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- 1. ACUTE CORONARY SYNDROMEDr. Rashidi Ahmad Med USM, MMed USM (Emergency) Consultant Emergency Physician IJN
- 2. Objectives Facts &figures Classification of acute coronary syndromes Pathophysiology of ACS Risk stratification Management of ACS Anti-ischemic agents Antithrombotic agents Reperfusion therapy Adjunctive therapies for AMI
- 3. ACS mortality Prehospital – 52% 24H in hospital – 8% 48H in hospital – 19% 30 days – 21% AHA statistical data + GUSTO trial data. Circulation, 1994; 90: 2658-65
- 4. Causes of deathArrythmias Cardiogenic shock LV rupture Delay in treatment
- 5. Incidence of VFOut-of-hospital - Br. Med J, 1983; 286: 1405-08: 4% - Br. Heart J, 981; 46: 351-7: 18% In-hospital - Circulation, 1994; 89: 998-1003: 5% GISSI - Early VF: 3.6% - Late VF: 0.69% Risky time: VF occurs within 4H after Sx onset
- 6. Incidence of cardiacshock & rupture Leading cause of early & late mortality after AMI is LV dysfunction with CCF Incidence of cardiac rupture: 10% AHA statistical data + GUSTO trial data. Circulation, 1994; 90: 2658-65
- 7. Delay to treatment*Progressive increase in death of 1.6/1000 per hour of delay Am J Cardiol 1998;82:259
- 8. In-hospital delay Threetime intervals of hospital delay 1. Door to data (ECG) 21 min : Goal <10 min 2. Data to decision 41 min : Goal <10 min 3. Decision to drug 9 min : Goal <10 min Cannon CP, et al. J Thromb Thrombolysis. 1994;1:27-34 In-hospital evaluation constitutes 25 – 33% of delay (Am Heart J. 1999;138:1046-57; Circulation 2000;102:173-8)
- 9. Time to treatmentremains poor GUSTO I 1990-93 n=41021 2.8h GUSTO II 1993-95 n=3053 2.9h GUSTO III 1995-97 n=15059 2.7h GUSTO V 1999-01 n=16588 2.7h InTIME II 1997-99 n=15060 2.9h ASSENT II 1997-98 n=16,949 2.8h ASSENT III 2000-01 n=6095 2.7h Large Scale Trials (n:113825; mean: 2.8H)
- 10. Predictors of Door-to-BalloonDelay in Primary Angioplasty Angeja BG, et al. Am J Cardiol 2002;89:1156-1161
- 11. Door to balloontime & mortality JAMA 2000;283:2941-7 Increased mortality if door to balloon > 2 H
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- 14. Plaque features thatpredispose to rupture
- 15. Pathophysiology of ACSAfter rupture of vulnerable plaque, its content is exposed to the passing blood stream. Vulnerable plaques are laden with lipid & collagen & tissue factor (TF), resulting in activation of the coagulation cascade resulting in deposition of fibrin Thrombin that is generated from activation of coagulation cascade is a PIVOTAL molecule – formation of fibrins & activation of platelets .
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- 19. Micro-embolization promotes occlusion/ spasm in the microvasculature Elevated Trop T/I
- 20. Spectrum of Clinicalsyndromes of CAD
- 21. Early outcomes inNSTEMI vs STEMI
- 22. Early & lateoutcome in NSTEMI vs STEMI
- 23. Risk stratification Directedtherapy Avoid unnecessary therapy Avoid the potential adverse consequences in pts at low risk
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- 28. Mortality related tocardiac troponin I The risk of subsequent death or MI is ~ 3x higher in patients with +ve troponin result than in those with a -ve result.
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- 30. Primary goals forpatients with ACS Rapid defibrillation when VF occurs Prevention of major adverse cardiac events (death, non-fatal MI, & need for urgent revascularization) Reduction of myocardial necrosis in patients with ongoing infarction
- 31. PURSUIT trial Thegreatest mortality & morbidity in those with ACS occurs in the first several days. Rapid, efficient, & effective care during this time frame.
- 32. 30 min 90min Consider PCI capable hospital CI to thrombolysis PCI can be initiated promptly High risk patients
- 33.
- 34. Improving Time toReperfusion Cannon CP, et al. J Thromb Thrombolysis. 1994;1:27-34 . Patient Transport Inhospital Drug Perfusion Current Target A B C D Methods of Speeding Time to Reperfusion A B C D Media campaign 999 Expansion MI protocol Bolus fibrinolytics Patient education Prehosp. Rx Prehosp. ECG Hours from Onset of Pain Door Reperfusion Onset of MI Patient Response Data Decision Drug Started 0 1 2 3 4
- 35. 2005 AHA Guidelinesfor ACS
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- 40. Management of AMIAnti-ischemic agents Antithrombotic agents - antiplatelets & anticoagulants Reperfusion therapy Adjunctive therapies for AMI Improves SUPPLY and Reduces DEMAND
- 41. Oxygen Advantages: maylimit ischemic myocardial injury & may reduce ST segment elevation Indications: overt pulmonary congestion OR arterial O2 saturation < 90% Reasonable: all pts with ACS for first 6 H of therapy Little justification for continuing its routine use beyond 6 H Disadvantages: Excess O2 may lead to systemic vasoconstriction. High flow rates may be harmful for COAD pts.
- 42. Nitrates ↓ preload & afterload Relaxation of epicardial coronary arteries Recurrent ischemia, nitrates are indicated in first 24-48 H IV GTN infusion at 5-20mcg/min Increase rate till SX are relieved, MAP by 10% of its baseline in normotensive pts & 30% for HPT pts Nitrates should not be used if hypotension limits administration of B-blockers, which improves survival.
- 43. Nitrates Pts withongoing ischemic discomfort - sublingual nitroglycerin(0.4mg) every 5 min for total of 3 doses, then an assessment should be made about the need for IV nitroglycerin IV nitroglycerin is indicated in ongoing ischemic chest discomfort, control of HPT, STEMI a/w LV failure Nitrates should not be administered to pts - SBP < 90 mmHg or ≥30 mmHg below baseline - HR < 50 or >100 OR suspected RV infarction - received a phosphodiesterase inhibitor within the last 24 hours
- 44. Analgesia AMI andpain contribute to ↑ sympathetic activity. Surges of catecholamines may contribute plaques fissuring & thrombus propogation & ↓ threshold for VF. Titrating Morphine is analgesic of choice for continuing pain unresponsive to nitrates. Cardiac pain is controlled with a combination of nitrates, morphine, O2 & B-blockers.
- 45. Morphine ↓ restlessness & activity of the sympathetic nervous system - ↓ heart’s metabolic demands. In pts with pulmonary oedema complicating MI, morphine : promotes peripheral arterial & venous dilatation, promotes slowing of HR
- 46.
- 47. Aspirin ASA reduceboth mortality & the reinfarction rate in the acute phase of MI. ASA also prevents reinfarction, stroke & death in patients with previous MI . ASA reduce the risk for progression to infarction in patients with UA .
- 48. Aspirin ASAproduces rapid clinical antithrombotic effect by immediate & near total inhibition of thromboxane A2 production Unlike fibrinolytic therapy, there is little evidence of time-dependent effect of ASA on early mortality ASA is the first choice of antiplatelet Dose: 162-325mg & continued at daily dose 75-162mg Chewable ASA is absorbed quicker than swallowed Aspirin suppositories (300mg) are safe & can be considered for pts with severe nausea, vomiting or disorders of upper GI tract.
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- 50. Clopidogrel I nhibitsADP-induced platelet aggregation Dose: 300mg loading dose Indications: - NSTEMI (elevated cardiac markers or new ECG changes consistent with ischemia) - suspected of ACS (without ECG or cardiac marker changes) who is unable to take aspirin because of hypersensitivity or major GI intolerance - STEMI (up to 75years of age who receive ASA, heparin & fibrinolysis.
- 51. ACS algorithm 2005 guidelines
- 52. Ticlopidine ADP InhibitorDelay to achieve full effect (benefit only after 2/52 of RX) Initial Rx with heparin & probably GP IIb/IIIa inhibitor is required in UA/NSTEMI Adverse effects: Neutropenia (2.4%, severe in 0.8%) & rarely TTP FBC (with differentials) monitoring every 2 weeks for 1 st 3 months. Clopidogrel is preferred to ticlopidine but more rapidly inhibits platelets & more favorably safety profile.
- 53. Reperfusion therapy AllSTEMI patients should undergo rapid evaluation for reperfusion therapy Prompt & complete restoration of flow in the infarct artery can be achieved by pharmacological means (fibrinolysis) or PCI (balloon angioplasty +/- stent, with support of pharmacological measures to prevent thrombosis). Expeditious restoration of flow in the obstructed infarct artery after onset of symptoms of STEMI is KEY DETERMIINANT of outcome , regardless of whether reperfusion is accomplished with PCI or fibrinolysis.
- 54. Fibrinolytic therapy The greatest benefit is when therapy is started within the first 3 hours Indications: - STEMI pts with onset of Sx ≤ 12 hours & ECG findings of STEMI (ST elevation >0.1mV in 2 or more contiguous precordial adjacent limb leads, new or presumably LBBB) - Reasonable to administer fibrinolytics to pts with onset of Sx <12 hours & ECG findings of true posterior MI
- 55. LBBB Direct PCImay be preferable to fibrinolytic therapy Pts with new or presumably new LBBB coupled with a typical ischemic history should be approached with a plan to rule in MI using 1 of 3 ECG criteria that provide independent diagnostic value (Sgarbossa criteria) LBBB
- 56. Sgarbossa criteria STElevation ≥ 1 mm & concordant with QRS complex ST Depression ≥ 1 mm in V1, V2, V3 ST Elevation ≥ 5 mm and discordant with QRS complex
- 57. True posterior MItall R waves in Right precordial leads & ST depression in V1-V4, especially when T waves are upright. Repeat ECG with incorporation of additional leads (V7-V9) are more specific for the detection of post infarct.
- 58. Fibrinolysis is Notrecommended Nor recommended: Pts presenting > 12 hours after onset of symptoms, although it may be considered if continuing ischemic pain is present with ST elevation >1mm in 2 or more contiguous precordial or adjacent limb leads Should not be given to asymptomatic pts who presents > 24 hours after onset of Sx Should not be given to pts who show ST-segment depression, unless true posterior MI suspecteD
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- 60. Source Gp Cstreptococci Recombinant human Recombinant Recombinant
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- 62. Mortality for fibrinolytictherapy vs control
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- 65. Limitation of fibrinolytictherapy Despite adequate restoration of flow in the epicardial infarct artery, perfusion of the infarct zone may still be compromised by a combination of microvascular damage & reperfusion injury. Microvascular perfusion may be impaired despite achievemnt of TIMI 3 flow & < 50% coronary narrowing. Abnormal microperfusion has negative prognostic implications .
- 66. Assessment of reperfusionRelief of symptoms Maintenance or restoration of hemodynamic & electrical stability Reduction of at least 50% of the initial ST-segment elevation on follow up ECG at 60-90 min after initiation of therapy – good indicator of myocardial perfusion.
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- 68. In experienced centers,PCI has been shown to be superior to fibrinolysis *Individuals who perform > 75 PCI procedures a year, in a lab that performs >200 PCI procedures per year, of which at least 36 are primary PCI for STEMI, and has cardiac surgical capability. PCI in STEMI
- 69. PCI versus fibrinolysis** PCI is preferred in high risk patients
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- 72. Fibrinolytic-ineligible pts within12 H of symptom onset Cardiogenic shock, heart failure (Killip class 3), persistent angina In hosp without PCI facilities, rapid administration for fibrinolytic agent & transfer the pt to a PCI facility centre if low-output syndrome or ischemia continues. Preferable for RV infarction & LBBB. Should not be performed in asymptomatic pts > 12 H after onset of STEMI if they are hemodynamically & electrically stable Recommendation for PCI in STEMI
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- 74. Heparin in STEMIUFH is recommended for pts ≥ 75yo as ancillary therapy to fibrinolysis (Class IIa) & for any STEMI pts undergoing revascularization. When UFH is used as adjunctive therapy with fibrin-specific fibrinolytics (alteplase/reteplase/tenecteplase) in STEMI, an IV bolus dose of 60U/kg is given followed by infusion at rate of 12U/kg/hr (max bolus 4000U & infusion 1000U/hr for pts >70kg).
- 75. Heparin in STEMIIV UFH should be given to pts treated with nonselective fibrinolytic agents (streptokinase) who are at high risk for systemic emboli (large or anterior MI, AF, previous embolus, known LV embolus). It may be reasonable to give IV UFH to pts undergoing reperfusion therapy with streptokinase. Aim aPTT of 50-70sec (1.5-2x control value).
- 76. Antithrombotic therapy inUA/ NSTEMI
- 77. LMWH Indication: UA/NSTEMI Enoxaparin is preferred to UFH in UA/NSTEMI , unless CABG is planned within 24 hrs. LMWH (enoxaparin) is acceptable alternative to UFH in the ED as ancillary therapy for pts < 75yo who are receiving fibrinolytic therapy (tenecteplase), provided that significant renal dysfunction (serum creatinine >2.5mg/dL in men & 2mg/dL in women) is not present and in pts with STEMI who are not receiving fibrinolysis or revascularization , LMWH in the ED setting
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- 79. LMWH vs UFHin UA
- 80. Direct antithrombins Directthrombin inhibitors very specifically block thrombin effects without the need of a cofactor such as ATIII. Hirudin (Lepirudin - prototype direct thrombin inhibitor, a naturally occuring anticoagulant from medicinal leech) is presently indicated only for anticoagulations in pts with heparin-induced thrombocytopenia & for prophylaxis of DVT after hip replacement surgery. Superior to UFH in the reduction of death & MI in UA/MSTEMI . Bivalirudin (synthetic analogue of hirudin, binds reversibly to thrombin) – could be considered as an alternative to heparin in pts with STEMI who is treated with streptokinase & who has heparin-induced thrombocytopenia (class IIa, LOE B).
- 81. Adjunctive therapy forAMI GP IIb/IIIa inhibitors B-adrenergic receptor blockers ACE inhibitor Statin therapy / CCB / Insulin
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Editor's Notes
- #3 GP IIb/IIIa inhibitors B-adrenergic receptor blockers ACE inhibitor Statin therapy / CCB / Insulin
- #13 The new classification scheme oriented toward evaluating the patient with acute ischemic heart disease allows the clinician to make decisions early in the diagnostic process. In this scheme, as outlined in the National Unstable Angina Guideline [1], patients are classified as having unstable angina until enzyme levels have been determined unless ST-segment elevation is evident early in the evaluation. Patients with this ECG finding are presumed to have acute MI and are treated aggressively to reperfuse the occluded infarct vessel. Patients without ST-segment elevation are carefully observed and undergo serial sampling of markers and ECG monitoring. Those with positive markers are then classified as having acute MI, whereas those with negative markers remain in the unstable angina category until a judgment is made about whether the symptoms actually represent ischemic heart disease or a noncardiac disorder. Only after all serial ECGs and markers have been reviewed can the clinician determine whether the infarction was a Q-wave or non–Q-wave one . It is now clear that a substantial proportion of patients with early ST-segment elevation on presentation will have non–Q-wave infarcts and that a substantial proportion without ST-segment elevation will eventually develop Q waves or be found to have Q waves on the baseline ECG. From this perspective, the distinction between Q-wave and non–Q-wave is relevant only for discharge planning.
- #14 The atherosclerotic plaque becomes transformed from a stable or “quiescent” phase to an unstable phase through a series of processes that lead to fissuring or “rupture” of the plaque—the “culprit lesion.” These forces include local features of the plaque itself as well as systemic triggers exerted upon the plaque by physiologic factors that often emanate from psychologic or social/environmental “stresses.” Once such fissuring or rupture occurs, transformation to total vessel occlusion depends predominantly on the balance between forces that lead to progressive thrombosis and forces that lead to inhibition of thrombosis. The tone of the vessel wall is also important, since vasodilation can increase coronary flow and reduce the propensity for progressive thrombosis. The elaboration of certain substances by the atherosclerotic wall leads to a propensity for vasoconstriction, partly as a direct result of dysfunction of the endothelium.
- #15 Specific features of the plaque that are thought to predispose to fissuring or rupture have been elucidated through a series of intricate pathologic studies. The atherosclerotic plaques most likely to lead to acute MI are those with a large lipid pool, which is thought to produce instability beneath the fibrous cap and thus to make the plaque more susceptible to shear forces. Most often these vulnerable plaques are not highly stenotic prior to the acute event and are relatively new, without a large amount of fibrotic material. In addition, atherosclerotic plaques located at vessel branch points are more likely to become fissured owing to increased shear forces that create turbulence at the branches . Finally, fissured or disrupted plaques more often show infiltration of macrophages into the fibrous cap . The stimulus to such infiltration remains unclear, but a leading theory is that oxidized low-density lipoprotein (LDL) cholesterol is the culprit ; in experimental models, oxidized LDL cholesterol attracts macrophages and other inflammatory cells into tissue and may thus provide a link between antioxidant status and risk for cardiac events. The potential role of infectious agents has been raised in light of these findings, although a direct link to such an agent has not been established. Another line of reasoning supposes that some plaque events are caused by thrombosis or hemorrhage of vasa vasorum, the vessels in the adventitia that supply the vessel wall. As the plaque enlarges, the vasa vasorum may become inadequate or may be compressed by other elements of the plaque.
- #16 Pathophysiology of acute coronary syndromes. Coronary arterial atherosclerotic plaque disruption (either as rupture or fissure) initiates thrombosis. The extent of the thrombotic process may be confined to intraplaque thrombus with no effect on coronary flow. Alternatively, an extensive intraluminal and propagating thrombus can result in transient or prolonged coronary artery occlusion. The magnitude and duration of the thrombotic occlusion and the risk of reocclusion lead to a range of clinical outcomes.The interaction between the arterial wall injury, the flow disturbance at the site of plaque rupture, the thrombotic potential of blood constituents, and the activity of intrinsic thrombolysis determines the stability and size of the thrombus and, most importantly, the risk of a recurrent occlusive thrombus.
- #18 The role of acute coronary thrombosis, generally resulting from an acute rupture of a coronary plaque, has been a key issue in the development of strategies to treat patients with acute coronary syndromes. Angiographic studies in the early 1980s demonstrated that early in the course of MI with ST-segment elevation, most patients had complete coronary occlusion [3]. Pathologic studies established the importance of plaque rupture in the pathogenesis of acute coronary syndromes [4], with the spectrum of acute coronary syndromes corresponding to the degree of obstruction from the resulting thrombus, ranging from a persistent complete occlusion corresponding to ST-segment elevation to a subocclusive thrombus corresponding to unstable angina [5].
- #19 Comments: ACS results from a common pathophysiological mechanism, i.e. plaque rupture or erosion leading to activation of platelet functions, activation of the coagulation cascade and thrombus formation. There are two different clinical presentations: ACS with ST segment elevation, corresponding to a total occlusion of a major epicardial vessel; and ACS without ST segment elevation, usually corresponding to a partially or intermittently occlusive thrombus. The therapeutic approach is different for each of these clinical presentations. Immediate reperfusion is required in ACS with persistent ST segment elevation; whereas in NSTE-ACS, an invasive strategy is recommended in intermediate to high-risk patients. In both cases, antiplatelets, anticoagulants and beta-blockers are necessary. Thrombolytic therapy may be necessary to achieve reperfusion in ST elevation ACS. In ST elevation MI, the thrombus is fibrin-rich, whereas it is platelet-rich in NSTE-ACS.
- #20 Figure 1-15. Recently, however, the importance of downstream platelet emboli has become evident. The common appearance of the cardiac troponin in the bloodstream in patients with non–ST-segment elevation MI (NSTEMI) is thought to result from small areas of myocardial necrosis resulting from plugged small vessels from these emboli.
- #21 The spectrum of clinical syndromes of coronary artery disease extends from stable exertional angina to the acute coronary syndromes (ACS). The acute coronary syndromes are classified according to the electrocardiogram recorded at the time of presentation. Although both non–ST segment elevation and ST segment ACS result from similar pathophysiology, non–ST segment ACS is associated with fewer coronary occlusions and a lower early mortality but with a similar (re)infarction rate and similar (if not greater) later mortality . The rationale for classifying ACS into non–ST segment elevation and ST segment elevation is the different response of the two groups to thrombolysis: patients with ST segment elevation ACS benefit with a 15% to 40% reduction in mortality [1], yet thrombolysis does not improve outcome in those with non–ST segment elevation ACS [2],[3],[4],[5].
- #22 Early mortality and (re)infarction in ST segment elevation and non–ST segment elevation acute coronary syndromes. Higher early mortality during the first 24 hours in ST segment elevation compared with non–ST segment elevation acute coronary syndromes , as seen in the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb study [6], is probably caused by fatal complications (eg, cardiogenic shock) related to larger infarct size in the ST segment elevation group. Despite the differences in early mortality, early (re)infarction occurs with a similar incidence in the two groups .
- #23 Early and late outcome with ST and non–ST elevation acute coronary syndrome acute myocardial infarction (MI) . A comparison of outcomes in patients with ST and non–ST elevation acute coronary syndromes (ACS) shows that early mortality is higher in the patients with ST elevation ACS [6]. However, death rates have almost equalized by day 30, and (re)infarction is the same [13]. Over the next 5 months, the mortality of patients presenting with ST depression continues to increase, exceeding that of the patients with ST elevation (B).The presence of isolated T-wave inversion was associated with a lower mortality that was not significantly different from the group with normal or nonspecific abnormalities. ST segment shift (either transient elevation, or transient or fixed depression) is associated with a high risk of both mortality and (re)infarction.
- #29 Figure 6-11. Mortality rates related to cardiac troponin I. In the TIMI (Thrombolysis In Myocardial Infarction) 3 study, Antman and coworkers [15] related mortality to the troponin I level at the time of presentation. A, The 42-day mortality according to troponin I level at entry into study. B, Risk ratios for mortality when adjusted for baseline variables. When the mortality risk ratios were adjusted for baseline variables, only ST depression, age, and troponin I level were predictive of 42-day mortality. In this model, low levels of troponin I (0.4 to 2.0) had modest predictive value compared with the presence of ST depression. CI—confidence interval; RR—relative risk. (Adapted from Antman and coworkers [15].)
- #32 Figure 11-3. The probability of survival and the probability of event-free survival for patients enrolled in the PURSUIT trial. This trial enrolled a broad spectrum of patients from North America, Europe, and South America with non–ST-segment elevation acute coronary syndromes (ACS). It is important to note that most of the events occurred within the first 30 days, but there is a continuing attrition of patients both because of mortality and because of nonfatal myocardial infarction (MI) to 180 days. A, The mortality rate at 180 days was 6%. B, The rate of death or nonfatal MI at 180 days was approximately 18%. The major point for the guidelines is that the greatest mortality and morbidity in those with ACS occurs in the first several days; for this reason, tremendous focus needs to be placed on rapid, efficient, and effective care during this time frame [2]. (Adapted from Braunwald and coworkers [2].)
- #37 The emergency department assessment of patients presenting with chest discomfort includes the history and physical examination and 12-lead electrocardiogram (ECG). An initial diagnosis of acute coronary syndrome (ACS) often depends on the history with symptoms being classified as definitely angina, possibly angina, or unlikely to be angina. The physical examination may identify complications of the acute ischemic event, such as hypotension, heart failure, or worsening mitral regurgitation, which are all important findings supporting both the diagnosis and risk stratification. The presence of chest wall tenderness and sharp or stabbing pain may suggest an alternative cause of the chest pain yet can lead to a false sense of security: 15% of patients with acute myocardial infarction (AMI) may complain of tenderness on chest wall palpation [10].The 12-lead ECG provides early diagnostic and prognostic information. The presence of ST segment elevation that does not resolve after sublingual nitroglycerin and has compatible symptoms is associated with myocardial infarction in more than 90% of patients [10]. It is also an indication for an immediate reperfusion strategy by either thrombolysis or primary percutaneous intervention.Because only approximately 10% of patients with AMI present with ST segment elevation [11], the remaining 90% of patients with symptoms compatible with acute coronary syndromes (ACS) fall into the non–ST segment elevation category. Diagnosis and risk stratification of this large cohort of patients with widely varying outcomes allows an appropriate choice of management. ASA—acetylsalicylic acid; LMW—low molecular weight.
- #38 Figure 1-8. The clinical approaches to the treatment of acute ischemic syndromes are oriented toward one or more of the following: lysing thrombus; preventing progression of thrombosis; promoting vasodilation; preventing or treating complications arising from acute myocardial ischemia/necrosis; or enhancing hemodynamics or the neurohumoral state either to promote myocardial healing or to sustain systemic circulation during the acute event. Selecting the most appropriate and effective regimen for the individual patient depends on whether the vessel is totally occluded, the presence and extent of myocardial necrosis, the time course of the occlusion, and systemic or comorbid complicating factors. In the acute phase of the event, it is critical to determine which active lesions are totally occluded, since therapy should focus on assuring blood flow to the downstream myocardium for totally occluded lesions and on increasing forces leading to quiescence of the lesion for nonocclusive lesions. The darker red area represents jeopardized myocardium. ACE—angiotensin-converting enzyme; BP—blood pressure; PTCA—percutaneous transluminal coronary angioplasty.
- #40 Figure 11-8. The critical decisions that must be made in the evaluation of a patient with acute coronary syndrome (ACS). A patient with symptoms suggestive of ACS should be placed in one of four categories: noncardiac diagnosis, chronic stable angina, possible ACS, or definite ACS. Patients with a noncardiac diagnosis should be treated for the alternative diagnosis. For patients with chronic stable angina in whom the symptoms requiring evaluation do not represent acceleration, treatment should be organized using the guidelines for chronic stable angina.Patients with possible ACS defined by a nondiagnostic electrocardiogram (ECG) and normal initial serum cardiac markers present major public health and individual dilemmas. Sending such patients home could result in unnecessary death and disability, but so many of these patients turn out not to have myocardial necrosis or ischemia that admitting them all to the hospital is a huge health care expense. This is a category in which early bedside testing can provide a very important initial measurement.Patients with definite ACS are divided into those with and those without ST-segment elevation on the ECG. Patients with ST-segment elevation on the ECG should be treated with acute reperfusion therapy, and those without ST-segment elevation should be divided into those with and those without high-risk markers.High-risk markers in the setting of definite ACS include ST-segment deviation or major T-wave changes, ongoing ischemic discomfort, positive cardiac markers, and hemodynamic abnormalities on physical examination. The critical hemodynamic abnormalities are mitral regurgitation, hypotension, hypoperfusion, and pulmonary edema. Patients with these findings should be admitted to the hospital and managed using the strategy for treating patients with acute ischemic syndromes.In patients with nondiagnostic ECGs and normal initial serum cardiac markers, observation for 48 hours with serial ECG and cardiac marker measurements is required. Of course, one of the most difficult decisions is distinguishing noncardiac diagnoses from possible or probable ACS.Patients without recurrent symptoms and with negative follow-up study results should undergo provocative tests for ischemia, and consideration should be given to measuring left ventricular (LV) function, particularly if ischemia is present. These tests can be performed either shortly after discharge or before discharge, if possible. Patients with negative provocative test results and good LV function are low-risk patients who should be followed with standard outpatient therapy. Patients with a positive test result for ischemia, particularly in the presence of LV dysfunction, should be managed with aggressive medical therapy and possible revascularization [2]. (Adapted from Braunwald and coworkers [2].)
- #43 ↓ preload & afterload – peripheral arterial & venous dilatation Relaxation of epicardial coronary arteries – improve coronary flow & dilatation of collateral vessels
- #46 2 ° combined withdrawal of sympathetic tone & augmentation of vagal tone
- #47 Figure 6-16. Anti-thrombotic and anti-platelet agents potentially available for the management of non–ST segment acute coronary syndromes. ASA—acetylsalicylic acid; LMW—low molecular weight.
- #48 Figure 1-17. A, Aspirin (ASA) provides the paradigm for an effective therapeutic agent in acute ischemic syndromes [8],[9]. This inexpensive drug has been shown to reduce both mortality and the reinfarction rate in the acute phase of MI (seeFig. 5-8) [8] and the risk for progression to infarction in patients with unstable angina (B). In addition, it effectively prevents reinfarction, stroke, and death in patients with previous MI and maintains patency of saphenous vein bypass grafts. (Part B adapted from Cairns and coworkers [9].
- #49 ASA produces rapid clinical antithrombotic effect by immediate & near total inhibition of thromboxane A2 production. ASA is the first choice of antiplatelet: Dose 162-325mg & continued indefinitely at daily dose 75-162mg Unlike fibrinolytic therapy, there is little evidence of time-dependent effect of ASA on early mortality.
- #50 Figure 6-18. Limitations of acetylsalicylic acid (ASA) as an antiplatelet agent. A, ASA irreversibly blocks cylooxygenase and hydroperoxidase inhibiting the synthesis of both thromboxane A2 and prostaglandin I2 (prostacyclin). As a result, platelet aggregation that is mediated through thromboxane A2 is reduced. B, However, other agonists, such as adenosine diphosphate (ADP), thrombin, collagen, and epinephrine can still cause platelet aggregation. In addition, neither platelet adhesion nor aggregation provoked by high shear stress is inhibited.The optimal dose of ASA in acute coronary syndromes is unknown. Doses of 75 to 1300 mg (seeFig. 6-17) have been shown to have clinical benefit. To minimize gastrointestinal irritation, 80 to 325 mg/d is considered adequate.
- #60 Figure 5-3. all share a common mechanism of converting the proenzyme plasminogen to the active enzyme plasmin, which lyses fibrin clot. Plasminogen is converted to plasmin by cleavage of the Arg-Val (560-561) peptide bond [6]. Plasmin, the active two-chain polypeptide, is a nonspecific serine protease capable of breaking down fibrin as well as fibrinogen and factors V and VIII. The plasmin(ogen) molecule has lysine binding sites, particularly in the kringle regions, which bind to and degrade fibrin. Fibrin-specific agents are much more active upon binding to fibrin, thereby increasing the affinity for plasminogen at the clot surface. Staphylokinase has a unique mechanism of fibrin specificity, involving both assembly of plasmin(ogen) complex on the fibrin surface and greater neutralization of circulating complex by alpha2-antiplasmin. Streptokinase (SK) is an indirect plasminogen activator that must first bind to plasminogen to form a plasminogen-streptokinase activator complex. Anisoylated plasminogen streptokinase activator complex (APSAC) is activated upon deacylation, which takes place gradually after rapid infusion into the blood stream. r-PA—recombinant plasminogen activator (reteplase); scu-PA—single-chain urokinase plasminogen activator; t-PA—tissue-type plasminogen activator TNK-tPA—tenecteplase. (Adapted from Granger and coworkers [7].
- #61 Figure 5-4. Streptokinase remains a commonly used fibrinolytic agent in many parts of the world, especially where there are greater cost restraints. Anistreplase is not commonly used, and saruplase (pro-urokinase) is promising based on patency studies and a trial showing similar clinical outcomes as streptokinase, but it is not approved for acute myocardial infarction in the United States. Alteplase (t-PA) [8], reteplase (rPA) [9], and tenecteplase (TNK-t-PA) [10] all have similar 90-minute coronary artery patency, with reteplase having the advantage of the ease of double-bolus administration, and tenecteplase the ease of single-bolus administration and lower risk of noncerebral bleeding. Staphylokinase, which is even more fibrin specific than tenecteplase, is in development [11]. Angiographic patency rates are derived from different trials and therefore are not directly comparable.
- #62 Figure 7-5. Advantages and disadvantages of thrombolytic therapy. Proponents of thrombolytic therapy are as vocal as those who support direct percutaneous coronary interventions (PCI). One of the most important advantages is that thrombolytic therapy can be given: in primary, secondary, and tertiary hospitals, in emergency rooms, and even in the field by trained paramedic personnel. It does not require access to a cardiac catheterization laboratory. This ability to administer the drug in a wider range of settings enhances the chance of giving it early and salvaging substantial myocardium. The other major advantage is that it has been documented to be effective in reducing morbidity and mortality in more than 150,000 patients in well designed, scientifically-controlled trials [11],[12],[13],[14],[15],[20],[21].There are several disadvantages as well. Even though thrombolytic therapy is widely available, the most recent data indicate that it is administered to only 30% to 40% of patients with acute myocardial infarction (MI) in the United States. The frequency of administration in patients with acute MI may be higher in other countries, and it is increasing in this country. A large number of patients presenting with acute MI do not receive thrombolytic therapy, either because of a relative or absolute contraindication or concerns about risk/benefit issues. Despite the fact that early reperfusion is the goal of therapy, in contrast to direct PCI, which is characterized by success rates of more than 90%, thrombolytic therapy results in early reperfusion in only 55% to 80% of patients depending on the agent used [22]. In addition, TIMI-3 flow is even less frequently achieved, although this may be the most important goal to optimize outcome. TIMI-3 flow is associated with substantially better improvement in left ventricular function and survival than TIMI-2 [22],[23]. Other disadvantages include the fact that reliable noninvasive assessment of reperfusion may not be possible, and a significant residual stenosis often remains.
- #63 Figure 5-9. Thirty-five day mortality for fibrinolytic therapy versus control by subgroups. Even though trials such as GISSI-1 and ISIS-2 each enrolled tens of thousands of patients, reliable estimates of treatment effect in subgroups of patients are only possible with even larger numbers of patients. The results of all major randomized clinical trials were pooled by the investigators organized as the Fibrinolytic Therapy Trialist’s (FTT) Collaborative Group [17] to provide the most accurate estimates possible. The overall reduction in 5-week mortality was from 11.5% to 9.6%, which is an 18% relative reduction (P&lt;0.00001). The benefit was present among patients with ST-segment elevation or bundle branch block (BBB) until 12 hours after symptom onset. The benefit was present regardless of MI location, age, and presenting blood pressure (BP) or heart rate. CI—confidence interval; ECG—electrocardiogram; SD—standard deviation. (Adapted from Fibrinolytic Therapy Trialist’s Collaborative Group [17].
- #64 Figure 5-15. Stroke model: Simoons et al.[19]. Risk factors for intracerebral hemorrhage with fibrinolytic therapy were identified in a case-control study by Simoons et al.[19], in which four major independent risk factors for intracerebral hemorrhage were identified. A, The risk factors included age older than 65 years, weight less than 70 kg, hypertension at the time of treatment, and use of t-PA. B, When the model developed from these data is applied to a typical population of patients with an overall rate of intracranial hemorrhage of 0.75%, patients without risk factors who receive streptokinase have a risk of intracranial hemorrhage of 0.26%, and patients with one, two, or three risk factors have probabilities of 0.96%, 1.32%, and 2.17%, respectively. Vertical bars indicate 95% CI. (Adapted from Simoons and coworkers [19].)
- #65 Figure 5-15. Stroke model: Simoons et al.[19]. Risk factors for intracerebral hemorrhage with fibrinolytic therapy were identified in a case-control study by Simoons et al.[19], in which four major independent risk factors for intracerebral hemorrhage were identified. A, The risk factors included age older than 65 years, weight less than 70 kg, hypertension at the time of treatment, and use of t-PA. B, When the model developed from these data is applied to a typical population of patients with an overall rate of intracranial hemorrhage of 0.75%, patients without risk factors who receive streptokinase have a risk of intracranial hemorrhage of 0.26%, and patients with one, two, or three risk factors have probabilities of 0.96%, 1.32%, and 2.17%, respectively. Vertical bars indicate 95% CI. (Adapted from Simoons and coworkers [19].)
- #71 Figure 7-36. Approach to acute MI. Percutaneous coronary intervention (PCI) will continue to play a major role in the treatment of acute myocardial infarction (MI). Its use will depend on patient factors, such as hemodynamic status and an estimate of the risk level of the patient, as well as on the facilities and equipment available. Future advances in thrombolytic therapy with more efficacious regimes capable of restoring flow promptly in a larger number of patients will undoubtedly affect the relative role of each strategy as will ongoing efforts to deliver thrombolytic therapy as soon as possible after symptom onset, preferably within 1 hour. For patients with large MI or those with hemodynamic compromise, PCI will remain the treatment of choice when immediately available in experienced centers.
- #72 Percutaneous coronary interventions (PCI) for acute myocardial infarction (MI). PCI can be used as part of several different strategies following the onset of acute myocardial infarction. Primary or direct PCI refers to balloon angioplasty with or without stenting within the first 24 hours after the onset of the symptoms of infarction. This treatment is administered in the absence of intravenous thrombolysis. Initially reserved for patients in whom thrombolysis was contraindicated, this form of treatment is now used in many centers as the frontline form of reperfusion therapy for acute myocardial infarction. Rescue (salvage) PCI is for patients who have clinical evidence that thrombolytic therapy has failed to achieve reperfusion. Defined as PCI within 12 hrs after failed fibrinolysis for pts with continuing or recurrent ischemia. The term facilitated PCI is used to refer to planned percutaneous intervention following thrombolytic therapy. The intent of this treatment is to achieve vascular patency with thrombolytic drugs to make the placement of angioplasty equipment easier. PCI is performed in many cases after thrombolysis has been completed. Theoretically, the intention of this treatment is to relieve myocardial ischemia that has been provoked on a functional test, although a recent survey based on insurance claims indicated that in the majority of cases, a functional test is not performed prior to the intervention [19].
- #74 Figure 7-3. Advantages and disadvantages of direct percutaneous coronary interventions (PCI). Proponents of both PCI and thrombolytic therapy have been vocal, and valid arguments can be made for either approach. Those favoring direct PCI have maintained that success rates (usually defined as restoration of normal antegrade flow in an occluded, infarct-related artery and a residual restenosis &lt; 50 %) are far better than those seen with thrombolytic therapy, with improved outcome and less recurrent ischemia. Not only are overall reperfusion rates with direct PCI superior to those with thrombolytic therapy, but PCI usually results in thrombolysis in myocardial infarction (TIMI) grade 3 flow, which has been shown to be associated with improved left ventricular (LV) function and improved survival compared with patients in whom only TIMI-2 flow is achieved. In several studies, TIMI-2 flow resulted in outcomes more similar to TIMI-0 flow than TIMI-3 flow. In experienced centers, contraindications to direct PCI are rare and include the lack of arterial access, the inability to administer any anticoagulant, and some specific angiographic subsets, such as significant left main coronary stenosis or inability to reach the infarct-related occlusion. An important part of PCI is the requirement for diagnostic angiography, which allows identification of the extent and severity of the underlying coronary artery disease. Patients with left main coronary artery stenosis or severe three-vessel disease and decreased LV function may be better served with coronary artery bypass grafting. Angiography can also substantiate the diagnosis of myocardial infarction in patients with typical symptoms but indeterminate electrocardiographic changes. In these patients, identification of an occlusion with coronary arterial thrombosis substantiates the diagnosis. Finally, having the patient in the catheterization laboratory facilitates placement of intra-aortic balloon pulsation devices.Major disadvantages of direct percutaneous coronary interventions (PCI) are systems related. Because salvage of myocardium is enhanced by early reperfusion, the patient must be able to have prompt access to a catheterization laboratory and trained personnel available 24 hours a day, if direct PCI is to be used. Not all patients live close enough to such hospitals, and not all hospitals are so equipped and trained. The direct and indirect costs of staffing a 24 hour laboratory are substantial. Another factor is that outcome is dependent on both the patient and the operator and is related to both the experience and the technical expertise of the invasive cardiologist. Although somewhat difficult to quantitate, these issues may have a major impact on individual patient outcomes. Dilatation for acute MI may be very difficult, particularly with complex coronary anatomy and hemodynamic instability.
- #80 Figure 11-13. Overview of comparative trials of low molecular weight heparin (LMWH) and unfractionated heparin (UFH). Two points of view can be taken about the choice of a LMWH: 1) the average is no significant difference between UFH and LMWH or 2) whereas enoxaparin produces a reduction in the risk of death, myocardial infarction, and urgent revascularization, the other LMWHs do not produce such an effect. The clinical community is divided on this issue [2]. (Adapted from Braunwald and coworkers [2].)
- #83 Figure 1-8. The clinical approaches to the treatment of acute ischemic syndromes are oriented toward one or more of the following: lysing thrombus; preventing progression of thrombosis; promoting vasodilation; preventing or treating complications arising from acute myocardial ischemia/necrosis; or enhancing hemodynamics or the neurohumoral state either to promote myocardial healing or to sustain systemic circulation during the acute event. Selecting the most appropriate and effective regimen for the individual patient depends on whether the vessel is totally occluded, the presence and extent of myocardial necrosis, the time course of the occlusion, and systemic or comorbid complicating factors. In the acute phase of the event, it is critical to determine which active lesions are totally occluded, since therapy should focus on assuring blood flow to the downstream myocardium for totally occluded lesions and on increasing forces leading to quiescence of the lesion for nonocclusive lesions. The darker red area represents jeopardized myocardium. ACE—angiotensin-converting enzyme; BP—blood pressure; PTCA—percutaneous transluminal coronary angioplasty.