early post-infarction unstable angina, elevated levels of cardiac troponins, haemodynamic instability during the observation period, major arrhythmias (repetitive ventricular tachycardia or ventricular fibrillation), and/or diabetes mellitus, is associated with high risk of progression to death or new myocardial infarction. For these patients, the ESC guidelines recommend treatment with aspirin, low-molecular-weight heparin or unfractionated heparin, clopidogrel, a β-blocker, nitrates, and a glycoprotein IIb-IIIa inhibitor while patients are awaiting coronary angiography, which is recommended to be performed within 48 hours. In patients in whom coronary angiography indicates the need for coronary artery bypass graft (CABG) surgery, treatment with clopidogrel should be discontinued for at least 5 days before CABG surgery should be performed. In patients in whom coronary angiography establishes the need for percutaneous coronary intervention (PCI), treatment with a GP IIb-IIIa inhibitor should be continued for 12 (abciximab) or 24 (INTEGRILIN®, tirofiban) hours after the PCI.
Bertrand et al. Eur Heart J. 2002;23: E684F324AF3A/0/ESC_ACS_Guidelines_slideset.pdf Accessed 7 October, 2004.
Infusion of GP IIb-IIIa Inhibitor
Invasive strategy
Conservative strategy

6. Troponin + is associated with presence of Thrombus on Angioscopy
86%
Only 1 of 5 thrombi
detected
% Thrombus
34%
P=0.41
18% 9%
Tn -
Tn +
Tn -
Tn +
Angiogram
Angioscope
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:

7. ESC PCI Guidelines for NSTE ACS
ASA, Clopidogrel, UFH, Betablockers, Nitrates, Statins (ACE)
Without upstream
GP IIb/IIIa RA
With upstream
GP IIb/III RA
Invasive approach
High risk
Low risk
Conservative approach
Early non invasive stress testing
ESC PCI Guidelines for NSTE ACS
The present guidelines focus on PCI to optimize the management of patients presenting NSTE ACS.
Patients presenting with NSTE-ACS (Unstable Angina or Non –ST Elevation Myocardial Infarction ) should first received a routine pre-treatment with (ASA, Clopidogrel, UFH, betablokers, nitrates) and have to be stratified for their risk for rapid progression to myocardial infarction or death.
Patients at high risk should undergo early angiography and when needed PCI within 48 hours. When angiography is immediate planned (<2,5h) GP 2b-3a inhibitor treatment with eptifibatide or abciximab can to postponed and apply in cathlab. When angiography is planned after 2,5 but up to 48 hours treatment with eptifibatide or tirofiban should be immediately administered and continued during PCI and after this procedure.
PCI with
abciximab
or eptifibatide
PCI with
eptifibatide
or tirofiban
Medical treatment
PCI with provisional
abciximab
or eptifibatide
Silber S. et al. ESC PCI guidelines 2005

8. Can the results of clinical trials be transferred to the real world
Can the results of clinical trials be transferred to the real world? – NRMI 4
In-hospital mortality by early use of GPIIb/IIIa inhibitor
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 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.
JACC 2003;42:45-53

9. JACC 2003;42:45-53

10. CRUSADE: Unadjusted Mortality According to Early
CRUSADE: Unadjusted Mortality According to Early* GP IIb-IIIa Inhibitor Use
∆ 41%
P < † ‡
CRUSADE: Unadjusted Mortality According to Early* GP IIb-IIIa Inhibitor Use
In CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines), patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) who received early (within first 24 hours) glycoprotein (GP) IIb-IIIa inhibitor therapy had significantly lower unadjusted in-hospital mortality than patients who did not receive a GP IIb-IIIa inhibitor in the first 24 hours (2.7% vs 4.6%, respectively, 41% relative reduction, P<0.0001; adjusted odds ratio: 0.96 [ ]). This finding underscores the importance of early initiation of therapy with a GP IIb-IIIa inhibitor in patients with NSTE ACS in order to achieve improved patient outcomes.
Source: Duke Clinical Research Institute. Accessed 11th October 2004.
*Within 24 hours
†Risk-adjusted odds ratio:
(0.86, 1.07)
CRUSADE - Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines; GP = glycoprotein.
Source: Duke Clinical Research Institute.

11. 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:

12. ESPRIT: 1-Year Death or MI
(adapted from The ESPRIT Investigators study, 2000) 14
placebo
35% RRR p=0.001 (at 12 months)
INTEGRILIN
12.4% 12 10
4.4%
3.9% 8
8.0%
Cumulative event rate (%) 6
NNT=23 (at 12 months) 4
ESPRIT: 1-Year Death or MI
The significant reduction in death or myocardial infarction (MI) at 48 hours with INTEGRILIN® (eptifibatide) in ESPRIT (Enhanced Suppression of the Platelet IIb-IIIa Receptor with Integrilin Therapy) was fully preserved and further enhanced over the long-term follow-up at 1 year, with a 0.5% incremental absolute benefit in favor of INTEGRILIN® in the period between 30 days and 1 year. At 1 year, the incidence of death or MI was reduced from 12.4% in the placebo group to 8.0% in the INTEGRILIN® group, a 37% relative risk reduction, with a highly significant P value (P=0.0010). These data demonstrate the maintenance of the early benefit with INTEGRILIN® during the long-term follow-up.
1. The ESPRIT Investigators. Lancet 2000;356: O’Shea et al. JAMA. 2001;285: O’Shea et al. JAMA. 2002;287:618. 2 2 4 6 8 10 12
Months

13. When to start GPIIb/IIIa inhibitor therapy (upstream or downstream)?
DEACON Study: Bivalirudin and Clopidogrel Alone Do Not Adequately Prevent Platelet Aggregation
- 20% 0%
20%
40%
60%
80%
Baseline
10 min
30 min
1 hr
100%
% Platelet Inhibition of ADP-induced Aggregation
% Platelet Inhibition of TRAP-induced Aggregation
100%
INTEGRILIN + Heparin + Clopidogrel
80%
INTEGRILIN + Heparin + Clopidogrel
60%
Heparin + Clopidogrel
40%
Heparin + Clopidogrel
Several studies have shown that only GP IIb-IIIa inhibitors are able to achieve this high level of inhibition of platelet aggregation. The DEACON study, performed by Dr. Jorge Sauceda, evaluated the combinations of UFH + clopidogrel, bivalirudin + clopidogrel, and eptifibatide + UFH + clopidogrel using the agonists ADP, TRAP (thrombin), and collagen, measured by light transmission aggregometry. The results indicate that the addition of a GP IIb-IIIa inhibitor is necessary in order to achieve significant inhibition. Importantly, at several timepoints the combination of bivalirudin + clopidogrel was shown to offer significantly lower levels of platelet inhibition compared to UFH + clopidogrel, possibly due to the broader mechanistic effects of UFH.
20%
Bivalirudin + Clopidogrel
Bivalirudin + Clopidogrel 0%
- 20%
Baseline
10 min
30 min
1 hr
Am J Cardiol 2005;95:1453–1456

14. Cumulative mortality rate Clin Cardiol 2000;23 (suppV):V1-V12
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.
Placebo and eptifibatide 180/2.0 combined
18.3%
MI within 72 h
12.8% ↓ (p=0.001)
Cumulative mortality rate
No MI within 72h
5.5% 1 2 3 4 5 6
Time in months
Clin Cardiol 2000;23 (suppV):V1-V12

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

16. 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
16.6
16.8
11.4
11.8
0.024
0.012
CABG <72 hours
32.7
33.5
19.3
18.4
0.009
0.001
No PCI <72 hours
14.5
15.6
14.6
0.035
0.226

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

18. 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