1. NSTEMI Acute Coronary Syndromes
Patrick Hildbrand

3. Trends and Prognosis in NSTEMI
Hospital year
Furman MI, JACC 2001, 37:

4. Hospital Outcome by Final Diagnosis

6. NSTEMI Acute Coronary Syndromes
Trends and Prognosis
Diagnosis and Risk assessment
Initial Management
Treatment <
Long-Term Management
Summary of Treatment Approaches

7. Diagnosis

8. Chest Pain

9. ECG
Kaul P, JACC 2001, 38:64-71

10. Biochemistry

11. Risk Stratification

12. Summary Diagnosis and Risk assessment
Diagnosis and short-term risk stratification should be based on a combination of
Clinical history
Symptoms
ECG and (10 minutes, 6h, 24h and before hospital discharge)
Biomarkers (admission and after 6-12 h)
Risk score results
Echocardiography is recommended to rule out differential diagnosis
Patient without recurrence of pain, normal ECG findings and negative troponins tests > non invasive stress testing

13. NSTEMI Acute Coronary Syndromes
Trends and Prognosis
Diagnosis and Risk assessment
Initial Management
Treatment <
Long-Term Management
Summary of Treatment Approaches

14. Therapeutic Options Anti-ischemic agents Anti-platelet agents
ASA
Clopidrogel
GP IIb/IIIa Inhibitors
NSTEMI
Anti-coagulants
UFH or LMWH
Factor-Xa inhibitors (Fondaparinux)
Direct Thrombin inhibitors (Bivalirudin)
Revascularization

15. Anti-Ischemic Agents
Aim: Decrease myocardial oxygen consumption and/or induce vasodilatation
Betablockers are recommended in absence of contraindications
(hypertension and tachycardia; cave inferior MI, acute LV dysfunction) (IB)
Nitrates are effective in symptom relief in the acute management of angina episodes (IC)
(Cave: Phospodiesterase-5-inhibitors, RV MI)
Calcium channel blockers provide symptom relief in patients already receiving betablockers and nitrates; patient with contraindication to betablockers; vasospastic angina (Ic)
Nifedipine or other dihydropyridine should not be used (IIIC) unless combined with betalockers (IIa-B)

16. Anti-ischemic agents Anti-platelet agents Anti-coagulants
ASA
Clopidrogel
GP IIb/IIIa Inhibitors
NSTEMI
Anti-coagulants
UFH or LMWH
Factor-Xa inhibitors (Fondaparinux)
Direct Thrombin inhibitors (Bivalirudin)
Revascularization

17. UFH
UFH
33% RR
LMWH

18. Enoxaparin (©Clexane) vs UFH
NON REVASC.
GP IIb/IIIa
Inhibitors
GP IIb/IIIa
Inhibitors

19. Enoxaparin was non-inferior to UFH in Reducing death or MI in the Synergy Trial
Synergy 14% versus 14.5% p=n.s.

20. Factor-Xa inhibitors (Fondaparinux, © Arixtra)
Oasis 5 Trial
Death, MI or refractory ischemia through day 9

21. Oasisi 5: Major bleeding through d9

22. Relation between bleeding and mortality in OASIS 5
Bleeding carries a high risk of death
Prevention of bleeding is as important as prevention of ischemic events and results in a significant rate reduction of death
> Risk stratification of bleeding should be part of the decision making process

23. Direct thrombin inhibitors (Bivalirudin, ©Angiox) UFH/LMWH

24. Primary Endpoint Measures
Acuity Trial
Primary Endpoint Measures
Net clinical outcome
Cave: hematoma > 5cm never used in any other definition

25. Summary Anti-coagulants
Anticoagulation is recommended for all Patient in addition to anti-platelet therapy
Anticoagulation should be selected to the risk of both ischemic and bleeding events
Choice of the anticoagulants (UFH, LMWH, fondaparinux and bivalirudin should depend on the strategy.
Urgent invasiv
UFH (I-C), Enoxaparin (IIa-B) or bivalirudin (I-B)
Non-urgent situation
Fondaparinux efficacy/safety profile (I-A)
Enoxaparin only if bleeding risk is low (IIa-B)
>> not LMWH (other then Enoxaparin) / UFH

26. Anti-ischemic agents Anti-platelet agents Anti-coagulants
ASA
Clopidrogel
GP IIb/IIIa Inhibitors
NSTEMI
Anti-coagulants
UFH or LMWH
Factor-Xa inhibitors (Fondaparinux)
Direct Thrombin inhibitors (Bivalirudin)
Revascularization

27. Anti-platelet agents

28. ASA
GI intolerance 5-40%, bleeding >0.9% in CAPRIE

29. Primary End Point—MI/Stroke/CV Death
CURE Study
Primary End Point—MI/Stroke/CV Death
20%
Relative Risk Reduction
Placebo + ASA*
P = †
N = 12,562
Clopidogrel + ASA* 3 6 9 12
Months of Follow-Up
The CURE Trial Investigators.
N Engl J Med. 2001;345:

30. PCI-CURE Study: CV Death or MI
.15
Placebo + Aspirin* (n=1345)
12.6%
Median
time to PCI
31%
Relative
Risk Reduction
.10
8.8%
Cumulative Hazard Rate
Clopidogrel + Aspirin* (n=1313)
.05
P=0.002
.00 10
100
200
300
400
Days of Follow-Up
*In combination with standard therapy.
Mehta SR, et al. Lancet. 2001;358:

31. GP IIb/IIIa Inhibitors
Tirofiban
Lamifibane
Eptifibatide
Abciximab
Lamifibane

32. Acuity timing

33. Summary GP IIb/IIIa Inhibitors
Intermediate to high risk (DM, ST segment depression and Troponin pos.) patients, either eptifibatide or tirofibane for initial early treatment is recommended in addition to oral antiplatelet agents (IIa-A)
Patient not pre-treated with GP IIb/IIIa inhibitors and proceeding to PCI; abciximab is recommended (IA)
GpIIb/IIIa inhibitors must be combined with anticoagulation I-A
Bivaluridin may be used as an alternative to GPIIb/IIIa inhibitors plus UFH/LMWH (IIa-B)
GPIIb/IIIa inhibitors only for invasive strategy

34. Coronary revascularization
Revascularization for NSTEMI is performed to
relieve angina
relieve ongoing myocardial ischemia
prevent progression to MI or death
30-38% single vessel
44-59% mutlivessel disease (TIMI-3B, FRISC-2)

35. Anti-ischemic agents Anti-platelet agents Anti-coagulants
ASA
Clopidrogel
GP IIb/IIIa Inhibitors
NSTEMI
Anti-coagulants
UFH or LMWH
Factor-Xa inhibitors (Fondaparinux)
Direct Thrombin inhibitors (Bivalirudin)
Revascularization

36. Coronary revascularization

37. Randomized trials comparing early invasive (dark bars) vs
Randomized trials comparing early invasive (dark bars) vs. conservative strategy (open bars)

38. Relative Mortality Benefit with the Revascularization vs
Relative Mortality Benefit with the Revascularization vs. Gradient in Rates of Revascularization Between both Randomization Arms

39. Summary Invasive vs. Conservative Strategies
New data coming from long-term follow up of RITA-3 and FRISC-2 and Mehta meta-analysis show significant risk reduction for death and „death & MI“ at long-term follow up
Early hazard shown in ICTUS Trial
Early hazard shown in Mehta meta-analysis
ICTUS, Lancet 2007
FRISC 2, Lancet 2000
RITA 3 Lancet 2005
Metha JAMA 2005

40. Summary Treatment Approaches

41. Summary Therapeutic Options
Anti-ischemic agents
Anti-platelet agents
ASA
Clopidrogel
GP IIb/IIIa Inhibitors
NSTEMI
Anti-coagulants
UFH or LMWH
Factor-Xa inhibitors (Fondaparinux)
Direct Thrombin inhibitors (Bivalirudin)
Revascularization

42. NSTEMI Acute Coronary Syndromes
Trends and Prognosis
Diagnosis and Risk assessment
Initial Management
Treatment <
Long-Term Management
Summary of Treatment Approaches

43. Long-term Post-PCI Management
What are our targets ?
Prevention of stent thrombosis/restenosis
Prevention of plaque rupture

44. ATC 2002: Indirect Comparisons ASA Doses on Vascular Events in High Risk Patients
ASA Dose # Trials OR
mg %
mg %
mg %
<75 mg %
Overall %
0.5
1.0
1.5
2.0
Antiplatelet Better
Antiplatelet Worse
Antithrombotic Trialists’ Collaboration
BMJ 2002; 324:71-86

45. Primary End Point—MI/Stroke/CV Death
CURE Study
Primary End Point—MI/Stroke/CV Death
20%
Relative Risk Reduction
Placebo + ASA*
P = †
N = 12,562
Clopidogrel + ASA* 3 6 9 12
Months of Follow-Up
The CURE Trial Investigators.
N Engl J Med. 2001;345:

46. PCI-CURE Study: CV Death or MI
.15
Placebo + Aspirin* (n=1345)
12.6%
Median
time to PCI
31%
Relative
Risk Reduction
.10
8.8%
Cumulative Hazard Rate
Clopidogrel + Aspirin* (n=1313)
.05
P=0.002
.00 10
100
200
300
400
Days of Follow-Up
*In combination with standard therapy.
Mehta SR, et al. Lancet. 2001;358:

47. Events Saved vs Life-threatening Bleeding Over Time: Net Clinical Benefit of Clopidogrel
Months of follow-up
Events/1000 patients treated -5 5 10 15 20 25 3 6 9 12
Events Saved: CV death, MI, stroke
Life-threatening bleeding
Yusuf S et al for the CURE Trial Investigators. Circulation. 2003;107:966

48. EUROPA HOPE PEACE ACE-Inhibitors Placebo Placebo Ramipril Perindopril14 12 10 8 6 4 2
HOPE
EUROPA 20
Placebo annual event rate: 2.4%
Placebo
Placebo 15
Ramipril
Patients Reaching Composite End Point
[MI, Stroke, CV Death] (%) 10
CV Death, MI, or Cardiac Arrest (%)
Perindopril
RRR=22%
P=.0003
RRR=20% 5
P<.001
500
1000
1500 1 2 3 4 5
Follow-Up (days)
Years
N = 12,218
PEACE 30 25 20 15 10 5
Placebo
Trandolapril
Incidence of Primary End Point (%)
HOPE: N Engl J Med. 2000;342:
EUROPA:. Lancet. 2003;362:
PEACE:N Engl J Med. 2004;351:
Years After Randomization

49. Leading and Lagging Hospitals Quartiles: Discharge Care
# LVEF < 40% * Known hyperlipidemia
Peterson et al, ACC 2004

50. Discharge Clopidogrel Use in CRUSADE
CRUSADE DATA: Q 4, 2004 – Q 3, (n=35,897)

51. Proven (mortality or death/MI/stroke) Medical Therapies Following (large*) MI Treated with Stent
Treatment RRR Abs benefit Cost/mo+
Aspirin1 23% 2.4% 1.00
Statin2 (simvastatin) 13% 1.8%
Eplerenone3 15% 2.3%
ACE-I*4 (ramipril) 13% 1.1% 55.99
 blockers*5 (carvedilol) 23% 3.0%
Clopidogrel**6 27% 3.0%
Total >70% $531.88
1. ISIS-2, Lancet HPS, Lancet, Pitt NEJM 2003;348; ACE-I Acute MI Collaborators Overview, Circulation 1998 (ant MI); HOPE. 5. CAPRICORN, Lancet, CREDO, JAMA, ** death, MI, stroke; all others death costs from january 2007

52. Improving Adherence, Outcome, and Cost by Providing EBM Coverage Post MI: Health Insurance Perspective
After 5 years of medicine coverage with good adherence to prevention - $6,500 saved per patient
Choudhry N. Health Affairs 2007;26:

53. Disease Modifying Drugs in Atherothrombosis
Statins
Prevent CV events
Prevent progression of CAD
Prevents development of DM
ACE-Inhibitors/ARB’s
Prevent renal dysfunction in DM
Clopidogrel
Prevents CV events

54. Long-term Post-PCI Management
There are two key targets in the post-PCI management
The lesion and the patient !
The use of ASA with clopidogrel should be used in all patients with PCI
Long-term use of the combination appears at least to be safe up to about 3 years
Important other therapies include statins, ACE/ARB, and beta-blockers

55. NSTEMI Acute Coronary Syndromes
Trends and Prognosis
Diagnosis and Risk assessment
Initial Management
Treatment <
Long-Term Management
Summary of Treatment Approaches

56. Clinical Outcomes for Patients Stratified by Age (Invasive Vs Conservative Strategies) from TACTICS–TIMI-18 Trial

57. Special Conditions & Populations chronic Kidney Disease
Outcomes According to Degree of Renal Function Impairment in NSTE-ACS Patients in GRACE Registry

58. Special Conditions& Populations Diabetes
Treatment Effect on 30-day Mortality Among Diabetic Patients with NSTEMI from Six Randomized Clinical Trials

59. Special Conditions& Populations Diabetes

60. Non-ST-segment Elevation Acute Coronary Syndromes
Anti-ischemic agents
Anti-coagulants
UFH or LMWH
Factor-Xa inhibitors (Fondaparinux)
Direct Thrombin inhibitors (Bivalirudin)
Anti-platelet agents
ASA
Clopidrogel
GP IIb/IIIa Inhibitors
Revascularization
NSTEMI
Non-ST-segment Elevation Acute Coronary Syndromes ?

61. Timing of Intervention
Few studies have shown superiority of very early intervention vs. deferred intervention
ISAR-COOL (small sample size) JAMA 2003
Many trials have shown early hazard with early intervention vs. deferred intervention
ICTUS trial NEJM 2005
Mehta meta-analysis JAMA 2005
Grace and Crusade registries Heart 2007, Arch Intern Med 2006
> Timing of intervention recommended on the basis of risk stratification

62. Risk Stratification

63. Summary Management Strategy

64. Summary Long-Term Management