1
Challenging practice in non-ST segment
elevation Acute Coronary Syndromes
(ACS)Professor Jennifer AdgeyRoyal Victoria
Hospital, Belfast26th January 2006Conflicts of
interest- Speaker symposia Eli-Lilly, MSD,
Sanofi-Aventis, BMS, GSK
2
Chest pain in the AE department

• Approximately 600,000 patients per annum attend
  AE in the UK with chest pain
• 25 will have NSTE-ACS

J R Coll Physicians Edinb 20033336-43
3
Epidemiology of Acute Coronary Syndromes
Non-ST-segment elevation ACS Prevalence 51-63
Death and non-fatal (re)-infarction at 6 months
13
4
Acute Coronary Syndromes Mortality at 6
Months
ST-segment elevationand depression9.1 (n1,769)
Mortality at 6 Months
10
ST-segment depression8.9 (n4,263)
8
ST-segment elevation6.8 (n3,369)
6
Mortality ()
4
T-wave inversion3.4 (n2,723)
2
0
180
0
20
40
60
80
100
160
120
140
Days from randomization
Savonitto et al. JAMA. 1999281707.
5
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 depressionNegative T waves, flat T
  waves, normal ECG

Infusion of GP IIb-IIIa Inhibitor Invasive
strategy
Conservative strategy
6
Troponin is associated with presence of
Thrombus on Angioscopy
P0.0001
86
Only 1 of 5 thrombi detected
Thrombus
34
P0.41
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 109465-470.
7
ESC PCI Guidelines for NSTE ACS
NSTE-ACS
ASA, Clopidogrel, UFH, Betablockers, Nitrates,
Statins (ACE)
Low risk
Conservative approach
Early non invasive stress testing
Medical treatment
PCI with abciximab or eptifibatide
PCI with eptifibatide or tirofiban
PCI with provisional abciximab or eptifibatide
Silber S. et al. ESC PCI guidelines 2005
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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 (N15, 379) No early use (N45, 391) Overall (N60,770) P
3.3 9.6 8 lt0.0001
In-hospital mortality for patients treated with a
glycoprotein (GP) IIb/IIIa inhibitor versus those
not treated, by the National Registry of
Myocardial Infarction nonST-elevation myocardial
infarction (NRMI-NSTEMI) risk score.
JACC 20034245-53
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JACC 20034245-53
10
CRUSADE Unadjusted Mortality According to
Early GP IIb-IIIa Inhibitor Use
? 41? P lt 0.0001

Within 24 hours Risk-adjusted odds ratio
0.96 (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.
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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 gt2
hours after clopidogrel T3 during eptifibatide
infusion following clopidogrel
JACC 200443162-168
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ESPRIT 1-Year Death or MI


(adapted from The ESPRIT Investigators study,
2000)
placebo
14
35 RRR p0.001 (at 12 months)
INTEGRILIN
12.4
12
4.4
10
3.9
8.0
8
Cumulative event rate ()
6
NNT23 (at 12 months)
4
2
0
2
4
6
8
10
12
Months
13
DEACON Study Bivalirudin and Clopidogrel Alone
Do Not Adequately Prevent Platelet Aggregation
When to start GPIIb/IIIa inhibitor therapy
(upstream or downstream)?
Platelet Inhibition of TRAP-induced Aggregation
Platelet Inhibition of ADP-induced Aggregation
100
INTEGRILIN Heparin Clopidogrel
80
INTEGRILIN Heparin Clopidogrel
60
Heparin Clopidogrel
Heparin Clopidogrel
40
20
Bivalirudin Clopidogrel
Bivalirudin Clopidogrel
0
- 20
Baseline
10 min
30 min
1 hr
Am J Cardiol 20059514531456
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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 ? (p0.001)
Cumulative mortality rate
No MI within 72h
5.5
2
3
1
4
5
6
Time in months
Clin Cardiol 200023 (suppV)V1-V12
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PURSUIT

• Patients receiving eptifibatide had significantly
  reduced incidence of MI at 72 hours (5.6 vs 6.9
  with placebo p0.009) as well as prior to PCI
  within 72 hours (1.8 vs 5.5 with placebo
  p0.001)

Clin Cardiol 200023 (suppV)V1-V12
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Incidence of death or MI at 30 days according to
management strategy during the first 72 hours
Placebo () Eptifibatide () P
Diagnostic CClt72 hours North America Worldwide 15.8 16.2 12.1 12.8 0.008 0.005
PCI lt72 hours North America Worldwide 16.6 16.8 11.4 11.8 0.024 0.012
CABG lt72 hours North America Worldwide 32.7 33.5 19.3 18.4 0.009 0.001
No PCI lt72 hours North America Worldwide 14.5 15.6 11.8 14.6 0.035 0.226
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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 gt12 hours

Clin Cardiol 200023 (suppV)V1-V12
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Challenging practice in non-ST segment elevation
Acute Coronary Syndromes (ACS)

• Identification of high risk patients admitted via
  the AE 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