The pain of acute MI is qualitatively similar to angina and is classically described as a severe pressure-type pain in the midsternum, often radiating to the left arm, neck, or jaw. Associated symptoms include dyspnea, diaphoresis, nausea, vomiting, and weakness. In the elderly and those with diabetes, pain is often atypical, and may not be present at all [4]. Not uncommonly, inferior STEMI presents with nausea and vagal symptoms rather than chest pain. Silent infarction may occur in 25% or more cases. Characterization of the quality of the pain may help to distinguish MI from other conditions that cause chest discomfort, such as aortic dissection, pulmonary embolism, pericarditis, and gastrointestinal (GI) disorders such as cholecystitis and peptic ulcer (Table 39.1).

Patients with acute MI often appear pale and clammy; in many cases, they are in obvious distress. Elderly patients, in particular, may be agitated and incoherent. In contrast, patients with cardiogenic shock may be confused and listless. The objective of the initial examination should be to rapidly narrow the differential diagnosis and assess the stability of the patient. A focused examination can help to differentiate ischemia from conditions such as pneumothorax, pericarditis, aortic dissection, and cholecystitis (Table 39.1). Concomitant conditions, such as valvular heart disease, peripheral vascular disease, and cerebrovascular disease, may complicate patient management and can be rapidly detected by physical examination. A brief survey for signs of congestive heart failure should be performed. Cool extremities or impaired mental status suggests decreased tissue perfusion, whereas elevated jugular venous pressure and rales suggest elevated cardiac filling pressures. Finally, the hemodynamic and mechanical complications of acute MI can often be detected by careful attention to physical findings.

An increasingly recognized syndrome that may mimic acute MI is Tako-Tsubo cardiomyopathy, or the apical ballooning syndrome. This syndrome, more common among elderly women, is typically precipitated by an acute stress, including severe emotional distress or acute noncardiac medical illness. Chest pain associated with anteroapical ST-segment elevation and T-wave inversions is usually indistinguishable from an evolving anterior infarct. The diagnosis is typically made when normal coronary arteries and the distinctive anteroapical wall motion abnormality (Fig. 39.1) are seen at the time of
emergent cardiac catheterization. In contrast to acute MI, cardiac enzymes usually elevate only modestly and the left ventricular (LV) functional abnormalities tend to be transient. The pathophysiology of this syndrome is thought to be due to catecholamine-mediated myocardial stunning.

Performance of the 12-lead ECG in the prehospital setting significantly reduces time to reperfusion and shows a strong trend toward reducing mortality [5]. Because only about 25% of patients with STEMI transported by emergency medical services in the United States receive a prehospital ECG, this represents an important target for improvement [5]. The ability to transmit the 12-lead ECG and activate a STEMI care team prior to hospital arrival has provided an opportunity for a major enhancement in systems for STEMI care.

The ST-segment elevation of acute MI must be distinguished from that due to pericarditis or even the normal early repolarization variant. Ischemic ST-segment elevation typically has a convex configuration, is limited to selected ECG leads, and is often associated with reciprocal ST-segment depression (Fig. 39.2). Pericarditis, on the other hand, is typically associated with diffuse ST-segment elevation and depression of the PR segment (Fig. 39.3). The contour of the elevated ST segment in pericarditis and early repolarization variant is typically concave (upward sloping), in contrast to that seen with myocardial injury. Reversible ischemic ST-segment elevation is also seen with coronary vasospasm (Prinzmetal’s variant angina).

A new (or presumed new) left bundle branch block (LBBB) in a patient with ischemic chest discomfort suggests a large
anterior infarction, and is also an indication for reperfusion therapy. A LBBB of unknown age, however, presents a diagnostic dilemma, because many of these patients do not have ongoing transmural myocardial ischemia. Here, emergent echocardiography (to look for an anterior wall motion abnormality); bedside testing of serum cardiac markers, such as myoglobin, CKMB, or troponin; and even emergent cardiac catheterization should be considered. It should be emphasized that an acute STEMI leading to LBBB requires a very large ischemic territory, and would not be expected to be a subtle clinical event. In patients with a preexisting LBBB, no ECG criteria are sufficiently sensitive and specific to diagnose acute MI [6], so alternative methods are needed to make the diagnosis.

Cardiac biomarkers of necrosis are considerably more important in the initial diagnosis of NSTEMI than they are in the diagnosis of STEMI. For patients with STEMI, cardiac marker measurements are used to confirm the diagnosis in patients with equivocal electrocardiographic changes, to help gauge prognosis, and to estimate the likelihood of successful reperfusion therapy. Cardiac markers also provide prognostic information. Patients with an elevated myoglobin, troponin, or B-type natriuretic peptide level prior to initiation of reperfusion therapy are at higher risk for death and congestive heart failure (CHF), even after accounting for baseline variables such as infarct location and time to treatment [7,8,9]. When combined with subsequent measures of the efficacy of reperfusion therapy, such as the degree of ST-segment resolution, an accurate assessment of prognosis can be made [8]. Although the rate of rise of cardiac biomarkers (particularly myoglobin) can be used to help determine which patients have had successful or unsuccessful reperfusion [10], the clinical role of biomarker testing for reperfusion assessment is limited. The peak levels of troponin, CK, or CKMB provide a crude estimation of infarct size. It should be noted that with successful reperfusion, although the total amount of biomarker released is reduced, the peak value may actually increase, with an earlier peak and more rapid fall in biomarker levels.

Information from the patient’s clinical presentation and physical examination are also very valuable for assessing the patient’s prognosis. Evidence for heart failure or hemodynamic stress at the time of presentation is weighted heavily in this assessment. For example, it is possible to use the patient’s age and vital signs at presentation to rapidly and accurately obtain a preliminary estimate of short-term survival [11]. Anterior infarct location, delays to therapy, and information regarding medical comorbidity all offer additional prognostic information [12]. As such, several tools that integrate age, the physical examination, the ECG, and other clinical parameters such as serum creatinine provide very strong discrimination of short- and long-term mortality risk, and may be implemented using either simple bedside calculation [12,13], handheld devices, or web-based tools [14,15] (Fig. 39.4).

Early successful coronary reperfusion limits infarct size and improves LV dysfunction 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 (TIMI grade 3) antegrade flow in the IRA had a 30-day mortality rate of 3.6%, versus 6.6% in patients
with slow (TIMI grade 2) antegrade flow, and 9.5% in patients with an occluded artery (TIMI grade 0 or 1 flow) [16].

Even among patients who achieve normal (TIMI grade 3) epicardial blood flow in the IRA after reperfusion therapy, however, tissue-level perfusion may be inadequate. Using a number of different diagnostic tools (Table 39.2), investigators have demonstrated that measures of tissue and microvascular perfusion provide prognostic information that is independent of TIMI flow grade [17] (Fig. 39.5). 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 blood flow after primary PCI: these patients were at increased risk for the development of CHF and death [18]. Impaired microvascular perfusion assessed with cardiac magnetic resonance imaging also correlates with higher mortality risk. Microvascular dysfunction is thought to occur in the setting of MI 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 ECG. Greater degrees of ST-segment resolution are associated with a higher probability of achieving a patent IRA and TIMI grade 3 flow [19]. Furthermore, patients who have normal epicardial blood flow, but persistence of ST-segment elevation on the 12-lead ECG, have been shown to have abnormal tissue and microvascular perfusion using a variety of specific imaging modalities such as contrast echocardiography and nuclear SPECT perfusion imaging [20,21]. In addition, persistent ST-segment elevation has been shown to predict poor recovery of infarct zone wall motion and the clinical endpoints of death and heart failure [22]. As a result, ST-segment resolution appears to integrate epicardial and myocardial (microvascular) reperfusion, and as such may actually provide a more clinically useful assessment of reperfusion than coronary angiography [23].

Regardless of the choice of reperfusion strategy, several common themes are evident. First, the benefits of reperfusion therapy are time dependent. Patients who receive fibrinolytic therapy within 1 hour from the onset of chest pain have an approximately 50% reduction in mortality, whereas those presenting more than 12 hours after onset of symptoms derive little, if any, benefit. For each hour earlier that a patient is treated, there is an absolute 1% decrease in mortality [24]. Similarly, for primary PCI, the “door-to-balloon” time has been shown to be directly correlated with clinical benefit [25].

The use of fibrinolytic therapy worldwide has decreased substantially. Nevertheless, fibrinolytic therapy remains the primary approach to reperfusion therapy in some countries and in some regions in the United States where there is no access to experienced centers for timely primary PCI.

Placebo-controlled trials using streptokinase, anistreplase (APSAC), and tissue plasminogen activator (tPA) established a clear benefit of fibrinolytic therapy for patients with STEMI. The Fibrinolytic Therapy Trialists’ overview of all the large placebo-controlled studies reported a 2.6% absolute reduction in mortality for patients with STEMI treated within the first 12 hours after the onset of symptoms [24]. This benefit has been shown to persist through 10 years of follow-up. Highlights of differences in dosing, pharmacokinetics, recanalization rates, and cost between agents are shown in Table 39.3.

Several mutant forms of tPA have been developed that have a prolonged half-life (to allow bolus administration), as well as increased fibrin specificity and resistance to endogenous inhibitors of plasminogen, such as PAI-1. Bolus administration may minimize the risk for dosing errors, decrease “door to needle” time, and allow for prehospital administration. Reteplase (rPA) is a double-bolus agent that was shown to have similar efficacy and bleeding risk to accelerated tPA in the GUSTO III trial [26]. In the ASSENT II trial, tenecteplase (TNK-tPA)—a single-bolus agent—was shown to be equivalent to tPA in terms of mortality and intracranial hemorrhage (ICH), but was associated with a lower rate of noncerebral bleeding complications [27]. The safety advantage of this agent may be due to its increased fibrin specificity and the fact that the dose is adjusted for body weight.

Although the bolus fibrinolytic agents have not been demonstrated in placebo-controlled trials to reduce mortality or ICH, they are easier to use and have largely replaced tPA for this reason in the United States. Tenecteplase appears to offer a modest advantage in safety over other agents. Readministration of streptokinase or anistreplase should be avoided for at least 4 years (preferably indefinitely) because potentially neutralizing antibodies may develop and because anaphylaxis can occur on reexposure to these drugs.

Fibrinolytic therapy is indicated as an option for reperfusion therapy in patients presenting within 12 hours of symptom onset if they have ST-segment elevation or new LBBB and no contraindications to lytic therapy (Table 39.4). Patients who are older than 75 years of age, those who present more than 12 to 24 hours after the onset of acute MI, and those who are hypertensive but present with high-risk MI have a less favorable balance of risk and potential benefit, but may be considered for treatment with a fibrinolytic therapy when primary PCI is not available. Patients should not be given fibrinolytic therapy if the time to treatment is longer than 24 hours or if they present only with ST-segment depression [28].

Current fibrinolytic regimens achieve patency (TIMI grade 2 or 3 flow) in approximately 80% of patients, but complete reperfusion (TIMI grade 3 flow) in only 50% to 60% of cases. In addition, as noted previously in the chapter, approximately one-third of patients with successful epicardial reperfusion have inadequate myocardial and microvascular reperfusion [18]. Finally, even after successful fibrinolysis, a 10% to 20% risk of reocclusion is present. Reocclusion and reinfarction are associated with a two- to threefold increase in mortality [29,30] (Fig. 39.6).

Bleeding is the most common complication of fibrinolytic therapy. Major hemorrhage occurs in 5% to 15% of patients. 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 0.5% to 0.9% of patients, but in clinical practice, where patient selection is less rigorous, rates are higher. Patients at particularly high risk for ICH include the elderly (particularly elderly females), patients with low body weight, and those who receive excessive doses of heparin.

Standard fibrinolytic therapy is directed at the fibrin-rich “red” portion of the coronary thrombus. Activated platelets are the critical component of the white portion of the arterial thrombus. Paradoxically, fibrinolytic agents directly and indirectly promote platelet activation [31], and activated platelets themselves contribute to fibrinolytic resistance by secreting PAI-1 and promoting clot retraction, thereby limiting penetration of the fibrinolytic agent into the thrombus. As a result of these observations, it was hypothesized that potent platelet inhibition with a GP IIb/IIIa inhibitor might augment the efficacy of fibrinolytic therapy.

Although a series of phase II studies comparing standard fibrinolytic therapy with various combinations of GP IIb/IIIa inhibitors and reduced doses of fibrinolytic agents suggested improved TIMI flow grade and ST-segment resolution with the combination regimens [32,33,34,35], definitive phase III trials revealed no convincing improvement in outcomes and an increase in ICH in the elderly with combination regimens [36,37]. Thus, despite initial promise, data do not support the use of GP IIb/IIIa inhibitor/fibrinolytic combinations as the primary reperfusion strategy for treatment of STEMI.

Because failure of fibrinolytic therapy is associated with high rates of morbidity and mortality, “rescue” PCI is frequently performed in such patients. Data to support rescue PCI in patients with an occluded infarct artery are limited, as tools to diagnose failed reperfusion are only modestly effective, and clinical trials evaluating rescue PCI have enrolled very slowly. In the MERLIN trial, 307 patients with ECG evidence of failed reperfusion (ST-segment resolution < 50% measured 60 minutes after fibrinolytic therapy) were randomized to rescue PCI or conservative therapy. Rescue PCI was performed an average of approximately 90 minutes after the qualifying ECG and was associated with a 26% reduction in the composite endpoint of death, reinfarction, stroke, heart failure, and revascularization at 30 days. However, mortality was not significantly reduced. The most recent study performed was the REACT trial, in which 427 patients with ECG evidence of failed fibrinolysis at 90 minutes were randomized to repeat fibrinolysis, conservative treatment, or rescue PCI. No benefit was observed for repeat fibrinolysis, but rescue PCI reduced the primary
endpoint of death, reinfarction, stroke, or severe heart failure at 6 months by 53%. Mortality was also reduced from 12.8% in the conservative therapy arm to 6.2% in the rescue PCI arm. We recommend urgent catheterization and PCI for all patients with persistent ST-segment elevation and ongoing chest pain 90 minutes after the administration of reperfusion therapy, unless they are at particularly low risk for complications (i.e., a young patient with an uncomplicated inferior MI). For patients who are pain free, but in whom the ST segments remain elevated, urgent catheterization should also be strongly considered, particularly if the patient has high-risk features, such as older age, anterior location of infarction, diabetes, or prior CAD.

In centers with adequate resources, experienced operators, and an institutional commitment to programmatic excellence, immediate or “primary” PCI has become the preferred reperfusion method for patients with STEMI. Randomized trials performed in both referral centers and experienced community hospitals have shown that primary PCI reduces the likelihood of death or MI when compared to fibrinolytic therapy [38]. Moreover, rates of major bleeding and stroke are also significantly lower with primary PCI than with fibrinolytic therapy (Fig. 39.7). 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 an increased ICH rate with fibrinolytic therapy). However, as with fibrinolytic therapy, rapid time to treatment is paramount to success [25]. In addition, while operator and institutional experience are critical to realize the full benefit of primary PCI, excellent results with primary PCI have been demonstrated in well-trained community hospitals without on-site cardiac surgery [39]. Current ACC/AHA guidelines recommend primary PCI over fibrinolytic therapy when it can be performed by experienced operators in experienced centers within 90 minutes of presentation. When the door-to-balloon time is expected to be longer than 90 minutes, fibrinolysis is generally preferred for patients presenting within 12 hours of symptom onset unless contraindications are present [28].

Advances in PCI technology have been rapidly translated from elective to emergent PCI. Compared with primary PTCA, primary stenting is associated with similar rates of death and reinfarction, but lower subsequent target vessel revascularization rates [40,41]. Initial fears about stent thrombosis when drug-eluting stents (DES) were placed in the setting of STEMI have not been realized, and recent studies demonstrate that the advantages of DES over bare metal stents (BMS) with regard to in-stent restenosis and target vessel revascularization extend to patients with STEMI [42,43]. One logistical issue merits comment regarding stent choice. It may be difficult in the setting of an evolving STEMI to determine whether a patient is a good candidate for at least 1 year of uninterrupted aspirin and thienopyridine therapy; a BMS would be preferred in situations where the clinician cannot make this determination.