Risk Stratification in ACS:

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Risk Stratification in ACS Beyond Troponin
Positivity
Nick Curzen PhD FRCP FESC Wessex Cardiac
Unit Southampton University Hospital
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Acute Coronary Syndromes
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PROGNOSIS IN ACUTE CORONARY SYNDROMES

• ? Death or myocardial infarction at 6 weeks
• Unstable angina 5.0 NQWI
  8.6
• TIMI IIIB J Am Coll Cardiol 1995 26 1643
• ? Mortality at 1 year
  
• 12 in unstable angina
  
• GUSTO IIb J Am Coll Cardiol 1998 32 2023
• 15 in NQWI
  
• Haim et al Am Heart J 1998 136 245

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Task Force of ESC
Patients at high risk for progression to MI or
death
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How did we get into this position?

• Observation about prognosis
• Observation about markers of risk.
• ? especially Troponin
• Studies suggesting prognostic benefit..
• ? especially FRISC II TACTICS-TIMI 18

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Biochemical Markers of Myocardial Cell Injury
() pos.
n 316 patients
CK
CK-MB mass
Myoglobin
Troponin I
Troponin T
Hamm et.al., NEJM 1997
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Use of Troponin T for prognosis

• TIMI IIIb
• FRISC
• Gusto IIa

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CAPTURE Troponin T
Event Rate
()
20 15 10 5 0
TnT neg. (lt 0.1 ng/ml)
Placebo
TnT pos.
Plt0.001 -73
PTCA
PTCA
Abciximab
12 24 36 48 60 72
12 24 36 48 60 72
Follow-up Hospital (hours)
Hamm et al, NEJM 1999
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Troponin Negative (Death/MI 30 days)
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• TIMI IIIb
• FRISC
• Gusto IIa

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How did we get into this position?

• Observation about prognosis
• Observation about markers of risk.
• ? especially Troponin
• Studies suggesting prognostic benefit..
• ? especially FRISC II TACTICS-TIMI 18

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FRISC II
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FRISC II (Fragmin Fast Revascularisation during
Instability in Coronary artery Disease)

• Prospective, randomised, multicentre study
• 2457 patients randomised to early invasive or
  non-invasive Rx
• with placebo-controlled LMWH for 3/12
• INVASIVE NON-INV
• (n1222) (n1235)
• Coronary angiography 96 10
• Revascularisation (10/7) 71 9

Lancet 1999354708-15
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FRISC II (Fragmin Fast Revascularisation during
Instability in Coronary artery Disease)
INVASIVE NON-INV (n1222) (n1235) PTC
A GROUP 522 220 stented 61 70 ReoPro
10 10 CABG GROUP 430 233 Hospital
Mortality 1.2 0.4
Lancet 1999354708-15
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FRISC II (Fragmin Fast Revascularisation during
Instability in Coronary artery Disease)

• 6 month follow up
• Composite end point deathMI
• INVASIVE NON-INV P
• Death MI 9.4 12.1 0.03
• MI alone 7.8 10.1 0.045
• Angina symptoms and re-admission were halved by
  the
• invasive strategy
• Results were independent of randomised LMWH Rx

Lancet 1999354708-15
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FRISC II (Fragmin Fast Revascularisation during
Instability in Coronary artery Disease)
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FRISC II (Fragmin Fast Revascularisation during
Instability in Coronary artery Disease)
The early invasive approach should be the
preferred strategy in most patients with
unstable coronary artery disease who have signs
of ischaemia on ECG or raised biochemical
markers of myocardial damage
Lancet 1999354708-15
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TACTICS TIMI 18DESIGN

• 2220 patients with UA or NSTEMI received medical
  treatment with aspirin, heparin, beta blockers as
  well as tirofiban (administered for 48 to 108
  hours).
• They were then randomized to catheterization
  within 4 to 48 hours or to a more conservative
  strategy where they were referred for
  catheterization only for recurrent rest pain or a
  positive functional test.
• The trial's primary endpoint was the combined
  incidence of death, MI or re-hospitalisation for
  ACS at 6 months follow-up.

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TACTICS - Study
Death, AMI, Rehosp. 6 months
19.4 15.9
30 days OR0.51 P0.002
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conserv.
16
patients
12
O.R. 0.78 95 CI (0.62, 0.97) p0.025
invasive
8
4
0
0
1
2
3
4
5
6
Months
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TACTICS - Troponin T
Death, AMI, Rehosp. 6 Months
CONS
INV
plt0.001
OR0.52 Interaction Plt0.001
pNS
()
N 414 396
463 495
TnT gt 0.01 ng/ml (54 of Pts TnT
)
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There is no question troponin is a marker of
riskSO Why do we need to go beyond
troponins? Whats the problem?

• The marker its assay
• Logistical Nightmare.
• ? huge numbers of patients waiting for
  transfer
• ? inequity of access postcode medicine
• Are we really identifying high risk.. ?
• ? how many patients treated for what level of
  risk?
• ? need to look at pathophysiological markers
  to target
• urgent treatment

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Why do we need to go beyond troponins? Whats the
problem?

• The marker its assay
• Logistical Nightmare.
• ? huge numbers of patients waiting for
  transfer
• ? inequity of access postcode medicine
• Are we really identifying high risk.. ?
• ? how many patients treated for what level of
  risk?
• ? need to look at pathophysiological markers
  to target
• urgent treatment

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Non-ACS Causes of Troponin Elevation
Scorpion sting Septic shock Tachycardia Ultraendur
ance events
Amyloid Contusion CVA Chemotherapy Acute
Chronic HF HIV Defib shocks ASD
closure LVH Myocarditis Pericardial
Effusion Pericarditis PCI PE Post surgery RF
Ablation
Assay Problems
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Why do we need to go beyond troponins? Whats the
problem?

• The marker its assay
• Logistical Nightmare.
• ? huge numbers of patients waiting for
  transfer
• ? inequity of access postcode medicine
• Are we really identifying high risk.. ?
• ? how many patients treated for what level of
  risk?
• ? need to look at pathophysiological markers
  to target
• urgent treatment

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Chest Pain
Acute Coronary Syndrome
ST
No ST

• Ongoing pain, or
• Troponin gt0.1ng/ml, or
• ECG ST depression

• Pain free
• Troponin normal
• ECG normal

STEMI
High Risk
Low Risk
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Waiting Times
plt0.0005
plt0.0005
15
13
6
5
Admission to angio
Admission to revasc.
Patient Journey
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I do not believe that one persons sickness is
made worse by anothers health
Michael Fascinating Howard
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Wasted Bed Days in District General Hospitals
the Unseen Cost of Urgent Angiography in
Patients with Acute Coronary Syndromes Jonas
Eichhöfer, Dorothy Crone, Nicholas Curzen
Objective To assess how many bed days are
occupied in DGH referring centres by patients
with ACS whilst waiting for transfer for coronary
angiography. Design Prospective observational
study Methods All ACS patients referred to the
Manchester Heart Centre for in-patient coronary
angiography over a 6 months period Results 212
non-emergency ACS patients occupied a total of
1755 bed days whilst waiting in DGHs.
Personal Communication
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Wasted Bed Days in District General Hospitals
the Unseen Cost of Urgent Angiography in
Patients with Acute Coronary Syndromes Jonas
Eichhöfer, Dorothy Crone, Nicholas Curzen

• Conclusions
• This bed occupancy
• makes for suboptimal patient care
• challenges our desire to treat such patients
  according to the evidence base
• contributes an unnecessary component to the
  considerable bed pressure
• experienced in DGHs.

Personal Communication
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Why do we need to go beyond troponins? Whats the
problem?

• The marker its assay
• Logistical Nightmare.
• ? huge numbers of patients waiting for
  transfer
• ? inequity of access postcode medicine
• Are we really identifying high risk.. ?
• ? how many patients treated for what level of
  risk?
• ? need to look at pathophysiological markers
  to target
• urgent treatment

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TACTICS - Study
ENDPOINT
Death, AMI, Rehosp. 6 months
No ENDPOINT
19.4 15.9
20
conserv.
16
patients
12
invasive
8
4
0
0
1
2
3
4
5
6
Months
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Why do we need to go beyond troponins? Whats the
problem?

• The marker its assay
• Logistical Nightmare.
• ? huge numbers of patients waiting for
  transfer
• ? inequity of access postcode medicine
• Are we really identifying high risk.. ?
• ? how many patients treated for what level of
  risk?
• ? need to look at pathophysiological markers
  to target
• urgent treatment

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Collagen
Thrombin
Vasopressin
Thromboxane
PAF
Serotonin
Aspirin
ADP
Epinephrine
ACTIVATION
Clopidogrel Ticlopidine
GP IIb/IIIA receptor complex
GP IIb/IIIa inhibitors antagonists
Fibrinogen binding
AGGREGATION
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Reproduced by courtesy of Red Hot Dutch Nympho
Platelet.com
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Reproduced by courtesy of Red Hot Dutch Nympho
Platelet.com
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Soluble CD40 Ligand in Acute Coronary
Syndromes Christopher Heeschen, M.D., Stefanie
Dimmeler, Ph.D., Christian W. Hamm, M.D., Marcel
J. van den Brand, M.D., Eric Boersma, Ph.D.,
Andreas M. Zeiher, M.D., Maarten L. Simoons,
M.D., for the CAPTURE Study Investigators
New England Journal of Medicine 20033481104-1111
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SUMMARY
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The Bob Monkhouse Memorial Slide
They laughed at me when I said I was going to
become a comic.. Well theyre not laughing
now!
Im a hard man to ignore but well worth
the effort
I still enjoy sex at 74. I live at 75 so its
not far to go
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FRISC II
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Circulation 2000 102 1193-1209
2.9