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Acute Coronary Syndrome

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5/98 MedSlides.com 1 Acute Coronary Syndrome

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5/98 MedSlides.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

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5/98 MedSlides.com 3 Myocardial Ischemia Spectrum of presentation silent ischemia exertion-induced angina unstable angina acute myocardial infarction

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5/98 MedSlides.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 MIUnstable anginaStable angina Duke Cardiovascular Database N = 21,761; 1985-1992 Diagnosis on adm to hosp

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5/98 MedSlides.com 5 Ischemic Heart Diseaseevaluation Based on the patient’s history / physical exam electrocardiogram Patients are categorized into 3 groups non-cardiac chest pain unstable angina myocardial infarction

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5/98 MedSlides.com 6 Acute Coronary Syndrome Ischemic DiscomfortUnstable Symptoms No ST-segmentelevation ST-segmentelevation Unstable Non-Q Q-Waveangina AMI AMI ECG AcuteReperfusion HistoryPhysical Exam

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5/98 MedSlides.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

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5/98 MedSlides.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) Agency for Health Care Policy Research - 1994 Canadian Cardiovascular Society Classification

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5/98 MedSlides.com 9 Unstable AnginaLikelihood of CAD Previous history of CAD presence of risk factors older age ST-T wave ischemic ECG changes Agency for Health Care Policy Research - 1994

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5/98 MedSlides.com 10 Unstable Anginaprecipitating 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

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5/98 MedSlides.com 11 Unstable Anginaprognostic 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)

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5/98 MedSlides.com 12 Unstable Anginapathogenesis Plaque disruption Acute thrombosis Vasoconstriction

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5/98 MedSlides.com 13 Unstable Anginapathogenesis Plaque disruption Passive plaque disruptionsoft plaque with high concentration of cholesteryl esters and a thin fibrous cap Active plaque disruptionmacrophage-rich area with enzymes that may degrade and weaken the fibrous cap; predisposing it to rupture

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5/98 MedSlides.com 14 Unstable Anginapathogenesis 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

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5/98 MedSlides.com 15 Unstable Anginapathogenesis 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 A2

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5/98 MedSlides.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

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5/98 MedSlides.com 17 Non-Q-Wave MIclues to diagnosis Prolonged chest pain Associated symptoms from the autonomic nervous system nausea, vomiting, diaphoresis Persistent ST-segment depression after resolution of chest pain

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5/98 MedSlides.com 18 Prinzmetal’s Anginaclues 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

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5/98 MedSlides.com 19 Unstable AnginaRisk 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)

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5/98 MedSlides.com 20 Unstable AnginaRisk 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

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5/98 MedSlides.com 21 Unstable AnginaRisk Stratification High Risk recurrent chest pain ST-segment change hemodynamic compromise elevation in cardiac enzymes Management monitor in the Coronary Care Unit

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5/98 MedSlides.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 changes 1-2%

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5/98 MedSlides.com 23 Unstable AnginaTherapeutic Goals Therapeutic Goals Reduce myocardial ischemia Control of symptoms Prevention of MI and death Medical Management Anti-ischemic therapy Anti-thrombotic therapy

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5/98 MedSlides.com 24 Unstable AnginaMedical 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

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5/98 MedSlides.com 25 Unstable AnginaAnti-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

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5/98 MedSlides.com 26 Unstable AnginaAnti-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

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5/98 MedSlides.com 27 Unstable AnginaAnti-thrombotic Therapy Thrombolytics are not indicated “lytic agents may stimulate the thrombogenic process and result in paradoxical aggravation of ischemia and myocardial infarction” TIMI IIIB InvestigatorsCirculation 1994; 89:1545-1556

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5/98 MedSlides.com 28 Platelets in Acute Coronary Syndromes Platelets play a key role in ACS Sources of platelet activation (triggers) thromboxane A2 (TXA2) ADP epinephrine collagen thrombin

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5/98 MedSlides.com 29 Unstable AnginaAnti-platelet Therapy aspirin is the “gold standard” irreversible inhibition of the cyclooxygenase pathway in platelets, blocking formation of thromboxane A2, 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

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5/98 MedSlides.com 30 GP IIb/IIIa ReceptorFinal 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

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5/98 MedSlides.com 31 GP IIb/IIIa ReceptorKVGFFGR 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

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5/98 MedSlides.com 32 Incidence of Ischemic Events No aspirin(early 1980s) Aspirin Aspirin + Heparin 16% 12% 9% Incidence of death and MI

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5/98 MedSlides.com 33 Unstable AnginaAnti-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

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5/98 MedSlides.com 34 Unstable AnginaAnti-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 Circulation 1990;82:17-26

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5/98 MedSlides.com 35 Unstable AnginaAnti-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 Lancet 1996;348:1329-1339Circulation 1998;97:1107

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5/98 MedSlides.com 36 Unstable AnginaAnti-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

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5/98 MedSlides.com 37 Unstable AnginaAnti-platelet Therapy Abciximab (Reo-Pro) EPIC Trialeffective in preventing death, MI, and abrupt closure associated with coronary angioplasty (see also EPIC slides) EPISTENT Trial(unpublished - see MedSlides News)

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5/98 MedSlides.com 38 Unstable AnginaAnti-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 Lancet 1997;349:1429-1435

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5/98 MedSlides.com 39 Unstable AnginaAnti-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 Lancet 1997;349:1429-1435

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5/98 MedSlides.com 40 Unstable AnginaAnti-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

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5/98 MedSlides.com 41 Unstable AnginaAnti-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. N Engl J Med 1998;338:1498-505

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5/98 MedSlides.com 42 Unstable AnginaAnti-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) N Engl J Med 1998;338:1488-97

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5/98 MedSlides.com 43 Unstable AnginaAnti-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% N Engl J Med 1998;338:1488-97

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5/98 MedSlides.com 44 Unstable AnginaAnti-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

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10/98 MedSlides.com 45 Unstable AnginaAnti-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 NEJM 1998;339:436-443

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10/98 MedSlides.com 46 Unstable AnginaAnti-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 NEJM 1998;339:436-443

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5/98 MedSlides.com 47 Platelet Inhibition and Bleeding Time IMPACT II PURSUIT 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

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5/98 MedSlides.com 48 Fibanincidence of intracranial bleeding Treatment (%) Study Compound Placebo Active Heparin RESTORE Tirofiban 0.3 0.1 EPIC Abciximab 0.3 0.1 0.4 EPILOG Abciximab 0.0 0.1 IMPACT II Integrelin 0.07 0.07 0.15 The EXCITE Trial Investigators Bolus Low dose High dose Bolus + Infusion

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5/98 MedSlides.com 49 Unstable AnginaAnti-platelet Therapy Summary the four “P trials” (PRISM, PRISM-PLUS, PARAGON, PURSUIT) all show reduction of death rate between1.3% and 3.4% - in addition to the benefit of aspirin useful in the management of patients with unstable angina and MI without ST elevation

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5/98 MedSlides.com 50 Unstable AnginaAnti-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

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5/98 MedSlides.com 51 Unstable AnginaAnti-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 1. Circulation 1994;89:81-88 2. JAMA 1996;276:811-815

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5/98 MedSlides.com 52 Unstable AnginaAnti-coagulant Therapy Low-molecular-weight heparinadvantages 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

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5/98 MedSlides.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 N Eng J Med 1997;337:447-452

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5/98 MedSlides.com 54 ESSENCE Trialincidence of death, MI, or recurrent angina N Eng J Med 1997;337:447-452 heparin Lovenox heparin Lovenox n=1564 n=1607 n=1564 n=1607 19.8% 16.6% P=0.019 23.3% 19.8% P=0.016 Day 14 Day 30

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5/98 MedSlides.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 Circulation 1994;89:1545-1556

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5/98 MedSlides.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 medical invasiveHosp discharge 3% 8%One year 18.5% 24% NEJM 1998;338:1785-1792

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5/98 MedSlides.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 J Am Col Cardiol 1996; 26:1381-6

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5/98 MedSlides.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)

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5/98 MedSlides.com 59 References Acute Coronary Syndromes: Unstable angina and Non-Q-wave MI. Pierre Theroux and Valentin Fuster. Circulation 1998:97:1195-1206 Aspirin, heparin, or both to treat acute unstable angina.TherouxP, et al. N Eng J Med. 1988;319:1105-1111. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary disease. The RISC Group. Lancet 1990;336:827-830. Protective effects of aspirin against myocardial infarction and death in men with unstable angina.Lewis HD, et al. N Eng J Med. 1983;309:396-403. Aspirin, sulfinpyrazone, or both in unstable angina.Cairns JA, et al. N Eng J Med. 1985;313:1369-1375.

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5/98 MedSlides.com 60 References Antiplatelet treatment with ticlopidine in unstable angina: a controlled multicenter clinical trial. Balsano F, et al. Circulation 1990;82:17-26. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events.CAPRIE Steering Committee. Lancet 1996;348:1329-1339. Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users.Antithrombotic Therapy in Acute Coronary Syndromes Research Group. Circulation 1994;89;81-88 Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patient s with unstable angina.Oler S, et al. JAMA 1996;276:811-815

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5/98 MedSlides.com 61 References Low molecular weight heparin versus unfractionated heparin for unstable angina and non-Q wave myocardial infarction. Efficacy and Safety of Subcutaneous Enoxaparin in non-Q-Wave Coronary Events Study Group. N Engl J Med 1997;337:447-452. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. PRISM - The Platelet Receptor Inhibition in Ischemic Syndrome Management Study Invistigators N Engl J Med 1998;338:1498-505

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pulmonary edema, new mitral regurgitation,; 3rd heart sound, hypotension. Other predictors. left ve more pulmonary edema, new mitral regurgitation,; 3rd heart sound, hypotension. Other predictors. left ventricular dysfunction, extensive CAD, age, … less