27 ST Segment ElevationMyocardial Infarction

489

From: Essential Cardiology: Principles and Practice, 2nd Ed.

Edited by: C. Rosendorff © Humana Press Inc., Totowa, NJ

Management of acute ST elevation myocardial infarction (STEMI) has been transformed in the last 20 yr by the results of large, prospective, randomized trials. Advances have been made in all components of acute myocardial infarction (AMI) management, from primary and secondary pre- vention to prehospital care, acute reperfusion therapy, adjunctive medical therapy, and manage- ment of complications. Despite this progress, however, acute MI remains the most common cause of death in industrialized nations; in addition, while mortality rates have been falling, the incidence of new infarction has not fallen in concert. The long-term consequences of myocardial infarction, congestive heart failure and ventricular arrhythmias, consume a large and growing proportion of health care resources. Thus, there is great need for continued progress in the prevention and treat- ment of acute MI.

OVERVIEW OF PATHOPHYSIOLOGIC MECHANISMS

The different acute coronary syndromes exist on a continuum of plaque rupture and thrombus formation (Fig. 1): the continuum ranges from a ruptured plaque with little or no thrombus (often asymptomatic), to a ruptured plaque with moderate thrombus leading to partial coronary occlu- sion (unstable angina and non-ST elevation MI), to a ruptured plaque with extensive thrombus and complete occlusion of the artery (ST segment elevation MI). In a minority of patients, superficial plaque erosion, rather than plaque rupture, may be the precipitating event.

Angiographic studies have consistently shown that MI more commonly develops from lesions associated with minor (<70%), rather than severe ( ³70%) luminal narrowing. Atherosclerotic lesions that lead to acute MI tend to be associated with positive (eccentric) vessel remodeling, in which the entire vessel, including the external elastic lamina, is enlarged to accommodate the grow- ing, lipid-rich plaque. Much work has been done to identify the factors that contribute to plaque erosion or rupture. The “vulnerable” atherosclerotic plaque has been characterized as having a dense lipid-rich core and a thin protective fibrous cap. The molecular factors that govern formation and breakdown of the extracellular matrix appear to regulate integrity of this protective fibrous cap. In vulnerable atherosclerotic lesions, inflammatory cells predominate at the shoulder region of the plaque; local release of cytokines from these inflammatory cells contributes to weakening of the fibrous cap at this critical site. When the plaque ruptures, platelets adhere and aggregate, thrombin is activated, and the fibrin clot forms, leading to myocardial ischemia or infarction.

In acute MI, thrombosis is composed of platelets, fibrin, erythrocytes, and leukocytes. Platelet

activation leads to the release of specific mediators including thromboxane A

, serotonin (5HT),

adenosine diphosphate (ADP), platelet-activating factor (PAF), thrombin, tissue factor, and oxygen-

derived free radicals. The presence of these mediators in conjunction with the relative absence of prostacyclin (PGI

), tissue plasminogen activator (t-PA), and endothelial nitric oxide at sites of vascular injury promotes platelet aggregation and obstruction of the narrowed coronary lumen.

On the surface of the activated platelet, the coagulation cascade is propagated, leading to the depo- sition of thrombin and fibrin, obstructing arterial blood flow and leading to myocardial necrosis.

The process of thrombotic occlusion of an epicardial coronary artery is not a static one. Varia- tion in vasomotor tone and in the balance of endogenous fibrinolytic and procoagulant factors can lead to cyclic occlusion and reperfusion of the occluded artery. Moreover, it has recently been appre- ciated that the coronary microcirculation plays a critical role in STEMI. Microvascular obstruc- tion can occur due to embolization of platelet and platelet-thrombin aggregates, microvascular spasm, and in situ leukocyte plugging. Even among patients with successful reperfusion of the occluded epicardial artery, microvascular obstruction is associated with adverse clinical outcomes.

Thus, the coronary microcirculation has emerged as an additional target for therapies in STEMI.

ST Elevation vs Non-ST Elevation MI

Experience with fibrinolytic therapy has identified important differences in the pathophysi- ologic mechanisms underlying different types of acute MI and has dramatically improved mor- tality in certain subsets of patients. Patients whose acute MI is manifested by ST segment elevation experience a substantial benefit from fibrinolytic therapy, while those whose MI is not associated with ST segment do not. Angiographic studies have shown that this difference is due to the initial status of the infarct-related artery: Patients with ST segment elevation exhibit 100% occlusion of the artery while patients without ST segment elevation exhibit a severely stenotic, but nevertheless patent, coronary artery (Fig. 1).

Fig. 1. The spectrum of acute coronary syndromes. The various clinical syndromes of coronary artery disease can be viewed as a spectrum, ranging from patients with stable angina to those with acute ST elevation MI.

Across the spectrum of the acute coronary syndromes, atherosclerotic plaque rupture leads to coronary artery

thrombosis: In acute ST elevation MI, complete coronary occlusion is present. In those with unstable angina

or non-Q wave MI, a flow-limiting thrombus is usually present. In patients with stable angina, thrombus is

rarely seen. (Adapted from Cannon CP, J Thrombolysis 1995;2:205–218.)

MI. Most patients complain of chest pain, which resembles classic angina pectoris, and describe a severe, pressure-type pain in the mid-sternum, often radiating to the left arm, neck, or jaw. The pain may be distinguished from angina by its intensity, duration (>30 min), and failure to resolve with nitroglycerin administration. The pain may be accompanied by dyspnea, diaphoresis, nausea, vomit- ing, and profound weakness.

In nearly half of the patients presenting with an acute MI, an inciting factor can be identified.

Heavy exercise, particularly among individuals who are fatigued or emotionally stressed, may trig- ger plaque rupture and precipitate an acute MI.

Particular attention should be given to the quality of pain, its variation with respiration and pos- ition, and whether it is similar to prior anginal episodes in quality. Characterization of the pain may help to distinguish it from other conditions that also cause chest discomfort. Aortic dissection, for example, typically causes a “tearing” pain, radiating through to the back. Pulmonary embolism is usually accompanied by pleuritic pain, shortness of breath, and occasionally hemoptysis. Peri- cardial pain is also usually pleuritic, and frequently changes with position, such that the patient may feel better sitting forward. The pain of pericarditis may radiate to the left shoulder or trapezius ridge. Not infrequently, inferior-wall myocardial infarction (IMI) masquerades as indigestion or nausea, rather than chest pain. Differentiating this from cholecystitis, peptic ulcer, and mesenteric ischemia by history alone may be very difficult, and a high index of suspicion for myocardial infarc- tion is necessary.

Many patients, particularly the elderly and women, present with “atypical” symptoms, which include dyspnea, indigestion, unusual locations of pain, agitation, altered mental status, profound weakness, and syncope. Furthermore, infarction may be silent in more than 25% of cases. This occurs more frequently in diabetic patients, as a result of the neuropathy that accompanies longstand- ing diabetes mellitus.

Physical Exam

The physical examination is usually unremarkable in patients with uncomplicated acute MI.

Particularly in the modern era, where noninvasive imaging has supplanted the physical examina- tion for confirmation of structural abnormalities, the examination should be performed efficiently, focusing on narrowing the differential diagnosis and assessing the stability of the patient. A focused examination can help to eliminate diagnoses such as pericarditis, pneumothorax, pulmonary embo- lus, and aortic dissection, which may mimic acute MI. It can also exclude aortic (or mitral) stenosis or regurgitation, which may complicate patient management. In addition, hemodynamic and mech- anical complications of acute MI can often be detected by careful attention to physical findings.

Patients with acute MI often appear pale, cool, and clammy; in many cases they are in obvious

distress. Elderly patients, in particular, may be agitated and incoherent. Patients with cardiogenic

shock may be confused and listless. Blood pressure and pulses should be checked in both arms,

since a pulse deficit or decreased blood pressure in the left arm would shift the focus of the diagnostic

workup toward aortic dissection. Cardiac examination should focus on eliciting murmurs and rubs.

A pericardial rub, although often difficult to appreciate, suggests that pericarditis may be the cause of a patient’s chest discomfort.

A brief survey for signs of congestive heart failure should be performed. Cool extremities or impaired mental status suggest decreased tissue perfusion, while elevated jugular venous pressure, rales on chest exam, and peripheral edema suggest elevated cardiac filling pressures. A careful examination of the peripheral arterial pulses and temperature can detect peripheral or cerebral vas- cular disease, which in itself increases the likelihood of coronary disease.

ECG Findings

The 12-lead ECG remains the most important initial diagnostic step in patients with suspected MI (see Chapter 8). Patients reporting to the emergency room with chest pain should have a 12-lead ECG performed immediately. If ST segment elevation is seen, and there are no contraindications to nitrates, a single sublingual nitroglycerin tablet should be given while patient assessment con- tinues. If chest pain and ST elevation resolve completely with sublingual nitroglycerin, a diagno- sis of coronary vasospasm (Prinzmetal’s variant angina) or possibly spontaneous reperfusion of a thrombotic coronary occlusion is likely. Persistent ST elevation is virtually diagnostic of occlu- sive thrombus, and immediate reperfusion therapy should be administered to all patients who are candidates. ST segment elevation suggestive of MI should be distinguished from that of pericardi- tis and the normal early repolarization variant. In pericarditis, ST elevation is usually diffuse, and may be associated with depression of the PR segment. In the early repolarization variant, the con- tour of the elevated ST segment is concave rather than convex. Patients with prior transmural infarc- tion and aneurysm formation may have persistent ST elevation, but this is generally associated with the presence of Q waves.

The presence of a new, or presumed new, left bundle branch block (LBBB) in the setting of chest pain is suggestive of a large anterior infarction; these patients should be considered for reperfusion therapy as well. Patients with LBBB of undetermined age present a diagnostic dilemma, and either emergency echocardiography (to look for an anterior wall motion abnormality) or cardiac catheter- ization should be considered. In patients with a preexisting LBBB, alternative methods are needed to make the diagnosis of acute MI, as ECG findings are not sufficiently reliable to guide therapy.

Cardiac Biomarkers

In recent years, many new serum markers for myocardial necrosis have been developed. Mea- surements of cardiac troponin T (cTNT) and I have become routine, and rapid whole blood assays for myoglobin, creatinine kinase (CK), its myocardial isoform (CKMB), and cTNT are now avail- able. The advent of more sensitive and specific cardiac biomarkers has facilitated the diagnosis of non-ST elevation MI; however, patients with STEMI are identified primarily on their clinical syn- drome and presenting ECG. As a result, interventions to facilitate reperfusion are implemented before the measurement of cardiac biomarkers has been completed. For patients with ST elevation MI, cardiac marker measurements are used to confirm the diagnosis in patients with equivocal elec- trocardiographic changes or a paced rhythm, to help gauge prognosis, and sometimes to estimate the likelihood of successful reperfusion therapy. The time course of rise and fall of the most com- monly measured cardiac enzymes is shown in Fig. 2.

While cardiac markers have little role in the emergent diagnosis of STEMI, they remain valua-

ble for prognostic assessment. For example, patients with evidence of myoglobin or troponin ele-

vation prior to the administration of reperfusion therapy are at increased risk for failure of fibrinolytic

therapy or primary percutaneous coronary intervention (PCI), and are at increased risk for death,

independent of the success or failure of reperfusion therapy. Interestingly, this association with

outcomes is also independent of infarct location and time to treatment, suggesting that measuring

cardiac markers at the time of emergency room presentation provides an objective assessment of

the amount of irreversible myocyte injury that has occurred prior to the initiation of therapy. In

addition, the rate of rise of cardiac biomarkers can be used to help determine which patients have had successful or unsuccessful reperfusion, and may help to select appropriate patients for coronary angiography. Myoglobin appears to be the most useful for this purpose, due to its smaller size, cyto- solic location, and rapid renal clearance (1).

B-type natriuretic peptide (BNP) is a cardiac hormone that is released in response to increases in wall stress. Levels of circulating BNP are in wide clinical use for diagnosis and prognostic assess- ment in patients with suspected heart failure. BNP levels also appear to be useful in ST elevation MI. Following STEMI, BNP levels rise and peak at approximately day 2. A second peak may occur several days later as the ventricular remodeling process begins. Higher levels of BNP, measured several days after MI, have been associated with a greater likelihood of death, CHF, and ventricu- lar remodeling after STEMI (2) and have a role for assessing prognosis (Fig. 3). Whether specific therapies should be applied to those with increased BNP is being investigated in clinical trials.

Echocardiography

Portable echocardiography can help to confirm myocardial ischemia or infarction in patients with nondiagnostic electrocardiograms, particularly in situations where rapid assays for serum markers are not available. In our experience, this is particularly useful when left bundle branch block of undetermined duration is present, or when it is necessary to distinguish pericarditis or early repolari-

Antman, EM. General hospital management. In: Julian DG, Braunwald E, eds. Management of Acute Myo- cardial Infarction. W. B. Saunders, Ltd., London, 1994, p. 63, reprinted with permission.)

Fig. 3. BNP levels greater than the median were associated with a higher 10-mo mortality among patients with

STEMI. (Adapted from ref. 2.)

zation from acute MI. Transmural ischemia is almost always associated with hypokinesis or akin- esis of the subtended myocardial segments. Therefore, absence of regional or global wall motion abnormalities argues strongly against transmural MI. Transesophageal echo (TEE) should be consid- ered when suspicion arises for aortic dissection. In expert hands, TEE has >90% sensitivity for the diagnosis of aortic dissection.

THERAPY FOR ACUTE MI Reperfusion Therapy E

D

“O

” R

Early, successful coronary reperfusion limits infarct size, and improves left ventricular dysfunc- tion and survival. These benefits are due at least in part to the early restoration of antegrade flow in the infarct-related artery (IRA). In a retrospective analysis of six angiographic trials of different fibrinolytic regimens, patients who achieved normal (Thrombolysis in Myocardial Infarction [TIMI]

grade 3) flow in the IRA had a 30-d mortality rate of 3.6%, vs 6.6% in patients with slow (TIMI grade 2) flow, and 9.5% in patients with an occluded artery (TIMI grade 0 or 1 flow) (3).

Even among patients who achieve normal (TIMI grade 3) epicardial blood flow in the IRA after reperfusion therapy, tissue-level perfusion may be inadequate. Using a number of different diag- nostic tools (Table 1), investigators have demonstrated that measures of tissue and microvascular perfusion provide prognostic information that is independent of TIMI flow grade (Fig. 4) (4). For example, Ito and colleagues, using myocardial contrast echocardiography, found impaired tissue and microvascular perfusion in approximately one third of patients with TIMI grade 3 flow after primary PCI (5). These patients were at increased risk for the development of CHF and death.

Microvascular dysfunction is thought to occur in the setting of myocardial infarction as a result of distal embolization of microthrombi, tissue inflammation from myocyte necrosis, and arteriolar spasm caused by tissue injury.

Perhaps the most clinically relevant measure of tissue perfusion is a simple bedside assessment of the degree of resolution of ST segment elevation on the 12-lead electrocardiogram. Greater degrees of ST resolution are associated with a higher probability of achieving a patent IRA and TIMI grade 3 flow (4). Furthermore, patients who have normal epicardial blood flow, but persistence of ST elevation on the 12-lead ECG, have been shown to have abnormal tissue and microvascular per- fusion using myocardial contrast echocardiography. In addition, persistent ST elevation has been shown to predict poor recovery of infarct zone wall motion and the clinical endpoints of death and heart failure (4). In summary, ST resolution appears to integrate epicardial and myocardial (micro- vascular) reperfusion. As a result, it may actually provide a more clinically useful assessment of reperfusion than coronary angiography.

Table 1

Diagnostic Tools Used to Evaluate Tissue

and Microvascular Perfusion in Patients With ST Elevation MI

Technique Finding suggestive of microvascular injury

Myocardial contrast echocardiography Absence of microbubble contrast uptake in the infarct zone Doppler flow wire Abnormal coronary flow reserve; systolic reversal of coronary flow PET scanning Impaired regional myocardial blood flow as measured with

NH

Nuclear SPECT imaging Absence of tracer uptake into infarct zone

Contrast angiography Abnormal myocardial “blush,” with failure to opacify myocardium or prolonged dye washout from myocardium MRI Hypoenhancement of infarct zone following gadolinium contrast

injection

ECG Failure to resolve ST elevation

a

Assumes that the epicardial infarct artery is patent. These techniques can be presumed to reflect microvascular and

tissue perfusion only when the infarct artery has been successfully recanalized.

Pharmacologic Reperfusion F

T

Time is a critical determinant in the success of any fibrinolytic regimen. Patients who are treated within 1 h from the onset of chest pain have an ~50% reduction in mortality, while those presenting more than 12 h after onset of symptoms derive little, if any, benefit from fibrinolysis. For each hour earlier that a patient is treated, there is an approximately absolute 1% decrease in mortality, which translates into an additional 10 lives saved per 1000 treated. Figure 5 illustrates the crucial time- dependence of administration of fibrinolytic therapy.

Fibrinolysis has been shown to reduce mortality in numerous placebo-controlled trials using streptokinase, anistreplase (APSAC), and tissue plasminogen activator (t-PA). These benefits have been shown to persist through at least 10 yr of follow up. The Fibrinolytic Therapy Trialists’ over- view of all the large placebo-controlled studies showed a 2.6% absolute reduction in mortality for patients with ST-segment elevation MI treated within the first 12 h after the onset of symptoms (6).

Patients presenting with left bundle branch block and a strong clinical history for acute MI also derive a large benefit from fibrinolysis. However, those without ST segment elevation or left bundle branch block do not benefit from fibrinolysis, and indeed may be harmed by it.

C

D

F

A

All the fibrinolytic agents currently available and under investigation are plasminogen activa- tors. They all work enzymatically, directly or indirectly, to convert the single-chain plasminogen molecule to the double-chain plasmin, which has potent intrinsic fibrinolytic activity.

The initial description of fibrinolytic therapy for STEMI involved intracoronary administra- tion of streptokinase (SK), a nonenzymatic protein produced by -hemolytic streptococci. SK forms an activator complex with plasminogen that results in its cleavage and the subsequent formation of plasmin. Plasmin degrades fibrin and fibrinogen as well as procoagulant factors V and VIII. The

Fig. 4. Relationship between epicardial perfusion, myocardial perfusion, and mortality after fibrinolytic

admin-istration in the TIMI 10B trial. TIMI Myocardial Perfusion Grade measures the degree of microvas-

cular flow during routine coronary angiogram. Findings from this study revealed that myocardial perfusion

was significantly associated with mortality independent of epicardial blood flow. (Adapted from Gibson CM,

Cannon CP,Murphy SA, et al., for the TIMI Study Group. The relationship of the TIMI Myocardial Perfusion

Grade to mortality after thrombolytic administration. Circulation 2000;101:125–130.)

Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI) trial and the Second International Study on Infarct Survival (ISIS)-2 demonstrated that the administration of SK for evolving MI reduced mortality when compared to standard (no reperfusion) therapy. Read- ministration of streptokinase to patients should be avoided for at least 4 yr (preferably indefinitely) because of a high prevalence of potentially neutralizing antibodies, and because there is a risk for anaphylaxis upon reexposure to these drugs.

The potential for improved survival with more specific fibrinolytic agents such as alteplase (t-PA) was suggested by the first TIMI trial, which demonstrated infarct-related artery patency in nearly twice as many patients randomly allocated to receive t-PA vs SK. In addition, the effect of early and sustained infarct-vessel patency on mortality was evaluated in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, conceived in 1989. The GUSTO trial (7) directly compared four thrombolytic regimens: “acceler- ated” or “front-loaded” t-PA and concomitant IV heparin, streptokinase with IV heparin, strepto- kinase with subcutaneous heparin, and a combination of t-PA and streptokinase with IV heparin. The accelerated t-PA and heparin regimen achieved the highest 90-min infarct-related artery patency, and was associated with the lowest mortality. The 14% mortality reduction associated with tPA versus streptokinase was highly significant (p = 0.001), although there was a significant excess of hemorrhagic stroke for tPA compared with streptokinase (0.7% of patients treated with tPA vs 0.5% of patients treated with streptokinase). When comparing the net clinical benefit (death or disabling stroke) between the different regimens, t-PA was still clearly beneficial compared to the other three regimens (9 fewer deaths or disabling strokes per 1000 patients treated with t-PA). Other complications of acute MI were less frequent with t-PA as well, including allergic reactions, CHF, cardiogenic shock, and atrial and ventricular arrhythmias.

Given the importance of rapid reperfusion, one would expect that a more aggressive fibrinoly- tic regimen, which achieves a higher rate of early infarct-related patency, would be associated with a lower mortality. Traditional fibrinolytic regimens, however, fail to induce early and sustained reperfusion in nearly half the patients (Fig. 6). In addition, reocclusion occurs in another 10 to 30%

of patients. As a result, recent efforts have concentrated on the development of newer fibrinolytics, anticoagulants, and antiplatelet therapies to improve early and sustained reperfusion.

Fig. 5. Absolute reduction in 35-d mortality versus delay from symptom onset to randomisation and treatment among 45,000 patients with ST segment elevation or LBBB. (From Fibrinolytic Therapy Trialists’ (FTT) Col- laborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients.

Lancet 1994;343:311–322. Reprinted with permission from Elsevier.)

Molecular modification of the recombinant tissue plasminogen activator (rt-PA) structure has provided agents such as reteplase and tenecteplase (TNK) with longer plasma half-lives that allow a simplified single or double bolus administration regimen (Table 2). Despite these more favor- able pharmacologic characteristics, however, improvements in 30-d mortality rates have not been observed in phase III clinical trials. Reteplase is a double bolus agent with limited fibrin specificity that was shown to have similar efficacy and risk to accelerated t-PA in the GUSTO III trial (8). Rete- plase, however, is easier to administer than t-PA, a factor that could prevent dosing errors and pos- sibly decrease “door to needle” time. ASSENT II (9) demonstrated that the single bolus agent TNK is equivalent to tPA in terms of efficacy. TNK was also equivalent in terms of ICH. One potential advantage of TNK over other agents is its fibrin specificity, which appears to result in a 20% reduc- tion in non-ICH bleeding when compared to tPA.

Overall, the benefits of tenecteplase or reteplase over tPA are modest and mostly related to a more convenient dosing regimen; the failure of these agents to improve outcomes over the accelerated regimen of alteplase (Fig. 7) suggests that we have reached a therapeutic plateau with fibrinolytic monotherapy and demonstrate the importance of continued evaluation of novel adjunctive anti- coagulant and antiplatelet or interventional reperfusion strategies for STEMI.

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/III

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The recognition of the pivotal role of platelets in the pathophysiology of STEMI has further improved our understanding of the limitations of fibrinolytic monotherapy. Fibrinolytic agents are believed to act on only one component of the clot and lead to platelet activation. Platelets induce release of PAI-1, -2 antiplasmin, and thromboxane A

, which lead to prothrombosis and vasocon- striction. Fibrinolytics also enhance fibrin activation by exposure of clot-bound thrombin (10).

The glycoprotein IIb/IIIa receptor is the final common pathway for platelet aggregation. By block- ing the final common pathway of platelet aggregation, fibrinogen-mediated cross-linkage, GP IIb/IIIa receptor inhibition may contribute to disaggregation of platelet-rich thrombus (10).

Preclinical studies have suggested that the use of GP IIb/IIIa receptor inhibitors with thrombo- lytic agents may accelerate reperfusion and reduce the risk of reocclusion. The combination of a

Fig. 6. Limitations of current fibrinolytic regimens. (From Lincoff AM, Topol EJ. Illusion of reperfusion. Does

anyone achieve optimal reperfusion during acute myocardial infarction? Circulation 1993;87:1792–1805.)

reduced-dose thrombolytic agent and a GP IIb/IIIa inhibitor was evaluated in the TIMI 14 trial, a phase II dose-ranging and confirmation trial. The rate of TIMI 3 flow was significantly higher at both 60 and 90 min in patients receiving half-dose tPA and abciximab (72% and 77%, respectively) (11). In addition, ST segment resolution was improved, even among those with TIMI grade 3 flow, suggesting an additional benefit of combination therapy in improving microvascular perfusion.

Major hemorrhage and intracranical hemorrhage (ICH) were similar between the combination tPA and abciximab and t-PA control groups. In follow-up trials only nonsignificant trends toward in- creased TIMI 3 flow were observed with half-dose reteplase (TIMI 14 and SPEED) and TNK in the ENTIRE-TIMI 23, INTEGRITI-TIMI 20, and FASTER-TIMI 24 trials.

Despite only modest increase in TIMI 3 flow in these follow-up trials, larger clinical endpoint trials were already under way. GUSTO-V examined mortality in patients with STEMI who were ran- domly allocated to receive either conventional dose reteplase and heparin or a combination of

Table 2

Thrombolytic Agents in Current Clinical Use

Alteplase Reteplase Tenecteplase Streptokinase

Fibrin-selective +++ ++ ++++ 

Half-life 5 min 14 min 17 min 20 min

Dose 15 mg bolus; then 0.75 Two 10 unit bolus 0.53 mg/kg 1.5 million mg/kg over 30 min; doses given as a single units over then 0.5 mg/kg over 30 min apart bolus 30–60 min 60 min (max 100 mg

total dose)

Weight-adjusted Partial No Yes No

Adjunctive heparin Yes Yes Yes No

Possible allergy No No No Yes

TIMI 2/3 flow 80% 80% 80% 60%

(90 min)

TIMI 3 flow 55–60% 60% 55–65% 32%

(90 min)

Efficacy vs tPA NA Similar Equivalent 1% 

mortality

Safety NA Similar Similar ICH  ICH

 non-ICH  overall bleeding bleeding

Cost +++ +++ +++ +

Fig. 7. Results from major clinical trials comparing different fibrinolytic regimens. Note the steady decline

in mortality over the decade, and the absence of improvement in mortality with newer fibrinolytic agents. (Abx,

abciximab; SK, streptokinase; tPA, alteplase; rPA, reteplase; TNK, tenecteplase.)

half-dose reteplase, abciximab, and reduced-dose heparin (12). This trial enrolled 16,588 patients who were within 6 h of evolving STEMI. At 30 d, the primary endpoint of all-cause mortality was not significantly different between the reteplase group and the combined reteplase and abciximab group. Although the combination regimen significantly reduced rates of reinfarction and emergent PCI within 7 d compared with fibrinolytic monotherapy, this did not result in improved 1-yr mor- tality (12). No differences in rates of intracranial hemorrhage were seen overall, but non-ICH bleed- ing, transfusions, and thrombocytopenia were all increased in the combination therapy arm (Fig. 8).

ASSENT-3 was a multicenter, randomized study of 6095 patients with STEMI who were ran- domly assigned to one of three treatment regimens: full-dose tenecteplase and enoxaparin; half- dose tenecteplase, abciximab, and low-dose unfractionated heparin (UFH); or full-dose tenecteplase with UFH (13). The tenexteplase-enoxaparin regimen will be discussed below. The findings in the combination arm (half-dose tenecteplase with abciximab) were virtually identical to those observed in GUSTO-V: nonfatal recurrent ischemic events were lower in the combination arm, but mortality was not reduced and bleeding complications were increased. Of particular importance, both GUSTO- V and ASSENT-3 showed that combination therapy was associated with increased rates of ICH in patients >75 yr old. In summary, despite great promise from phase II trials, appropriately powered endpoint trials have demonstrated that the combination of GP IIb/IIIa inhibitors with reduced doses of fibrinolytics are not superior to fibrinolytic monotherapy. These regimens cannot be recom- mended outside of an ongoing clinical trial, and are contraindicated in the elderly. Future studies will evaluate whether these regimens might have a role in facilitated PCI (see “Mechanical Per- fusion” following).

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H

In acute ST-segment elevation MI, unfractionated heparin (UFH) is also an important adjunc- tive agent to decrease reocclusion following administration of t-PA. Although no difference in infarct-related artery patency is seen at 90 min, patency is higher between 18 h and 5 d in patients randomized to receive intravenous heparin, suggesting that the benefit of heparin is a result of decreased reocclusion rather than enhanced fibrinbolysis. Furthermore, long-term patency rates are highest in patients who are effectively anticoagulated at a target APTT range of 50–70 s.

Recently, it has become appreciated that the dose of intravenous heparin is also an important risk factor for the development of ICH. Therefore, the ACC/AHA guidelines recommend a reduced dose of UFH to be given with tPA, rPA, or TNK: a bolus of 60 U/kg (maximum 4000 U) and an infusion of 12 U/kg/h (maximum 1000 U/h).

Fig. 8. Combination therapy with reduced dose reteplase and abciximab in GUSTO-V led to increased rates

of nonintracranial bleeding. (Adapted from ref. 11.)

Following streptokinase or anistreplase (APSAC), the role of heparin is less clear. Patients treated with streptokinase and intravenous or subcutaneous heparin in the GUSTO-I trial had similar infarct-related artery patency at 90 min and 24 h, but those receiving intravenous heparin had sig- nificantly higher patency at 5 to 7 d (84% vs 72%, p = 0.04). Nonetheless, overall mortality and the rate of clinical reinfarction were the same between these two groups. Therefore intravenous heparin may be considered optional in streptokinase-treated patients. Subcutaneous heparin has been shown to be of no benefit in preventing reinfarction or death.

Low-molecular-weight heparins (LMWHs) are created by depolymerization of standard, unfrac- tionated heparin and selection of those fragments with lower molecular weight. As compared with unfractionated heparin, which has nearly equal anti-IIa and anti-Xa activity, LMWHs have increased ratios of anti-Xa to anti-IIa activity: either 2:1 (dalteparin) or 3:1 (enoxaparin or nadroparin). Greater factor Xa inhibition is thought to be responsible for the greater anticoagulant potency of LMWH over UFH. The high bioavailability and reproducible anticoagulant response of LMWH allows for subcutaneous administration without monitoring of the coagulation system. While this is an advantage in patients with non-ST elevation ACS, the long half-life of LMWH could be a disadvan- tage early in STEMI when patients are being considered for fibrinolytic therapy or primary PCI.

The ASSENT-3 trial evaluated the potential role of low-molecular-weight heparin used in com- bination with fibrinolytic therapy. As described above, ASSENT-3 randomized 6095 patients with STEMI to either full-dose tenectaplase and enoxaparin, the combination of reduced-dose tenecte- plase, abciximab, and UFH, or full-dose tenecteplase with UFH (13). Patients receiving enoxaparin were treated until hospital discharge, whereas those receiving UFH were treated for only 48 h, a design feature of the trial that has led to considerable criticism. Patients treated with full-dose tenecteplase plus enoxaparin had a significantly lower composite occurrence of mortality, in-hos- pital reinfarction, or refractory ischemia to 30 d compared with patients treated with tenecteplase plus UFH (11.4% vs 15.4%; p = 0.0002) (13). The rate of ICH was comparable between the two treatment arms. The primary benefit of enoxaparin was a reduction in nonfatal recurrent MI, which is somewhat difficult to interpret because the duration of enoxaparin therapy was longer than UFH therapy. Similar results to ASSENT-3 were observed in the Enoxaparin and TNK-tPA with or with- out GP IIb/IIIa Inhibitor as Reperfusion Strategy in ST-Elevation MI (ENTIRE-TIMI)-23 trial.

While the results of ENTIRE-TIMI-23 and ASSENT-3 suggested that enoxaparin might be a potential replacement for UFH in multiple pharmacologic reperfusion strategies for STEMI, caution was raised after the ASSENT-3 PLUS trial was reported. This extension of the ASSENT-3 trial eval- uated the safety and feasibility of reperfusion therapy with tenecteplase and enoxaparin in the pre- hospital setting (14). In this trial, 1639 patients with STEMI were randomly assigned to treatment with tenecteplase and either enoxaparin or UFH. The composite of 30-d mortality or in-hospital reinfarction tended to be lower in the enoxaparin group; however, there was an increased risk of stroke and ICH in this group compared with UFH. The increased risk of stroke and ICH occurred exclusively in the older population (>75 yr). In summary, insufficient data are available to recom- mend enoxaparin as an adjunct to reperfusion therapy in STEMI. More data are needed to deter- mine the efficacy and safety of enoxaparin in combination with fibrinolytics in the elderly. In an ongoing phase III trial, Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarc- tion Trial (EXTRACT), the enoxaparin dose has been reduced for those greater than 75 yr of age.

This trial will enroll more than 21,000 patients and should definitively determine the role for enox- aparin as an adjunct to fibrinolysis.

D

T

I

Direct thrombin inhibitors have also undergone extensive evaluation. One such agent is the anti- coagulant hirudin, which binds in a 1:1 relationship to thrombin, the last step in the coagulation cas- cade. In the TIMI 9B trial, although hirudin reduced the rate of recurrent MI following thrombolytic therapy, there was no difference in the primary endpoint, death, MI or severe CHF/shock at 30 d.

Hirudin was compared with unfractionated heparin in more than 12,000 patients across the full spec-

trum of acute coronary syndromes in the GUSTO IIb trial. There was a reduction in reinfarction (5.4%

vs 6.3%, p = 0.04) but only a trend toward reduction in death or MI at 30 d (8.9% vs 9.8%, p = 0.06) (15). Bivalirudin, a synthetic polypeptide that forms a temporary high-affinity stoichiometric com- plex with thrombin, was evaluated in HERO-2 (16). This trial compared bivalirudin with unfraction- ated heparin in more than 17,000 patients receiving streptokinase. No difference was observed in the primary outcome of death at 30 d; however, there was a 30% reduction in the incidence of new myocardial infarction in the bivalirudin group at 96 h, a benefit that was maintained out to 30 d.

There was a small but significant excess of moderate bleeding with bivalirduin compared with heparin and a similar trend for excess severe bleeding (0.7% vs 0.5%, p = 0.07). In summary, mul- tiple trial data do not support direct thrombin inhibitors as a replacement for UFH in patients treated with fibrinolytic therapy.

C

G

F

T

Fibrinolytic therapy is indicated for patients presenting within 12 h of symptom onset if they have ST segment elevation (or new left bundle branch block) provided they have no contrain- dications to thrombolytic therapy (Table 3). Less clear indications include patients who are older than 75 yr of age, those who present with ongoing pain between 12 and 24 h after the onset of acute MI, and those who are hypertensive but present with high-risk MI. Patients should not be treated if the time to treatment is >24 h, or if they present only with ST segment depression.

L

F

T

Current fibrinolytic regimens achieve patency (TIMI grade 2 or 3 flow) in approx 80% of patients, but complete reperfusion (TIMI grade 3 flow) in only 50 to 60% of cases (Fig. 6). As described above, incomplete reperfusion is associated with a poor prognosis. In addition, even after successful fibrinolysis, 10 to 30% of patients suffer reocclusion of the infarct related artery and experience reinfarction in the following 3 mo (17). Reocclusion and reinfarction are associated with a two- to threefold increase in mortality. Despite widespread availability of fibrinolytic agents, most patients who present with STEMI do not receive such therapy. A disproportionate number of patients eligible for receiving thrombolytic therapy include women, the elderly, and those with a history of prior myocardial infarction, multivessel coronary disease, or depressed left ventricular systolic function.

Finally, bleeding is the most common complication of fibrinolytic therapy; major hemorrhage, as defined by the TIMI criteria, occurs in 5 to 15% of patients. Intracranial hemorrhage (ICH) is the most devastating of the bleeding complications, causing death in the majority of patients affected and almost universal disability in survivors. In major clinical trials ICH has occurred in 0.6 to 1.4%

Puncture of a noncompressible vessel

CNS, central nervous system; SK, streptokinase; APSAC, anisolylated plasminogen streptokinase activator complex

(anistreplase).

of patients receiving thrombolytic therapy. Patients at particularly high risk for ICH include elderly persons (particularly elderly females) and patients with low body weight.

Mechanical Reperfusion P

PCI

The emerging method of achieving coronary reperfusion is the use of immediate or “primary”

PCI. Many randomized controlled trials have evaluated both pharmacologic and mechanical reperfusion during STEMI. A meta-analysis of the 23 randomized controlled trials evaluated the short- and long-term clinical events among the 3872 patients randomized to primary PCI with the 3867 patients randomized to thrombolytic therapy (18). Primary PCI was superior to thrombolytic therapy in reducing mortality, nonfatal reinfarction, stroke, and the combined endpoint of death, nonfatal reinfarction, and stroke (Table 4). The reductions in mortality and recurrent MI were par- ticularly striking. PCI remained a better option than thrombolytic therapy during long-term follow- up as well. These results are consistent with prior meta-analyses that have compared fibrinolytic therapy with primary PCI.

Recent clinical studies in patients with STEMI have sought to evaluate the effect of primary PCI among particular patient subsets. The relative benefits of primary PCI are greatest in patients at highest risk, including those with cardiogenic shock, right ventricular infarction, large anterior MI, and increased age (due partly to increased ICH rate with thrombolytic therapy). Primary PCI has traditionally been performed only in hospitals with surgical backup because of the potential for complications that might require immediate bypass surgery. The incidence of emergency bypass surgery with primary PCI, however, is now reported to be less than 0.5%. Coronary artery dissection and closure can be managed effectively with intracoronary stents. The Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT) trial examined whether primary PCI could be performed safely at community hospitals with primary PCI programs but without access to on-site cardiac sur- gery. After a formal primary PCI development program was completed at all sites, 451 patients with STEMI of less than 12 h duration and eligible for thrombolytic therapy were enrolled. The incidence of the composite endpoint of death, reinfarction, and stroke was reduced in the primary PCI group at both 6 wk and 6 mo after index MI (19). Though this trial was small and underpowered, it sug- gests that PCI can be performed safely, promptly, and effectively in community hospitals follow- ing an extensive development program, even if these centers do not have an elective PCI or cardiac surgery program.

Table 4

Summary of 23 Randomized Trials

of Primary Angioplasty Versus Thrombolytic Therapy

Study group PTCA Thrombolytic therapy p value

Mortality

Short-term 7% 9% 0.0002

Long-term 9.6% 12.8% 0.0019

Nonfatal MI

Short-term 3% 7% <0.0001

Long-term 4.8% 10% <0.0001

Total stroke

Short-term 1% 2% 0.0004

Long-term * *

Death, nonfatal MI or stroke

Short-term 8% 14% <0.0001

Long-term 12% 19% <0.0001

a

Data not available.

More recently, clinical trials have evaluated whether patients with STEMI should be transferred emergently to a site where PCI can be performed as compared with the administration of fibrino- lytic therapy locally without transfer. A summary of DANAMI-2, PRAGUE-2, and Air PAMI trials reveals a benefit for catheter-based perfusion over on-site fibrinolytic therapy with respect to the combined endpoint of death, reinfarction, or stroke (Fig. 9). In all three transport trials, there is a similar rate of adverse events in the PCI group (8–8.5%) and in the fibrinolytic assigned patients (13.5–15%), demonstrating a 40 to 50% reduction of the combined endpoint. The aggregate data suggests that catheter-based reperfusion therapy reduces the composite outcome of death, rein- farction, and stroke. In addition the rate of ICH is virtually eliminated with primary PCI compared with thrombolysis.

I

S

Intracoronary stents reduce the risk of early reocclusion and restenosis when used for elective PCI and have been investigated for the treatment of STEMI. In the first trial comparing stents to balloon angioplasty, 900 STEMI patients were randomly assigned to primary PTCA or implanta- tion of a heparin-coated stent during primary PCI. Although there was no difference in death, rein- farction, or stroke, both reocclusion and restenosis occurred less frequently in the stent group at 6 mo. A recent trial showed a trend for decreased mortality rates at 6 mo for primary stenting ver- sus primary balloon angioplasty with significant reductions in other major adverse events (20).

More recently, stents coated with polymers that elute antiproliferative compounds have been introduced; these drug-eluting stents markedly lower rates of in-stent restenosis compared with traditional bare-metal stents in patients undergoing routine PCI. Although data on drug-eluting stents in the setting of primary PCI are limited, a recent observational study demonstrated an excel- lent safety profile and very low restenosis rates when these new stents were used in STEMI. It is highly likely that drug-eluting stents will become the standard of care when primary PCI is per- formed within a short time period.

GP II

/III

I

A

M

R

GP IIb/IIIa inhibitors were originally shown to reduce the ischemic complications of urgent and elective PCI. As a result, these agents were evaluated in patients undergoing mechanical and phar- macologic reperfusion. The ADMIRAL trial recently demonstrated that abciximab therapy ini- tiated before primary PCI with stenting improved outcomes in patients with STEMI (21). In this 300- patient trial comparing primary PCI with and without abciximab pretreatment, the group receiving

(DANAMI 2). (Adapted from Andersen HR, Nielsen TT, Rasmussen K for the DANAMI 2 Investigators.

A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med

2003;349:733–742.)

abciximab had higher procedural success rates, reduced rates of reocclusion, better epicardial blood flow, and a markedly lower rate of clinical adverse events. The largest study of GP IIb/IIIa inhib- itors during primary PCI was the CADILLAC study, which enrolled 2082 patients with STEMI.

These patients were randomly assigned to primary percutaneous transluminal coronary angioplasty (PTCA) alone, primary PTCA plus abciximab, stenting alone, or stenting plus abciximab. Major adverse events occurred in 20% of patients in the primary PTCA group, 16.5% with primary PTCA plus abciximab, 11.5% with stenting alone, and 10.2% with stenting plus abciximab (p < 0.001) (20). As described previously, this study suggests primarily that stent implantation should be the preferred reperfusion strategy. In addition, the combination of abciximab and stenting leads to a modest but significant reduction in the need for repeat revascularization at 6 mo (Table 5). These studies support a consistent benefit when GP IIb/IIIa inhibitors are used for patients treated with mechanical reperfusion.

R

PCI

Because failure of fibrinolytic therapy is associated with increased rates of morbidity and mor- tality, “rescue” PCI is frequently performed in such patients. Data to support rescue PCI in patients with persistent infarct artery occlusion are limited, but the totality of evidence supports rescue PCI in moderate or high-risk patients with an occluded IRA after fibrinolytic therapy. The relative bene- fits of rescue PCI have likely increased in recent years with the widespread utilization of intracoro- nary stenting and glycoprotein IIb/IIIa inhibitors.

Identifying candidates for rescue PCI remains a challenge, due to limitations of the noninvasive measures that determine either success or failure of reperfusion therapy. We recommend urgent catheterization and PCI for all patients with persistent ST elevation and ongoing chest pain 90 to 120 min after the administration of fibrinolytic therapy, unless they are at particularly low risk for complications. If chest pain has resolved but ST segments remain elevated, urgent catheterization should also be considered, particularly in high-risk patients such as those with older age, anterior infarction, or diabetes. Additional information may be obtained from evaluation of the early levels of cardiac markers, particularly myoglobin. A rapid rise in serum myoglobin (a ratio of myoglobin at 60 min/baseline >4.0) identifies patients who are highly likely to have a patent infarct artery.

Urgent catheterization may not be needed in these patients even if persistent ST elevation is present.

R

I

PCI A

F

T

—“F

” PCI

While rescue PCI in patients with suspected failure of fibrinolysis is generally accepted, there has been considerable controversy as to the role of PCI after apparently successful fibrinolytic therapy. In the late 1980s, the ECSG, TAMI-1, and TIMI 2A investigators reported no benefit with respect to mortality, reinfarction, or vessel patency in patients randomized to an early invasive strategy (immediate catheterization and PTCA for suitable lesions) following administration of fibrinolytic therapy.

Since these trials were published, dramatic advances in interventional cardiology have taken place. Intracoronary stenting has significantly decreased the incidence of abrupt vessel closure after PTCA, the need for emergency coronary artery bypass surgery for failed PTCA, and the need

Table 5

CADILLAC Outcomes at 6 Mo

PTCA PTCA + Abx Stent Stent + Abx

(n = 518) (n = 528) (n = 512) (n = 524) p value

Death 4.5% 2.5% 3.0% 4.2% 0.23

Recurrent MI 1.8% 2.7% 1.6% 2.2% 0.64

CVA 0.2% 0.2% 0.4% 0.4% 0.88

Target vessel revascularization 16.9% 14.8% 8.9%

5.7%

<0.001

a

p < 0.001 vs either PTCA group.

for tar-get vessel reintervention due to restenosis. Glycoprotein IIb/IIIa inhibitors have further decreased complications following both elective and emergent procedures. In addition, the man- agement of vascular access sites has changed in parallel. Today’s sheaths are smaller and removed earlier after PCI; less heparin is used during procedures; and new percutaneous closure devices have been developed that can reduce local bleeding complications. These factors have combined to improve procedural efficacy and reduce complications, and have rekindled enthusiasm among interventional cardiologists to perform adjunctive PCI following fibrinolysis.

The term “facilitated” PCI has been coined to signify the administration of a pharmacologic reperfusion regimen en route to the cardiac catheterization laboratory for “primary” PCI. The ration- ale for facilitated PCI is as follows. First, it is well known that patients who arrive in the catheter- ization laboratory with a patent IRA prior to “primary” PCI, due either to spontaneous fibrinolysis or to pharmacologic reperfusion, have an extraordinarily low risk for mortality (Fig. 10). Second, it is clear that a range of agents, including fibrinolytics (in full or reduced dosages), GP IIb/IIIa inhibitors, or their combination, increase the probability of early reperfusion. Finally, it is known that after initial, successful fibrinolytic therapy, reocclusion and reinfarction are common, in con- trast to primary PCI, which is associated with very low rates of reocclusion and reinfarction. There- fore, administration of a pharmacologic reperfusion regimen prior to primary PCI may increase the probability of reperfusion prior to PCI, minimizing myocardial necrosis and facilitating an excel- lent long-term result of PCI.

Results from the PACT trial support the safety of immediate PCI in the setting of fibrinolytic monotherapy (22). In this study, patients were randomized to either reduced-dose tPA or to placebo and were then taken immediately to cardiac catheterization, where angioplasty was performed unless TIMI 3 flow was found. Patients receiving tPA prior to catheterization had higher initial rates of TIMI grade 3 flow than those receiving placebo (32.8% vs 14.8%); after PCI, TIMI flow grade was similar between the two groups, indicating that tPA administration did not adversely impact procedural outcomes. Most importantly, there were no significant differences in bleeding or recurrent ischemic complications, suggesting that angioplasty could be performed safely imme- diately after a reduced dose of tPA.

Other investigators have evaluated combination reperfusion regimens (reduced-dose lytics and GP IIb/IIIa inhibitors) prior to PCI. In a substudy of the TIMI 14 trial described above, early adjunctive PCI appeared to improve tissue perfusion (as reflected in greater resolution of ST ele- vation) after combination therapy, but not after fibrinolytic therapy alone, suggesting that abciximab may prevent distal embolization at the time of PCI in the platelet- and fibrin-rich milieu character-

Fig. 10. Spontaneous reperfusion prior to primary PCI results in improved outcomes including less cardio-

genic shock, better preservation of left ventricular function, and reduced mortality. (Adapted from Brodie BR,

Stuckey TD, Hansen C, Muncy D. Benefit of coronary reperfusion before intervention on outcomes after pri-

mary angioplasty for acute myocardial infarction. Am J Cardiol 2000;85:13–18.)

istic of AMI. The SPEED investigators have shown that this “facilitated” approach (combination reperfusion therapy followed by PCI 60–90 min later) was associated with very high TIMI 3 flow rates and improved clinical outcomes (23). Patients treated with PCI after combination reperfusion therapy had significantly fewer episodes of recurrent MI and urgent revascularization without an increase in bleeding complications. It is important to acknowledge that the interventional strategy was not a randomized variable of the study. Selection bias, therefore, may explain part of the result.

A recent small randomized trial, the BRAVE study (24), evaluated whether early administration of the combination of half-dose reteplase plus abciximab produced better results compared with abciximab alone in patients with acute MI referred for PCI. The primary outcome measure was assessment of the final infarct size according to a single-photon emission computed tomography perfusion imaging performed between 5 and 10 d after randomization in the 228 patients studied.

As expected, patients who received combination therapy had higher coronary patency rates than those treated with abciximab alone (40% vs 18%, respectively) at the time of initial angiography.

This angiographic advantage, however, did not translate into improved myocardial salvage as mea- sured by nuclear scintigraphy. Moreover, bleeding rates were higher in the group receiving the com- bination of reteplase and abciximab prior to PCI. Other trials, including TIMI 14, GRAPE, TIGER PA, and RAPIER have shown have also suggested that GP IIb/IIIa inhibitors alone may be the best facilitation strategy prior to PCI. In each of these studies, administration of GP IIb/IIIa inhibitors in the emergency room resulted in significantly greater rates of TIMI grade 3 flow at the time of pri- mary PCI.

Several large randomized trials are now under way evaluating a number of different strategies of facilitated PCI, including GP IIb/IIIa inhibitors alone, fibrinolytic monotherapy, and combina- tion therapy with GP IIb/IIIa inhibitors and reduced-dose lytics. Until these trials have been com- pleted, only GP IIb/IIIa inhibitors should be considered for facilitated PCI. GP IIb/IIIa inhibitors are safe (they do not increase ICH), they improve reperfusion rates prior to PCI, and they may prevent microvascular injury post-PCI. Moreover, data from the ADMIRAL study (discussed above), in which glycoprotein IIb/IIIa was started prior to PCI, support the role for this agent in facilitated PCI.

Long-Term Antithrombotic Therapy A

In the setting of acute ST segment elevation MI, aspirin has been shown to decrease reocclusion after successful fibrinolysis by over 50%, reinfarction by nearly 50%, and mortality by 25% (25).

Aspirin should be given immediately on presentation (or preferably in the ambulance) in an oral dose of 160 to 325 mg daily. Following MI, aspirin also reduces subsequent cardiac events, a sec- ondary prevention benefit that has now been observed to persist for up to 4 yr of follow-up. Low- dose aspirin, 75 to 81 mg, is now preferred as it is associated with lower rates of bleeding. Thus, aspirin has had a dramatic effect in reducing adverse clinical events and thus constitutes primary therapy for all acute coronary syndromes.

C

Clopidogrel is a thienopyridine derivative that inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor, blocking ADP-mediated platelet activation and aggregation. This agent has replaced its sister drug ticlopidine as an adjunctive agent following coronary stenting due to its more favorable safety and side effect profile. Recent studies have shown that a longer duration (1 yr) of treatment with clopidogrel following coronary stenting is associated with lower recurrent ischemic event rates than the standard one month regimen. Moreover, in patients with non-ST elevation acute coronary syndromes, the combination of clopidogrel and aspirin, administ- ered for 3 to 12 mo, has been shown to reduce cardiac event rates vs therapy with aspirin alone (26).

Finally, among patients less than 75 yr of age who received fibrinolytic therapy and aspirin, the

addition of clopidogrel prevents early reocclusion and reinfarction, as well as mortality, and should

be considered as standard adjunctive therapy (26a).

W

/O

A

Results from a number of clinical trials suggest that warfarin monotherapy appears to be at least as effective as aspirin for secondary prevention post-MI. There are several circumstances in which the benefit or potential benefit with warfarin therapy exceeds that of aspirin. First, warfarin is superior to aspirin in preventing systemic emboli in patients with atrial fibrillation. In addition, warfarin has beneficial effects in reducing systemic emboli in patients post-MI with documented left ventricular dysfunction. Since there is a substantial risk of systemic embolization following a large anterior MI, even if thrombus is not visible on echocardiography, one should consider 3 to 6 mo of coumadin therapy in these patients if they are suitable candidates for anticoagulation.

However, in patients who have undergone primary stenting and are maintained on aspirin and clo- pidogrel, we do not recommend the concomitant administration of warfarin unless thrombus is visualized on echocardiography.

Studies have also evaluated the combination of warfarin and aspirin post-MI. Neither fixed- dose warfarin nor low dose warfarin titrated to an international normalized ratio (INR) of ~1.5 appears to be superior to monotherapy with either agent alone, and the combination is associated with excess bleeding risk (27). More recently, several studies have shown benefit for the combi- nation of low-dose aspirin and warfarin when the INR is maintained at a higher level consistently (28). However, these findings are of questionable significance in light of the results of the CURE trial, which has demonstrated similar benefits with a simpler regimen of aspirin and clopidogrel.

Thus, warfarin plus low-dose aspirin may be a good choice in patients who have another indication for anticoagulation (such as atrial fibrillation or prosthetic valve) provided the bleeding risk is low and a warfarin clinic is available for very careful monitoring.

Antiischemic Therapy



 



-B

-Blockers exert their beneficial effect in acute MI by preventing catecholamine-mediated 

activation, leading to decreased contractility and heart rate, thereby improving the balance between oxygen supply and demand. These drugs also exert an antiarrhythmic effect, as evidenced by an increase in the threshold for ventricular fibrillation in animals and a reduction in complex ventric- ular arrhythmias in humans. -Blockers may prevent plaque rupture by reducing the mechanical stresses imposed on the plaque. Finally, -blockers appear to attenuate adverse remodeling post- MI and prevent the development of heart failure.

-Blockers were among the first therapeutic interventions used to limit the size of an acute MI.

Administration of a -blocker very early following onset of acute MI decreases infarct size, recur-

rent MI, and mortality (Table 6). When -blockers have been used in conjunction with thrombo-

lytic therapy they provide incremental benefit, particularly if they can be administered early after

the onset of infarct symptoms. Tabulation of the results from the available studies indicates a highly

significant reduction of approx 30% in the incidence of sudden death and a nonsignificant reduc- tion of only about 12% in the incidence of non-sudden death. The fact that -blockers were partic- ularly effective in reducing sudden death again suggests that they exert much of their early beneficial effect by reducing the frequency and severity of arrhythmias. In addition, -blockers appear to significantly decrease the risk of cardiac rupture.

In addition to the early benefits of -blockers, when given long-term, these agents significantly reduce the incidence of nonfatal reinfarction and also reduce long-term mortality (Table 6) (29).

The benefits from routine beta-blocker use seem to persist as long as the active agent is continued and appear to extend to most patient subgroups. The long-term mortality benefits of the -blockers extend to most members of this class of agents. There does not seem to be a significant difference between agents with or without cardioselectivity. Considering the low cost of routine -blocker use and its substantial benefit, such therapy has a very favorable cost-effectiveness ratio and repre- sents one of the few “bargains” left in contemporary cardiology practice.

The Carvedilol Postinfarction Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial examined the incremental effect of -blockade (with carvedilol) in the post-MI setting over and above the effects of other established therapies, including ACE inhibitors. Over a 6-mo treat- ment period post-MI, the group treated with carvedilol had smaller LV volumes and improved LV ejection fraction and wall motion score index vs the placebo group. In addition, they also had a more favorable clinical course (30). Thus, -blockade appears to add favorable and independent effects on the post-MI remodeling process in the presence of ACE inhibition.

In summary, -blockers remain a cornerstone of treatment for acute MI. Treatment should be initiated intravenously, especially if it can be administered within 12 h of symptom onset followed by continuous oral therapy. -Blockers are consistently useful for secondary prevention following MI and should be maintained indefinitely.

N

The clinical effects of nitrates are mediated through several distinct mechanisms, including dila- tion of large coronary arteries and arterioles with redistribution of blood flow from epicardial to endocardial regions. Further, peripheral venodilation leads to an increase in venous capacitance and a substantial decrease in preload, thereby reducing myocardial oxygen demand. Finally, periph- eral arterial dilation, typically of a modest degree, may decrease afterload. In addition, nitrates have been shown to relieve dynamic coronary constriction caused by vasospasm. Nitrates may also have an inhibitory effect on platelet aggregation, though the clinical significance of this finding is unclear.

More recent studies have investigated the use of nitrate therapy in the setting of routine use of thrombolytic therapy and aspirin. The GISSI-3 trial (31) randomly assigned 19,394 patients to a 24-h infusion of nitroglycerin (beginning within 24 h of onset of pain), followed by topical nitro- glycerin (10 mg daily) for 6 wk (with patch removed at bedtime, allowing a 10-h nitrate-free interval to avoid tolerance), or placebo. There was a nonsignificant reduction in mortality at 6 wk in the group randomly assigned to nitrate therapy alone compared with the control group (6.5% vs 6.9%). The other large trial, ISIS-4 (32), compared 28-d treatment of controlled-release oral isosorbide mono- nitrate with placebo control in 58,050 patients with suspected MI. Nitrate therapy was not asso- ciated with a reduction in 35-d mortality compared with the control group (7.34% vs 7.54%; p = NS). In both GISSI-3 and ISIS-4, the power to detect potential beneficial effects of routine nitrate therapy was reduced by the extensive early use (greater than 50%) of off-protocol nitrates in patients in the control group.

A review of evidence from all pertinent randomized clinical trials does not support routine use

of intermediate or long-term nitrate therapy in patients with uncomplicated acute MI. However,

it is reasonable to use nitroglycerin for the first 24 to 48 h in patients with acute MI and recurrent

ischemia, CHF, or hypertension. Intravenous administration is recommended in the early stage

of acute MI because of its immediate onset of action, ease of titration, and the opportunity for prompt

termination in the event of side effects.

particularly in elderly patients with potentially serious adverse consequences. Sustained release preparations, on the other hand, appear to avoid these rapid hemodynamic changes and are safe when properly used. Amlodipine, a third-generation dihydropyridine agent, causes less reflex tachy- cardia than other dihydropyridines and usually has a neutral effect on heart rate. Dihydropyridines have been uniformly unsuccessful in reducing either mortality or the rate of reinfarction in mul- tiple trials. Thus, while sustained-release dihydropyridine preparations remain useful for treating hypertension, they should be used in AMI only when other evidence-based medications such as

-blockers, ACE inhibitors, and angiotensin receptor blockers have been exhausted.

Verapamil and diltiazem can be considered together because their net pharmacologic effect is that of slowing the heart rate and, to some extent, reducing myocardial contractility and myocardial oxygen demand. Of the two agents, verapamil has greater negative inotropic and chronotropic effects. A recent pooled analysis indicated that verapamil and diltiazem had no effect on mortality following acute MI (33). In patients with CHF or LV dysfunction, these agents have been associ- ated with an increase in mortality. Although diltiazem and verapamil have been shown to reduce nonfatal MI, it must be noted that these studies compared diltiazem and verapamil with placebo and not with a -blocker. Because -blockers consistently reduce both mortality and reinfarction, they are recommended for all patients who can tolerate such medications. Verapamil or diltiazem may be a reasonable alternative for those patients who cannot tolerate a -blocker provided they have no evidence of CHF and do not have severe LV dysfunction. It should be noted that many patients who cannot tolerate a -blocker because of concern of excessive bradycardia or CHF may experi- ence similar complications from diltiazem or verapamil.

A

R

–A

–A

S

Inhibiting the renin–angiotensin–aldosterone system (RAAS) has proven to be one of the most fruitful therapeutic strategies in cardiovascular medicine. Many therapies that have proven bene- ficial in heart failure patients have also shown benefit in patients following MI. This is in part due to the fact that a large percentage of heart failure patients are survivors of MI and that many of the neurohormonal systems—including the RAAS—that are activated in heart failure are also activated following infarction. Additionally, the RAAS has been implicated in healing and remod- eling following MI: angiotensin is directly involved in collagen synthesis and breakdown path- ways and may mediate post-MI tissue repair.

ACE inhibitors have become a mainstay in the treatment of patients with acute MI because they

prevent the deleterious left ventricular chamber remodeling and the progression of vascular pathol-

ogy. LV remodeling is characterized by alterations in ventricular mass, chamber size, and shape, all

of which result from myocardial injury, or pressure or volume overload. These processes, which

occur in the noninfarcted myocardium, contribute to progressive LV remodeling and LV dysfunc-

tion. Substantial experimental and clinical data exist that support the pivotal role of the RAAS in

contributing to these cellular processes.