Risk Stratification in ACS: Beyond Troponin Positivity

1. Risk Stratification in ACS: Beyond Troponin Positivity Nick Curzen PhD FRCP FESC Wessex Cardiac Unit Southampton University Hospital

2. Acute Coronary Syndromes

3. Plaque erosion/fissuring/rupture Platelet activation Activation of white cells Cytokines Platelet aggregation Vasoactive Mediators Vasospasm Thrombus Vascular inflammatory response Spectrum of clinical presentation UNSTABLE ANGINA No troponin release ACUTE MI Troponin/CK/AST/ LDH release UNSTABLE ANGINA/ NON-Q MI Troponin release

4. PROGNOSIS IN ACUTE CORONARY SYNDROMES  Death or myocardial infarction at 6 weeks Unstable angina 5.0% NQWI 8.6% TIMI IIIBJ 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

5. Patients with recurrent ischemia Recurrent chest pain • Dynamic ST-segment changes • Elevated troponin levels • Hemodynamic instability • Major arrhythmias (VF, VT) • Early post infarction angina • Introduction of • GPIIB/IIIA blocker • early coronary • angiography Task Force of ESC Patients at high risk for progression to MI or death

6. 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

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

9. Use of Troponin T for prognosis • TIMI IIIb • FRISC • Gusto IIa

10. CAPTURE: Troponin T Event Rate (%) 20 15 10 5 0 TnT neg. (< 0.1 ng/ml) Placebo TnT pos. P<0.001 -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

11. Troponin Positive (Death/MI 30 days) Troponin Negative (Death/MI 30 days)

13. TIMI IIIb • FRISC • Gusto IIa

14. 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

15. FRISC II

16. 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 • (n=1222) (n=1235) • Coronary angiography 96% 10% • Revascularisation (10/7) 71% 9% Lancet 1999;354:708-15

17. FRISC II (Fragmin & Fast Revascularisation during Instability in Coronary artery Disease) INVASIVE NON-INV (n=1222) (n=1235) PTCA GROUP 522 220 % stented 61% 70% ReoPro 10% 10% CABG GROUP 430 233 Hospital Mortality 1.2% 0.4% Lancet 1999;354:708-15

18. FRISC II (Fragmin & Fast Revascularisation during Instability in Coronary artery Disease) • 6 month follow up • Composite end point= death+MI • 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 1999;354:708-15

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

20. 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 1999;354:708-15

21. 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.

22. TACTICS - Study Death, AMI, Rehosp. : 6 months 19.4% 15.9% 30 days OR=0.51 P=0.002 20 conserv. 16 % patients 12 O.R. 0.78 95% CI (0.62, 0.97) p=0.025 invasive 8 4 0 0 1 2 3 4 5 6 Months

23. TACTICS - Troponin T Death, AMI, Rehosp. 6 Months CONS INV p<0.001 OR=0.52 Interaction P<0.001 p=NS (%) N= 414 396 463 495 TnT > 0.01 ng/ml (54% of Pts TnT +)

24. There is no question troponin is a marker of risk……SO: Why do we need to go beyond troponins? What’s 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

25. Why do we need to go beyond troponins? What’s 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

27. Another Cause of Raised Troponin: Acute Cholecystitis Fox D, Grimm J, Curzen N J Roy Soc Med 2004 (in press) Non-ACS Causes of Troponin Elevation Scorpion sting Septic shock Tachycardia Ultraendurance 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

30. Why do we need to go beyond troponins? What’s 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

32. Chest Pain Acute Coronary Syndrome No ST ST • Ongoing pain, or • Troponin: >0.1ng/ml, or • ECG: ST depression • Pain free • Troponin normal • ECG normal STEMI Low Risk High Risk

33. Waiting Times p<0.0005 p<0.0005 15 13 6 5 Admission to revasc. Admission to angio Patient Journey

34. “I do not believe that one person’s sickness is made worse by another’s health” Michael “Fascinating” Howard

35. 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

36. 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

37. Why do we need to go beyond troponins? What’s 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

38. 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

39. EVENT No ENDPOINT

40. Why do we need to go beyond troponins? What’s 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

41. Plaque erosion/fissuring/rupture Platelet activation Activation of white cells Cytokines Platelet aggregation Vasoactive Mediators Vasospasm Thrombus Vascular inflammatory response Spectrum of clinical presentation UNSTABLE ANGINA No troponin release ACUTE MI Troponin/CK/AST/ LDH release UNSTABLE ANGINA/ NON-Q MI troponin release

42. Activating Factors Inflammatory Mediators Adhesion Molecules Collagen Thrombin Vasopressin Thromboxane PAF Serotonin Aspirin ADP ACTIVATION Epinephrine Clopidogrel Ticlopidine GP IIb/IIIA receptor complex GP IIb/IIIa inhibitors & antagonists Fibrinogen binding AGGREGATION

43. Reproduced by courtesy of “Red Hot Dutch Nympho Platelet.com”

44. Reproduced by courtesy of “Red Hot Dutch Nympho Platelet.com”

47. 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 2003:348:1104-1111

48. ★Troponin is a marker of increased risk in NSTEACS ★Troponin is a product of myocardial damage, not a component of the inflammatory process ★Troponin identification of patients at risk is a blunt tool ★Using Troponin as our main marker is causing a logistical nightmare and leads to compromise of care ★We need markers of the inflammatory process to refine our ability to identify risk above & beyond troponin SUMMARY

49. The Bob Monkhouse Memorial Slide “They laughed at me when I said I was going to become a comic…….. Well they’re not laughing now!” “I’m a hard man to ignore……………… but well worth the effort” “I still enjoy sex at 74………. I live at 75 so it’s not far to go”

50. FRISC II