1. Acute Coronary Syndrome Dr.A.S.Mannoun dasmannoun.com

2. Worldwide Statistics Each year: > 4 million patients are admitted with unstable angina and acute MI > 900,000 patients undergo PTCA with or without stent dasmannoun.com

3. Myocardial Ischemia Spectrum of presentation –silent ischemia –exertion-induced angina –unstable angina –acute myocardial infarction dasmannoun.com

4. Cumulative 6-month mortality from ischemic heart disease 0 1 2 3 4 5 6 5 10 0 15 20 25 Months after hospital admission Deaths / 100 pts / month Acute MI Unstable angina Stable angina Duke Cardiovascular Database N = 21,761; 1985-1992 Diagnosis on adm to hosp dasmannoun.com

5. Ischemic Heart Disease evaluation Based on the patient’s –history / physical exam –electrocardiogram Patients are categorized into 3 groups –non-cardiac chest pain –unstable angina –myocardial infarction dasmannoun.com

6. Acute Coronary Syndrome Ischemic Discomfort Unstable Symptoms No ST-segment elevation ST-segment elevation Unstable Non-QQ-Wave angina AMI AMI ECG Acute Reperfusion History Physical Exam dasmannoun.com

7. Acute Coronary Syndrome The spectrum of clinical conditions ranging from: –unstable angina –non-Q wave MI –Q-wave MI characterized by the common pathophysiology of a disrupted atheroslerotic plaque dasmannoun.com

8. Unstable Angina - Definition angina at rest (> 20 minutes) new-onset (< 2 months) exertional angina (at least CCSC III in severity) recent (< 2 months) acceleration of angina (increase in severity of at least one CCSC class to at least CCSC class III) dasmannoun.com

9. Unstable Angina Likelihood of CAD Previous history of CAD presence of risk factors older age ST-T wave ischemic ECG changes dasmannoun.com

10. Unstable Angina precipitating factors Inappropriate tachycardia –anemia, fever, hypoxia, tachyarrhythmias, thyrotoxicosis High afterload –aortic valve stenosis, LVH High preload –high cardiac output, chamber dilatation Inotropic state –sympathomimetic drugs, cocaine intoxication dasmannoun.com

11. Unstable Angina prognostic indicators Presence of ST-T-wave changes with pain Hemodynamic deterioration –pulmonary edema, new mitral regurgitation, –3rd heart sound, hypotension Other predictors –left ventricular dysfunction, extensive CAD, age, comorbid conditions (diabetes mellitus, obstructive pulmonary disease, renal failure, malignancy) dasmannoun.com

12. Unstable Angina pathogenesis Plaque disruption Acute thrombosis Vasoconstriction dasmannoun.com

13. Unstable Angina pathogenesis Plaque disruption –Passive plaque disruption soft plaque with high concentration of cholesteryl esters and a thin fibrous cap –Active plaque disruption macrophage-rich area with enzymes that may degrade and weaken the fibrous cap; predisposing it to rupture dasmannoun.com

14. Unstable Angina pathogenesis Acute Thrombosis –Vulnerable plaque disrupted plaque with ulceration occurring in 2/3 of unstable patients the exposed lipid-rich core abundant in cholesteryl ester is highly thrombogenic – Systemic Hypercoagulable State disrupted plaque with erosion occurring in 1/3 of unstable patients dasmannoun.com

15. Unstable Angina pathogenesis Vasoconstriction –the culprit lesion in response to deep arterial damage or plaque disruption –area of dysfunctional endothelium near the culprit lesion –platelet-dependent and thrombin- dependent vasoconstriction, mediated by serotonin and thromboxane A 2 dasmannoun.com

16. Acute Coronary Syndrome Process of resolution –spontaneous thrombolysis –vasoconstriction resolution –presence of collateral circulation Delayed or absence of resolution may lead to non-Q-wave or Q-wave myocardial infarction dasmannoun.com

17. Non-Q-Wave MI clues to diagnosis Prolonged chest pain Associated symptoms from the autonomic nervous system –nausea, vomiting, diaphoresis Persistent ST-segment depression after resolution of chest pain dasmannoun.com

18. Prinzmetal’s Angina clues to diagnosis Transient ST-segment elevation during chest pain Intermittent chest pain –often repetitive –usually at rest –typically in the early morning hours –rapidly relieved by nitroglycerine Syncope (rare), Raynaud’s, migraine dasmannoun.com

19. Unstable Angina Risk Stratification Low Risk new-onset exertional angina minor chest pain during exercise pain relieved promptly by nitroglycerine Management can be managed safely as an outpatient (assuming close follow-up and rapid investigation) dasmannoun.com

20. Unstable Angina Risk Stratification Intermediate Risk prolonged chest pain diagnosis of rule-out MI Management observe in the ER or Chest Pain Unit monitor clinical status and ECG obtain cardiac enzymes (troponin T or I) every 8 to 12 hours dasmannoun.com

21. Unstable Angina Risk Stratification High Risk recurrent chest pain ST-segment change hemodynamic compromise elevation in cardiac enzymes Management monitor in the Coronary Care Unit dasmannoun.com

22. Risk Stratification by ECG The risk of death or MI at 30 days is strongly related to the ECG at the time of chest pain. ST depression 10% T-wave inversion 5% No ECG changes1-2% dasmannoun.com

23. Unstable Angina Therapeutic Goals Therapeutic Goals Reduce myocardial ischemia Control of symptoms Prevention of MI and death Medical Management Anti-ischemic therapy Anti-thrombotic therapy dasmannoun.com

24. Unstable Angina Medical Therapy Anti-ischemic therapy –nitrates, beta blockers, calcium antagonists Anti-thrombotic therapy –Anti-platelet therapy aspirin, ticlopidine, clopidogrel, GP IIb/IIIa inhibitors –Anti-coagulant therapy heparin, low molecular weight heparin (LMWH), warfarin, hirudin, hirulog dasmannoun.com

25. Unstable Angina Anti-ischemic Therapy restrict activities morphine oxygen nitroglycerine –pain relief, prevent silent ischemia, control hypertension, improve ventricular dysfunction –nitrate free period recommended after the first 24-48 hours dasmannoun.com

26. Unstable Angina Anti-ischemic Therapy beta-blockers –lowering angina threshold –prevent ischemia and death after MI –particularly useful during high sympathetic tone calcium antagonists –particularly the rate-limiting agents –nifedipine is not recommended without concomitant ß-blockade dasmannoun.com

27. Unstable Angina Anti-thrombotic Therapy Thrombolytics are not indicated “lytic agents may stimulate the thrombogenic process and result in paradoxical aggravation of ischemia and myocardial infarction” dasmannoun.com

28. Platelets in Acute Coronary Syndromes Platelets play a key role in ACS Sources of platelet activation (triggers) –thromboxane A 2 (TXA 2 ) –ADP –epinephrine –collagen –thrombin dasmannoun.com

29. Unstable Angina Anti-platelet Therapy aspirin is the “gold standard” –irreversible inhibition of the cyclooxygenase pathway in platelets, blocking formation of thromboxane A 2, and platelet aggregation –in AMI, ASA reduced the risk of death by 20-25% –in UA, ASA reduced the risk of fatal or nonfatal MI by 71% during the acute phase, 60% at 3 months, and 52% at 2 years –bolus dose of 160-325 mg, followed by maintenance dose of 80-160 mg/d dasmannoun.com

30. GP IIb/IIIa Receptor Final Pathway to Platelet Aggregation Platelet activation and aggregation are early events in the development of coronary thrombosis GP IIb/IIIa receptors on activated platelets undergo a conformational change allowing recognition and binding of fibrinogen Fibrinogen “acts like glue”, bridging GP IIb/IIIa receptors on adjacent platelets, leading to platelet aggregation dasmannoun.com

31. GP IIb/IIIa Receptor KVGFFGR There are approximately 50,000 GP IIb/IIIa receptors on each platelet KVGFFGR is a specific region within GP IIb/IIIa receptor that is thought to be involved in platelet activation dasmannoun.com

32. Incidence of Ischemic Events No aspirin (early 1980s) Aspirin 16% 12% 9% Incidence of death and MI dasmannoun.com

33. Unstable Angina Anti-platelet Therapy Thienopyridines –ticlopidine (Ticlid; Hoffmann-La Roche) –clopidogrel (Plavix; Bristol-Myers Squibb) block platelet aggregation induced by ADP and the transformation of GP IIb/IIIa into its high affinity state dasmannoun.com

34. Unstable Angina Anti-platelet Therapy Ticlopidine –in an open-label, randomized study in patients with unstable angina –ticlopidine 250 mg bid vs. placebo reduced the risk of fatal or nonfatal MI by 46% at 6 months –benefit not seen at 7 days, but became apparent after 10 days of therapy (the time required for full antiplatelet activity) –an alternative for patient with aspirin intolerance dasmannoun.com

35. Unstable Angina Anti-platelet Therapy Clopidogrel –CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) –19,000 patients randomly assigned to clopidogrel (75 mg/d) or to aspirin (325 mg/d) –there was an 8.7% reduction in the combined incidence of stroke, MI, or death (P=.043) –patients with MI did better with aspirin –patients with PVD or stroke did better with clopidogrel dasmannoun.com

36. Unstable Angina Anti-platelet Therapy GP IIb/IIIa inhibitors –abciximab (monoclonal antibody) –eptifibatide (peptidic inhibitor) –lamifiban and tirofiban (non-peptides) direct occupancy of the GP IIb/IIIa receptor by a monoclonal antibody or by synthetic compounds mimicking the RGD sequence for fibrinogen binding prevents platelet aggregation dasmannoun.com

37. Unstable Angina Anti-platelet Therapy Abciximab (Reo-Pro) –EPIC Trial effective in preventing death, MI, and abrupt closure associated with coronary angioplasty (see also EPIC slides) –EPISTENT Trial (unpublished - see MedSlides News) dasmannoun.com

38. Unstable Angina Anti-platelet Therapy Abciximab (Reo-Pro) –CAPTURE (Chimeric 7E3 Antiplatelet in Unstable Angina Refractory to Standard Treatment) –1,000 patients with angiographically documented unstable angina, not responding to ASA, nitrates, heparin,and other anti-anginals, received either abciximab or placebo within 18-24 hours dasmannoun.com

39. Unstable Angina Anti-platelet Therapy Abciximab (ReoPro; Centocor) –CAPTURE –At 30 days, there was a 29% reduction in the primary composite endpoint of death, MI, or urgent revascularization in the abciximab group –At 6 months, this benefit was not evident dasmannoun.com

40. Unstable Angina Anti-platelet Therapy Lamifiban –PARAGON (Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network) –2000 patients received two different doses of lamifiban compared with placebo + heparin –at 6 months, there was a lower event rate (12.6% vs 17.9%) with low dose lamifiban dasmannoun.com

41. Unstable Angina Anti-platelet Therapy Tirofiban (Aggrastat; Merk & Co.) –PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management) –3,200 patients with unstable angina were treated with either heparin or tirofiban –At 48 hours, there was significant risk reduction (5.9% to 3.6%) in the rate of death, MI, or refractory ischemia. The benefit was lost at 30 days. dasmannoun.com

42. Unstable Angina Anti-platelet Therapy Tirofiban –PRISM -PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms) –randomized 1,915 patients with UA and non- Q-MI to tirofiban alone, heparin alone, or a combination of the two (all received aspirin) dasmannoun.com

43. Unstable Angina Anti-platelet Therapy Tirofiban –PRISM -PLUS –angiography was performed after 48 hr of initial medical therapy –combination therapy (tirofiban, aspirin, and heparin) reduced the risk of death and MI at 48 hr from 2.6% to 0.9%, and at 30 days from 11.9% to 8.7% dasmannoun.com

44. Unstable Angina Anti-platelet Therapy Tirofiban –RESTORE (Randomized Efficacy Study of Tirfiban for Outcomes and Restenosis) –evaluate the impact of tirofiban on angioplasty for acute coronary syndromes –tirofiban reduced the frequency of events associated with intervention in ACS dasmannoun.com

45. Unstable Angina Anti-platelet Therapy Eptifibatide (Integrilin; Cor/Schering) –PURSUIT (Platelet IIb/IIIa Underpinning the Receptor for Suppression of Unstable Ischemia Trial) –~11,000 patients admitted with unstable angina or non-Q-wave myocardial infarction –a broad-based trial encompassing a variety of clinical practices and practice styles dasmannoun.com

46. Unstable Angina Anti-platelet Therapy Eptifibatide (Integrilin; Cor/Schering) PURSUIT –randomized to eptifibatide or placebo; all patients received aspirin and heparin –significantly reduced the risk of death and MI at 30 days from 15.7% to 14.2%, a 9% risk reduction dasmannoun.com

47. Platelet Inhibition and Bleeding Time IMPACT IIPURSUIT 135 / 0.5 180 / 2.0 Inhibition of platelet aggregation 15 minutes after bolus 69% 84% at steady state 40-50% >90% 4h after infusion discontinuation <30% <50% Bleeding-time prolongation at steady state <5x <5x 6h after infusion discontinuation 1x 1.4x dasmannoun.com

48. Fiban incidence of intracranial bleeding Treatment (%) StudyCompound Placebo ActiveHeparin RESTORETirofiban 0.3 0.1 EPICAbciximab 0.3 0.1 0.4 EPILOGAbciximab 0.0 0.1 IMPACT IIIntegrelin 0.07 0.07 0.15 Bolus Low dose High dose Bolus + Infusion dasmannoun.com

49. Unstable Angina Anti-platelet Therapy Summary –the four “P trials” (PRISM, PRISM-PLUS, PARAGON, PURSUIT) –all show reduction of death rate between 1.3% and 3.4% - in addition to the benefit of aspirin –useful in the management of patients with unstable angina and MI without ST elevation dasmannoun.com

50. Unstable Angina Anti-platelet Therapy Summary The question is no longer “Is there a reason to use GP IIb/IIIa inhibitors?” but “Is there a reason not to use them?” Eric Topol, MD dasmannoun.com

51. Unstable Angina Anti-coagulant Therapy Heparin –recommendation is based on documented efficacy in many trials of moderate size –meta-analyses (1,2) of six trials showed a 33% risk reduction in MI and death, but with a two fold increase in major bleeding –titrate PTT to 2x the upper limits of normal dasmannoun.com

52. Unstable Angina Anti-coagulant Therapy Low-molecular-weight heparin advantages over heparin: –better bio-availability –higher ratio (3:1) of anti-Xa to anti-IIa activity –longer anti-Xa activity, avoid rebound –induces less platelet activation –ease of use (subcutaneous - qd or bid) –no need for monitoring dasmannoun.com

53. Unstable Angina Anti-coagulant Therapy Low-molecular-weight heparin –ESSENCE Trial (Efficacy and Safety of Subcutaneous Enoxaparin in non-Q-Wave Coronary Events Study) –at 30days, there was a relative risk reduction of 15% -16% in the rate of death, MI, or refractory ischemia as compared to standard heparin dasmannoun.com

54. ESSENCE Trial incidence of death, MI, or recurrent angina heparin Lovenox n=1564 n=1607 19.8% 16.6% P=0.019 23.3% 19.8% P=0.016 Day 14 Day 30 dasmannoun.com

55. Unstable Angina Coronary Interventions TIMI 3B –early intervention vs conservative strategy (coronary angiography within 24-48 hrs, followed by angioplasty or bypass surgery) –1473 patients with UA or non-Q-wave MI were randomized, there were no difference between the groups in the rates of death or MI at 1 year dasmannoun.com

56. Unstable Angina Coronary Interventions VANQWISH (Veteran Affairs non-Q- Wave Infarction Strategies in Hospital) –better outcome with initial conservative therapy with lower rates of death and MI medicalinvasive Hosp discharge 3% 8% One year 18.5% 24% dasmannoun.com

57. Unstable Angina role of non-ionic contrast Ionic contrast media seem to perform better in ACS prospective, randomized control trial of 211 patient a much greater need for CABG was seen in the non-ionic contrast medium group dasmannoun.com

58. Trials Underway GUSTO-IV (abciximab vs placebo) EXCITE ( Eval of Oral Xemilofiban in Controlling Thrombotic Events) OPUS (Orofiban in Patients with Unstable Coronary Syndromes) SYMPHONY (Sibrafiban vs Aspirin to Yield Maximum Protection from Ischemic Events Post ACS) dasmannoun.com