When a client is experiencing acute coronary syndrome

Acute myocardial infarction (AMI) and unstable angina (UA) are part of a spectrum of clinical disease collectively identified as acute coronary syndromes (ACS). The pathophysiology common to this spectrum of disease is a ruptured or eroded atheromatous plaque.1–5 The electrocardiographic (ECG) presentation of these syndromes encompasses ST-segment elevation myocardial infarction (STEMI), ST-segment depression, and nondiagnostic ST-segment and T-wave abnormalities. A non–ST-elevation myocardial infarction (NSTEMI) is diagnosed if cardiac markers are positive with ST-segment depression or with nonspecific or normal ECGs. Sudden cardiac death may occur with any of these conditions. ACS is the most common proximate cause of sudden cardiac death.6–10

Effective interventions for patients with ACS, particularly STEMI, are extremely time-sensitive. The first healthcare providers to encounter the ACS patient can have a big impact on patient outcome if they provide efficient risk stratification, initial stabilization, and referral for cardiology care. It is critical that basic life support (BLS) and advanced cardiovascular life support (ACLS) healthcare providers who care for ACS patients in the out-of-hospital, emergency department (ED), and hospital environments be aware of the principles and priorities of assessment and stabilization of these patients.

These guidelines target BLS and ACLS healthcare providers who treat patients with ACS within the first hours after onset of symptoms, summarizing key out-of-hospital, ED, and some initial critical-care topics that are relevant to stabilization. They also continue to build on recommendations from the ACC/AHA Guidelines,11,12 which are used throughout the United States and Canada.13 As with any medical guidelines, these general recommendations must be considered within the context of local resources and application to individual patients by knowledgeable healthcare providers.

The primary goals of therapy for patients with ACS are to

• Reduce the amount of myocardial necrosis that occurs in patients with MI, preserving left ventricular (LV) function and preventing heart failure

• Prevent major adverse cardiac events (MACE): death, nonfatal MI, and need for urgent revascularization

• Treat acute, life-threatening complications of ACS, such as ventricular fibrillation (VF)/pulseless ventricular tachycardia (VT), symptomatic bradycardias, and unstable tachycardias (see Part 7.2: “Management of Cardiac Arrest” and Part 7.3: “Management of Symptomatic Bradycardia and Tachycardia”)

An overview of recommended care for the ACS patient is illustrated in Figure 1, the Acute Coronary Syndromes Algorithm. Part 8 provides details of the care highlighted in the numbered algorithm boxes. Box numbers in the text correspond to the numbered boxes in the algorithm.

Figure 1. Acute Coronary Syndromes Algorithm.

In this part the abbreviation AMI refers to acute myocardial infarction, whether associated with STEMI or NSTEMI. The diagnosis and treatment of AMI, however, will often differ for patients with STEMI versus NSTEMI. Note carefully which is being discussed.

Out-of-Hospital Management

Recognition (Figure 1, Box 1)

Treatment offers the greatest potential benefit for myocardial salvage in the first hours of STEMI. Thus, it is imperative that healthcare providers evaluate, triage, and treat patients with ACS as quickly as possible. Delays to therapy occur during 3 intervals: from onset of symptoms to patient recognition, during out-of-hospital transport, and during in-hospital evaluation. Patient delay to symptom recognition often constitutes the longest period of delay to treatment.14

The classic symptom associated with ACS is chest discomfort, but symptoms may also include discomfort in other areas of the upper body, shortness of breath, sweating, nausea, and lightheadedness. The symptoms of AMI are characteristically more intense than angina and last >15 minutes. Atypical symptoms or unusual presentations of ACS are more common in elderly, female, and diabetic patients.15–19

Public education campaigns increase public awareness and knowledge of the symptoms of heart attack but have only transient effects.20 For patients at risk for ACS (and for their families), physicians should discuss the appropriate use of nitroglycerin and aspirin, activation of the emergency medical services (EMS) system, and location of the nearest hospital that offers 24-hour emergency cardiovascular care. Recent ACC/AHA guidelines recommend that the patient or family members activate the EMS system rather than call their physician or drive to the hospital if chest discomfort is unimproved or worsening 5 minutes after taking 1 nitroglycerin tablet or using nitroglycerin spray.12

Initial EMS Care (Figure 1, Box 2)

Half of the patients who die of AMI do so before reaching the hospital. VF or pulseless VT is the precipitating rhythm in most of these deaths,21–23 and it is most likely to develop during the first 4 hours after onset of symptoms.24–27 Communities should develop programs to respond to out-of-hospital cardiac arrest that include prompt recognition of symptoms of ACS, early activation of the EMS system, and if needed, early CPR (see Part 4: “Adult Basic Life Support”) and early access to an automated external defibrillator (AED) through community AED programs (see Part 5: “Electrical Therapies”).28 EMS and dispatch system personnel should be trained to respond to cardiovascular emergencies.

Dispatchers and EMS providers must be trained to recognize symptoms of ACS. Dispatchers should advise patients with no history of aspirin allergy or signs of active or recent gastrointestinal bleeding to chew an aspirin (160 to 325 mg) while awaiting the arrival of EMS providers (Class IIa).29

EMS providers should be trained to determine the time of onset of symptoms and to stabilize, triage, and transport the patient to an appropriate facility and to provide prearrival notification. EMS providers should monitor vital signs and cardiac rhythm and be prepared to provide CPR and defibrillation if needed.

EMS providers may administer oxygen to all patients. If the patient is hypoxemic, providers should titrate therapy based on monitoring of oxyhemoglobin saturation (Class I).30–44 If the patient has not taken aspirin and has no history of aspirin allergy and no evidence of recent gastrointestinal bleeding, EMS providers should give the patient nonenteric aspirin (160 to 325 mg) to chew (Class I).45–48

EMS providers should administer up to 3 nitroglycerin tablets (or spray) for ongoing symptoms at intervals of 3 to 5 minutes if permitted by medical control and if the patient remains hemodynamically stable (systolic blood pressure [SBP] >90 mm Hg [or no more than 30 mm Hg below baseline], heart rate between 50 and 100 beats per minute [bpm]).49,50 EMS providers can administer morphine for chest pain unresponsive to nitroglycerin if authorized by protocol or medical control. Additional information about out-of-hospital stabilization and care is included in the following sections.

Out-of-Hospital ECGs

Out-of-hospital 12-lead ECGs and advance notification to the receiving facility speed the diagnosis, shorten the time to fibrinolysis, and may be associated with decreased mortality rates.51–64 The reduction in door-to–reperfusion therapy interval in most studies ranges from 10 to 60 minutes. EMS providers can efficiently acquire and transmit diagnostic-quality ECGs to the ED53,58,65,66 with a minimal increase (0.2 to 5.6 minutes) in the on-scene time interval.52,56,65–68

Qualified and specially trained paramedics and prehospital nurses can accurately identify typical ST-segment elevation (>1 mm in 2 or more contiguous leads) in the 12-lead ECG with specificity ranging from 91% to 100% and sensitivity ranging from 71% to 97% when compared with emergency medicine physicians or cardiologists.69,70 Using radio or cell phone, they can also provide advance notification to the receiving hospital of the arrival of a patient with ACS.56,61–64

We recommend implementation of out-of-hospital 12-lead ECG diagnostic programs in urban and suburban EMS systems (Class I). Routine use of 12-lead out-of-hospital ECG and advance notification is recommended for patients with signs and symptoms of ACS (Class IIa). A 12-lead out-of-hospital ECG with advance notification to the ED may be beneficial for STEMI patients by reducing time to reperfusion therapy. We recommend that out-of-hospital paramedics acquire and transmit either diagnostic-quality ECGs or their interpretation of them to the receiving hospital with advance notification of the arrival of a patient with ACS (Class IIa). If EMS providers identify STEMI on the ECG, it is reasonable for them to begin to complete a fibrinolytic checklist (Figure 2).

Figure 2. Fibrinolytic Checklist.

Out-of-Hospital Fibrinolysis

Clinical trials have shown the benefit of initiating fibrinolysis as soon as possible after onset of ischemic-type chest pain in patients with STEMI or new or presumably new left bundle branch block (LBBB).67,71 Several prospective studies (LOE 1)72–74 have documented reduced time to administration of fibrinolytics and decreased mortality rates when out-of-hospital fibrinolytics were administered to patients with STEMI and no contraindications to fibrinolytics.

Physicians in the Grampian Region Early Anistreplase Trial (GREAT)73 administered fibrinolytic therapy to patients at home 130 minutes earlier than to patients at the hospital and noted a 50% reduction in hospital mortality rates and greater 1-year and 5-year survival rates in those treated earlier.75,76 Delaying fibrinolytic treatment by 1 hour increased the hazard ratio of death by 20%, which is equivalent to the loss of 43 lives per 1000 patients over 5 years.

A meta-analysis of out-of-hospital fibrinolytic trials found a relative improvement of 17% in outcome associated with out-of-hospital fibrinolytic therapy, particularly when therapy was initiated 60 to 90 minutes earlier than in the hospital.71 A meta-analysis of 6 trials involving 6434 patients (LOE 1)72 documented decreased all-cause hospital mortality rates among patients treated with out-of-hospital fibrinolysis compared with in-hospital fibrinolysis (odds ratio [OR]: 0.83; 95% confidence interval [CI]: 0.70 to 0.98) with a number needed to treat of 62 to save 1 extra life with out-of-hospital fibrinolysis. Results were similar regardless of the training and experience of the provider.

The ECC Guidelines 200077 recommended consideration of out-of-hospital fibrinolysis for patients with a transport time >1 hour. But in a recent Swiss study (LOE 1),74 prehospital administration of fibrinolytics significantly decreased the time to drug administration even in an urban setting with relatively short transport intervals (<15 minutes).74

In summary, out-of-hospital administration of fibrinolytics to patients with STEMI with no contraindications is safe, feasible, and reasonable (Class IIa). This intervention may be performed by trained paramedics, nurses, and physicians for patients with symptom duration of 30 minutes to 6 hours. System requirements include protocols with fibrinolytic checklists, ECG acquisition and interpretation, experience in ACLS, the ability to communicate with the receiving institution, and a medical director with training/experience in management of STEMI. A process of continuous quality improvement is required. Given the operational challenges required to provide out-of-hospital fibrinolytics, most EMS systems should focus on early diagnosis with 12-lead ECG, rapid transport, and advance notification of the ED (verbal interpretation or direct transmission of ECG) instead of out-of-hospital delivery of fibrinolysis.

Triage and Transfer

Out-of-Hospital Triage

Hospital and EMS protocols should clearly identify criteria for transfer of patients to specialty centers and conditions under which fibrinolytics should be initiated before transfer. When transfer is indicated, the ACC/AHA guidelines recommend a door-to-departure time ≤30 minutes.12 It may be appropriate for the EMS medical director to institute a policy of out-of-hospital bypass of hospitals that provide medical therapy only, particularly for patients who require interventional therapy. Patients who require interventional therapy may include those with cardiogenic shock, pulmonary edema, large infarctions, and contraindications to fibrinolytic therapy.

At present no randomized studies have directly compared triage with an experienced percutaneous coronary intervention (PCI) center with medical management at the local hospital. Extrapolation from several randomized trials on interfacility transfer78–80 suggests that STEMI patients triaged directly to a primary PCI facility may have better outcomes related to the potential for earlier treatment. A cost-efficacy substudy of the Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction (CAPTIM) trial81 suggests that direct transport to a primary PCI facility may be more cost-effective than out-of-hospital fibrinolysis when transport can be completed in ≤60 minutes with a physician in a mobile intensive care unit. There is no direct evidence, however, to suggest that these strategies are safe or effective. Patients judged to be at highest risk for a complicated transfer were excluded from some of these studies.

In summary, at this time there is inadequate evidence to recommend out-of-hospital triage to bypass non–PCI-capable hospitals to bring patients to a PCI center (Class Indeterminate). Local protocols for EMS providers are appropriate to guide the destination of patients with suspected or confirmed STEMI.

Interfacility Transfer

All patients with STEMI and symptom duration of ≤12 hours are candidates for reperfusion therapy with either fibrinolysis or PCI (Class I). When patients present directly to a facility capable of providing only fibrinolysis, 3 treatment options are available: administering fibrinolytics with admission to that hospital, transferring the patient for primary PCI, or giving fibrinolytics and then transferring the patient to a specialized center. The decision is guided by a risk-benefit assessment that includes evaluation of duration of symptoms, complications, contraindications, and the time delay from patient contact to fibrinolysis versus potential delay to PCI balloon inflation.

In 2 prospective studies (LOE 2)78–80 and a meta-analysis,82 patients with STEMI who presented 3 to 12 hours after onset of symptoms to a hospital without capability for primary PCI had better outcome (improved 30-day combined incidence of death, reinfarction, or stroke) when they were transferred to a skilled PCI center (interventionalist performing >75 procedures per year) rather than receiving fibrinolytics at the presenting hospital. In these studies balloon inflation occurred ≤93 minutes after decision to treat.80,83–85 Thus, interfacility transfer is indicated for patients with STEMI presenting >3 hours from onset of symptoms from hospitals that lack primary PCI capability to centers capable of providing primary PCI when the transfer can be accomplished as soon as possible. The ACC/AHA guidelines recommend a treatment delay of no more than 90 minutes.12 In patients with STEMI presenting <3 hours from onset of symptoms, the superiority of immediate administration of fibrinolytics in the hospital or transfer for primary PCI is not established (Class Indeterminate).

In-Hospital Fibrinolytics and Interfacility Transfer for PCI

Data from the 1980s to 1990s did not support a strategy of fibrinolytic therapy combined with transfer for facilitated PCI (LOE 186–88 and meta-analyses89–91). But all of the studies involved in-hospital administration of fibrinolytics, and most were completed before the era of coronary stenting and without use of contemporary pharmacologic therapies or PCI techniques. Three small randomized trials (LOE 1)92–94 supported the strategy of fibrinolytics plus transfer for PCI; however, the timing of PCI after administration of fibrinolytics, the inclusion of patients who required transfer for PCI, the use of coronary stents, and the control group interventions differ considerably among these trials. The most recent study79 was fairly small and showed a benefit of early PCI with 1-year follow-up.94

At present there is inadequate evidence to recommend the routine transfer of patients for early PCI (ie, within 24 hours) after successful administration of fibrinolytics in a community hospital. The use of out-of-hospital administration of fibrinolytics followed by early PCI has not been specifically studied.

Special Transfer Considerations

Special transfer considerations are appropriate for patients with signs of shock (pulmonary congestion, heart rate >100 bpm, and SBP <100 mm Hg). The Second National Registry of Myocardial Infarction found that the mortality rate in patients with AMI and shock was lower in those treated with PCI as a primary strategy than in those treated with fibrinolysis.95 In the SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial, 152 patients with cardiogenic shock were randomly assigned to an early revascularization (ERV) strategy, 150 patients were assigned to a strategy of initial medical stabilization that included fibrinolytics, and 25% had delayed revascularization.96 Although there was no difference in the 30-day mortality rate, the mortality rate at 6 months was significantly lower in the ERV group (50.3% versus 63.1%). In a prespecified subgroup analysis for patients <75 years of age, early revascularization was associated with a 15.4% reduction in 30-day mortality and improvement in 1-year survival rates.97 A direct comparison of the outcome of primary or early PCI patients with patients who received fibrinolytic therapy only was not reported.

There is inadequate evidence to recommend routine transfer of stable patients for early PCI after successful administration of fibrinolytics in community hospitals or the out-of-hospital setting. Patients <75 years of age and selected patients >75 years of age who develop cardiogenic shock or persistent ischemic symptoms within 36 hours of STEMI should be transferred to experienced facilities capable of ERV if ERV can be performed within 18 hours of onset of shock.12

ED Evaluation and Risk Stratification (Figure 1, Boxes 3 and 4)

Focused Assessment and ECG Risk Stratification

ED providers should quickly assess patients with possible ACS. Ideally within 10 minutes of ED arrival, providers should obtain a targeted history while a monitor is attached to the patient and a 12-lead ECG is obtained (if not done in the prehospital setting).98 The evaluation should focus on chest discomfort, associated signs and symptoms, prior cardiac history, risk factors for ACS, and historical features that may preclude the use of fibrinolytics or other therapies. This initial evaluation must be efficient because if the patient has STEMI, the goals of reperfusion are to administer fibrinolytics within 30 minutes of arrival (30-minute interval “door-to-drug”) or to provide PCI within 90 minutes of arrival (90-minute interval “door-to–balloon inflation” in the catheterization suite).

Potential delay during the in-hospital evaluation period may occur from door to data, from data (ECG) to decision, and from decision to drug (or PCI). These 4 major points of in-hospital therapy are commonly referred to as the “4 D’s.”99 All providers must focus on minimizing delays at each of these points. Out-of-hospital transport time constitutes only 5% of delay to treatment time; in-hospital evaluation constitutes 25% to 33% of this delay.100,101

The physical examination is performed to aid diagnosis, rule out other causes of the patient’s symptoms, and evaluate the patient for complications related to ACS. Although the use of clinical signs and symptoms may increase suspicion of ACS, evidence does not support the use of any single sign or combination of clinical signs and symptoms alone to confirm the diagnosis.102–105

When the patient presents with signs of ACS, the clinician uses ECG findings (Figure 1, Box 4) to classify the patient into 1 of 3 groups:

Cardiac Biomarkers

New cardiac biomarkers, which are more sensitive than the myocardial muscle creatine kinase isoenzyme (CK-MB), are useful in diagnosis, risk stratification, and determination of prognosis. An elevated level of troponin correlates with an increased risk of death, and greater elevations predict greater risk of adverse outcome.106 Patients with increased troponin levels have increased thrombus burden and microvascular embolization.

Cardiac biomarkers should be obtained during the initial evaluation of the patient, but therapeutic decisions and reperfusion therapy for patients with STEMI should not be delayed pending the results of these tests. Important limitations to these tests exist because they are insensitive during the first 4 to 6 hours of presentation unless continuous persistent pain has been present for 6 to 8 hours. For this reason cardiac biomarkers are not useful in the prehospital setting.107–112

Serial marker testing (CK-MB and cardiac troponin) over time improves sensitivity for detection of myocardial infarction but remains insensitive in the first 4 to 6 hours.113,114

ST-Segment Elevation MI (Figure 1, Boxes 5 Through 8)

Patients with STEMI usually have complete occlusion of an epicardial coronary vessel. The mainstay of treatment is reperfusion therapy through administration of fibrinolytics (pharmacologic reperfusion) or primary PCI (mechanical reperfusion). Providers should rapidly identify patients with STEMI and quickly screen them for indications and contraindications to fibrinolytic therapy and PCI.

The first physician who encounters a patient with AMI should be able to determine the need for reperfusion therapy and direct its administration (see Tables 1 and 2). If the patient meets the criteria for fibrinolytic therapy, a door-to-needle time (needle time is the beginning of infusion of a fibrinolytic agent) ≤30 minutes is desired. Results of cardiac biomarkers do not delay the administration of fibrinolytic therapy or referral for PCI. They are normal in a significant percentage of patients who present early with STEMI. Consultation with a cardiologist or the patient’s personal physician delays therapy, is associated with increased hospital mortality rates, and is recommended only in equivocal or uncertain cases.115 Hospitals with capabilities for angiography and PCI should have a clear protocol directing ED triage and initial management. Confusion about the method of reperfusion, eg, fibrinolysis or PCI, delays definitive therapy.

UA and NSTEMI (Figure 1, Boxes 9 Through 17)

In the absence of ST-segment elevation, patients with ischemic-type chest pain can present with ST-segment depression or nondiagnostic or normal ECGs. ST-segment depression identifies a population at increased risk for MACE. Patients with ischemic-type pain and ECGs consistent with NSTEMI or normal or nondiagnostic ECGs do not benefit from fibrinolytic therapy, and fibrinolysis may be harmful.116

Although many patients will not have ACS (ie, the ECG change is due to an alternative diagnosis, such as LV hypertrophy), initial triage and therapy appropriately includes antiplatelet, antithrombin, and antianginal therapy. These patients usually have a partially or intermittently occluding thrombus. Clinical features can correlate with the dynamic nature of clot formation and degradation, eg, waxing and waning clinical symptoms.

Serial cardiac markers are often obtained during evaluation, including CK-MB and cardiac troponins. At any point during evaluation, elevation of cardiac troponin places a patient at increased risk for MACE. Studies have shown that patients with increased troponin are best managed with a strategy of small-molecule glycoprotein (GP) IIb/IIIa inhibitor therapy and an early invasive strategy (cardiac catheterization with possible revascularization). Troponin serves as an additional and incremental adjunct to the ECG. Physicians need to appreciate that other disorders can increase cardiac troponin, eg, myocarditis, congestive heart failure, and pulmonary embolism.

Risk Stratification

Braunwald Stratification

There are many ways to risk-stratify patients with chest pain. A well-recognized approach is the one initially proposed and later refined by Braunwald and colleagues on the ACC/AHA Task Force on the Management of Patients With Unstable Angina.11,117–120 This approach is based on a combination of historical, clinical, laboratory, and ECG variables.

Table 3 is a modified version of what has been a work in progress by Braunwald and colleagues over several publications.118,120,121 Patients are initially risk-stratified according to the likelihood that symptoms are due to unstable coronary artery disease (CAD). Patients at intermediate or high risk for CAD are further classified by their risk of MACE. This second classification is useful for prospectively identifying patients at intermediate or high risk who can benefit from an invasive strategy and more aggressive pharmacology with antiplatelet and antithrombin agents.

TIMI Risk Score

The risk of MACE has been further studied and refined. Researchers who derived the important Thrombolysis in Myocardial Ischemia (TIMI) risk score used data from the TIMI-11B and ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events) trials for UA/NSTEMI122,123 and from the In-TIME trial for STEMI.124 The TIMI risk score comprises 7 independent prognostic variables (Table 4). These 7 variables were significantly associated with the occurrence within 14 days of at least one of the primary end points: death, new or recurrent MI, or need for urgent revascularization. The score is derived from complex multivariate logistic regression and includes variables that seem counterintuitive. It is useful to note that traditional cardiac risk factors are only weakly associated with MACE. Use of aspirin within the previous 7 days, for example, would not seem to be an indicator of a bad outcome. But aspirin use was in fact found to be one of the most powerful predictors.122 It is possible that aspirin use identified a subgroup of patients at higher risk or on active but failed therapy for CAD.

The creators of the TIMI risk score validated it with 3 groups of patients, and 4 clinical trials showed a significant interaction between the TIMI risk score and outcome.124–128 These findings confirm the value of the TIMI risk score as a guide to therapeutic decisions. A PDA download of this risk assessment is available at www.TIMI.org.

By classifying patients into 1 of 3 risk strata, the Braunwald (Table 3) and TIMI (Table 4) risk scores serve as the dominant clinical guides for predicting the risk of MACE in patients with ACS. Risk stratification is applicable to patients at intermediate or high risk of symptoms due to CAD and not the larger general population of patients presenting with chest pain or symptoms possibly due to anginal equivalents. Risk stratification enables clinicians to direct therapy to those patients at intermediate or high risk of MACE and avoids unnecessary therapy and the potential for adverse consequences in patients who are at lower risk.

The TIMI risk score has become the primary tool for evaluating therapeutic recommendations. Incrementally greater benefit from some of the newer therapies may be gained for patients with higher risk scores.

One additional product of the TIMI trials is the TIMI grading system of coronary artery blood flow. Investigators from the TIMI study developed and validated a coronary artery perfusion scoring system, characterizing the degree of reperfusion of a coronary artery on a scale of 0 (no flow) to 3 (normal, brisk flow). This TIMI grading system is now used as an outcome measure in many studies of ACS interventions.

Indicators for Early Invasive Strategies

Risk stratification (Figure 1, Box 12) helps the clinician identify patients with NSTEMI and UA who should be managed with an invasive strategy. Coronary angiography then allows the clinician to determine whether patients are appropriate candidates for revascularization with PCI or coronary artery bypass grafting (CABG).

The2005 AHA Guidelines for CPR and ECC define high-risk patients with indicators that overlap to a considerable degree with the more rigorously validated TIMI risk score122:

• New ST-segment depression and positive troponins

• Persistent or recurrent symptoms

• Hemodynamic instability or VT

• Depressed LV function (ejection fraction <40%)

• ECG or functional study that suggests multivessel CAD

Normal or Nondiagnostic ECG Changes (Boxes 13 to 17)

The majority of patients with normal or nondiagnostic ECGs do not have ACS. Patients in this category with ACS are most often at low or intermediate risk. The physician’s goal involves risk stratification (see above) to provide appropriate diagnostic or treatment strategies for an individual patient. These strategies then target patients at increased risk for benefit while avoiding risk (eg, anticoagulation therapy and invasive cardiac catheterization) in patients with low or minimal risk.

Initial General Therapy for ACS

Several initial measures are appropriate for all patients with suspected ACS in both the out-of-hospital and ED setting. These include immediate oxygen therapy, continuous cardiac monitoring, establishment of intravenous (IV) access, and several medications discussed below.

Oxygen

Administer oxygen to all patients with overt pulmonary congestion or arterial oxygen saturation <90% (Class I). It is also reasonable to administer supplementary oxygen to all patients with ACS for the first 6 hours of therapy (Class IIa). Supplementary oxygen limited ischemic myocardial injury in animals,31 and oxygen therapy in patients with STEMI reduced the amount of ST-segment elevation.35 Although a human trial of supplementary oxygen versus room air failed to show a long-term benefit of supplementary oxygen therapy for patients with MI,30 short-term oxygen administration is beneficial for the patient with unrecognized hypoxemia or unstable pulmonary function. In patients with severe chronic obstructive pulmonary disease, as with any other patient, monitor for hypoventilation.

Aspirin

Early administration of aspirin (acetylsalicylic acid [ASA]), including administration in the out-of-hospital setting,47 has been associated with decreased mortality rates in several clinical trials.47,129–131 Multiple studies support the safety of aspirin administration. Therefore, unless the patient has a known aspirin allergy, nonenteric aspirin should be given as soon as possible to all patients with suspected ACS.

Aspirin produces a rapid clinical antiplatelet effect with near-total inhibition of thromboxane A2 production. It reduces coronary reocclusion and recurrent ischemic events after fibrinolytic therapy. Aspirin alone reduced death from AMI in the Second International Study of Infarct Survival (ISIS-2), and its effect was additive to that of streptokinase.129 In a review of 145 trials, aspirin was found to substantially reduce vascular events in all patients with AMI, and in high-risk patients it reduced nonfatal AMI and vascular death.132 Aspirin is also effective in patients with UA. The standard dose (160 to 325 mg) is recommended, although higher doses may be used. Chewable or soluble aspirin is absorbed more quickly than swallowed tablets.133,134

The early administration of a single chewed dose of aspirin (160 to 325 mg) is recommended in either the out-of-hospital or ED setting for patients with suspected ACS (Class I). Other formulations of ASA (soluble, IV) may be as effective as chewed tablets. Aspirin suppositories (300 mg) are safe and can be considered for patients with severe nausea, vomiting, or disorders of the upper gastrointestinal tract.

Nitroglycerin (or Glyceryl Trinitrate)

Nitroglycerin is an effective analgesic for ischemic chest discomfort. It also has beneficial hemodynamic effects, including dilation of the coronary arteries (particularly in the region of plaque disruption), the peripheral arterial bed, and venous capacitance vessels. The treatment benefits of nitroglycerin are limited, however, and no conclusive evidence has been shown to support routine use of IV, oral, or topical nitrate therapy in patients with AMI.135 With this in mind, these agents should be carefully considered, especially when low blood pressure precludes the use of other agents shown to be effective in reducing morbidity and mortality (eg, β-blockers and angiotensin-converting enzyme [ACE] inhibitors).

IV nitroglycerin is indicated in the following clinical situations (Class I):

• Ongoing ischemic chest discomfort

• Management of hypertension

• Management of pulmonary congestion

Patients with ischemic discomfort may receive up to 3 doses of sublingual or aerosol nitroglycerin at 3- to 5-minute intervals until pain is relieved or low blood pressure limits its use (Class I). IV nitroglycerin is indicated for ongoing chest discomfort, control of hypertension, or management of pulmonary congestion in patients with STEMI associated with LV failure (Class I). In patients with recurrent ischemia, nitrates are indicated in the first 24 to 48 hours. IV rather than long-acting preparations should be used acutely to enable titration.

Do not use nitrates (Class III) in patients with hypotension (SBP <90 mm Hg or >30 mm Hg below baseline), extreme bradycardia (<50 bpm), or tachycardia (>100 bpm). Administer nitrates with extreme caution if at all to patients with suspected inferior wall MI with possible right ventricular (RV) involvement because these patients require adequate RV preload. Do not administer nitrates (Class III) to patients who have received a phosphodiesterase inhibitor for erectile dysfunction within the last 24 hours (longer for some preparations).

Morphine Sulfate

Morphine sulfate is the analgesic of choice for continuing pain unresponsive to nitrates, and it is also effective in patients with pulmonary vascular congestion complicating ACS. Morphine is a venodilator that reduces ventricular preload and oxygen requirements. For this reason it should not be used in patients who may have hypovolemia. If hypotension develops, elevate the patient’s legs, administer volume, and monitor for signs of worsening pulmonary vascular congestion. Start with a 2 to 4 mg IV dose, and give additional doses of 2 to 8 mg IV at 5- to 15-minute intervals.

Reperfusion Therapies (Figure 1, Box 8)

Perhaps the most significant advance in the treatment of cardiovascular disease in the last decade is reperfusion therapy for AMI. Many clinical trials have established early fibrinolytic therapy as a standard of care for patients with AMI who present within 12 hours of the onset of symptoms with no contraindications.136–140 Reperfusion reduces mortality, and the shorter the time to reperfusion, the greater the benefit: a 47% reduction in mortality was noted when fibrinolytic therapy was provided within the first hour after onset of symptoms.139,140

The major determinants of myocardial salvage and long-term prognosis are

• Short time to reperfusion136,140

• Complete and sustained patency of the infarct-related artery with normal (TIMI grade 3) flow141,142

• Normal microvascular perfusion116,143–145

Fibrinolytics

In the absence of contraindications and the presence of a favorable risk-benefit stratification, fibrinolytic therapy is one option for reperfusion in those STEMI patients with onset of symptoms of ≤12 hours and ECG findings of STEMI (elevation >1 mm in 2 or more contiguous precordial or adjacent limb leads or new or presumably new LBBB) (Class I). In the absence of contraindications, it is also reasonable to administer fibrinolytics to patients with onset of symptoms within the prior 12 hours and ECG findings consistent with true posterior MI (Class IIa).

The ED physician should administer fibrinolytics to eligible patients as early as possible according to a predetermined process of care developed by the ED and cardiology staff. The goal is a door-to-needle time of ≤30 minutes. Every effort must be made to minimize the time to therapy. Patients treated within the first 70 minutes of onset of symptoms have >50% reduction in infarct size and 75% reduction in mortality rates.146 Pooled data from 22 randomized controlled trials of fibrinolytic therapy documents 65 lives saved per 1000 patients treated if fibrinolytics are provided in the first hour and pooled total of 131 lives saved per 1000 patients treated if fibrinolytics are provided within the first 3 hours of onset of symptoms.147 Fibrinolytics may be beneficial ≤12 hours after onset of symptoms.148,149

Fibrinolytic therapy is generally not recommended for patients presenting >12 hours after onset of symptoms, although it may be considered if continuing ischemic pain is present with ST elevation >1 mm in 2 or more contiguous precordial or adjacent limb leads (Class IIa).

Fibrinolytic therapy should not be administered (Class III) to patients who present >24 hours after the onset of symptoms or to patients who show ST-segment depression (unless a true posterior MI is suspected).

Risks of Fibrinolytic Therapy

Physicians who administer fibrinolytic agents should be aware of the indications, contraindications, benefits, and major risks of administration so that they may be able to weigh the net clinical benefit for each patient (see Table 1).150,151 This net clinical benefit requires integration of relative and absolute contraindications versus overall potential clinical gain.

Patients who present with extensive ECG changes (consistent with a large AMI) and a low risk of intracranial bleeding receive the greatest benefit from fibrinolytic therapy.136 Patients with symptoms highly suggestive of ACS and ECG findings consistent with LBBB are also appropriate candidates for intervention because they have the highest mortality rate when LBBB is due to extensive AMI. Fibrinolytics have been shown to be beneficial across a spectrum of patient subgroups with comorbidities such as previous MI, diabetes, cardiogenic shock, tachycardia, and hypotension.136 The benefits of fibrinolytic therapy are less impressive in inferior wall infarction except when it is associated with RV infarction (ST-segment elevation in lead V4R or anterior ST-segment depression).

Although older patients (>75 years) have a higher absolute risk of death, their absolute benefit appears to be similar to that of younger patients. There is only a small trend for benefit of fibrinolytic therapy administered 12 to 24 hours following the onset of symptoms. The incidence of stroke does increase with advancing age,152,153 reducing the relative benefit of fibrinolytic therapy. Older age is the most important baseline variable predicting nonhemorrhagic stroke.152 Although 1 large trial reported lower early and 1-year mortality rates with accelerated administration of tissue plasminogen activator (tPA) in patients <85 years of age,154 a recent retrospective analysis found no specific survival advantage and possible risk for patients >75 years of age.155 Additional studies are needed to clarify risk-benefit parameters in the elderly.

The presence of high blood pressure (SBP >175 mm Hg) on presentation to the ED increases the risk of stroke after fibrinolytic therapy.156 Current clinical practice is directed at lowering blood pressure before administration of fibrinolytic agents, although this has not been shown to reduce the risk of stroke.156 Fibrinolytic treatment of ACS patients who present with an SBP >180 mm Hg or a diastolic blood pressure >110 mm Hg is relatively contraindicated. Note that this SBP limit is slightly lower than the upper limit of 185 mm Hg used in eligibility criteria for fibrinolytic therapy for acute ischemic stroke; the diastolic limit of 110 mm Hg is consistent with the diastolic limit for tPA administration for stroke (see Part 9: “Adult Stroke”).

Several fibrinolytics are available for clinical use, including streptokinase,129,140,157 anistreplase,158,159 various regimens of alteplase,147,160,161 reteplase,162,163 and tenecteplase.138,164 Choice of agent is typically based on ease of administration, cost, and preferences of each institution.

Intracranial Hemorrhage

Fibrinolytic therapy is associated with a small but definite increase in the risk of hemorrhagic stroke, which contributes to increased mortality.136 More intensive fibrinolytic regimens using tPA (alteplase) and heparin pose a greater risk than streptokinase and aspirin.147,165 Clinical factors that may help risk-stratify patients at the time of presentation are age (≥65 years), low body weight (<70 kg), initial hypertension (≥180/110 mm Hg), and use of tPA. The number of risk factors can be used to estimate the frequency of stroke, which ranges from 0.25% with no risk factors to 2.5% with 3 risk factors.151 Several risk factor estimates are available for use by clinicians, including Simoons,151 the Co-Operative Cardiovascular Project,166 and the In-Time 2 trial.167

Percutaneous Coronary Intervention

Coronary angioplasty with or without stent placement is the most common form of PCI. PCI has been shown to be superior to fibrinolysis in combined end points of death, stroke, and reinfarction in many studies.78,80,82,96,168–173 These results, however, have been achieved in experienced medical environments with skilled providers (performing >75 PCIs per year) at a skilled PCI facility (performing >200 PCIs annually for STEMI, with cardiac surgery capabilities).

At this time primary PCI is preferred in patients with STEMI and symptom duration of >3 and ≤12 hours if skilled personnel can ensure that door-to-balloon time is ≤90 minutes or the difference in time between administration of fibrinolysis versus inflation of the PCI balloon is ≤60 minutes (Class I). PCI is also preferred in patients with contraindications to fibrinolysis and is reasonable in patients with cardiogenic shock or heart failure complicating MI.

In patients with STEMI presenting ≤3 hours from onset of symptoms, treatment is more time-sensitive, and there is inadequate research to recommend one treatment over the other (Class Indeterminate). In these “early presenters,” any possible benefit from primary PCI will be lost in prolonged transfers.

Complicated AMI

Cardiogenic Shock, LV Failure, and Congestive Heart Failure

Infarction of ≥40% of the LV myocardium usually results in cardiogenic shock and carries a high mortality rate. Of those who developed shock,174 patients with ST-segment elevation developed shock significantly earlier than patients without ST-segment elevation.

Cardiogenic shock and congestive heart failure are not contraindications to fibrinolysis, but PCI is preferred if the patient is at a facility with PCI capabilities. The ACC/AHA guidelines note that primary PCI is reasonable in those who develop shock within 36 hours of MI and are suitable candidates for revascularization that can be performed within 18 hours of the onset of shock.12 In hospitals without PCI facilities, rapidly administer a fibrinolytic agent and transfer the patient to a tertiary care facility where adjunct PCI can be performed if low-output syndromes or ischemia continues.175 The ACC/AHA STEMI guidelines recommend a door-to-departure time of ≤30 minutes for transfer.12

RV Infarction

RV infarction or ischemia may occur in up to 50% of patients with inferior wall MI. The clinician should suspect RV infarction in patients with inferior wall infarction, hypotension, and clear lung fields. In patients with inferior wall infarction, obtain a right-sided or 15-lead ECG; ST-segment elevation (>1 mm) in lead V4R is sensitive (sensitivity, 88%; specificity, 78%; diagnostic accuracy, 83%) for RV infarction and a strong predictor of increased in-hospital complications and mortality.176 The in-hospital mortality rate of patients with RV dysfunction is 25% to 30%, and these patients should be routinely considered for reperfusion therapy. Fibrinolytic therapy reduces the incidence of RV dysfunction.177 Similarly PCI is an alternative for patients with RV infarction and is preferred for patients in shock. Patients with shock caused by RV failure have a mortality rate similar to that for patients with shock due to LV failure.

Patients with RV dysfunction and acute infarction are dependent on maintenance of RV “filling” pressure (RV end-diastolic pressure) to maintain cardiac output.178 Thus, nitrates, diuretics, and other vasodilators (ACE inhibitors) should be avoided because severe hypotension may result. This hypotension is often easily treated with an IV fluid bolus.

Adjunctive Therapies for ACS and AMI

Clopidogrel

Clopidogrel irreversibly inhibits the platelet adenosine diphosphate receptor, resulting in a reduction in platelet aggregation through a different mechanism than aspirin. Since the publication of the ECC Guidelines 2000, several important clopidogrel studies have been published that document its efficacy for patients with both UA/NSTEMI and STEMI.

Clopidogrel was shown to be effective in 2 in-hospital randomized controlled trials (LOE 1)179,180 and 4 post-hoc analyses (LOE 7).181–184 In these studies patients with ACS and a rise in cardiac biomarkers or ECG changes consistent with ischemia had reduced stroke and MACE if clopidogrel was added to aspirin and heparin within 4 hours of hospital presentation. One study confirmed that clopidogrel did not increase risk of bleeding in comparison with aspirin.185 Clopidogrel given 6 hours or more before elective PCI for patients with ACS without ST elevation reduced adverse ischemic events at 28 days (LOE 1).186

In patients up to 75 years of age with STEMI who are treated with fibrinolysis, aspirin, and heparin (low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]), a 300-mg oral loading dose of clopidogrel given at the time of initial management (followed by a 75-mg daily dose for up to 8 days in hospital) improved coronary artery patency and reduced MACE.187

The Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial documented an increased rate of bleeding (but not intracranial hemorrhage) in the 2072 patients undergoing CABG within 5 to 7 days of administration of this agent.184 In addition, a post-hoc analysis of this trial reported a trend toward life-threatening bleeding. A subsequent risk-to-benefit ratio analysis concluded that the bleeding risk with clopidogrel in patients undergoing CABG was modest.184 One recent large prospective trial (LOE 1)187 failed to show any increase in bleeding in 136 patients undergoing CABG within 5 to 7 days of administration of clopidogrel. In patients with ACS, the risk of bleeding must be weighed against the risk of perioperative ACS events recurring if these agents are withheld. Current ACC/AHA guidelines, published soon after the large CURE trial, recommend withholding clopidogrel for 5 to 7 days in patients for whom CABG is anticipated.12 Ongoing studies are evaluating the efficacy and risk-benefit issues.

On the basis of these findings, providers should administer a 300-mg loading dose of clopidogrel in addition to standard care (aspirin, UFH, or LMWH and GP IIb/IIIa inhibitors if indicated) to ED patients with ACS with elevated cardiac markers or new ECG changes consistent with ischemia (excluding STEMI)184 in whom a medical approach or PCI is planned (Class I). It is reasonable to administer a 300-mg oral dose of clopidogrel to ED patients with suspected ACS (without ECG or cardiac marker changes) who are unable to take aspirin because of hypersensitivity or major gastrointestinal intolerance (Class IIa). Providers should administer a 300-mg oral dose of clopidogrel to ED patients up to 75 years of age with STEMI who receive aspirin, heparin, and fibrinolysis.

β-Adrenergic Receptor Blockers

In-hospital administration of β-blockers reduces the size of the infarct, incidence of cardiac rupture, and mortality in patients who do not receive fibrinolytic therapy.188–190 They also reduce the incidence of ventricular ectopy and fibrillation.191,192 In patients who do receive fibrinolytic agents, IV β-blockers decrease postinfarction ischemia and nonfatal AMI. A small but significant decrease in death and nonfatal infarction has been observed in patients treated with β-blockers soon after infarction.193 IV β-blockers may also be beneficial for NSTEMI ACS.

Oral β-blockers should be administered in the ED for ACS of all types unless contraindications are present. They should be given irrespective of the need for revascularization therapies (Class I). Use IV β-blockers for the treatment of tachyarrhythmias or hypertension (Class IIa).

Contraindications to β-blockers are moderate to severe LV failure and pulmonary edema, bradycardia (<60 bpm), hypotension (SBP <100 mm Hg), signs of poor peripheral perfusion, second-degree or third-degree heart block, or reactive airway disease. In the presence of moderate or severe heart failure, oral β-blockers are preferred. They may need to be given in low and titrated doses after the patient is stabilized. This permits earlier administration of ACE inhibitors that are documented to be efficacious in reducing 30-day mortality rates (see below).

Heparins

Heparin is an indirect inhibitor of thrombin that has been widely used in ACS as adjunctive therapy for fibrinolysis and in combination with aspirin and other platelet inhibitors for the treatment of UA and NSTEMI. UFH is a heterogeneous mixture of sulfated glycosaminoglycans with varying chain lengths. UFH has several disadvantages, including an unpredictable anticoagulant response in individual patients, the need for IV administration, and the requirement for frequent monitoring of the activated partial thromboplastin time (aPTT). Heparin can also stimulate platelet activation, causing thrombocytopenia.194

When UFH is used as adjunctive therapy with fibrin-specific lytics in STEMI, the current recommendations call for a bolus dose of 60 U/kg followed by infusion at a rate of 12 U/kg per hour (a maximum bolus of 4000 U and infusion of 1000 U/h for patients weighing >70 kg).195 An aPTT of 50 to 70 seconds is considered optimal. Because of the limitations of heparin, newer preparations of LMWH have been developed.

Unfractionated Heparin Versus Low-Molecular-Weight Heparin in UA/NSTEMI

Six in-hospital randomized controlled trials (LOE 1196,197 and LOE 2130,198,199 <24 hours; LOE 1200 <36 hours) and additional studies (including 7 meta-analyses [LOE 1201–207]) document similar or improved composite outcomes (death, MI and/or recurrent angina, or recurrent ischemia or revascularization) when LMWH is given instead of UFH to patients with UA/NSTEMI within the first 24 to 36 hours after onset of symptoms.

Although major bleeding events are not significantly different with LMWH compared with UFH, there is a consistent increase in minor and postoperative bleeding with the use of LMWH.208 Omission of LMWH (enoxaparin) on the morning of angiography resulted in vascular complication rates comparable to that of UFH.209

Four trials have compared UFH and LMWH in patients with NSTEMI who were treated with a GP IIb/IIIa inhibitor.210–213 In terms of efficacy, LMWH compared favorably with UFH, and in terms of safety there were similar or less frequent major bleeding events with LMWH but again an increased frequency of minor bleeding complications.

In summary, ED administration of LMWH (specifically enoxaparin) is beneficial compared with UFH when given in addition to antiplatelet therapy such as aspirin for patients with UA/NSTEMI (Class IIb). UFH should be considered if reperfusion is planned in the first 24 to 36 hours after onset of symptoms. Changing from one form of heparin to another (crossover of antithrombin therapy) during an acute event is not recommended because it may lead to an increase in bleeding complications.214

Unfractionated Heparin Versus Low-Molecular-Weight Heparin in STEMI

LMWHs have been found to be superior to UFH in patients with STEMI in terms of overall TIMI flow215,216 and reducing the frequency of ischemic complications,217 with a trend to a 14% reduction in mortality rates in a meta-analysis.218 No superiority was found in studies in which an invasive strategy (PCI) was used.

Two randomized controlled trials compared UFH with LMWH as ancillary treatment with fibrinolysis in the out-of-hospital setting.219,220 Administration of LMWH for patients with STEMI showed superiority in composite end points compared with UFH. This must be balanced against an increase in intracranial hemorrhage in patients >75 years of age who received LMWH (enoxaparin) documented in one of these randomized controlled trials (LOE 2).220

LMWH (enoxaparin) is an acceptable alternative to UFH in the ED as ancillary therapy for patients <75 years of age who are receiving fibrinolytic therapy, provided that significant renal dysfunction (serum creatinine >2.5 mg/dL in men or 2 mg/dL in women) is not present (Class IIb). UFH is recommended for patients ≥75 years of age as ancillary therapy to fibrinolysis (Class IIa) and for any STEMI patient who is undergoing revascularization. In patients with STEMI who are not receiving fibrinolysis or revascularization, LMWH (specifically enoxaparin) may be considered an acceptable alternative to UFH in the ED setting (Class IIb).

Glycoprotein IIb/IIIa Inhibitors

After plaque rupture in the coronary artery, tissue factor in the lipid-rich core is exposed and forms complexes with factor VIIa, setting in motion the coagulation cascade resulting in platelet activation. The integrin GP IIb/IIIa receptor is considered the final common pathway to platelet aggregation. GP IIb/IIIa inhibitors modulate this receptor activity. Three agents are available for use: abciximab, eptifibatide, and tirofiban.

GP IIb/IIIa Inhibitors in UA/NSTEMI

Several large studies of GP IIb/IIIa inhibitors in UA/NSTEMI have shown a clear benefit when combined with standard aspirin and heparin and a strategy of mechanical reperfusion (LOE 1221; LOE 2222; and 3 meta-analyses221,223,224). Severe bleeding complications (and no increase in intracranial hemorrhage) in the GP IIb/IIIa group were offset by the large benefit of these agents. The benefit of GP IIb/IIIa inhibitors extends to high-risk patients with UA/NSTEMI treated with PCI.223

In UA/NSTEMI patients not treated with PCI, the effect of GP IIb/IIIa inhibitors has been mixed. In 2 studies (LOE 1)212,221 and 3 meta-analyses (LOE 1),223–225 GP IIb/IIIa inhibitors produced no mortality advantage and only a slight reduction in recurrent ischemic events in one large meta- analysis224 but did show a reduction in 30-day mortality in a later, equally large meta-analysis.225 Of note, the benefit of GP IIb/IIIa inhibitors was dependent on coadministration of UFH or LMWH. Interestingly abciximab appears to behave differently from the other 2 GP IIb/IIIa inhibitors. In the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) IV-ACS trial and 1-year follow-up involving 7800 patients,226,227 abciximab showed a lack of treatment effect compared with placebo in patients treated medically only.

On the basis of these findings, GP IIb/IIIa inhibitors should be used in patients with high-risk stratification UA/NSTEMI as soon as possible in conjunction with aspirin, heparin, and clopidogrel and a strategy of early PCI (Class I). High-risk features include persistent pain, hemodynamic or rhythm instability, diabetes, acute or dynamic ECG changes, and any elevation in cardiac troponins attributed to cardiac injury. Extrapolation from efficacy studies suggests that this therapy may be administered in the ED once a decision has been made to proceed to PCI (Class IIa).

GP IIb/IIIa inhibitors tirofiban and eptifibatide may be used in patients with high-risk stratification UA/NSTEMI in conjunction with standard therapy if PCI is not planned (Class IIb), although studies are not conclusive at this time. As a result of the lack of benefit demonstrated in the GUSTO IV ACS trial, abciximab should not be given unless PCI is planned (Class III).

GP IIa/IIIb Inhibitors in STEMI

There is insufficient evidence to recommend for or against GP IIb/IIIa inhibitor therapy in STEMI; studies are ongoing. These agents have been used to facilitate antiplatelet therapy in patients undergoing direct PCI, but relatively few patients have been evaluated. GP IIb/IIIa inhibitors are now being evaluated early in STEMI to “facilitate” fibrinolytic therapy and serve as “upstream” adjuncts to planned direct PCI for STEMI, for example, achieving some degree of infarct artery patency during preparation or transfer. One study using abciximab (Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events [FINESSE]) is ongoing. Use of these agents in STEMI requires institutional-individualized protocols developed in conjunction with interventional cardiologists.

Calcium Channel Blockers

Calcium channel blocking agents may be added as an alternative or additional therapy if β-blockers are contraindicated or the maximum dose has been achieved.

The 1996 ACC/AHA guidelines for the management of patients with AMI228 make the following comment about calcium channel blockers:

Calcium channel blocking agents have not been shown to reduce mortality after acute MI, and in certain patients with cardiovascular disease there is data to suggest that they are harmful. There is concern that these agents are still used too frequently in patients with acute MI and that β-adrenergic receptor blocking agents are a more appropriate choice across a broad spectrum of patients with MI. In general, give calcium antagonists only when β-blockers are contraindicated or have been given at maximum clinical doses without effect (Class Indeterminate).

ACE Inhibitor Therapy

ACE inhibitor therapy has improved survival rates in patients with AMI, particularly when started early.229–233 Evidence from 7 large clinical trials,135,232–237 2 meta-analyses,238,239 and 10 minor trials237,240–249 documents consistent improvement in mortality when oral ACE inhibitors are administered in the hospital setting to patients with AMI with or without early reperfusion therapy. In these studies ACE inhibitors were not administered in the presence of hypotension (SBP <100 mm Hg or more than 30 mm Hg below baseline). The beneficial effects are most pronounced in patients with anterior infarction, pulmonary congestion, or LV ejection fraction <40%.

Administration of an oral ACE inhibitor is recommended within the first 24 hours after onset of symptoms in STEMI patients with pulmonary congestion or LV ejection fraction <40%, in the absence of hypotension (SBP <100 mm Hg or more than 30 mm Hg below baseline) (Class I). Oral ACE inhibitor therapy can also be recommended for all other patients with AMI with or without early reperfusion therapy (Class IIa). IV administration of ACE inhibitors is contraindicated in the first 24 hours because of risk of hypotension (Class III).

HMG Coenzyme A Reductase Inhibitors (Statins)

A variety of studies documented consistent reduction in indicators of inflammation and complications such as reinfarction, recurrent angina, and arrhythmias when statin treatment is administered within a few days after onset of an ACS.250–253 There is little data to suggest that this therapy should be initiated within the ED; however, early initiation (within 24 hours of presentation) of statin therapy is safe and feasible in patients with an ACS or AMI (Class I). If patients are already on statin therapy, continue the therapy (Class IIb).

Glucose-Insulin-Potassium

Although glucose-insulin-potassium (GIK) therapy was formerly thought to reduce the chance of mortality during AMI by several mechanisms, recent clinical trials found that GIK did not show any benefit in STEMI.254,255 At this time there is little evidence to suggest that this intervention is helpful.

Management of Arrhythmias

This section discusses management of arrhythmias during acute ischemia and infarction.

Ventricular Rhythm Disturbances

Treatment of ventricular arrhythmias during and after AMI has been a controversial topic for 2 decades. Primary VF accounts for the majority of early deaths during AMI.21–23 The incidence of primary VF is highest during the first 4 hours after onset of symptoms24–27 but remains an important contributor to mortality during the first 24 hours. Secondary VF occurring in the setting of CHF or cardiogenic shock can also contribute to death from AMI. VF is a less common cause of death in the hospital setting with the early use of fibrinolytics in conjunction with β-blockers.

Although prophylaxis with lidocaine reduces the incidence of VF, an analysis of data from ISIS-3 and a meta-analysis suggest that lidocaine increased all-cause mortality rates.256 Thus, the practice of prophylactic administration of lidocaine has been largely abandoned.

Routine IV administration of β-blockers to patients without hemodynamic or electrical contraindications is associated with a reduced incidence of primary VF. Low serum potassium but not magnesium has been associated with ventricular arrhythmias. It is prudent clinical practice to maintain serum potassium >4 mEq/L and magnesium >2 mEq/L.

Routine administration of magnesium to patients with MI has no significant clinical mortality benefit, particularly in patients receiving fibrinolytic therapy. The definitive study on the subject is the ISIS-4 study (LOE 1).135 ISIS-4 enrolled >58 000 patients and showed a trend toward increased mortality rates when magnesium was given in-hospital for primary prophylaxis to patients within the first 4 hours of known or suspected AMI.

Following an episode of VF, there is no conclusive data to support the use of lidocaine or any particular strategy for preventing VF recurrence. β-Blockers are the preferred treatment if not initiated before the episode of VF. If lidocaine is used, continue it for a short time after MI but no more than 24 hours unless symptomatic VT persists. Exacerbating or modulating factors should be identified and corrected. Further management of ventricular rhythm disturbances is discussed in Part 7.2: “Management of Cardiac Arrest” and Part 7.3: “Management of Symptomatic Bradycardia and Tachycardia.”

Summary

There has been tremendous progress in reducing disability and death from ACS. But many patients still die before reaching the hospital because patients and family members fail to recognize the signs of ACS and fail to activate the EMS system. Once the patient with ACS contacts the healthcare system, providers must focus on support of cardiorespiratory function, rapid transport, and early classification of the patient based on ECG characteristics. Patients with STEMI require prompt reperfusion; the shorter the interval from symptom onset to reperfusion, the greater the benefit. Patients with UA/NSTEMI or nonspecific or normal ECGs require risk stratification and appropriate monitoring and therapy. Healthcare providers can improve survival rates and myocardial function of patients with ACS by providing skilled, efficient, and coordinated out-of-hospital and in-hospital care.

This special supplement to Circulation is freely available at http://www.circulationaha.org

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December 13, 2005
Vol 112, Issue 24_supplement