ST-Elevation Myocardial Infarction: Management

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The care of patients with ST-elevation myocardial infarction (STEMI) has transformed in conjunction with the shift in approach to reperfusion therapy from primarily pharmacologic to catheter-based strategies. With simultaneous advances in medical therapy, the case-fatality rate for patients with STEMI has continued to decline ( Fig. 38.1 ). ^, Nevertheless, optimal management of patients at high risk for or with established major complications of STEMI remains critical to the care of this condition. A discussion of the management of STEMI can follow the clinical course of the patient. Chapter 25, Chapter 40 address primary and secondary prevention of coronary artery disease (CAD). Chapter 35 reviews the emergency evaluation of patients with chest pain. This chapter addresses treatment at the time of onset of STEMI (prehospital care, initial recognition and management in the emergency department (ED), and reperfusion), hospital management (medications, complications, and preparation for discharge), and early secondary prevention after STEMI. Chapter 41 discusses percutaneous coronary intervention (PCI) in patients with STEMI. Chapter 69 describes the use of implantable defibrillators for prevention of sudden cardiac death after myocardial infarction (MI). Chapter 40 discusses the long-term management of the patient with established stable ischemic heart disease, including patients with prior acute MI.

Prehospital Management

Given the progressive loss of functioning myocytes with persistent occlusion of the infarct-related artery in STEMI (see Chapter 37 ), initial management aims to restore blood flow to the infarct zone as rapidly as possible. Primary PCI is generally the preferred option, provided that an experienced operator and team can perform it in a timely fashion. ^, Missed opportunities for improvement in the care of STEMI include failure to deliver any form of reperfusion therapy in approximately 15% of patients and failure to minimize delays in reperfusion because of inefficient systems of care. ^, The “chain of survival” for STEMI involves a highly integrated strategy beginning with patient education about the symptoms of MI and early contact with the medical system, coordination of destination protocols in emergency medical service (EMS) systems, efficient practices in EDs to shorten door-to-reperfusion time, and expeditious implementation of the reperfusion strategy by a trained team. ^, The American Heart Association (AHA) has maintained a national initiative engineering improved health care delivery for STEMI, including implementation of systems that shorten total ischemic time while emphasizing overall quality of care for STEMI ( Tables 38.1 and 38.2 ).

TABLE 38.1

Criteria for a System of Care for ST-Elevation Myocardial Infarction (STEMI)

1.
The system should be registered with Mission: Lifeline.

2.
Ongoing multidisciplinary team meetings should occur, including EMS, non-PCI hospitals/STEMI referral centers, and PCI hospitals/STEMI receiving centers, to evaluate outcomes and quality improvement data. Operational issues should be reviewed, problems identified, and solutions implemented.

3.
Each STEMI system should include a process for prehospital identification and activation, destination protocols to STEMI receiving centers, and transfer for patients who arrive at STEMI referral centers and are primary PCI candidates, are ineligible for fibrinolytic therapy, and/or are in cardiogenic shock.

4.
Each system should have a recognized system coordinator, physician champion, and EMS medical director.

5.
Each system component (EMS, STEMI referral centers, and STEMI receiving centers) should meet the appropriate criteria.

EMS, Emergency medical services; PCI, percutaneous coronary intervention.

TABLE 38.2

Interventions to Improve Door-to-Device Times

From O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol . 2013;61:e78.

1.
A prehospital ECG for diagnosing STEMI is used to activate the PCI team while the patient is en route to the hospital.

2.
Emergency physicians activate the PCI team.

3.
A single call to a central page operator activates the PCI team.

4.
A goal is set for the PCI team to arrive at the catheterization laboratory within 20 min after being paged.

5.
Timely data feedback and analysis are provided to members of the STEMI care team.

ECG, Electrocardiogram; PCI, percutaneous coronary intervention, STEMI , ST-elevation myocardial infarction.

Prehospital Care

The prehospital care of patients suspected of having STEMI bears directly on the likelihood of survival. Most deaths associated with STEMI occur within the first hour of its onset and usually result from ventricular fibrillation (VF) (see Chapter 70 ). Therefore, immediate implementation of resuscitative efforts and rapid transportation of the patient to a hospital have prime importance. Major components of the time from the onset of ischemic symptoms to reperfusion include (1) the time for the patient to recognize the problem and seek medical attention; (2) prehospital evaluation, treatment, and transportation; (3) the time for diagnostic measures and initiation of treatment in the hospital (e.g., “door-to-device” time for patients undergoing a catheter-based reperfusion strategy and “door-to-needle” time for patients receiving a fibrinolytic agent); and (4) the time from initiation of treatment to restoration of flow.

Patient-related factors that correlate with a longer delay until deciding to seek medical attention include older age; female sex; black race; low socioeconomic or uninsured status; history of angina, diabetes, or both; consulting a spouse or other relative; and consulting a physician. ^, Health care professionals should heighten the level of awareness of patients at risk for STEMI (e.g., those with hypertension, diabetes, history of angina pectoris). They should use elective patient encounters to review and reinforce with patients and their families the need to seek urgent medical attention for a pattern of symptoms that includes chest discomfort, or dyspnea. Patients should also be instructed in the proper use of sublingual nitroglycerin and to call emergency services if the ischemic-type discomfort persists for more than 5 minutes.

Emergency Medical Service Systems

EMS systems have three major components: emergency medical dispatch, first response, and the EMS ambulance response (see Chapter 35 ). The expanded capability to record a prehospital 12-lead electrocardiogram (ECG) represents a major advance in EMS systems (see Table 38.2 ). ^, ^, The ability to transmit such ECGs and to activate the STEMI care team before arrival at the hospital places EMS efforts at the center of the early response to STEMI. Efforts to shorten the time until treatment of patients with STEMI include improvement in the medical dispatch component by expanding 911 coverage, providing automated external defibrillators to first responders, placing automated external defibrillators in critical public locations, and greater coordination of the EMS ambulance response. Well-equipped ambulances and helicopters staffed by personnel trained in the acute care of patients with STEMI allow definitive therapy to begin during transport to the hospital. Electronic transmission of the ECG to a medical control officer facilitates the triage of patients with STEMI ( Fig. 38.2 ).

FIGURE 38.2, System goals and initial reperfusion treatment of patients with STEMI. Reperfusion in STEMI patients can be accomplished by pharmacologic (fibrinolysis) or catheter-based (primary PCI) approaches and may involve transfer from a non-PCI-capable to a primary PCI-capable center. A, Patient transported by the emergency medical services (EMS). The STEMI systems goal is to maintain a network of transportation and destination hospitals so that the total ischemic time is kept to less than 120 minutes. In addition to this overall goal, three additional time objectives exist. (1) If the EMS has fibrinolytic capability and the patient qualifies for therapy, prehospital fibrinolysis may be considered and, if used, should be started within 30 minutes of arrival of the EMS on scene. (2) For patients transported to a non-PCI-capable hospital where a fibrinolytic is to be administered, the hospital door-to-needle time should be 30 minutes or less. (3) If the patient is transported to a PCI-capable hospital, the time from first medical contact (FMC) to deployment of the first PCI device (FMC-to-device time) should be 90 minutes or less. Patient self-transportation is discouraged. If the patient arrives at a non-PCI-capable hospital and a fibrinolytic is to be administered, the door-to-needle time should be 30 minutes or less. If the patient arrives at a PCI-capable hospital, the door-to-balloon time should be 90 minutes or less. The treatment options and time recommendations after arrival at the hospital are the same. Consideration of emergency interhospital transfer of the patient to a PCI-capable hospital for mechanical revascularization is also appropriate if the use of a fibrinolytic is contraindicated or PCI can be initiated promptly (anticipated FMC-to-device time ≤120 minutes) or if fibrinolysis is unsuccessful (i.e., “rescue PCI”). Secondary nonemergency interhospital transfer can be considered for recurrent ischemia or routine invasive evaluation 3 to 24 hours after fibrinolysis. B, Reperfusion strategies for patients with STEMI, regardless of whether they go to a PCI-capable or to a non–PCI-capable hospital. The optimal strategy depends on the timing of the onset of symptoms, the patient’s eligibility for fibrinolysis, and the options for timely transfer to a PCI-capable hospital. The denoted class I and class II recommendations are from the ACCF/AHA guidelines for the management of STEMI. For patients who receive fibrinolysis, noninvasive risk stratification is recommended to guide decisions regarding delayed coronary revascularization. CABG , Coronary artery bypass grafting.

In addition to prompt defibrillation, the efficacy of prehospital care appears to depend on several factors, including early relief of pain with its deleterious physiologic sequelae, reduction of excessive activity of the autonomic nervous system, and treatment of arrhythmias such as ventricular tachycardia (VT)—but these efforts must not delay rapid transfer to the hospital (see Fig. 38.2 ).

Prehospital Fibrinolysis

Multiple observational studies and several randomized trials have evaluated the potential benefits of prehospital versus in-hospital fibrinolysis. ^, Although none of the individual trials showed a significant reduction in mortality with prehospital-initiated fibrinolytic therapy, earlier treatment generally provides greater benefit, and a meta-analysis of all the available trials demonstrated a 17% reduction in mortality. ^, In the STREAM (Strategic Reperfusion Early After Myocardial Infarction) trial, prehospital fibrinolysis offered similar efficacy to primary PCI in 1892 patients with STEMI who presented within 3 hours of symptom onset and who could not undergo primary PCI within 1 hour of first medical contact. The primary endpoint of death, shock, heart failure, or reinfarction at 30 days occurred in 12.4% of the fibrinolysis arm and 14.3% in the primary PCI arm (p = 0.21) ( Fig. 38.3 ). Rescue or urgent PCI was required in 36% of patients initially receiving fibrinolysis, with the remainder undergoing coronary angiography per protocol a median of 17 hours after randomization. The rate of intracranial hemorrhage was higher in the fibrinolysis group (1.0% versus 0.2%, p= 0.04), but non-intracranial bleeding rates were similar between the treatment groups. Prehospital fibrinolysis is reasonable in settings in which substantial time can be saved by prehospital treatment because of long transportation times (60 to 90 minutes or longer), and physicians are present in the ambulance, or there is a well-organized EMS system with full-time paramedics who can obtain and transmit 12-lead ECG recordings from the field to an online medical command able to authorize prehospital fibrinolysis (see Fig. 38.2 ).

Management in the Emergency Department

When evaluating patients with chest pain in the ED, physicians must confront the difficult tasks of rapidly identifying patients who require urgent reperfusion therapy, triaging lower-risk patients to the appropriate setting within the hospital, and not discharging patients inappropriately while avoiding unnecessary admissions. A history of ischemic-type discomfort and the initial 12-lead ECG are the primary tools for screening patients with possible acute coronary syndrome (ACS) for STEMI (see Chapter 35 ). Because the 12-lead ECG is at the center of the decision pathway for initiation of reperfusion therapy, it should be obtained promptly (≤10 minutes after hospital arrival) in patients with suspected ischemic symptoms. More extensive use of prehospital 12-lead ECGs has also facilitated early triage of patients with STEMI. ^, ^, Because lethal arrhythmias can occur suddenly in patients with STEMI, all patients should have bedside monitoring of the ECG and intravenous (IV) access.

The presence of ST-segment elevation on the ECG in a patient with ischemic discomfort suggests thrombotic occlusion of an epicardial coronary artery and should trigger a well-rehearsed sequence of rapid assessment of the patient for initiation of a reperfusion strategy ( eFig. 38G.1 ). Critical factors that weigh into selection of a reperfusion strategy include the time elapsed since the onset of symptoms, the risk associated with STEMI, the time required to initiate an invasive strategy, and if that time is expected to be prolonged, the risk related to administering a fibrinolytic (see Fig. 38.2 ). In non-PCI-capable hospitals, the initial assessment should include evaluation of the contraindications to administration of a fibrinolytic ( Table 38.3 ). Patients with an initial ECG that reveals ST-segment depression and/or T wave inversion without ST-segment elevation are not considered candidates for immediate reperfusion therapy unless a posterior (or inferobasal) injury current is suspected (see Chapter 14 ).

TABLE 38.3

Contraindications to and Cautions in the Use of Fibrinolytics for Treating ST-Elevation Myocardial Infarction ∗

From O’ Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol . 2013;61:e78.

Absolute Contraindications

Any previous intracranial hemorrhage
Known structural cerebral vascular lesion (e.g., arteriovenous malformation)
Known malignant intracranial neoplasm (primary or metastatic)
Ischemic stroke within 3 months except acute ischemic stroke within 4.5 hr
Suspected aortic dissection
Active bleeding or bleeding diathesis (excluding menses)
Significant closed-head or facial trauma within 3 months
Intracranial or intraspinal surgery within 2 months
Severe uncontrolled hypertension (unresponsive to emergency therapy)
For streptokinase, previous treatment within the previous 6 months

Relative Contraindications

History of chronic, severe, poorly controlled hypertension
Significant hypertension at initial evaluation (SBP >180 mm Hg or DBP >110 mm Hg) ^†
History of previous ischemic stroke >3 months
Dementia
Known intracranial pathology not covered in Absolute Contraindications
Traumatic or prolonged (>10 min) cardiopulmonary resuscitation
Major surgery (<3 weeks)
Recent (within 2 to 4 weeks) internal bleeding
Noncompressible vascular punctures
Pregnancy
Active peptic ulcer
Oral anticoagulant therapy

DBP, Diastolic blood pressure; SBP, systolic blood pressure.

∗ Viewed as advisory for clinical decision making and may not be all-inclusive or definitive.

† Could be an absolute contraindication in low-risk patients with myocardial infarction.

Given the importance of time to reperfusion, emphasis has shifted to overall medical system goals, starting at the point of first medical contact with the patient. ^, ^, Benchmarks for medical systems to use when assessing the quality of their performance are a door-to-needle time of 30 minutes or less for initiation of fibrinolytic therapy and a door-to-device time of 90 minutes or less for percutaneous coronary perfusion (see Fig. 38.2 ). ^, In patients with a clinical history suggestive of STEMI (see Chapter 35 ) and an initial nondiagnostic ECG (i.e., no ST-segment deviation or T wave inversion), serial tracings should be obtained during evaluation in the ED. ED staff can seek the sudden development of ST-segment elevation by periodic visual inspection of the bedside electrocardiographic monitor, by continuous ST-segment recording, or by auditory alarms when the ST-segment deviation exceeds programmed limits. Decision aids such as computer-based diagnostic algorithms, identification of high-risk clinical indicators, rapid determination of cardiac biomarkers, and echocardiographic evaluation for regional wall motion abnormalities have the greatest clinical usefulness when the findings on the ECG are not diagnostic.

General Treatment Measures

Aspirin

Aspirin is effective across the entire ACS spectrum and is part of the initial management strategy for patients with suspected STEMI. Because low doses take several days to achieve a full antiplatelet effect, 162 to 325 mg should be administered at the first opportunity after initial medical contact. To achieve therapeutic blood levels rapidly, the patient should chew a non–enteric-coated tablet to promote buccal absorption bypassing the gastric mucosa.

Control of Cardiac Pain

Initial management of patients with STEMI should target relief of pain and its associated heightened sympathetic activity. Control of cardiac pain uses a combination of analgesics (e.g., morphine) and interventions to improve the balance of myocardial oxygen supply and demand, including oxygen (in the setting of hypoxia), nitrates, and in appropriately selected patients, beta-adrenergic receptor-blocking agents (beta blockers).

Analgesics

Although a wide variety of analgesic agents, including meperidine, pentazocine, and morphine, can treat the pain associated with STEMI, morphine remains the drug of choice, except in patients with well-documented morphine hypersensitivity. An initial dose of 4 to 8 mg can be administered intravenously initially, followed by doses of 2 to 8 mg repeated at intervals of 5 to 15 minutes until the pain is relieved or side effects emerge—hypotension, depression of respiration, or vomiting. Appropriate dosing of morphine sulfate will vary, however, depending on the patient’s age, body size, blood pressure (BP), and heart rate (HR).

Reduction of anxiety with successful analgesia diminishes the patient’s restlessness and the activity of the autonomic nervous system, with a consequent reduction in the heart’s metabolic demands, and possible favorable effects on myocardial healing (see Chapter 37 ). Morphine has beneficial effects in patients with pulmonary edema as a result of peripheral arterial and venous dilation (particularly in those with excessive sympathoadrenal activity); it reduces the work of breathing and slows the HR secondary to combined withdrawal of sympathetic tone and augmentation of vagal tone. Counterbalancing these potential benefits, observational studies have suggested an association between the administration of morphine and adverse outcomes in patients with ACS, with the putative mechanism being a slowing of antiplatelet agent absorption.

Maintaining the patient in a supine position and elevating the lower extremities if BP falls can minimize hypotension following the administration of nitroglycerin and morphine. Such positioning is undesirable in patients with pulmonary edema, but morphine rarely produces hypotension in these circumstances. IV administration of atropine may be helpful in treating excessive vagomimetic effects of morphine.

Nitrates

By virtue of their ability to enhance coronary blood flow by coronary vasodilation and to decrease ventricular preload by increasing venous capacitance, sublingual (SL) nitrates are indicated for most patients with an ACS. At present, the only groups of patients with STEMI in whom SL nitroglycerin should not be given are those with suspected right ventricular (RV) infarction or marked hypotension (e.g., systolic BP <90 mm Hg), especially if accompanied by bradycardia.

Once hypotension is excluded, an SL nitroglycerin tablet should be administered and the patient observed for improvement in symptoms or change in hemodynamics. If an initial dose is well tolerated and appears to be beneficial, further nitrates should be administered while monitoring vital signs. Even small doses can produce sudden hypotension and bradycardia, a reaction that can usually be reversed with IV atropine. Long-acting oral nitrate preparations should be avoided in the early course of STEMI because of the frequently changing hemodynamic status of the patient. In patients with a prolonged period of waxing and waning chest pain, continuous IV nitroglycerin infusion may help control the symptoms and lessen the ischemia, but this requires frequent BP monitoring. Initiation of a reperfusion strategy in patients with STEMI should not await assessing the patient’s response to SL or IV nitrates.

Beta-Adrenergic Blocking Agents

Beta blockers aid in the relief of ischemic pain, reduce the need for analgesics in many patients, and reduce infarct size and life-threatening arrhythmias. Avoiding early IV beta blockers in patients with Killip class II or greater is important, however, because of the risk of precipitating cardiogenic shock. Routine use of IV beta blockers is no longer recommended in patients with STEMI, but IV administration of a beta blocker at the initial evaluation of patients with STEMI who are hypertensive and have ongoing ischemia is reasonable.

A practical protocol for use of a beta blocker is the following. First, exclude patients with heart failure (HF), hypotension (systolic BP <90 mm Hg), bradycardia (HR <60 beats/min), or significant atrioventricular (AV) block. Second, administer metoprolol in three 5-mg IV boluses. Third, observe the patient for 2 to 5 minutes after each bolus, and if HR falls below 60 beats/min or systolic BP falls below 100 mm Hg, do not administer any further drug. Fourth, if hemodynamic stability continues 15 minutes after the last IV dose, begin oral metoprolol tartrate, 25 to 50 mg every 6 hours for 2 to 3 days as tolerated and then switch to 100 mg twice daily. Lower doses may be used in patients who have a partial decline in BP with the initial dosing or who appear to be at higher risk (e.g., larger infarction) for development of HF because of poor left ventricular (LV) performance. Infusion of an extremely short-acting beta blocker, such as esmolol, 50 to 250 μg/kg/min, may be useful in patients with relative contraindications to the administration of a beta blocker and in whom HR slowing is considered highly desirable.

Oxygen

Hypoxemia can occur in patients with STEMI and generally results from ventilation-perfusion abnormalities that are sequelae of LV failure; concomitant intrinsic pulmonary disease may also contribute to hypoxemia in some patients. Treating all patients hospitalized for STEMI with oxygen for at least 24 to 48 hours is an historical common practice based on the empiric assumption that increased oxygen in the inspired air may protect ischemic myocardium. However, augmentation of the fraction of oxygen in inspired air (F io ₂ ) does not elevate O ₂ delivery significantly in patients who are not hypoxemic. Furthermore, it may increase systemic vascular resistance and arterial pressure, promote coronary vasoconstriction, and result in greater oxidative stress. Moreover, in a randomized trial comparing oxygen (8 L/min) with no supplemental oxygen in 441 patients with STEMI but without hypoxia, compared with the control therapy, supplemental O ₂ therapy demonstrated a trend toward increased early myocardial injury measured with cardiac troponin. In a secondary analysis, O ₂ supplementation was associated with increased myocardial infarct size assessed by cardiac magnetic resonance imaging (CMR) at 6 months.

In view of these considerations, arterial oxygen saturation (Sa o ₂ ) can be estimated by pulse oximetry, and O ₂ therapy can be omitted if the oximetric findings are normal. On the other hand, patients with STEMI and arterial hypoxemia (e.g., Sa o ₂ <90%) should receive oxygen. ^, In patients with severe pulmonary edema, endotracheal intubation and mechanical ventilation may be necessary to correct the hypoxemia and reduce the work of breathing.

Limitation of Infarct Size

Infarct size is an important determinant of prognosis in patients with STEMI. Patients who succumb from cardiogenic shock generally exhibit either a single massive infarct or a moderate infarct superimposed on multiple previous infarctions. Survivors with large infarcts frequently exhibit late impairment of ventricular function, and their long-term mortality rate is higher than that of survivors with small infarcts. In view of the prognostic importance of infarct size, the possibility of modifying infarct size has attracted much experimental and clinical attention (see Chapter 37 ). Efforts to limit infarct size have used several different (sometimes overlapping) approaches: (1) early reperfusion, (2) reduction of myocardial energy demands, (3) manipulation of energy production sources in the myocardium, and (4) prevention of reperfusion injury. ^,

Dynamic Nature of Infarction

STEMI is a dynamic process that does not occur instantaneously but rather evolves over hours. The fate of jeopardized, ischemic tissue can be ameliorated by interventions that restore myocardial perfusion, reduce microvascular damage in the infarct zone, decrease myocardial oxygen requirements, inhibit accumulation or facilitate washout of noxious metabolites, augment the availability of substrate for anaerobic metabolism, or blunt the effects of mediators of injury that compromise the structure and function of intracellular organelles and constituents of cell membranes. Strong evidence in experimental animals and suggestive evidence in patients indicate that ischemic preconditioning, a form of endogenous protection against STEMI, before sustained coronary occlusion decreases infarct size and associates with a more favorable outcome, along with decreased risk for extension of infarction and recurrent ischemic events. Brief episodes of ischemia in one coronary vascular bed may precondition myocardium in a remote zone and thereby attenuate the size of infarction in the latter when sustained coronary occlusion occurs.

Perfusion of myocardium in the infarct zone appears to fall maximally immediately following coronary occlusion. Spontaneous recanalization of an occluded infarct-related artery occurs in up to one-third of patients beginning at 12 to 24 hours. This delayed spontaneous reperfusion may enhance LV function because it improves healing of infarcted tissue, prevents ventricular remodeling, and reperfuses hibernating myocardium. Yet, strategies involving pharmacologically induced and catheter-based reperfusion of the infarct vessel can maximize the amount of salvaged myocardium by accelerating the process of reperfusion and also implementing it in patients who would otherwise have a persistently occluded infarct-related artery. An overarching concept that applies to all methods of reperfusion is the critical importance of time. The earlier the infarct artery is reperfused, the greater the reduction in mortality ( Fig. 38.4 ).

FIGURE 38.4, Importance of time to reperfusion in patients undergoing fibrinolysis (A) or primary PCI (B) for STEMI. A, Graph based on data from 85,589 patients treated with fibrinolysis. A progressive increase in the in-hospital mortality rate occurs for every 30-minute delay. B, Based on data from 43,801 patients, this graph depicts the adjusted in-hospital mortality rate as a function of door-to-balloon time. Estimated mortality ranged from 3% with a door-to-balloon time of 30 minutes to 10.3% in patients with a door-to-balloon time of 240 minutes.

Additional factors that may limit infarct size during reperfusion include relief of coronary spasm, prevention of damage to the microvasculature, improved systemic hemodynamics (augmentation of coronary perfusion pressure and reduced LV end-diastolic pressure), and collateral circulation. Prompt implementation of measures designed to protect ischemic myocardium and support myocardial perfusion may provide sufficient time for the development of compensatory mechanisms that limit the ultimate extent of infarction (see Chapter 37 ). Interventions designed to protect the ischemic myocardium during the initial event may also reduce the extension of infarction or early reinfarction. An area of active investigation includes LV unloading with a microaxial LV assist device prior to revascularization, attempting to reduce LV oxygen demands and therefore minimize ischemia and reperfusion injury.

Routine Measures for Limitation of Infarct Size

Although timely reperfusion of ischemic myocardium is the most important intervention to limit infarct size, several routine measures to accomplish this goal apply to all patients with STEMI, regardless of whether they receive reperfusion therapy. The treatment strategies discussed in this section can be initiated at first medical contact and can be continued throughout the hospital phase of care.

Myocardial oxygen consumption should be minimized by maintaining the patient at rest both physically and emotionally and by using mild sedation and a quiet atmosphere—in addition to the interventions already discussed. Administration of adrenergic agonists should be avoided whenever possible. All forms of tachyarrhythmia require prompt treatment because they increase myocardial oxygen needs. HF should also be treated swiftly to minimize increases in adrenergic tone and hypoxemia (see later, Left Ventricular Failure). If ongoing ischemia occurs, severe anemia (hemoglobin <7 g/dL) can be corrected by the cautious administration of packed red blood cells, accompanied by a diuretic if there is any evidence of LV failure. Associated conditions, particularly infections and accompanying tachycardia, fever, and elevated myocardial oxygen needs, require management.

Reperfusion Therapy

General Concepts

Although late spontaneous reperfusion occurs in some patients, thrombotic occlusion persists in most patients with STEMI. Timely reperfusion of jeopardized myocardium is the most effective way of restoring the balance between myocardial oxygen supply and demand. The dependence of myocardial salvage on the time elapsed until treatment pertains to patients treated with either fibrinolysis or PCI ^, ( Fig. 38.5 ). The efficacy of fibrinolytic agents decreases as coronary thrombi mature over time. Analyses have identified a linear relationship between delay to revascularization with PCI and mortality (see Fig. 38.4 ), with a greater increase in mortality for a given delay in patients presenting with out-of-hospital cardiac arrest or cardiogenic shock.

FIGURE 38.5, The reduction in mortality as a benefit of reperfusion therapy is greatest in the first 2 to 3 hours after the onset of symptoms of acute MI, most likely a consequence of myocardial salvage. The exact duration of this critical early period may be modified by several factors, including the presence of functioning collateral coronary arteries, ischemic preconditioning, myocardial oxygen demands, and the duration of sustained ischemia. After this early period, the magnitude of the mortality benefit is much reduced, and as the mortality reduction curve flattens, time to reperfusion therapy is less critical. The magnitude of the benefit depends on how far up the curve the patient can be shifted. The benefit of a shift from point A or B to point C would be substantial, but the benefit of a shift from point A to point B would be small. This schematic illustrates how a treatment strategy that delays therapy during the early critical period, such as transfer of a patient for PCI with a long transportation time, could be harmful (shift from point D to point C or point B).

In some patients, particularly those with cardiogenic shock, tissue damage occurs in a “stuttering” manner rather than abruptly . This scenario underscores the need for careful history taking to ascertain whether the patient appears to have had repetitive cycles of spontaneous reperfusion and reocclusion. Determining the precise time of onset of the infarction process in these patients, however, can be difficult and sometimes misleading. In such patients with waxing and waning ischemic discomfort, a rigid time interval from the first episode of pain should not be used when determining whether a patient is “outside the window” for benefit from acute reperfusion therapy.

Pathophysiology of Myocardial Reperfusion

Prevention of cell death by restoration of blood flow depends on the severity and duration of the preexisting ischemia. Substantial experimental and clinical evidence indicates that the earlier blood flow is restored, the more favorable the recovery of LV systolic function, improvement in diastolic function, and reduction in overall mortality. Collateral coronary vessels also appear to influence LV function after reperfusion. They provide sufficient perfusion of myocardium to slow cell death and probably have greater importance in patients undergoing reperfusion later than 1 to 2 hours after coronary occlusion. Even after successful reperfusion and despite the absence of irreversible myocardial damage, a period of postischemic contractile dysfunction can occur—a phenomenon called myocardial stunning .

Reperfusion Injury

Reperfusion, although beneficial in terms of myocardial salvage, may cause adverse sequelae described by the term reperfusion injury (see Chapter 37 ). ^, Several types of reperfusion injury occur in experimental animals: (1) lethal reperfusion injury, which refers to reperfusion-induced death of cells that were still viable at restoration of coronary blood flow; (2) vascular reperfusion injury, which is progressive damage to the microvasculature such that there is an expanding area of no-reflow and loss of coronary vasodilatory reserve; (3) stunned myocardium, in which salvaged myocytes display a prolonged period of contractile dysfunction after restoration of blood flow because of abnormalities in intracellular metabolism, leading to reduced energy production; and (4) reperfusion arrhythmias, which refer to bursts of VT (and occasionally VF) that occur within seconds of reperfusion. ^, ^, Vascular reperfusion injury, stunning, and reperfusion arrhythmias can all occur in patients with STEMI. The concept of lethal reperfusion injury to potentially salvageable myocardium remains controversial, both in animals and in humans. ^,

Microvasculature damage in the reperfused myocardium can lead to a hemorrhagic infarct (see Chapter 37 ). Fibrinolytic therapy appears more likely than catheter-based reperfusion to produce hemorrhagic infarction. Although there is a theoretical concern that this hemorrhage may lead to extension of the infarct, this does not appear to be the case. Histologic study of patients not surviving despite successful reperfusion has revealed hemorrhagic infarcts, but this hemorrhage does not usually extend beyond the area of necrosis.

Protection Against Reperfusion Injury

A variety of adjunctive therapies have been proposed to mitigate the injury that occurs after reperfusion, including modulators of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) signaling, such as atrial natriuretic peptide, exenatide, and NO, and inhibitors of mitochondrial permeability and dysfunction, such as cyclosporine A. ^, Also, using antiplatelet agents and antithrombins to minimize embolization of atheroembolic debris, and prevention of subsequent inflammatory damage may serve to maintain microvascular integrity. However, with the exception of antithrombotic therapy, at present, none of these interventions are recommended for clinical practice.

The effectiveness of interventions directed against reperfusion injury appears to decline rapidly the later that they are administered after reperfusion. In animals, no beneficial effect is detectable after 45 to 60 minutes of reperfusion has elapsed. Transient ischemia produced in other vascular beds may also reduce reperfusion injury, a concept called remote ischemic conditioning (RIC). ^, Application of this concept to patients undergoing coronary artery bypass grafting (CABG), using repeated cycles of prolonged BP cuff inflation on the upper extremity, reduced perioperative myocardial injury but did not improve clinical outcomes in two randomized trials. Several studies have also identified a reduction in MI size in STEMI patients treated with RIC. However, in a large study of 5401 STEMI patients undergoing primary PCI (CONDI2/ERIC-PPCI; Effect of Remote Ischaemic Conditioning on Clinical Outcomes in STEMI Patients Undergoing PPCI), remote ischemic preconditioning did not decrease the incidence of cardiovascular death or hospitalization for heart failure. ^,

An alternative experimental approach to protection against reperfusion injury is called postconditioning , which involves introducing brief, repetitive episodes of ischemia alternating with reperfusion. ^, This appears to activate the cellular protective mechanisms centering around pro-survival kinases. Many of these protective kinases are also activated during ischemic preconditioning. Several clinical studies in patients with STEMI undergoing PCI have provided evidence that postconditioning associates with reduced infarct size and improvement in myocardial perfusion, but others have failed to show a benefit. ^, In a study of 1234 patients with STEMI and thrombolysis in MI (TIMI) flow grade 0 to 1, postconditioning failed to reduce the outcome of death or hospitalization for heart failure. Despite the intense interest in pre- and postconditioning, the current clinical data do not support adoption in routine practice.

Reperfusion Arrhythmias

Transient sinus bradycardia occurs in many patients with inferior infarcts at the time of acute reperfusion, often accompanied by some degree of hypotension. This combination of hypotension and bradycardia with a sudden increase in coronary flow may involve activation of the Bezold-Jarisch reflex. Premature ventricular contractions (PVCs), accelerated idioventricular rhythm, and nonsustained VT also usually follow successful reperfusion. Although some investigators have postulated that early afterdepolarizations participate in the genesis of reperfusion-related ventricular arrhythmias, they are present during both ischemia and reperfusion and therefore not likely to be involved in the development of reperfusion-associated VT or VF.

When present, rhythm disturbances may actually indicate successful restoration of coronary flow, but their specificity for successful reperfusion is limited. In general, clinical features are inaccurate markers of reperfusion, with no single clinical finding or constellation of findings being reliably predictive of angiographically demonstrated coronary artery patency. Although reperfusion arrhythmias may show a temporal clustering at restoration of coronary blood flow in patients after successful fibrinolysis, this brief “electrical storm” is generally innocuous and therefore does not warrant prophylactic antiarrhythmic therapy or specific treatment, except in rare cases of symptomatic or hemodynamically significant reperfusion arrhythmias.

Late Establishment of Patency of the Infarct Vessel

The improved survival and ventricular function after successful reperfusion may not result entirely from limitation of infarct size. Poorly contracting or noncontracting myocardium in a zone that is supplied by a stenosed infarct-related artery with slow anterograde perfusion may still contain viable myocytes. PCI can augment flow in the infarct-related artery and thus improve the function of hibernating myocardium.

Fibrinolysis

Although catheter-based reperfusion strategies for STEMI are preferable, when access is delayed or in practice environments where an invasive strategy is impractical, successful fibrinolysis can reduce infarct size and improves myocardial function and survival over both the short and the long term. Therefore, if the time from first medical contact to performing primary PCI is anticipated to exceed 120 minutes, administration of a fibrinolytic is indicated for the treatment of STEMI within 12 hours of onset in the absence of contraindications (see eFig. 38G.1 ). Patients treated within the first 1 to 2 hours after the onset of symptoms seem to have the greatest potential for long-term improvement in survival with fibrinolysis.

Assessment Of Reperfusion

Thrombolysis in Myocardial Infarction (TIMI) Flow Grade

To provide a level of standardization both for clinical communication and for studies comparing various reperfusion regimens, most clinicians and investigators describe the flow in the infarct vessel according to the TIMI trial grading system ( eFig. 38.1 ). However, an angiographic snapshot in time does not reflect the fluctuating status of flow in the infarct vessel, which may undergo repeated cycles of patency and reocclusion before or during fibrinolysis. When assessed 60 to 90 minutes after the start of fibrinolytic therapy, the finding of TIMI grade 3 flow is far superior to grade 2 in terms of the reduction of infarct size and both short-term and long-term mortality benefit. Therefore, TIMI grade 3 flow should be the goal for achieving reperfusion of the epicardial infarct artery (see eFig. 38.1 ).

eFIGURE 38.1, Correlation of TIMI (thrombolysis in myocardial infarction) flow grade and mortality. A pooled analysis of data from 5498 patients in several angiographic trials of reperfusion for STEMI showed a gradient of mortality when the angiographic findings were stratified by TIMI flow grade. Patients with TIMI 0 or TIMI 1 flow had the highest rate of mortality, TIMI 2 flow associated with an intermediate rate of mortality, and the lowest rate of mortality was observed in patients with TIMI 3 flow.

Thrombolysis in Myocardial Infarction (TIMI) Frame Count

To provide a more quantitative statement of the briskness of coronary blood flow in the infarct artery and to account for differences in the size and length of vessels (e.g., left anterior descending versus right coronary artery) and interobserver variability, Gibson and coworkers developed the TIMI frame count—a simple count of the number of angiographic frames elapsed until the contrast material arrives in the distal bed of the vessel of interest. This objective and quantitative index of coronary blood flow independently predicts in-hospital mortality from STEMI and also separates patients with TIMI grade 3 flow into low-risk and high-risk groups. The TIMI frame count can also be used to quantitate coronary blood flow (mL/sec), as calculated by:

21 \div (Observed TIMI frame count) \times 1.7

$21 \div (Observed TIMI frame count) \times 1.7$

based on Doppler velocity wire data showing that normal flow equals 1.7 cm ³ /sec, which 21 frames encompass. The calculated coronary perfusion relates to mortality in patients treated with fibrinolytics or primary PCI and can be used to assess various modalities for reperfusion in patients with STEMI.

Myocardial Perfusion

Even patients with TIMI grade 3 flow in the culprit artery may not always achieve adequate myocardial perfusion ( eFig. 38.2 ), especially if the delay between the onset of symptoms and restoration of epicardial flow is long. The terms myocardial “no-reflow” and “coronary microvascular obstruction” describe a state of reduced myocardial perfusion after the opening of an epicardial infarct-related artery. The four major impediments to normalization of myocardial perfusion are ischemia-related injury, reperfusion-related injury, distal embolization, and individual susceptibility of the microcirculation to injury ( Fig. 38.6 ). Obstruction of the distal microvasculature in the downstream bed of the infarct-related artery results from platelet or microparticle microemboli and thrombi. Fibrinolysis may exacerbate microembolization of platelet aggregates because of the exposure of clot-bound thrombin, an extremely potent platelet agonist. Spasm can also occur in the microvasculature as a result of the release of substances from activated platelets. Reperfusion injury results in endothelial cell edema, production of reactive oxygen species, and calcium overload. In addition, endothelial activation leads to the accumulation of neutrophils and inflammatory mediators that contribute to tissue injury. Interstitial edema from ischemia and reperfusion injury can compress intramyocardial vessels, further compromising perfusion. Several techniques can evaluate the adequacy of myocardial perfusion.

FIGURE 38.6, Multiple mechanisms involved in the pathogenesis of no-reflow that might be targeted by appropriate therapy. ET , Endothelin; TXA 2 , thromboxane A 2 .

EFIGURE 38.2, Points of possible failure of reperfusion therapy. Complete reperfusion requires successful restoration of normal flow in both the epicardial coronary artery and the distal coronary microvasculature, termed myocardial tissue-level reperfusion . Failure of epicardial reperfusion can result from failure to induce a lytic state or from persistent mechanical obstruction at the site of occlusion. Failure of microvascular reperfusion is caused by a combination of platelet microthrombi followed by endothelial swelling and myocardial edema (“no-reflow”). Reperfusion may fail because of persistent occlusion of the epicardial infarct-related artery (TIMI grades 0 and 1), patency of an epicardial artery in the presence of impaired (TIMI grade 2) flow, or microvascular occlusion in the presence of angiographically normal (TIMI grade 3) flow. Successful reperfusion requires a patent artery with an intact microvascular network.

Electrocardiography

Electrocardiographic ST-segment resolution, when present, has a high positive predictive value (PPV) of greater than 90% for infarct artery patency with, but persistent ST-segment elevation (i.e., lack of ST-segment resolution) is a poor predictor of infarct-related artery occlusion, with a negative predictive value (NPV) of approximately 50%. However, the persistence of ST-segment elevation after angiographically successful primary PCI identifies patients with a higher risk for LV dysfunction and mortality, presumably because of microvascular damage in the infarct zone. Thus, the 12-lead ECG can reflect the biologic integrity of myocytes in the infarct zone and indicate inadequate myocardial perfusion even in the presence of TIMI grade 3 flow. The extent of ST-segment resolution provides powerful prognostic information early in the management of patients with STEMI.

Noninvasive Imaging

Defects in perfusion patterns seen with contrast-enhanced echocardiography correlate with regional wall motion abnormalities and lack of myocardial viability on dobutamine stress echocardiography (see Chapter 16 ). Contrast-enhanced CMR can also identify regions of microvascular obstruction that associate with an adverse long-term prognosis (see Chapter 19 ).

Invasive Assessment

Doppler flow wire studies can also define abnormalities in myocardial perfusion. In addition, Gibson and colleagues developed an angiographic method for assessing myocardial perfusion: the TIMI myocardial perfusion (TMP) grade ( eFig. 38.3 ). Abnormalities associated with increased myocardial perfusion, as assessed by the TMP grade, correlate with unfavorable ventricular remodeling and risk for mortality, even after adjusting for the presence of TIMI grade 3 flow or a normal TIMI frame count.

EFIGURE 38.3, Relationship between angiographic assessment of myocardial tissue-level reperfusion categorized by TIMI myocardial perfusion (TMP) grade and mortality. TMP grade 0 or no perfusion of the myocardium is associated with the highest rate of mortality. If a stain of the myocardium is present (grade 1), mortality is also high. A reduction in mortality is seen if the dye enters the microvasculature but is still persistent at the end of the washout phase (grade 2). The lowest mortality rate is observed in patients with normal perfusion (grade 3), with the dye being minimally persistent at the end of the washout phase.

Effect of Fibrinolytic Therapy on Mortality

Early IV fibrinolysis improves survival in patients with STEMI. The Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group performed a comprehensive overview of nine trials of fibrinolytic therapy, and each of which enrolled more than 1000 patients. The overall results indicated an 18% reduction in short-term mortality, but as much as a 25% reduction in mortality in the subset of 45,000 patients with ST-segment elevation or bundle branch block ( eFig. 38.4 ). Two trials, LATE (Late Assessment of Thrombolytic Efficacy) and EMERAS (Estudio Multicéntrico Estreptoquinasa Repúblicas de América del Sur), when viewed together provide evidence that a reduction in mortality may still be observed in patients treated with thrombolytic agents between 6 and 12 hours after the onset of ischemic symptoms. These data form the basis for extending the window of treatment with fibrinolytics up to 12 hours after the onset of symptoms. Pooled analysis from more than 10 trials across six time categories from the onset of symptoms to randomization demonstrates a nonlinear relationship of treatment benefit to time, with the best outcome occurring in the first 1 to 2 hours after the onset of symptoms.

EFIGURE 38.4, Differences in mortality during days 0 to 35, subdivided by initial features, in a collaborative overview of results from nine trials of thrombolytic therapy. Absolute mortality rates are shown for the fibrinolytic and control groups in the center of the figure for each of the clinical features at the initial encounter, listed on the left side of the figure. The ratio of the odds of death in the fibrinolytic group to that in the control group is shown for each subdivision (colored squares), along with its 99% confidence interval (CI) (horizontal line). The summary odds ratio (OR) at the bottom of the figure corresponds to an 18% proportional reduction in 35-day mortality and is highly statistically significant. BBB, Bundle branch block; BP, blood pressure; SD, standard deviation.

The effect of fibrinolytic therapy on mortality in elderly patients has been controversial. Although patients older than 75 years were initially excluded from randomized trials of fibrinolytic therapy, they ultimately comprised approximately 15% of those studied in trials of fibrinolysis and 35% of those analyzed in registries of patients with STEMI. Barriers to initiation of therapy in older patients with STEMI include a protracted period of delay in seeking medical care, a lower incidence of ischemic discomfort and greater incidence of atypical symptoms and concomitant illnesses, and an increased incidence of nondiagnostic findings on the ECG. ^, Younger patients with STEMI achieved a slightly greater relative reduction in mortality than elderly patients, but the higher absolute mortality in elderly patients yielded similar absolute reductions in mortality (see eFig. 38.4 ). The STREAM (Strategic Reperfusion Early After Myocardial Infarction) study comparing an early pharmacoinvasive strategy to primary PCI found that a half-dose of tenecteplase had similar efficacy with lower rates of intracranial hemorrhage in patients 75 years or older. ^, This regimen, which has been incorporated into guidelines, is being studied in an expanded population of patients 60 years or older in the STREAM-2 trial.

Several models have integrated the many clinical variables available before the administration of fibrinolytic therapy that are associated with a patient’s risk for death. A convenient, simple, bedside risk-scoring system predicts 30-day mortality at initial evaluation of fibrinolytic-eligible patients with STEMI ( eFig. 38.5 ). Modeling of mortality risk cannot cover all clinical scenarios, however, and should only supplement clinical judgment in individual cases. For example, patients with inferior STEMI who might otherwise be considered to have a low risk for mortality, and for whom many physicians have questioned the benefits of fibrinolytic therapy, might be in a higher mortality risk subgroup if their inferior infarction is associated with RV infarction, precordial ST-segment depression, or ST-segment elevation in the lateral precordial leads. The short-term survival benefit enjoyed by patients who receive fibrinolytic therapy endures after 1 to 10 years. Advances in adjunctive antiplatelet and antithrombin therapies have led to reductions in the rate of reinfarction after fibrinolysis for STEMI.

eFIGURE 38.5, TIMI risk score for STEMI predicting 30-day mortality. h/o , History of; HTN , hypertension; LBBB , left bundle branch block.

Comparison of Fibrinolytic Agents

Table 38.4 presents the comparative features of the approved fibrinolytic agents for IV therapy. All fibrinolytic agents exert their effect by converting the proenzyme plasminogen to the active enzyme plasmin. The so-called fibrin-specific fibrinolytics are those that are relatively inactive in the absence of fibrin but in its presence substantially increase their activity on plasminogen (see Chapter 95 ). The tissue plasminogen activator (t-PA) molecule contains five domains ( eFig. 38.6 ). In the absence of fibrin, t-PA is a weak plasminogen activator; fibrin provides a scaffold on which t-PA and plasminogen are held in such a way that the catalytic efficiency of t-PA increases many-fold. A dose regimen of t-PA administered over a 90-minute period produces more rapid thrombolysis than a 3-hour fixed-rate infusion. Therefore, the recommended dosage for t-PA is the 90-minute “accelerated” regimen. Modifications in the native t-PA structure have yielded a group of fibrinolytic agents with prolonged clearance that allows them to be administered as a bolus (see eFig. 38.6 and Table 38.4 ). Reteplase (double fixed-dose bolus) and tenecteplase (single weight-based bolus) confer mortality benefits similar to that achieved with accelerated t-PA, but with more convenient dosing. In one large trial, tenecteplase had a lower rate of major bleeding than accelerated t-PA or other regimens. Streptokinase, a protein derived from streptococci, binds and activates human plasminogen and is an inexpensive and effective fibrinolytic agent that is still used in some regions of the world.

TABLE 38.4

Comparison of Approved Fibrinolytic Agents

Fibrinolytic Agent	Dose	Fibrin Specificity ∗	Fibrinogen Depletion	Antigenic	Patency Rate (90-min Timi 2 OR 3 Flow)
Fibrin Specific
Tenecteplase (TNK)	Single IV weight-based bolus ^†	++++	Minimal	No	85%
Reteplase (r-PA)	10 units + 10-unit IV boluses given 30 min apart	++	Moderate	No	84%
Alteplase (t-PA)	90-min weight-based infusion ^‡	++	Mild	No	73–84%
Non-Fibrin Specific
Streptokinase ^§	1.5 million units IV given over 30–60 min	No	Marked	Yes ^¶	60–68%

r-PA, Reteplase plasminogen activator; t-PA, tissue plasminogen activator.

∗ Strength of fibrin specificity: ++++ is stronger; ++ is less strong.

† Bolus of 30 mg for weight less than 60 kg, 35 mg for 60 to 69 kg, 40 mg for 70 to 79 kg, 45 mg for 80 to 89 kg, and 50 mg for 90 kg or greater.

‡ Bolus of 15 mg, infusion of 0.75 mg/kg for 30 minutes (maximum, 50 mg), then 0.5 mg/kg (maximum, 35 mg) over the next 60 minutes; the total dose not to exceed 100 mg.

§ Streptokinase is no longer marketed in the United States but is available in other countries.

¶ Streptokinase is highly antigenic and absolutely contraindicated within 6 months of previous exposure because of the potential for serious allergic reaction.

EFIGURE 38.6, Molecular structure of alteplase (t-PA), reteplase (r-PA), and tenecteplase (TNK). Streptokinase (SK) is the least fibrin-specific thrombolytic agent in clinical use; the progressive increase in relative fibrin specificity for the various thrombolytics is shown at the bottom. See also Fig. 95.16.

The choice of fibrinolytic in hospital systems is generally driven by the desire to establish consistent protocols within the health care system by weighing ease of dosing, cost, and other institutional preferences. In patients seen early with acceptable bleeding risk, a high-intensity fibrin-specific regimen, such as accelerated t-PA, reteplase, or tenecteplase, is usually preferable. Bolus fibrinolytics have a lower chance of medication errors and are associated with less noncerebral bleeding—as well as offering the potential for prehospital treatment. ^,

Effect on Left Ventricular Function

As with survival, improvement in global LV function is related to the time of initiation of fibrinolytic treatment, with the greatest improvement occurring with the earliest therapy. Nevertheless, left ventricular ejection fraction (LVEF) is not adequate as a surrogate for infarct size because little difference is seen in EF between groups that show a significant difference in mortality. However, patients with smaller end-systolic volumes and better-preserved ventricular shape have better survival. The myocardial salvage index is defined as the difference between the initial perfusion defect (e.g., by CMR or sestamibi scintigraphy) and the final perfusion defect. ^, CMR can characterize LV volumes, the extent of the scar by gadolinium delayed hyperenhancement, and the presence of ischemia with stress perfusion imaging, providing significant incremental prognostic information over other clinical variables. ^,

Complications of Fibrinolytic Therapy

Bleeding complications are most common, and intracranial hemorrhage is the most serious complication of fibrinolytic therapy; its frequency is generally less than 1% but varies with the clinical characteristics of the patient and the fibrinolytic agent used ( Fig. 38.7 ). Intracranial bleeding in the setting of fibrinolysis for STEMI is associated with a high case-fatality rate. Nonintracranial bleeding can also increase morbidity, but whether it causes higher overall mortality after taking into account the higher-risk clinical characteristics that also predispose patients to bleeding during treatment of STEMI is uncertain. ^,

FIGURE 38.7, Estimation of risk for intracranial hemorrhage (ICH) with fibrinolysis. Common risk factors include increased age, low body weight, and hypertension on admission. See reference for further discussion.

Reports have demonstrated an “early hazard” with fibrinolytic therapy—that is, an excess of deaths in the first 24 hours in fibrinolytic-treated patients compared with controls, especially in elderly patients treated more than 12 hours after symptom onset. However, this excess early mortality is more than offset by deaths prevented beyond the first day, with an average 18% (range, 13% to 23%) reduction in mortality by 35 days compared with offering no reperfusion therapy. The mechanisms responsible for this early hazard are probably multiple, including an increased risk for myocardial rupture, fatal intracranial hemorrhage, and possibly myocardial reperfusion injury.

Recent exposure to streptococci or streptokinase produces some degree of antibody-mediated resistance to streptokinase (and anistreplase) in most patients. Although such resistance is only rarely of clinical consequence, patients should not receive streptokinase for STEMI if they have been treated with a streptokinase product within the past 6 months.

Late Therapy

No mortality benefit was demonstrated in the LATE and EMERAS trials when fibrinolytics were routinely administered to patients between 12 and 24 hours, although we believe that it is still reasonable to consider fibrinolytic therapy when PCI is not available for appropriately selected patients with clinical and electrocardiographic evidence of ongoing ischemia within 12 to 24 hours of symptom onset and a large area of myocardium at risk or hemodynamic instability. Because elderly patients treated with fibrinolytic agents more than 12 hours after the onset of symptoms have an increased risk for cardiac rupture, we believe that restricting late administration of a fibrinolytic to patients younger than 65 years with ongoing ischemia is preferable. An elderly patient with ongoing ischemic symptoms but initially seen late (>12 hours) is better managed with PCI than with fibrinolytic therapy.

Intracoronary Fibrinolysis

In contemporary practice, patients are more likely to be treated with PCI. This evolution has revived the concept of delivering fibrinolytic agents by the intracoronary route, but current efforts are largely restricted to adjunctive use during complicated PCI procedures.

Catheter-Based Reperfusion Strategies

Catheter-based strategies can also achieve reperfusion of the infarct artery. This approach has evolved from passage of a balloon catheter over a guidewire in the culprit vessel only to now include potent oral antiplatelet therapy, multiple options for anticoagulants, and coronary stents, with the possibility of multivessel revascularization. PCI used as primary reperfusion therapy in patients with STEMI is referred to as direct or primary PCI (see Fig. 38.2 and eFig. 38G.1 ). The approach to primary PCI, including device selection, the technical approach to percutaneous revascularization, and decision making regarding nonculprit vessel disease are discussed in more detail in Chapter 41 . As an alternative to pharmacologic reperfusion therapy, primary PCI has evolved significantly. Several randomized trials have suggested that a strategy of multivessel PCI, either at the time of primary PCI or as a planned, staged procedure, may be safe and may improve outcomes in hemodynamically stable patients with STEMI ( Fig. 38.8 ). These findings have prompted a change in recommendation from class III to IIa or IIb for consideration of multivessel PCI in stable patients with STEMI. However, in patients with cardiogenic shock, immediate revascularization of only the infarct artery at the time of initial presentation is preferred based on improved outcomes for the composite of death or the need for renal replacement therapy in the CULPRIT-SHOCK study. Aspiration thrombectomy at primary PCI has a class III recommendation based on trial data showing no improvement in cardiovascular (CV) outcomes and a possible increase in stroke risk. ^, ^, ^, Radial artery access is favored over femoral artery access in primary PCI based on the MATRIX (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of AngioX) trial, which demonstrated a reduction in bleeding and mortality ( Fig. 38.9 ). ^, Finally, newer-generation drug-eluting stents (DESs) appear to result in lower rates of repeat revascularization with equivalent or lower rates of stent thrombosis compared to contemporary bare-metal stents (BMSs).

FIGURE 38.8, Meta-analysis of randomized controls trials comparing culprit-vessel only PCI and complete revascularization in patients with STEMI without shock for the endpoints of (A) cardiovascular death and (B) myocardial infarction. Compare Acute indicates Fractional Flow Reserve–Guided Multivessel Angioplasty in Myocardial Infarction; COMPLETE, Complete versus Culprit‐Only Revascularization Strategies to Treat Multivessel Disease after Early PCI for STEMI; CvLPRIT, Complete Versus Lesion‐Only Primary PCI trial; DANAMI 3 PRIMULTI, Complete revascularisation versus treatment of the culprit lesion only in patients with ST‐segment–elevation myocardial infarction and multivessel disease; PRAMI, Preventive Angioplasty in Acute Myocardial Infarction.

FIGURE 38.9, Comparison of radial versus femoral access for PCI in STEMI in the MATRIX study for the co-primary endpoints of (A) all-cause mortality, myocardial infarction or stroke and (B) all-cause mortality, myocardial infarction, stroke, or Bleeding Academic Research Consortium type 3 or 5 bleeding.

eFIGURE 38G.1, Reperfusion therapy for patients with ST-segment elevation myocardial infarction (STEMI). The bold arrows and boxes are the preferred strategies. Performance of percutaneous coronary intervention (PCI) is dictated by an anatomically appropriate culprit stenosis. ∗Patients with cardiogenic shock or severe heart failure initially seen at a non-PCI-capable hospital should be transferred for cardiac catheterization and revascularization as soon as possible, irrespective of the delay in time after the onset of MI (class I; LOE: B). † Angiography and revascularization should not be performed within the first 2 to 3 hours after the administration of fibrinolytic therapy. CABG, Coronary artery bypass graft surgery; DIDO, door in–door out; FMC, first medical contact.

Surgical Reperfusion

Providing surgical reperfusion in a timely fashion during STEMI is usually not logistically possible. Therefore, patients with STEMI who are candidates for reperfusion should undergo either immediate PCI or if not practical then fibrinolysis. However, patients with STEMI may be referred for CABG for persistent or recurrent ischemia after fibrinolysis or primary PCI with residual coronary disease not amenable to PCI, high-risk coronary anatomy (e.g., left main stenosis) discovered at initial catheterization or a complication of STEMI such as ventricular septal rupture or severe mitral regurgitation caused by papillary muscle dysfunction. STEMI patients with continued severe ischemic and hemodynamic instability will probably benefit from emergency revascularization.

Patients who successfully undergo fibrinolysis but have important residual stenoses and on anatomic grounds are more suitable for surgical revascularization than for PCI have undergone CABG with quite low rates of mortality (approximately 4%) and morbidity, provided that the procedure is carried out more than 24 hours after STEMI; patients requiring urgent or emergency CABG within 24 to 48 hours of STEMI have mortality rates between 12% and 15%. Surgery performed under urgent conditions with active and ongoing ischemia or cardiogenic shock, are associated with higher operative mortality rates, in large part reflecting the patient’s overall condition that necessitated emergency surgery.

Selection of Reperfusion Strategy

When performed rapidly after arrival at an experienced center, primary PCI is superior to pharmacologic reperfusion therapy. ^, However, registry and randomized data remind us that very early fibrinolysis may be at least as effective as primary PCI. ^, Improvements in catheterization laboratory facilities, new stents, evolution of adjunctive antithrombotic therapy, and development of collaborative systems for rapid transfer for invasive therapy have improved the efficacy and safety of primary PCI in patients with STEMI, including those being transferred for primary PCI (see Chapter 41 ). Selection of the optimal form of reperfusion therapy therefore involves judgments regarding both system resources and individual patient characteristics.

For patients who arrive at an experienced primary PCI center, primary PCI should be performed in those with STEMI who present within 12 hours of symptom onset and those with later arrival who have ongoing ischemia, HF, or shock. In patients taken to centers that are not PCI capable, the primary consideration is the time required for transportation to a PCI-capable center. The greatest operational impediment to routine implementation of a PCI reperfusion strategy is the delay required for transportation to a skilled PCI center (see Fig. 38.2 and Table 38.1 ). Trials conducted in health care systems with extremely short transportation and door-to-balloon times at PCI centers have demonstrated that referral to a PCI center can be superior to fibrinolysis administered at a local hospital. If the delay to implementation of primary PCI is substantial, however, the mortality advantage over administration of a fibrin-specific agent is lost ( Fig. 38.10 ). The best estimate of the time delay at which this advantage is lost is 1 to 2 hours, but it may vary depending on the timing of initial evaluation and the extent of myocardium at risk.

FIGURE 38.10, Relationship between PCI-related delay (minutes) during transfer from a non-PCI-capable hospital to a PCI-capable hospital and in-hospital mortality. The red lines represent 95% CIs. XDB-DN indicates transfer delay (transfer door-to-balloon minus door-to-needle time). With delays longer than 120 minutes between administration of a fibrinolytic on-site and balloon (or device) time at a receiving hospital, the on-site fibrinolytic strategy becomes preferable with respect to mortality risk when compared with transfer for PCI. O-FT , On-site fibrinolytic therapy; X-PCI , transfer PCI.

If the time from first medical contact to PCI is expected to be more than 120 minutes, fibrinolysis is recommended in the absence of (1) significant contraindications to fibrinolysis, (2) shock or acute severe heart failure, or (3) late presentation. Otherwise, transfer for primary PCI is generally favored if any of these conditions are present, even if the delay to revascularization will be greater than 120 minutes (see Fig. 38.2 and Table 38.3 ):

1.
High risk for bleeding. In patients with an increased risk for bleeding, particularly intracranial hemorrhage, therapeutic decision making strongly favors a PCI-based reperfusion strategy. If PCI is unavailable, the benefit of pharmacologic reperfusion should be balanced against the risk for bleeding. A decision analysis suggests that when PCI is not available, fibrinolytic therapy should still be favored over no reperfusion treatment until the risk for life-threatening bleeding exceeds 4%.
2.
Presence of shock or acute severe heart failure. Patients in cardiogenic shock have improved survival if they are treated with an early revascularization strategy of PCI and/or CABG. Therefore, immediate transfer to a PCI-capable hospital is recommended in patients with shock or acute severe HF regardless of the time delay. ^, ^,
3.
Prolonged time from onset of symptoms to initiation of reperfusion therapy. PCI is preferable in patients with late arrival, particularly those initially seen 12 to 24 hours after symptom onset. Fibrinolysis can be considered in the 12- to 24-hour window for patients with evidence of ongoing ischemia and where PCI is not available, although the benefit has not been established.

When the diagnosis of STEMI is in doubt, an invasive strategy is clearly the preferred strategy because it not only provides key diagnostic information regarding the patient’s symptoms but does so without the risk for intracranial hemorrhage associated with fibrinolysis.

Referral for Angiography with Intent of Revascularization after Initial Fibrinolysis

Patients with STEMI who are initially managed by fibrinolysis at a non–PCI-capable center should be transferred urgently to a PCI-capable center if the patient develops cardiogenic shock or severe HF or has failed reperfusion with a fibrinolytic. Transfer should also be considered (class IIa) as a part of a pharmacoinvasive strategy in stable patients with the intention of performing angiography, and PCI as necessary, 3 to 24 hours after fibrinolysis ( Table 38.5 ; see Fig. 38.2 ). ^,

TABLE 38.5

Indications for Coronary Angiography in Patients Who Were Managed with Fibrinolytic Therapy or Who Did Not Receive Reperfusion Therapy

Modified from O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol . 2013;61:e78.

Recommendation	Cor	Loe
Cardiogenic shock or acute severe heart failure that develops after initial evaluation	I	B
Intermediate- or high-risk findings on predischarge noninvasive ischemia testing	I	B
Spontaneous or easily provoked myocardial ischemia	I	C
Failed reperfusion or reocclusion after fibrinolytic therapy	IIa	B
Stable ∗ patients after successful fibrinolysis—before discharge and ideally between 3 and 24 hours	IIa	B

COR, Class of recommendation; LOE, level of evidence.

∗ Although individual circumstances vary, clinical stability is defined as the absence of low output, hypotension, persistent tachycardia, apparent shock, high-grade ventricular or symptomatic supraventricular tachyarrhythmias, and spontaneous recurrent ischemia.

Patients undergoing angiography and PCI after the suspected failure of reperfusion with fibrinolysis tend to have a lower mortality rate and significantly lower rates of recurrent MI and HF compared with patients who continue medical therapy, including readministration of a fibrinolytic agent. In the REACT (Rapid Early Action for Coronary Treatment) study, patients with suspected failed reperfusion at 90 minutes by electrocardiographic criteria were randomly assigned to one of three treatment arms: rescue PCI, conservative care, or repeated fibrinolytic therapy. The composite of death, reinfarction, stroke, or severe HF at 6 months was significantly lower in patients randomly assigned to rescue PCI than in the two other treatment groups. More minor bleeding, however, occurred in patients randomly assigned to rescue PCI. The option of administration of a fibrinolytic agent at non-PCI-capable hospitals, followed by routine transfer for angiography and PCI if indicated, has been advanced as an attractive strategy to offer timely reperfusion therapy and arrange a “nonemergency” transfer for subsequent procedures to reduce the risk for subsequent reinfarction. Retrospective analyses of trials of fibrinolytic therapy indirectly support this approach because they suggest a lower risk for recurrent MI and a lower 2-year mortality rate in patients who subsequently undergo early PCI. The limited randomized trials evaluating a strategy of routine catheterization after fibrinolysis have provided mixed results. Nevertheless, overall, these trials have suggested improvement in clinical outcomes in patients transferred for early catheterization, particularly those at higher risk for death and recurrent ischemia ( Fig. 38.11 and eFig. 38.7 ). In the largest of these studies, TRANSFER-AMI (Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction; n = 1059), immediate transfer for angiography versus conservative care reduced the composite endpoint of death, recurrent MI, recurrent ischemia, new or worsening HF, or shock at 30 days. In a meta-analysis that included seven randomized trials of early transfer for catheterization, a strategy of routine early catheterization after fibrinolysis yielded a statistically significant 35% reduction in the incidence of death or MI at 30 days (odds ratio [OR], 0.65; 95% confidence interval [CI] 0.49 to 0.88) without an increase in the risk for major bleeding (see Fig. 38.11 ). ^,

FIGURE 38.11, A meta-analysis of seven randomized trials of early transfer for catheterization, a strategy of routine early catheterization after fibrinolysis, was associated with a statistically significant 35% reduction in the incidence of death or MI at 30 days (top) with no increase in major bleeding (bottom), for combined death-reinfarction and recurrent ischemia between early PCI and standard therapy. Size of data markers indicates the weight of each trial.

EFIGURE 38.7, Primary outcome of trials of routine versus ischemia-driven (or delayed) catheterization and percutaneous coronary intervention (PCI) after fibrinolytic therapy. Trials comparing routine early catheterization after fibrinolytic therapy with either an ischemia-driven approach or routine-delayed catheterization generally showed a consistent pattern of benefit with a strategy of routine transfer for invasive evaluation. The darker bars represent patients who underwent routine early catheterization after fibrinolytic therapy. The lighter bars represent patients who underwent either an ischemia-guided or routine-delayed catheterization approach. arrhy , Arrhythmia; CAPITAL-AMI , Combined Angioplasty and Pharmacological Intervention Versus Thrombolysis Alone in Acute Myocardial Infarction; CARESS-in-AMI , Combined Abciximab Reteplase Stent Study in Acute Myocardial Infarction; CHF , congestive heart failure; D , death; GRACIA , Grupo de Análisis de la Cardiopatía Isquémica Aguda; NORDISTEMI , Norwegian Study on District Treatment of ST-Elevation Myocardial Infarction; revasc , ischemia-driven revascularization; RI , recurrent ischemia; TLR , target lesion revascularization. SIAM-3 , Southwest German Interventional Study in Acute Myocardial Infarction; TRANSFER-AMI , Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction; WEST , Which Early ST-Elevated Myocardial Infarction Therapy.

Notably, the clinical trials that assessed routine invasive evaluation after initial fibrinolysis used a time window of 0 to 24 hours for the “early invasive” strategy, thus supporting earlier transfer after administration of fibrinolytic therapy, even for patients without high-risk features. Although we believe that there will probably be continued benefit even beyond 24 hours in patients with a patent but stenotic infarct artery after initial successful reperfusion, later time windows have not been directly examined. Because of the associated increased bleeding risk, very early (<2 to 3 hours) catheterization after the administration of fibrinolytic therapy with the intent to perform revascularization should be reserved for patients with evidence of failed fibrinolysis and significant myocardial jeopardy, for whom rescue PCI would be appropriate. In addition, when STEMI is suspected to have occurred by a mechanism other than thrombotic occlusion at the site of atherosclerotic plaque, coronary angiography may provide diagnostic information and direct specific therapy.

In summary, delayed coronary angiography with PCI of the infarct artery is indicated in patients initially treated with a noninvasive strategy (i.e., with fibrinolysis or without reperfusion therapy) who become unstable with cardiogenic shock, acute severe HF, or ongoing ischemia, provided that invasive management is not considered futile or inappropriate (see Table 38.5 ). Delayed PCI also appears to be reasonable in patients with failed fibrinolysis or reocclusion of the infarct artery or in those who demonstrate significant residual ischemia during hospitalization after initial noninvasive management. The benefits of routine (non-ischemia-driven) PCI on an angiographically significant stenosis in a patent infarct artery more than 24 hours after STEMI are less well established, and delayed PCI on a totally occluded infarct artery longer than 24 hours after STEMI should not be undertaken in clinically stable patients without evidence of severe ischemia.

Patients Not Eligible for Reperfusion Therapy

Aspirin and antithrombin therapy can be prescribed for patients who are not candidates for acute reperfusion because of the lack of availability of PCI and contraindications to fibrinolysis. In the setting of absolute contraindications to fibrinolysis (see Table 38.3 ) and lack of access to PCI facilities, antithrombotic therapy should be initiated because of the slight chance (approximately 10%) of restoring TIMI grade 3 flow in the infarct vessel and decreasing the chance of complications of STEMI.

Anticoagulant and Antiplatelet Therapy

Anticoagulant Therapy

The rationale for administering anticoagulant therapy acutely to patients with STEMI includes establishing and maintaining patency of the infarct-related artery, regardless of whether a patient receives fibrinolytic therapy ( eFig. 38.8 ), and preventing deep venous thrombosis, pulmonary embolism, ventricular thrombus formation, and cerebral embolization.

EFIGURE 38.8, Targets for therapy during reperfusion of patients with STEMI. This schematic view shows a longitudinal section of an infarct-related artery at the level of the obstructive thrombus. Following rupture of a vulnerable plaque ( bottom center ), the coagulation cascade activates, which ultimately leads to the deposition of fibrin strands; platelets also activate and begin to aggregate. Platelets that aggregate with the incorporation of relatively few red cells form a white thrombus. The mesh of fibrin strands and platelet aggregates obstructs flow in the infarct-related artery. Pharmacologic reperfusion is a multipronged approach consisting of fibrinolytic agents that digest fibrin, anticoagulants that prevent the formation of thrombin and inhibit the activity of formed thrombin, and antiplatelet therapy.

Effect of Heparin on Mortality

Randomized trials of patients with STEMI conducted in the prefibrinolytic era showed a lower risk for reinfarction, pulmonary embolism, and stroke in those who received IV heparin, thus supporting the administration of heparin to STEMI patients not treated with fibrinolytic therapy. With the introduction of the fibrinolytic era and, importantly, after publication of the ISIS-2 (Second International Study of Infarct Survival) trial, the situation became more complicated because of strong evidence of a substantial reduction in mortality with aspirin alone and confusing and conflicting data regarding the risk/benefit ratio of heparin used as an adjunct to aspirin or in combination with aspirin and a fibrinolytic agent. Nevertheless, a meta-analysis of trials in the fibrinolytic era suggested that for every 1000 patients treated with heparin versus aspirin alone, five fewer deaths ( P = 0.03) and three fewer recurrent infarctions ( P = 0.04) occur, but at the expense of three more major bleeding episodes ( P = 0.001).

Other Effects of Heparin

Several angiographic studies have examined the role of heparin therapy in establishing and maintaining patency of the infarct-related artery in patients with STEMI. Although evidence favoring the use of heparin in conjunction with a fibrin-specific fibrinolytic agent for enhancing patency of the infarct artery is not conclusive, the suggestion of a mortality benefit and amelioration of LV thrombi after STEMI supports the use of heparin for at least 48 hours after fibrinolysis.

The most serious complication of anticoagulant therapy is bleeding (see Chapter 95 ), especially intracranial hemorrhage. Major hemorrhagic events occur more frequently in patients with low body weight, advanced age, female sex, marked prolongation of the activated partial thromboplastin time (APTT) (>90 to 100 seconds), and performance of invasive procedures. Frequent monitoring of the APTT reduces the risk for major hemorrhagic complications in patients treated with heparin. During the first 12 hours after fibrinolytic therapy, however, the APTT may be elevated as a result of the fibrinolytic agent alone (particularly if streptokinase is administered), thus making it difficult to interpret accurately the effects of a heparin infusion on the patient’s coagulation status.

Disadvantages of Heparin

Potential disadvantages of unfractionated heparin (UFH) include dependency on antithrombin III for inhibition of thrombin activity, sensitivity to platelet factor 4, inability to inhibit clot-bound thrombin, marked interpatient variability in therapeutic response, and the need for frequent monitoring of the APTT. Several alternative anticoagulants can circumvent these disadvantages of UFH.

Hirudin and Bivalirudin

In patients undergoing fibrinolysis, direct thrombin inhibitors such as hirudin or bivalirudin reduce the incidence of recurrent MI by 25% to 30% compared with heparin but have not reduced mortality. In addition, either hirudin or bivalirudin causes higher rates of major bleeding than heparin when used with fibrinolytic agents. As direct thrombin inhibitors have not been studied with fibrin-specific agents, there is no evidence to guide recommendations on their use in fibrinolysis.

In contrast, when administered for a short period as an adjunct to primary PCI in the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial, bivalirudin (open label), versus heparin plus glycoprotein (GP) IIb/IIIa inhibitors, reduced the 30-day rate of major bleeding or major adverse CV events, including death, reinfarction, target vessel revascularization for ischemia, and stroke (RR, 0.76; 95% CI 0.63 to 0.92; P = 0.005), driven by a significant 40% reduction in major bleeding ( eFig. 38.9 ). Treatment with bivalirudin significantly reduced mortality at 30 days and at 1 year but increased the early risk for stent thrombosis. Similarly, in the EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial, when started during transport for primary PCI in STEMI, bivalirudin reduced the primary outcome of death or major bleeding compared to heparin with optional GP IIb/IIIa, with a reduction in major bleeding but increase in stent thrombosis. However, there was no significant difference in mortality. A meta-analysis of 16 randomized controlled trials (RCTs), including four with predominantly STEMI patients, reported an increased risk of major adverse cardiovascular events (MACE) (RR, 1.09; 95% CI 1.01 to 1.17; P = 0.0204) with bivalirudin, primarily from increases in MI, ischemia-driven revascularization, and acute stent thrombosis ( Fig. 38.12 ). There was no difference in mortality, and bleeding rates were generally lower with bivalirudin, with the magnitude of the reduction dependent on the rates of GP IIb/IIIa co-administration in the relevant trials. The findings were consistent in the subset with STEMI.

FIGURE 38.12, Meta-analysis of 33,958 patients from 16 randomized trials of bivalirudin versus heparin during PCI. There was an increase in the risk of major adverse cardiac events (MACE) at 30 days with bivalirudin-based regimens compared with heparin-based regimens (risk ratio, 1.09; 95% CI 1.01 to 1.17; P = 0.0204) in the overall study population (A). While there was no difference in death or ischemia-driven revascularization, there was a significant increase in MI and acute stent thrombosis in the overall study population with bivalirudin-based regimens versus heparin-based regimens. There was a similar 10% increase in MACE (B) and numerically larger relative risk of stent thrombosis (risk ratio, 2.25; 95% CI 1.07 to 4.71) (C) in the four trials predominantly enrolling STEMI patients. Overall, bivalirudin-based regimens lowered the risk of major bleeding (risk ratio, 0.62; 95% CI 0.49 to 0.78; P < 0.0001), but the magnitude of this effect varied depending on whether glycoprotein IIb/IIIa inhibitors (GPI) were used predominantly in the heparin arm only, provisionally in both arms, or planned in both arms (D).

$EFIGURE 38.9, Results of an open-label randomized clinical trial comparing bivalirudin to unfractionated heparin (UFH) and a GP IIb/IIIa receptor antagonist as adjunctive medical therapy to support primary PCI in patients with STEMI. A, Treatment with bivalirudin was associated with significantly lower rates of major bleeding and mortality at 30 days. B, Kaplan–Meier curves of the cumulative incidence of major adverse cardiac events (MACE) did not differ between the two strategies at 30 days. C, Acute stent thrombosis during the first 24 hours was higher in patients treated with bivalirudin alone, but cardiovascular mortality was reduced in the bivalirudin group after 1 year of follow-up, thus providing strong evidence for this treatment strategy.$

Low-Molecular-Weight Heparins

Advantages of low-molecular-weight heparins (LMWHs) include a stable, reliable anticoagulant effect, high bioavailability permitting administration via the subcutaneous (SC) route, and a high anti-Xa/anti-IIa ratio producing blockade of the coagulation cascade in an upstream location and greatly reducing thrombin generation. The primary role of LMWH for the management of STEMI is as an adjunct to fibrinolytic therapy. Although LMWHs do not improve the rate of early (60 to 90 minutes) reperfusion of the infarct artery, LMWH reduces rates of reocclusion of the infarct artery, reinfarction, or recurrent ischemic events. This effect may underlie the significant reduction in recurrent MI with a strategy of extended anticoagulation with LMWHs, or a factor Xa antagonist versus standard therapy, in patients with STEMI undergoing fibrinolysis.

Moreover, in a placebo-controlled trial, an LMWH reduced the incidence of death, recurrent MI, or stroke at 30 days. This finding demonstrated not only that LMWHs are clinically effective in patients with STEMI, but also that anticoagulant therapy provides benefit as part of a fibrinolytic reperfusion strategy.

Several trials have compared an LMWH with UFH as part of a pharmacologic reperfusion strategy and demonstrated the LMWH to be superior. In the ASSENT (Assessment of the Safety and Efficacy of a New Thrombolytic) 3 trial, enoxaparin (30-mg IV bolus, followed by SC injections of 1 mg/kg every 12 hours until discharge from the hospital) reduced 30-day mortality, in-hospital reinfarction, or in-hospital refractory ischemia compared with UFH (RR, 0.74; 95% CI 0.63 to 0.87). The rate of intracranial hemorrhage was similar with UFH and enoxaparin (0.93% versus 0.88%; P = 0.98). In the ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis in Myocardial Infarction 25) trial, a strategy of enoxaparin administered for the duration of the index hospitalization was superior ( Fig. 38.13A ) to the conventional antithrombin strategy of UFH administration for 48 hours after fibrinolysis, with a 33% reduction ( P = 0.001) in reinfarction and a nonsignificant favorable trend on overall mortality ( P = 0.11). This improvement in recurrent MI was balanced by an increase in the incidence of major bleeding (1.4% and 2.1%, P = 0.001). In a meta-analysis of trials of LMWH versus UFH, LMWH clearly reduced recurrent MI but with a pattern of increased bleeding ( Fig. 38.13B ).

$FIGURE 38.13, Comparison of enoxaparin with unfractionated heparin (UFH) as adjunctive therapy in patients with STEMI receiving fibrinolysis. A, Primary results from the ExTRACT-TIMI 25 trial showing that the rate of the primary endpoint (death or nonfatal MI) at 30 days was significantly lower in the enoxaparin group than in the UFH group (9.9% versus 12%, P < 0.001 by log-rank test). The dashed vertical line indicates the comparison at day 2 (direct pharmacologic comparison), at which time a trend in favor of enoxaparin was seen. B, Results of a meta-analysis of seven randomized controlled clinical trials of low-molecular-weight heparin (LMWH) versus UFH, including 27,577 patients with STEMI. Individual outcomes of all-cause death, reinfarction, and major bleeding are shown.$

Parenteral Factor Xa Antagonists

The OASIS-6 (Organization for the Assessment of Strategies for Ischemic Syndromes) trial evaluated the specific factor Xa antagonist fondaparinux (2.5 mg subcutaneously) in 12,092 patients with STEMI. The trial design compared fondaparinux given for 8 days with placebo in patients when the treating physician thought that UFH was not indicated (stratum I) and with UFH for 48 hours when the treating physician thought that heparin was indicated (stratum II). Fondaparinux reduced the composite of death or reinfarction in stratum I (hazard ratio [HR], 0.79; 95% CI, 0.68 to 0.92), but not in stratum II (HR, 0.96; 95% CI, 0.81 to 1.13). The outcome of patients in stratum II who underwent PCI tended to be worse with fondaparinux than with UFH probably because of an increased risk for catheter thrombosis.

Oral Factor IIa and Factor Xa Antagonists

See later section, Secondary Prevention of Acute Myocardial Infarction.

Recommendations for Anticoagulant Therapy

Adjunctive Anticoagulation for Primary Percutaneous Coronary Intervention (see Chapter 41 )

Either UFH or bivalirudin is recommended as an anticoagulant to support primary PCI, with a preference for bivalirudin or heparin without a concomitant GP IIb/IIIa inhibitor for patients at high risk for bleeding. ^, ^, Fondaparinux is not recommended as the sole anticoagulant in this setting. LMWH has not had sufficient evaluation in primary PCI to formulate recommendations for treatment. Some investigators who have used enoxaparin to support primary PCI for STEMI administer 0.5 mg/kg intravenously at the time of the procedure.

Anticoagulation with Fibrinolysis

Given the pivotal role of thrombin in the pathogenesis of STEMI (see eFig. 38.8 ), antithrombotic therapy remains an important intervention. A regimen of an IV UFH bolus of 60 units/kg to a maximum of 4000 units, followed by an initial infusion at 12 units/kg/hr to a maximum of 1000 units/hr for 48 hours, adjusted to maintain the APTT at 1.5 to 2 times control (approximately 50 to 70 seconds), is effective in patients receiving fibrinolytic therapy.

Both the ExTRACT-TIMI 25 and the OASIS-6 trials indicated that prolonged administration of an anticoagulant for the duration of hospitalization is beneficial compared with the previous practice of administering UFH only for 48 hours unless clear-cut indications for discontinuing anticoagulation were present. Accordingly, patients managed with pharmacologic reperfusion therapy should receive anticoagulant therapy for a minimum of 48 hours and preferably for the duration of hospitalization after STEMI, up to 8 days. Enoxaparin or fondaparinux is preferred when the administration of an anticoagulant for longer than 48 hours is planned in patients with STEMI treated with a fibrinolytic. Enoxaparin should be administered according to age, weight, and creatinine clearance and be given as an IV bolus, followed in 15 minutes by SC injection for the duration of the index hospitalization, up to 8 days or until revascularization. Fondaparinux should be administered as an initial IV dose, followed in 24 hours by daily SC injections if the estimated creatinine clearance is higher than 30 mL/min. ^, If PCI is performed in a patient treated with fondaparinux, co-administration of an additional antithrombin agent with anti-factor IIa activity is required to mitigate the risk of catheter-related thrombosis.

In patients with a known history of heparin-induced thrombocytopenia, bivalirudin in conjunction with streptokinase is a useful alternative to heparin. For patients who are referred for CABG, UFH is the preferred antithrombin.

Patients Treated Without Reperfusion Therapy

Treatment with an anticoagulant is reasonable, and agents shown to be more effective than UFH in other groups with STEMI may be preferable. For example, in patients with STEMI not receiving reperfusion therapy, fondaparinux reduced the composite of death or recurrent MI without an increase in severe bleeding compared with placebo or UFH in the OASIS-6 trial.

Antiplatelet Therapy

Platelets play a major role in the response to the disruption of coronary artery plaque, especially in the early phase of thrombus formation. Fibrinolysis can activate platelets, and platelet-rich thrombi resist fibrinolysis more than fibrin and erythrocyte-rich thrombi (see eFig. 38.8 ). Thus, a sound scientific basis exists for inhibiting platelet aggregation in all patients with STEMI, regardless of the reperfusion management strategy. The agent most extensively tested has been aspirin, and treatment with aspirin and a second antiplatelet agent, such as clopidogrel, prasugrel, ticagrelor, or cangrelor, has become the standard of care for patients with STEMI.

Antiplatelet Therapy for Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction

All patients with STEMI should receive aspirin as soon as possible after an initial encounter in the absence of contraindications. Adding the P2Y ₁₂ inhibitor clopidogrel to aspirin appears to offer additional benefit in patients undergoing PCI after STEMI ( Fig. 38.14 ). In patients undergoing either primary PCI or delayed PCI after initial therapy for STEMI, the more potent P2Y ₁₂ inhibitor prasugrel was superior to clopidogrel in reducing the risk for CV death, MI, or stroke. In the subgroup of patients with STEMI enrolled in TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction; n = 3534), the primary endpoint was lowered by 32% at 30 days with prasugrel compared with aspirin (6.5% versus 9.5%; P = 0.0017) and by 21% at 15 months (10.0% versus 12.4%; P = 0.022) ( Fig. 38.15 ). Prasugrel reduced definite or probable stent thrombosis by 42% compared with clopidogrel. Analogously, in the PLATO (Platelet Inhibition and Patient Outcomes) trial, compared with clopidogrel, treatment with the reversible P2Y ₁₂ inhibitor ticagrelor in patients with STEMI undergoing primary PCI ( n = 7544) tended to reduce the primary endpoint of CV death, recurrent MI, or stroke by 13%, a magnitude similar to that for the overall trial population (see Fig. 38.15 ); there was a 26% reduction in definite or probable stent thrombosis and an 18% reduction in all-cause mortality.

FIGURE 38.14, Impact of the addition of clopidogrel to aspirin (ASA) in patients with STEMI. A, Effects of the addition of clopidogrel in patients receiving fibrinolysis for STEMI. Patients in the clopidogrel group ( n = 1752) had a 36% reduction in the odds of dying, sustaining a recurrent infarction, or having an occluded infarct artery compared with the placebo group ( n = 1739) in the CLARITY-TIMI 28 trial. B, Effect of the addition of clopidogrel on in-hospital mortality after STEMI. These time-to-event curves show a 0.6% absolute reduction in mortality in the group receiving clopidogrel plus aspirin ( n = 22,961) versus placebo plus aspirin ( n = 22,891) in the COMMIT trial.

FIGURE 38.15, A, Efficacy of prasugrel in the subgroup of patients with STEMI enrolled in a randomized clinical trial of prasugrel versus clopidogrel in patients undergoing PCI after an ACS. Treatment with prasugrel associated with a 21% relative reduction in the risk for cardiovascular (CV) death, MI, or stroke during 15 months of follow-up . B, Major bleeding (TIMI non-CABG) increased with prasugrel in the trial overall but did not reach statistical significance in patients with STEMI. C, Efficacy results for ticagrelor (versus clopidogrel) in patients with STEMI enrolled in the PLATO trial. The effect of ticagrelor on the primary endpoint (incidence of MI, stroke, or CV death) was consistent with the superiority of ticagrelor versus clopidogrel in the overall trial. D, Rates of major bleeding (TIMI non-CABG) are shown. CABG, Coronary artery bypass grafting.

Current evidence does not support initiation of P2Y ₁₂ inhibitor therapy before PCI for STEMI unless the strategy is for delayed invasive evaluation. As part of the PCI-CLARITY (PCI-Clopidogrel as Adjunctive Reperfusion Therapy) study, the investigators performed a meta-analysis of PCI-CLARITY, PCI-CURE (PCI-Clopidogrel in Unstable angina to prevent Recurrent Events), and CREDO (Clopidogrel for the Reduction of Events During Observation) and found that pretreatment with clopidogrel significantly reduced the risk for 30-day CV death or MI in a population that included both patients with STEMI and non-ST elevation ACS. ^, In a subsequent meta-analysis that included data from randomized trials and registries, higher-risk STEMI patients had a lower risk for major coronary events with clopidogrel pretreatment, but not a reduction in mortality or an increase in bleeding. Prehospital administration of ticagrelor did not improve the primary endpoint of coronary reperfusion but did reduce the secondary endpoint of stent thrombosis without any additional bleeding compared to in-hospital administration in patients with STEMI undergoing primary PCI in the ATLANTIC (Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation Myocardial Infarction to Open the Coronary Artery) trial. Chapter 41 discusses the use of GP IIb/IIIa inhibitors as part of adjunctive therapy for patients with STEMI undergoing PCI.

Cangrelor, a potent, fast-acting reversible, IV P2Y12 inhibitor, can be used during PCI in patients who have not received a P2Y12 inhibitor before PCI based on CHAMPION-PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) findings demonstrating a lower rate of death, MI, revascularization, or stent thrombosis, compared with clopidogrel in patients undergoing PCI, including primary PCI for STEMI.

Antiplatelet Therapy with Fibrinolysis

The ISIS-2 study was the largest trial of aspirin in patients with STEMI; it provided the single strongest piece of evidence that aspirin reduces mortality in patients treated with or without fibrinolytic. In contrast to the observations of a time-dependent mortality effect of fibrinolytic therapy, the reduction in mortality with aspirin was similar in patients treated within 4 hours (25% reduction in mortality), between 5 and 12 hours (21% reduction), and between 13 and 24 hours (21% reduction). An overall 23% reduction in mortality with aspirin occurred in ISIS-2 that was largely additive to the 25% reduction in mortality from streptokinase such that patients receiving both therapies experienced a 42% reduction in mortality. The reduction in mortality was as high as 53% in patients who received both aspirin and streptokinase within 6 hours of symptoms.

Obstructive platelet-rich arterial thrombi resist fibrinolysis and have an increased tendency for reocclusion after initial successful reperfusion in patients with STEMI. Despite inhibition of cyclooxygenase (COX) by aspirin, platelet activation leading to platelet aggregation and increased thrombin formation continues through thromboxane A ₂ –independent pathways. Adding other antiplatelet agents to aspirin has benefited patients with STEMI. Inhibitors of the P2Y ₁₂ adenosine diphosphate receptor help prevent the activation and aggregation of platelets. In the CLARITY-TIMI 28 trial, addition of the P2Y ₁₂ inhibitor clopidogrel to background treatment with aspirin in patients with STEMI who were younger than 75 years and received fibrinolytic therapy reduced the risk for clinical events (death, reinfarction, stroke) and reocclusion of a successfully reperfused infarct artery ( Fig. 38.14A ). An ST Resolution (STRes) electrocardiographic substudy from CLARITY-TIMI 28 provided insight into the mechanism of the benefit of clopidogrel in STEMI. No difference was seen in the rate of complete STRes between the clopidogrel and placebo groups at 90 minutes (38.4% versus 36.6%). When patients were stratified by STRes category, treatment with clopidogrel resulted in greater benefit in those with evidence of early STRes, with greater odds of having an open artery at late angiography in patients with partial or complete STRes, but no improvement in those with no STRes evident at 90 minutes. Thus, it appears that clopidogrel did not increase the rate of complete opening of occluded infarct arteries when fibrinolysis was administered but was effective in preventing reocclusion of an initially reperfused infarct artery.

In COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial), 45,852 patients with suspected MI were randomly assigned to clopidogrel, 75 mg/day (without a loading dose), or placebo in addition to aspirin, 162 mg/day ( Fig. 38.14B ). Patients in the clopidogrel group had a lower rate of the composite endpoint of death, reinfarction, or stroke (9.2% versus 10.1%; P = 0.002). They also had a significantly lower rate of death (7.5% versus 8.1%; P = 0.03). No excessive bleeding with clopidogrel occurred in this trial.

Combination Pharmacologic Reperfusion

Although trials of GP IIb/IIIa inhibitors combined with either full or reduced doses of fibrinolytics showed improvements in reperfusion, subsequent large outcomes trials revealed no significant effect on survival, and reductions in reinfarction were outweighed by the increases in bleeding. Therefore, the combination of a GP IIb/IIIa inhibitor and a fibrinolytic as a pharmacologic reperfusion regimen is not recommended.

Recommendations for Antiplatelet Therapy

Patients who have not taken aspirin before the development of STEMI should chew non-enteric-coated aspirin, and the dose should be 162 to 325 mg initially. During the maintenance phase of antiplatelet therapy following STEMI, the dose of aspirin should be reduced to 75 to 162 mg to minimize the risk of bleeding. Lower doses are preferable because of the increased risk for bleeding with higher doses reported in several studies; the CURRENT-OASIS 7 trial did not find differences in terms of efficacy or safety in STEMI patients randomly assigned to 81 versus 325 mg of aspirin. If true aspirin allergy is present, other antiplatelet agents such as clopidogrel or ticlopidine can be substituted.

The addition of a P2Y ₁₂ inhibitor to aspirin is warranted in most patients with STEMI. Based on the results of the COMMIT and CLARITY-TIMI 28 trials, clopidogrel, 75 mg/day orally, is an option for all patients with STEMI regardless of whether they receive fibrinolytic therapy, undergo primary PCI, or do not receive reperfusion therapy. The data available suggest that a loading dose of 300 mg of clopidogrel should be given to patients younger than 75 years who receive fibrinolytic therapy. Data are insufficient in elderly patients to recommend a loading dose in those 75 years or older who receive a fibrinolytic; however, this is being addressed in an ongoing study of half-dose fibrinolytic in older patients. When primary PCI is the mode of reperfusion therapy, an oral loading dose of 600 mg of clopidogrel before stent implantation is an established treatment, followed by 75 mg daily. ^, Interpatient variability in the response to clopidogrel can occur (see Chapter 39, Chapter 9, Chapter 95 ), and individuals with lesser degrees of platelet inhibition have increased risk for death and ischemic complications.

Prasugrel and ticagrelor generally achieve greater degrees of platelet inhibition than clopidogrel and can be used to treat patients with STEMI. On the basis of the results of TRITON-TIMI 38, prasugrel administered as an oral loading dose of 60 and 10 mg daily thereafter demonstrated benefit in patients with STEMI but should not be used in patients with a history of cerebrovascular disease or who are at higher risk for life-threatening bleeding, including patients older than 75 years or those with low body weight. Ticagrelor also reduced CV events compared with clopidogrel, and in PLATO, ticagrelor was administered as an oral loading dose of 180 mg and then 90 mg twice daily. ^, When using ticagrelor, the recommended maintenance dose of aspirin is 81 mg daily. The duration of combined antiplatelet therapy for secondary prevention after STEMI is discussed in Chapter 41 (see also eFig. 38G.2 ).

eFIGURE 38G.2, Treatment algorithm for the duration of P2Y 12 inhibitor therapy in patients with recent acute coronary syndrome (NSTE-ACS or STEMI). Arrows at the bottom of the figure denote that the optimal duration of prolonged DAPT is not established. Aspirin therapy is almost always continued indefinitely in patients with coronary artery disease. ∗High bleeding risk denotes those who have or develop a high risk of bleeding (e.g., treatment with oral anticoagulant therapy) or are at increased risk of severe bleeding complication (e.g., major intracranial surgery). BMS, Bare-metal stent; CABG, coronary artery bypass graft surgery; DAPT, dual-antiplatelet therapy; DES, drug-eluting stent; lytic, fibrinolytic therapy; NSTE-ACS, non–ST-elevation acute coronary syndrome; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.

Hospital Management

Coronary Care and Intermediate Care Units

Development of the coronary care unit (CCU) established the practice of continuously monitoring the cardiac rhythm by highly trained nurses with the skills and authority to initiate immediate treatment of arrhythmias in the absence of physicians and with the availability of specialized equipment (defibrillators, pacemakers). The clustering of patients with STEMI in the CCU greatly enhanced efficient use of the trained personnel, facilities, and equipment to improve patient outcomes. These benefits of geographic clustering with specialized nursing contribute to the optimal care of patients with STEMI, and in some hospitals, such care can be provided in “intermediate care” telemetry units with well-trained staff outside the CCU. Such intermediate care units, when equipped with continuous electrocardiographic monitoring and resuscitation equipment, may be appropriate for initial admission of STEMI patients with a low risk for mortality and has become standard in many institutions for STEMI patients stable after primary PCI. This strategy has proved cost-effective and may reduce CCU use by one-third, shorten hospital stays, and have no deleterious effect on patients’ recovery.

With increasing attention directed to limitations on resources and to the economic impact of intensive care, the proportion of appropriately selected patients with STEMI cared for in an intermediate care unit will likely increase. Nevertheless, a dedicated cardiac intensive care unit (CICU) plays a pivotal role in the management of patients with major complications of STEMI, which may require treatment of refractory arrhythmias, use of invasive hemodynamic monitoring, mechanical circulatory support, or with multiple organ failure. In patients with STEMI managed in a CICU, those with an uncomplicated status, such as patients without HF, hypotension, heart block, hemodynamically compromising ventricular arrhythmias, or persistent ischemic-type discomfort, can be safely transferred out of the CICU within 24 to 36 hours. In patients with complicated STEMI, the duration of the CICU stay should be dictated by the need for “intensive” care—that is, hemodynamic monitoring, close nursing supervision, IV vasoactive drugs, and frequent changes in the medical regimen.

General Measures

The managing clinical staff should be sensitive to patient concerns about prognosis and future productivity. Beginning education on lifestyle changes, including dietary interventions, is an important component of an overall strategy for secondary prevention (see Chapter 40 ).

The results of laboratory tests should be scrutinized for any derangements potentially contributing to arrhythmias, such as disturbances in acid-base balance or electrolytes. Delirium can be provoked by medications frequently used in the hospital, including antiarrhythmic drugs, H ₂ blockers, narcotics, and beta blockers. Use of potentially offending agents should be discontinued in patients with an abnormal mental status. Haloperidol, a butyrophenone, can be used safely in patients with STEMI.

Physical Activity

In the absence of complications, stabilized patients with STEMI need not be confined to bed for more than 12 hours, and unless they are hemodynamically compromised, they may use a bedside commode shortly after admission. Progression of activity should be individualized depending on the patient’s clinical status, age, and physical capacity. In patients without hemodynamic compromise, early mobilization (e.g., sitting in a chair, standing, walking around the bed) does not usually cause important changes in HR, BP, or pulmonary wedge pressure. As long as BP and HR are monitored, early mobilization offers considerable psychological and physical benefit without any clear medical risk.

Pharmacologic Therapy

Beta Blockers

Use of beta blockers for the treatment of patients with STEMI can cause both immediate effects (when the drug is given early in the course of infarction) and long-term effects (secondary prevention), as discussed previously. Because beta-adrenergic blockade diminishes circulating levels of free fatty acids (FFAs) by antagonizing the lipolytic effects of catecholamines and because elevated FFA levels augment myocardial oxygen consumption and probably increase the incidence of arrhythmias, these metabolic actions of beta blockers may also benefit the ischemic heart. As noted earlier, because early administration of IV beta blockers can cause detrimental effects in some patients, the present guidelines omit this therapy for most patients.

More than 52,000 patients have been randomly assigned to treatment in clinical trials studying beta-adrenergic blockade for acute MI. These trials cover a range of beta blockers and timing of administration and were largely conducted in the era before reperfusion strategies were developed for STEMI. Data available in the pre-reperfusion era suggested favorable trends toward a reduction in mortality, reinfarction, and cardiac arrest. In the reperfusion era, adding an IV beta blocker to fibrinolytic therapy was not associated with a reduction in mortality but helped reduce the rate of recurrent ischemic events. Concern arose regarding the potential risk of provoking cardiogenic shock if early IV followed by oral beta-adrenergic blockade was routinely administered to all patients with STEMI. The largest trial of beta blockers in patients with acute MI was COMMIT, which randomly assigned 45,852 patients within 24 hours of MI to metoprolol given as sequential IV boluses of 5 mg up to 15 mg, followed by 200 mg/day orally, or to placebo. The rate of the composite endpoint of death, reinfarction, or cardiac arrest in the metoprolol group (9.4%) did not differ from that in the placebo group (9.9%). Significant reductions occurred in reinfarction and episodes of VF in the metoprolol group, which translated into five fewer events for each of these endpoints per 1000 patients treated; yet, there were 11 more episodes of cardiogenic shock in the metoprolol group per 1000 patients treated. Risk for the development of cardiogenic shock (recorded as part of COMMIT protocol, in contrast to earlier studies) was greatest in patients with moderate to severe LV dysfunction (Killip class II or greater).

The combined results of the low-risk patients from COMMIT and data from earlier trials provide an overview of the effects of early IV therapy followed by oral therapy with beta blockers ( Fig. 38.16 ). A 13% reduction occurred in all-cause mortality (7 lives saved per 1000 patients treated), along with a 22% reduction in reinfarction (5 fewer events per 1000 patients treated) and a 15% reduction in VF or cardiac arrest (5 fewer events per 1000 patients treated). To achieve these benefits safely, early administration of beta blockers to patients with relative contraindications should be avoided ( Table 38.6 ).

FIGURE 38.16, Meta-analysis of the effects of intravenous and then oral beta (β)-blocker therapy on death, reinfarction, and cardiac arrest during the scheduled treatment periods in 26 small randomized trials, MIAMI, ISIS-1, and the low-risk subset of COMMIT. For COMMIT, data are included only for patients with a systolic blood pressure higher than 105 mm Hg, a heart rate greater than 65 beats/min, and Killip class I (as in MIAMI). Five small trials included in the ISIS-1 report had no data on reinfarction. In the ISIS-1 trial, data on reinfarction in the hospital were available for the last three-quarters of the study and involved 11,641 patients. ORs (odd ratios) in each ( blue squares with the area proportional to the number of events) were determined by comparing outcomes in patients allocated to β-blocker therapy with those in patients allocated to control, along with 99% CIs (confidence intervals) (horizontal lines). Overall ORs and 95% CIs are plotted by the diamonds, with value and significance given alongside.

TABLE 38.6

Recommendations for Beta-Blocker Therapy for ST-Elevation Myocardial Infarction (STEMI)

Recommendation	Cor	Loe
Oral beta blockers should be initiated in the first 24 hr in patients with STEMI who do not have any of the following: Signs of heart failure or evidence of a low-output state Increased risk for cardiogenic shock ∗ : Age >70 years Systolic blood pressure <120 mm Hg Sinus tachycardia >110 beats/min or heart rate <60 beats/min Increased time since the onset of symptoms of STEMI Other relative contraindications to use of oral beta blockers: PR interval longer than 0.24 second Second- or third-degree heart block Active asthma or reactive airways disease	I	B
Beta blockers should be continued during and after hospitalization for all patients with STEMI and no contraindications to their use.	I	B
Patients with initial contraindications to the use of beta blockers in the first 24 hours after STEMI should be reevaluated to determine their subsequent eligibility.	I	C
It is reasonable to administer IV beta blockers at initial encounter to patients with STEMI and no contraindications to their use who are hypertensive or have ongoing ischemia.	IIa	B

COR, Class of recommendation; LOE, level of evidence.

∗ The greater the number of risk factors present, the higher the risk for development of cardiogenic shock.

Recommendations

Given the evidence of a benefit of early administration of beta blockers for STEMI, patients without a contraindication, regardless of the administration of concomitant fibrinolytic therapy or performance of primary PCI, should receive oral beta blockers within the first 24 hours (see Table 38.6 ). IV administration of beta-blocking therapy during this period is also reasonable if a tachyarrhythmia or hypertension is present, in the absence of signs of HF/low output, indicators of high risk for the development of shock, or other relative contraindications to beta blockers.

Beta blockers are especially helpful in STEMI patients with significant residual unrevascularized CAD and evidence of recurrent ischemia or tachyarrhythmias early after the onset of infarction. If adverse effects of beta blockers develop or if patients have complications of infarction that are contraindications to these agents, such as HF or heart block, beta blockers should be withheld. Unless there are contraindications (see Table 38.6 ), beta blockers probably should be continued in patients in whom STEMI develops. Moreover, patients who initially have contraindications to beta blockers, such as acute HF, should be reevaluated with respect to their candidacy for such therapy after 24 hours.

Selection of Beta Blockers

Favorable effects have been reported with metoprolol, atenolol, carvedilol, timolol, and alprenolol; these benefits probably occur with propranolol and with esmolol, an ultrashort-acting agent, as well. In the absence of any favorable evidence supporting the benefit of agents with intrinsic sympathomimetic activity, such as pindolol and oxprenolol, and with some unfavorable evidence for these agents in secondary prevention, beta blockers with intrinsic sympathomimetic activity should probably not be chosen for the treatment of STEMI. The CAPRICORN (Carvedilol Post Infarction Survival Control in Left Ventricular Dysfunction) trial randomly assigned 1959 patients with MI and systolic dysfunction (EF <40%) to carvedilol or placebo in addition to contemporary pharmacotherapy, including angiotensin-converting enzyme (ACE) inhibitors in 98% of patients. All-cause mortality was reduced over a mean follow-up of 1.3 years by 23% with carvedilol compared to placebo ( P = 0.031), with a similar pattern noted during the first 30 days. ^, Thus, CAPRICORN confirmed the benefit of administration of a beta blocker in addition to ACE inhibitor therapy in patients with transient or sustained LV dysfunction after MI.

Occasionally, clinicians may decide to proceed with therapy with a beta blocker even in patients with relative contraindications, such as a history of mild asthma, mild bradycardia, mild HF, or first-degree heart block. In this situation, a trial of esmolol may help determine whether the patient can tolerate beta-adrenergic blockade. Because the hemodynamic effects of this drug (half-life of 9 minutes) disappear in less than 30 minutes, it offers an advantage over longer-acting agents when the risk for complications with a beta blocker is relatively high.

Inhibition of the Renin-Angiotensin-Aldosterone System

The rationale for inhibition of the renin-angiotensin-aldosterone system (RAAS) includes experimental and clinical evidence of a favorable impact on ventricular remodeling, improvement in hemodynamics, and a reduction in HF incidence. Unequivocal evidence from RCTs has shown that ACE inhibitors reduce mortality from STEMI. These trials can be grouped into two categories. The first group selected MI patients for randomization on the basis of features indicative of increased mortality, such as LVEF lower than 40%, clinical signs and symptoms of HF, anterior location of infarction, and abnormal wall motion score index ( Fig. 38.17 ). The second group consisted of unselective trials that randomized all patients with MI provided that they had a minimum systolic BP of approximately 100 mm Hg (ISIS-4, GISSI-3 [Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico], CONSENSUS II [Cooperative New Scandinavian Enalapril Survival Study II], and Chinese Captopril Study) ( Fig. 38.18 ). All selective trials initiated ACE inhibitor therapy between 3 and 16 days (except for SMILE) and maintained it for 1 to 4 years, whereas the unselective trials all initiated treatment within the first 24 to 36 hours and maintained it for only 4 to 6 weeks.

$FIGURE 38.17, Effect of ACE inhibitors on mortality after MI. Data are from six randomized controlled trials of an ACE inhibitor versus placebo in patients with MI with varying criteria based on ejection fraction (EF), clinical history of heart failure (HF), and the timing of randomization after presentation with MI. Presented are the mortality rates for the specified follow-up interval and the absolute risk difference with ACE inhibitor therapy. AIRE , Acute Infarction Ramipril Efficacy; d , days; GISSI , Gruppo Italiano per lo Studio della Soprawivenza nell’Infarto Miocardico; h , hours; ISIS , International Study of Infarct Survival; SAVE , Survival and Ventricular Enlargement; SMILE , Survival of Myocardial Infarction Long-term Evaluation; TRACE , Trandolapril Cardiac Evaluation; wk , weeks; mo , months; y , years.$

FIGURE 38.18, Effects of ACE inhibitors on mortality after MI—results from short-term trials.

A consistent survival benefit was observed in all the trials already noted, except for CONSENSUS II, the one study that used an IV preparation early in the course of MI. An estimate of the mortality benefit of ACE inhibitors in the unselective trials with a short duration of therapy was 5 lives saved per 1000 patients treated. Analysis of these unselective short-term trials indicates that approximately one-third of the lives saved occurred within the first 1 to 2 days. Certain subgroups, such as patients with anterior infarction, showed proportionately greater benefit with the early administration (11 lives saved per 1000) of ACE inhibitors. Not unexpectedly, greater survival benefits of 42 to 76 lives saved per 1000 patients treated were obtained in the selective trials with a long duration of therapy. Of note, a general 26% reduction in the risk for death attributable to ACE inhibitor treatment occurred in the selective trials. The reduction in mortality with ACE inhibitors was accompanied by significant reductions in the development of HF, thus supporting the underlying pathophysiologic rationale for administering this class of drugs to patients with STEMI.

The mortality benefits of ACE inhibitors add to those achieved with aspirin and beta blockers. The benefits of ACE inhibition appear to be a class effect because several agents reduce mortality and morbidity. To replicate these benefits in clinical practice, however, physicians should select a specific agent and prescribe the drug according to the protocols and dosages used in the clinical trials. The major contraindications to ACE inhibitors in patients with STEMI include hypotension in the setting of adequate preload, known hypersensitivity, and pregnancy. Adverse reactions include hypotension, especially after the first dose, and intolerable cough; much less often, angioedema can occur.

An alternative method of pharmacologic inhibition of the RAAS is the administration of angiotensin II receptor-blocking agents (ARBs). The VALIANT (Valsartan in Acute Myocardial Infarction) trial compared the effects of the ARB valsartan, valsartan and captopril, and captopril alone on mortality in patients with acute MI complicated by LV systolic dysfunction and/or HF within 10 days of MI. ^, Mortality rates were similar in the three treatment groups: 19.9% with valsartan, 19.3% with valsartan plus captopril, and 19.5% with captopril alone. The combination of the ACE and the ARB caused more unwanted actions; thus, drugs from these classes should not be combined.

Aldosterone blockade is another pharmacologic strategy for inhibition of the RAAS. The EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival) trial randomly assigned 6642 patients with acute MI complicated by left ventricular dysfunction and heart failure to the selective aldosterone-blocking agent eplerenone or placebo in conjunction with contemporary postinfarction pharmacotherapy. ^, During a mean follow-up of 16 months, a 15% reduction occurred in the RR for mortality in favor of eplerenone. Eplerenone also reduced CV mortality or hospitalization for CV events ( Fig. 38.19 ). Serious hyperkalemia (serum potassium [K ⁺ ] concentration, 6 mmol/L) occurred in 5.5% of patients in the eplerenone group compared with 3.9% in the placebo group ( P = 0.002). In contrast, in the ALBATROSS (Aldosterone Lethal Effects Blocked in Acute MI Treated with or without Reperfusion to Improve Outcome and Survival at Six Months Follow-up) trial, early mineralocorticoid antagonism versus placebo in an expanded population of patients with MI, including both STEMI and non-ST elevation MI, and patients without left ventricular function or heart failure , did not reduce the primary outcome of death, cardiac arrest, ventricular arrhythmia, implantable cardioverter-defibrillator (ICD) placement, or HF. However, an exploratory analysis by MI type found a reduction in all-cause death (HR, 0.20; 95% CI 0.06 to 0.70) in the subgroup of patients with STEMI ( n = 1229). Further studies are necessary to determine if a mineralocorticoid receptor antagonist (MRA) improves outcomes in all STEMI patients regardless of HF or LV dysfunction.

FIGURE 38.19, Mineralocorticoid receptor antagonism (MRA) following MI in patients with and without heart failure or left ventricular dysfunction. A, Eplerenone significantly reduced death from cardiovascular causes or hospitalization for cardiovascular events in the EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival) trial in patients with acute MI complicated by left ventricular dysfunction and heart failure . B, The ALBATROSS (Aldosterone Lethal Effects Blocked in Acute MI Treated with or without Reperfusion to Improve Outcome and Survival at Six Months Follow-up) trial found no difference in the primary outcome of death, cardiac arrest, ventricular arrhythmia, ICD placement, or heart failure with early MRA versus placebo in acute MI with or without left ventricular function or heart failure . C, An exploratory subgroup analysis in patients with STEMI identified a reduction in all-cause death.

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Prehospital Management

Prehospital Care

Emergency Medical Service Systems

Prehospital Fibrinolysis

Management in the Emergency Department

General Treatment Measures

Aspirin

Control of Cardiac Pain

Analgesics

Nitrates

Beta-Adrenergic Blocking Agents

Oxygen

Limitation of Infarct Size

Dynamic Nature of Infarction

Routine Measures for Limitation of Infarct Size

Reperfusion Therapy

General Concepts

Pathophysiology of Myocardial Reperfusion

Reperfusion Injury

Protection Against Reperfusion Injury

Reperfusion Arrhythmias

Late Establishment of Patency of the Infarct Vessel

Fibrinolysis

Assessment Of Reperfusion

Thrombolysis in Myocardial Infarction (TIMI) Flow Grade

Thrombolysis in Myocardial Infarction (TIMI) Frame Count

Myocardial Perfusion

Electrocardiography

Noninvasive Imaging

Invasive Assessment

Effect of Fibrinolytic Therapy on Mortality

Comparison of Fibrinolytic Agents

Effect on Left Ventricular Function

Complications of Fibrinolytic Therapy

Late Therapy

Intracoronary Fibrinolysis

Catheter-Based Reperfusion Strategies

Surgical Reperfusion

Selection of Reperfusion Strategy

Referral for Angiography with Intent of Revascularization after Initial Fibrinolysis

Patients Not Eligible for Reperfusion Therapy

Anticoagulant and Antiplatelet Therapy

Anticoagulant Therapy

Effect of Heparin on Mortality

Other Effects of Heparin

Disadvantages of Heparin

Hirudin and Bivalirudin

Low-Molecular-Weight Heparins

Parenteral Factor Xa Antagonists

Oral Factor IIa and Factor Xa Antagonists

Recommendations for Anticoagulant Therapy

Adjunctive Anticoagulation for Primary Percutaneous Coronary Intervention (see Chapter 41 )

Anticoagulation with Fibrinolysis

Patients Treated Without Reperfusion Therapy

Antiplatelet Therapy

Antiplatelet Therapy for Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction

Antiplatelet Therapy with Fibrinolysis

Combination Pharmacologic Reperfusion

Recommendations for Antiplatelet Therapy

Hospital Management

Coronary Care and Intermediate Care Units

General Measures

Physical Activity

Pharmacologic Therapy

Beta Blockers

Recommendations

Selection of Beta Blockers

Inhibition of the Renin-Angiotensin-Aldosterone System

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