Early myocardial infarction management: In perspective

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Joseph L. Komfeld, Guest Editor activator (t-PA) offers no mortality advantage over streptokinase when used in a standard three-hour dosing regimen that includes subcutaneous heparin but that it does offer speedier angiographic reperfusion and a mortality advantage when infused more rapidly and combined with intravenous heparin. However, t-PA poses a higher hemorrhagic stroke risk than does streptokinase. A more important issue is unnecessary in-hospital delay to initiation of thrombolytic therapy, a common problem offering the greatest opportunity for reducing AM1 mortality. Given the hazards of performing PTCA promptly after thrombolytic therapy, this strategy is generally reserved for patients with ongoing ischemia in a large amount of myocardium, since their potential benefit is relatively large. Primary angioplasty (PTCA used as the initial method of reperfusion) clearly yields higher angiographic patency rates and shorter hospital stays than does thrombolytic therapy, but evidence of a mortality benefit and greater myocardial salvage is not yet conclusive. However, because 85% of AMIs occur within a 60-minute drive from a catheterization laboratory that performs primary angioplasty and because many patients are ineligible for thrombolytic therapy, primary angioplasty probably merits more extensive use.

From ACC Current Journal Review: January/February 1995

Early Myocardial Infarction Management: In Perspective Ferdinand 5. Leya, MD, and Rolf M. Gunnar, MD, HacNeal Hospital, Bmvyn, and Loyola University Medical Center, Maywood, Illinois

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Acute myocardial infarction (AMI) is usually caused by rupture of an atheromatous coronary artery plaque and consequent occlusive thrombosis. Such rupture, often occurring when a plaque is only moderately obstructive, is likely to occur if a plaque has a large eccentrically located lipid pool separated from the arterial lumen by a thin fibrous cap. Diagnosis Enzymatically confirmed AMI is often accompanied by negative or equivocal electrocardiographic evidence. Among blood tests, the traditional one for creatine kinase (CK)-MB as well as the newer ones for rapid CK-MB isoform, serum troponin-T, and myoglobin help distinguish between unstable angina, non-Q-wave myocardial infarction (MI), and Q-wave MI. But none has the requisite combination of rapid turnaround time and demonstrated accuracy to direct early therapy of suspected AMI, particularly when eligibility for thrombolytic therapy is uncertain. Because perioperative MI generally occurs without a rise in heart rate or blood pressure, CK-MB is routinely measured but postsurgical increases in this enzyme due to skeletal muscle injury cause false positives. Cardiac troponin I is a more specific marker of perioperative infarction, but an assay for it is not widely available. Acute diagnostic cardiac catheterization is generally not indicated unless acute percutaneous transluminal coronary angioplasty (PTCA) is contemplated or mechanical or other AMI complications are suspected. Two-dimensional transthoracic and transesophageal echocardiography are optimal for detecting left ventricular mural thrombus, right ventricular MI, papillary muscle pathology, pericardial effusion or tamponade, and cardiac rupture.

Post-MI Management Patients with evidence of continuing ischemia, hemodynamic compromise or arrhythmia propensity early after thrombolytic therapy should generally undergo diagnostic catheterization.

RJZVISITATION Frank 5. Sahel, MD, Ferdinand 5. Leya, MD, and fblf M. Gunnar, MD. MacNeal Hospital, Berwyn, and Loyola University Hedical Center, Haywood, Illinois

Since the publication of our original review article on the management of early myocardial infarction, there have been several refinements in the diagnosis and treatment of acute coronary thrombosis. However, the basic tenants of management have not changed. The goal remains to rapidly and accurately diagnose thrombotic occlusion, and achieve early and sustained patency of the infarct related artery. Diagnosis The mainstay of clinical diagnosis remains the evaluation of symptoms in conjunction with the standard 12-lead electrocardiogram (ECG). However, the use of early laboratory markers of myocardial necrosis (rapid CK-MB, myoglobin, and troponin) appear to enhance the speed and accuracy of diagnosis. Several assays for these markers are now widely available. Although these markers are detectable in the serum at a much earlier time than the standard enzymatic

Management Goals The earlier the initiation of thrombolytic therapy, the greater the mortality benefit. It is uncertain if the window of benefit extends beyond six hours from symptom onset, but it may extend to 18 hours, particularly for patients with extensive coronary collateralization or intermittent occlusion. Evidence from major trials indicates that tissue plasminogen ACC 0 1996 by the Amencan College of Cardiology Published by Elsewr Science Inc

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markers (3 to 6 h vs 8 to 24 h), their use seems best suited in more rapidly excluding coronary thrombosis as the etiology of chest discomfort rather than in establishing the diagnosis of acute MI. The measurement of troponin appears most useful since its presence in the serum is as early but less transient than myoglobin. The use of continuous ECG ST segment monitoring has also been investigated in the early evaluation of chest pain, but its utility remains unclear.

trials with lower doses of hirudin are currently being conducted. Angioplusty Direct PTCA of the infarct related artery (when performed in a timely manner) has become established as, at least, an equally effective treatment for AM1 as compared to thrombolytic therapy. The favorable clinical outcomes attained with PTCA persist through at least 6 months after the acute event. In the Primary Angioplasty in Myocardial Infarction (PAMI) trial, the only predictors for freedom from death or reinfarction at 6 month follow-up were young age and the use of PTCA (as opposed to t-PA). Residual intracoronary thrombus as well as embolization of thrombotic material into the microcirculation continues to be a vexing problem for PTCA performed in the setting of AMI. Several mechanical methods for extracting thrombus are being investigated but their clinical utility remains to be established. There are also several devices currently approved for the local delivery of drug therapy during PTCA. However, the optimal drug and dosing regimens have as yet not been determined. The use of intracoronary stents in the setting of acute coronary thrombosis was initially limited secondary to the fear of stent thrombosis. However, several studies have demonstrated that stents can be placed safely and effectively (even with the presence of residual angiographic thrombus) with a low incidence of subsequent stent thrombosis. Moreover, this has been accomplished without resorting to warfarin anticoagulation after stent placement. Intracoronary stents with antithrombotic coatings are currently in clinical trials, and their impact on the use of stents in direct infarct angioplasty seems promising. Adjunctive pharmacological therapies to direct PTCA have also significant therapeutic benefits. The Evaluation of IIb/IIIa platelet receptor antagonist 7E3 in Preventing Ischemit Complications (EPIC) trial evaluated the use of c7E3 (a noncompetitive inhibitor of the glycoprotein IIb/IIIa platelet receptor) for high risk angioplasty, including PTCA performed for AMI. When given as a bolus followed by infusion, c7E3 resulted in a marked decrease in the rate of the combined clinical end-point of reinfarction, urgent revascularization, or death in the first 30 days after the procedure. This clinical benefit was sustained at 6 months with a 23% reduction in target lesion revascularization or major ischemit events. However, there was a significantly higher incidence of hemorraghic complications in those patients treated with c7E3 as compared to placebo. In the subsequent EPILOG trial (Evaluation of PTCA to Improve Long-term Outcome by c7E3 GPIIb/IIIa receptor blockade), a lower, weight-adjusted heparin dose was compared to the standard heparin dosing used in the EPIC trial. The EPILOG trial was discontinued early secondary to the positive benefit demon-

Management Goals Thrombolytic Therapy The prompt initiation of therapy directed at reperfusion remains paramount in the early management of AMI. Thrombolytic medications remain the most common therapeutic modality for achieving reperfusion. The accelerated regimen of nonrecombinant t-PA established in the first Global Utilization of Streptokinase and t-PA for Occluded Arteries (GUSTO-I) trial has become the standard protocol given its documented mortality benefit. The angiographic substudy of GUSTO-I demonstrated that accelerated t-PA resulted in improved patency and particularly for Thrombolysis in MI (TIMI) grade 3 flow at 90 min as compared to streptokinase or the standard regimen of t-PA. TIM1 3 flow at 90 min was also shown to be a significant predictor of mortality at 30 days. This would, thus, indicate that the mechanism for improved survival with accelerated t-PA is the result of early and complete reperfusion. The routine use of early angiography after thrombolysis remains unsupported. The angiographic substudy of GUSTO-I revealed that TIM1 grade flow, visible thrombus, complex lesion morphology, percent diameter stenosis, and minimal lumen diameter all failed to predict subsequent coronary reocclusion. Intracerebral hemorrhage is the most feared complication of thrombolytic therapy. Moreover, stroke rates are significantly higher with the accelerated regimen of t-PA and in elderly patients. Analysis of the GUSTO-I data revealed that stroke, bleeding, and mortality related directly to the activated partial thromboplastin time (aPTT) achieved with the concomitant use of heparin therapy. The GUSTO-I protocol targeted an aPTT range of 60 to 85 s. However, an aPTT of 50 to 70 s at 12 h was associated with the lowest 30 day mortality. These data dictate a decrease in heparin dosing to achieve that level of anticoagulation. Unlike heparin, hirudin and hit-ulog are direct antithrombotic agents with an affinity for clot-bound thrombin. Several small trials indicated that when these agents were used as adjunctive therapy to thrombolysis, a higher early patency rate was achieved. However, subsequent large clinical trials comparing these agents to heparin have demonstrated a dose dependent increase in the risk of hemorrhagic stroke. Both the TIM1 9A and GUSTO-IIa trials were discontinued early secondary to an excess number of strokes. Further ACC CURRENT

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strated in the first 1500 patients. Although the clinical benefits of c7E3 were sustained, even with the lower dose of heparin used, the rate of hemorrhagic complications was not significantly different from placebo. Several other powerful antiplatelet agents directed against the glycoprotein IIb/IIIa receptor are also being investigated both as primary therapy for unstable coronary syndromes and as adjunctive therapy for PTCA. The results of these studies as well as those of the EPBXPILOG trials may have a profound effect on the management of AMI. In those patients treated by thrombolysis who have evidence for ongoing or recurrent ischemia, urgent cardiac catheterization is indicated. Rescue angioplasty for failed reperfusion in anterior wall myocardial infarctions has been shown to decrease the combined clinical endpoints of death or severe heart failure from 17% to 6%, while increasing exercise ejection fraction from 38% to 43%. In the GUSTO-I trial, cardiogenic shock occurred in 7.2% of patients, most often developing after hospital admission. Those patients who developed shock had the same high mortality (55%) as those initially presentingwith shock (57%), regardless of the thrombolytic regimen utilized. Only those patients subsequently treated with PTCA had a significantly lower 30 day mortality.

After Early Management The routine use of beta-blockers after MI, as well as the withdrawal of calcium channel blockers in patients with significant left ventricluar dysfunction is well established. Similarly, the benefit of angiotensin converting enzyme (ACE) inhibitors in those patients with residual severe left ventricular dysfunction is clear. However, the early initiation of ACE inhibitors in AM1 remains controversial. Finally, the Cardiac Arrhythmia Suppression Trials (CAST) failed to demonstrate beneficial effects of antiarrythmic therapy after MI, even in those patients with left ventricular dysfunction and high degrees of ambient ventricular ectopy. These trials indicated a possible increase in mortality with the use of those antiarrythmic agents tested. However, several studies have now shown that amiodarone therapy following MI may be used safely, without the increased risk of proarrythmic events or mortality. Whether amiodarone therapy can reduce either the incidence of sudden death or total mortality after MI remains unclear. The justification for its use routinely in this setting awaits the result of larger, randomized clinical trials. Address correspondence and reprint requests to Frank S. Saltiel, MD, MacNeal Cardiology Group, 3231 S. Euclid Avenue, Suite 201, Berwyn, IL 60402.

From ACC Current Journal Review: January/February 1994

REVZSZTATZON David P. Faxon, HD, Los Angeles, California

Management of Acute Angioplasty Complications

The major complications of PTCA have remained unchangedover the last few years,with acutevesselclosurethe most important and most responsiblefor AMI, hemodynamic collapse, emergency bypass surgery, or emergency PTCA. Abrupt closure continues to account for nearly 50% of the acute mortality of angioplasty. However, with advancesin technology, particularly coronary stent placement, thesecomplicationsare significantly lessfrequent than they were severalyearsago (1,2). As a result, a higher percentage of patients with complex anatomy are now undergoing angioplasty with improved successratesand similar overall complications rates. The expansion of the indications of angioplasty is in large part due to the increasedsafety of the procedure and improved managementof the major complications of angioplasty.

Davii P. Faxon, MD, Uniiersitj of Southern California, Department of Medicine, Division of Cardiology, Los Angeles, California

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The major complications of percutaneoustransluminal coronary angioplasty (PTCA) are acute vessel closure, acute myocardial infarction (AMI) and hemodynamic collapse. Advances in their prevention or managementhave reduced the need for emergency coronary artery bypass grafting (CABG) and made PTCA feasible for more high-risk patients. Editor’s Note: Becauseof the remarkable changesthat have occurred in the managementof the major complications after PTCA, ACC CurrentJournal Review haschosennot to reprint the original material. The revisitation is significantly updated by Dr. Faxon. ACC 0 1996 by the Amencan College of Card~?lqy Published by Elsewr Saence lnc

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Acute Closure Acute vesselclosure occurs in approximately 5 to 10% of patientsand is due to coronary dissection,acute thrombosis or, infrequently, atherosclerotic emboli (1,2>. The major

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