The 2007 ACC/AHA guidelines for ACS recommend early stratification for risk of short-term death or nonfatal MI to determine the site of care, specific therapy, approach (early invasive versus conservative strategy), and prognosis. Treatment of possible, probable, or definite ACS should occur in a chest pain unit (CPU), medical telemetry unit, or coronary care unit (CCU) depending on the level of suspicion or confirmation of ACS. Low-risk patients can be evaluated in a CPU or medical telemetry unit. Patients with evidence of STEMI or other significant ECG changes, as well as those with any hemodynamic instability or new arrhythmia, should be evaluated in the CCU setting.
Treatment goals depend on the underlying pathophysiology. In STEMI, the initial approach involves immediate pharmacologic or catheter-based reperfusion to obtain normal coronary blood flow in a previously totally occluded artery. Time is critical for initial perfusion therapy: the golden hour is the first 60 minutes after presentation, and total ischemic time should be less than 90 to 120 minutes. The majority of patients will receive concomitant treatments with proven efficacy. In unstable angina and NSTEMI, the goal is to identify and remedy secondary causes that may increase myocardial oxygen demand or impair myocardial oxygen delivery, provide antithrombotic therapy to prevent further thrombosis and allow endogenous fibrinolysis to dissolve the thrombus, and employ revascularization to increase blood flow and prevent reocclusion. Although reperfusion therapy improves outcomes for STEMI, fibrinolysis has no role in the management of either UA or NSTEMI ACS. A meta-analysis not only showed no benefit in this setting, but showed an increased rate of MI. Therefore, treatment hinges on distinguishing between STEMI and UA/NSTEMI and then identifying high-risk patients with UA/NSTEMI who may benefit from invasive evaluation. The goal of secondary prevention for all patients is to stabilize and halt the progression of atherosclerotic plaques.
The key question to ask is whether the patient is having a STEMI. A broad array of management strategies for STEMI requires emergent cardiology consultation and possible expedited interhospital transfer. Reperfusion therapy has the advantages of being widely available and quick to administer; percutaneous coronary intervention (PCI) is more effective and has a lower bleeding risk but has limited availability and may cause treatment delays (Figure 124-2).
If initial testing suggests that the patient is having a NSTEMI, it is then incumbent on the practitioner to identify high-risk clinical subgroups to guide clinical decision making in order to salvage as much myocardium as possible. The clinical spectrum of non-ST-segment elevation ACS ranges from low-risk patients who would not benefit from early angiography with PCI or a selectively invasive strategy to intermediate and high-risk patients who would likely benefit due to a higher likelihood of adverse cardiac events.
All patients with STEMI should receive dual therapy with aspirin and clopidogrel regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion (class Ia). In patients for whom coronary artery bypass graft (CABG) surgery is planned, clopidogrel should be held at least five days, preferably seven days, unless the urgency for revascularization outweighs the risk of increased bleeding (class I). In patients less than 75 years of age, it is reasonable to administer a loading dose of clopidogrel 300 mg (class IIa); no data are available to support loading in older patients. Long-term maintenance of one year may be reasonable for patients with STEMI regardless of whether they underwent reperfusion therapy (class IIa).
Morphine for pain control remains a class I recommendation for STEMI, although it may increase adverse events in NSTEMI.
What Is the Optimal Reperfusion Strategy for This Patient with STEMI?
Following recognition and diagnosis of an acute STEMI, a rapid decision with regard to reperfusion eligibility (whether fibrinolysis or PCI) and strategy must be made by the physician.
Ongoing treatment should then be carried out in the coronary care setting. The current ACC/AHA guidelines stipulate that all hospitals performing primary PCI should achieve a median door-to-balloon time of less than 90 minutes, with at least 75% of patients treated reaching this 90-minute target from first medical contact. If these time constraints cannot be met, fibrinolysis should be administered unless contraindicated.
The European Society of Cardiology (ESC) guidelines extend the 90-minute timeframe from first medical contact to PCI to 120 minutes. Furthermore, patients who present late with STEMI (> 12 hours) and who are hemodynamically stable should be transferred for PCI rather than receive thrombolysis. High-risk patients (elderly, those with anterior MI, renal impairment, or LV dysfunction) appear to sustain higher mortality rates undergoing primary PCI when a PCI-related delay is encountered.
When performed at a high-volume center (> 200 PCI procedures yearly) by experienced and skilled operators (> 75 PCI per year), primary PCI is the superior treatment modality for STEMI. Primary PCI leads to higher infarct-related artery (IRA) patency compared to fibrinolytic therapy alone. Primary PCI as opposed to thrombolysis has been shown to prevent 2 deaths per 100 patients treated (NNT = 50). Sicker STEMI patients appear to derive most benefit from PCI. Furthermore, primary PCI is associated with a lower risk of hemorrhagic stroke (0.05% versus 1.1%).
One of the major limitations to primary PCI therapy in the setting of an acute STEMI is achieving rapid transfer and access to a PCI-equipped center. It is estimated that less than one-quarter of acute care hospitals in the U.S. have PCI capabilities, though approximately 80% of the population reside within one hour of facilities with such capabilities. As the extent of myocardial necrosis and clinical outcomes are intrinsically linked to the duration of occlusion of the infarct-related artery, the point at which the delay in initiating PCI negates the advantages of prompt fibrinolysis is hotly debated. Primary PCI in a center without cardiac surgery availability is given a class IIb recommendation in 2007 ACC/AHA guidelines, although considerable data exist demonstrating excellent results compared with those facilities that have on-site cardiothoracic surgery.
Pharmacologic reperfusion is indicated in those circumstances where ECG criteria are met and symptom onset is < 12 hours (class IA) where prompt access to PCI is not possible, and no contraindications exist. Patients with a posterior STEMI presenting within 12 hours of symptom onset with no contraindications to fibrinolysis should also receive pharmacologic reperfusion (class IIA level of evidence C). Those STEMI patients who present 12 to 24 hours after symptom onset, who meet ECG criteria with recurrent ischemic symptoms also are given a class IIA recommendation for fibrinolytic therapy.
The U.S. Food and Drug Administration has approved tissue plasminogen activator (tPA), streptokinase, tenecteplase (TNK), and reteplase (rPA) as fibrinolytic agents, all of which promote the conversion of plasminogen to plasmin. Patients treated within one to three hours of the onset of symptoms clearly benefit the most regarding reduction of infarct size, limiting LV dysfunction, septal rupture, cardiogenic shock, ventricular arrhythmias, and death. Unlike streptokinase, newer fibrinolytic agents do not provoke an immune response and have been shown to result in greater infarct-related artery patency rates and a lower 30-day mortality benefit (Table 124-4).
Table 124-4 Common Fibrinolytic Agents ||Download (.pdf)
Table 124-4 Common Fibrinolytic Agents
|Fibrinolytic||Mean Plasma Half-life (minutes)||Relative Fibrin Specificity||% Patients with TIMI-3 Flow IRA at 90 minutes||Dose|
|Steptokinase||23||–||32||IV infusion of 1.5 million units over 60 minutes|
|Alteplase||4–6||++||54||tPA 15 mg bolus, followed by 50 mg IV over first 30 minutes, followed by 35 mg over next 60 minutes|
|Tenecteplase||20||+++||63||Single weight-based bolus of 30 to 50 mg (depending on the exact weight) over 10 seconds|
Patients receiving fibrinolysis should be treated with dual antiplatelet therapy in addition to anticoagulation. 2007 ACC/AHA guidelines recommend that anticoagulation (unfractionated heparin [UFH], enoxaparin, or fondaparinux) should be continued for a minimum of 48 hours and up to eight days unless contraindicated. The TIMI risk score for STEMI enables the physician to rapidly assess the patient's 30-day mortality based on history and clinical exam, and ECG. Importantly, delay in treatment is associated with a higher mortality. Of 14 possible points, if the risk score is greater than 8 points, the associated mortality is 35.9% at 30 days.
The TIMI risk score for STEMI
|• Age 65–74 (2 points); Age ≥ 75 (3 points)||(2 or 3 points)|
|• Systolic blood pressure < 100 mm Hg||(3 points)|
|• Heart rate > 100 beats per minute||(2 points)|
|• Killip II-IV||(2 points)|
|• Anterior ST elevation or LBBB||(1 point)|
|• Diabetes, history of HBP, angina||(1 point)|
|• Weight < 67 kg||(1 point)|
|• Time to treatment > 4 hours||(1 point)|
When Should an Invasive Strategy Be Considered Post Fibrinolysis for STEMI?
The timing of when to refer for PCI appears crucial in relation to maximizing potential benefits of restoring infarct-related artery (IRA) myocardial blood flow while minimizing major bleeding risks attendant with recent fibrinolysis. The process whereby a patient with acute STEMI is initially treated with a therapeutic agent with the aim of increasing the likelihood of IRA patency prior to immediate scheduled PCI is described as facilitated PCI. Medications used in this setting include high-dose heparin, GPIIbIIIa inhibitors, fibrinolytic therapy, or reduced-dose fibrinolysis in conjunction with a GPIIbIIIa-inhibiting drug. Possible advantages include more rapid flow restoration, thrombus burden reduction, and restoration of hemodynamic or electrical stability while awaiting PCI. Despite the conceptual appeal of such a management plan, particularly where significant delays may be unavoidable prior to PCI, the 2007 updated ACC/AHA guidelines do not recommend routine facilitated PCI, as it does not offer any evident clinical benefit. However, the guidelines do allow for a facilitated PCI strategy when a high-risk patient with a low risk of a major bleeding complication has received pretreatment with a pharmacologic regimen other than full-dose fibrinolysis (eg, for a patient with a large MI with hemodynamic or electrical instability whose transfer to the catheterization suite would involve a delay). For these patients PCI post fibrinolysis may be most beneficial if performed in the 2- to 24-hour period after administration of pharmacologic reperfusion therapy.
Approximately 5–10% of those undergoing urgent coronary angiography for STEMI are referred for urgent or deferred CABG within several days to weeks post the index event. Patients post fibrinolysis who demonstrate evidence of electrical or hemodynamic instability or recurrent ischemia should be considered for catheterization with a view to revascularization at any time after presentation.
The role of PCI within 12 hours of failed fibrinolytic therapy or rescue PCI is less clear. Guidelines recommend rescue PCI for suitable candidates less than 75 years of age who develop shock within 36 hours of MI and are suitable for revascularization that can be performed within 18 hours of the onset of hemodynamic instability (class IB), and in those with Killip class III heart failure and onset of symptoms within 12 hours (class IB).
In summary, a planned reperfusion strategy using full-dose fibrinolytic therapy followed by immediate PCI is not recommended and may be harmful (class IIIB). PCI of a significant stenosis in a patent infarct artery more than 24 hours after STEMI may be considered as part of an invasive strategy. Rescue PCI for patients who have failed fibrinolytic therapy (defined as less than 50% of ST elevation resolved after 90 minutes following reperfusion drug administration—in the lead with the greatest initial ST-segment elevation) and who have a moderate or large area of myocardium at risk (anterior MI, inferior MI with right ventricular involvement, precordial ST segment depression) is associated with a 28% risk reduction in the composite endpoints of death, reinfarction, and heart failure. PCI of totally occluded artery greater than 24 hours after STEMI is not recommended in asymptomatic patients with one- or two-vessel disease who are hemodynamically and electrically stable with no evidence of severe ischemia (class III).
Is This Patient Experiencing Cardiogenic Shock?
Cardiogenic shock due to acute MI retains a mortality rate of approximately 50%. Risk factors for cardiogenic shock include age greater 70 years, increased time from onset of symptoms of STEMI to presentation, systolic blood pressure (SBP) less than 120 mm Hg, sinus tachycardia greater than 110 beats per minute (bpm) or heart rate less than 60 bpm, and heart failure.
Despite the significant advances in reperfusion therapies, the current overall STEMI 30-day mortality rate remains at 6% to 10%. Careful recognition and management of potential MI complications that may have adverse hemodynamic consequences, such as cardiogenic shock (frequently ensuing due to infarction of greater than 40% of the LV mass), RV infarction–induced hypotension or associated atrioventricular dyssynchrony, are vital.
What Is the Short-Term and Long-Term Risk of Adverse Cardiac Events for Patients Experiencing NSTEMI or UA?
The TIMI, GRACE, and PURSUIT risk scores powerfully predict recurrent MI, death, or heart failure in patients with NSTEMI or UA and can be used at the bedside to tailor therapy. Despite proven accuracy, these risk stratification tools are frequently underutilized at the bedside.
The TIMI risk score for NSTEMI
- Age ≥ 65 years
- ≥ 3 risk factors for CAD (family history of CAD, hypertension, hypercholesterolemia, diabetes, current smoker)
- Significant coronary stenosis (stenosis ≥ 50%)
- ST segment deviation
- Severe anginal symptoms (≥ 2 anginal episodes within last 24 hrs)
- Aspirin usage within the previous 7 days
- Elevated serum cardiac biomarkers
Two phase-3 international randomized, double-blind trials totaling over 5000 patients with UA/NSTEMI validated the TIMI (Thrombolysis in Myocardial Infarction) risk score (TIMI-11B and the ESSENCE [Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave MI]).
Higher TIMI scores are associated with greater risk of all-cause mortality, MI, and worsening ischemia necessitating urgent revascularization through 14 days, as follows:
- Low risk (0–2 points): 4.7 % event rates (0–1 points), 8.3% (2 points)
- Intermediate risk (3–4 points): 13.2% event rates (3 points), 19.9% (4 points)
- High risk (5–7 points): 26.2% event rates (5 points), 40.9% (6–7 points)
The TIMI III registry of over 1100 patients with ACS reinforced the validity of the TIMI scoring system. Six-week mortality increased from 1.0% to 2.9% to 5.9%, and one-year mortality increased from 3.9% to 6.5% to 21.0%, across low, intermediate, and high TIMI score groups. TACTICS TIMI-18 demonstrated that
- Early invasive strategy reduced the composite end point of death, nonfatal MI, or readmission with ACS to 15.9% versus 19.4% at six months.
- Patients in the intermediate and high-risk groups gained most from an early invasive management strategy.
- Patients classified as low risk (< 3 points) derived no benefit from early angiography or PCI.
The GRACE risk score: The Global Registry of Acute Coronary Events (GRACE) risk score uses eight variables that yielded almost 90% of the prognostic information with regard to predicting the probability of in-hospital mortality. Risk factors include age, Killip class (a clinical classification system used in AMI based on the assessment of the patient's hemodynamic status, Table 124-5), SBP, ST-segment deviation, cardiac arrest upon admission, creatinine, biochemical evidence of myocardial necrosis, and heart rate. This risk model has been validated to accurately predict the risk of in-hospital mortality and the cumulative risk of death or MI in those with ACS (including STEMI) in approximately 15,000 patients derived from the GRACE multinational registry (C-statistic = 0.81 for death, C-statistic = 0.73 for death or MI). (An online risk calculator for use with this scoring system is available at www.outcomes.org/grace.)
Table 124-5 Clinical Findings and Associated Killip Class ||Download (.pdf)
Table 124-5 Clinical Findings and Associated Killip Class
|Clinical Findings||Killip Class|
|No features of heart failure||I|
|Pulmonary rales, elevated jugular venous pressure or S3||II|
Risk stratification NSTEMI
- Determination of site of care, selecting therapy (eg, glycoprotein IIb/IIIa inhibitors), and early invasive strategy in non-ST-segment elevation ACS hinges on risk stratification of recurrent MI, death, or heart failure.
- Older age, diabetes, vascular disease elsewhere, congestive heart failure (Killip class II or higher), and ACS despite chronic aspirin therapy (TIMI score ≥ 3) are clinical characteristics associated with significantly increased risk of adverse events.
According to ACC/AHA Guidelines the presence of the following predict high risk:
- Hemodynamic instability, ventricular tachycardia
- Depressed LV function, presence of congestive heart failure, worsened mitral regurgitation
- ST-segment depression
- Elevated biomarkers
- Recurrent angina at low-level exertion despite intensive therapy, angina with hypotension
- High-risk findings on stress testing
- PCI within the previous six months, prior CABG
- High-risk patients benefit from GP IIb/IIIa inhibitors (versus placebo), LMWH (versus UFH), and invasive (versus conservative) therapy
Does This Patient with UA or NSTEMI Require Urgent Coronary Angiography?
Early coronary angiography allows delineation of the anatomy enabling the physician to rule out ACS in the 10% to 20% of patients with no significant coronary lesion, ensuring that they are not then inappropriately treated. Coronary angiography facilitates prognostic prediction and may appropriately direct patients with multivessel and left main disease to CABG. On the other hand, a considerable proportion of patients respond well to intensive medical therapy, and may not need to undergo an invasive procedure with its associated risks.
The ACC/AHA guidelines recommend coronary angiography leading to revascularization for patients with refractory angina or hemodynamic or electrical instability and for those patients initially managed conservatively who are judged to be at high risk unless there are concomitant severe comorbidities or specific contraindications (class IB).
Patients with higher-risk profiles should undergo catheterization within 48 hours for diagnosis and intervention.
Contraindications to exercise testing include hemodynamic compromise, acute myocardial infarction or unstable angina, aortic dissection, acute pulmonary embolism, pericarditis or pericardial tamponade, severe anemia, critical aortic stenosis, thyrotoxicosis, pheochromocytoma, and severe uncontrolled hypertension.
Noninvasive risk stratification in ACS
For patients who have had diagnostic angiography:
If the patient has undergone complete revascularization, there is usually no need for functional cardiac testing prior to discharge.
If the patient has multivessel disease and PCI of the culprit vessel, ETT with imaging is usually indicated to localize residual ischemia.
For patients treated conservatively:
To diagnose exercise-induced ischemia and to assess extent and severity: At the time of testing patients should be free of angina at rest, the ECG should be stable for at least 24 hours prior to the test, and cardiac biomarkers should be declining.
The clinical spectrum of non-ST-segment elevation ACS ranges from
Chronic stable angina to crescendo angina to rest pain, no ECG changes, negative biomarkers to rest pain ECG changes, negative biomarkers (UA)
Rest pain, ECG changes, positive biomarkers to transient ST elevations (NSTEMI)
- Management hinges on risk stratification of individual patients with non-ST-segment elevation ACS for adverse cardiac events. Two validated, powerful risk prediction models allow for rapid bedside evaluation of individual risk. As the risk score increases, event rates significantly increase.
TIMI Risk Score: All-cause mortality, new or recurrent MI, severe recurrent ischemia requiring revascularization within 14 days
GRACE Risk Score: All-cause mortality from hospital discharge after any form of ACS.
- Early invasive strategy (PCI) compared with medical therapy reduces the composite end point of death, nonfatal MI, or readmission with ACS to 15.9% versus 19.4% at six months in intermediate and high-risk TIMI groups (TIMI score 3–4 and 5–7 respectively).
The 2007 ACC/AHA guidelines recommend noninvasive testing after 12–24 hours in low- and intermediate-risk patients with either UA or NSTEMI who remain symptom free with no evidence of LV dysfunction. Limited data compare the relative prognostic value of different noninvasive testing modalities in this setting. Options include exercise or pharmacologic stress treadmill testing with or without nuclear imaging, in addition to stress echocardiography depending on the clinical circumstances of the patient (addition of imaging in presence of uninterpretable ECG) and facilities within the institution. Perfusion imaging is preferred for patients whose baseline ECG has ST-segment abnormalities, LBBB, or pacing, and for those who have a significant pretest likelihood for CAD to determine the extent of ischemia. Dobutamine or adenosine are generally reserved for those patients who cannot exercise and do not have contraindications such as severe hypertension (dobutamine) or acute bronchospasm or hypotension (adenosine).
Cardiac-computed tomography (CCT) is able to visualize nonstenotic calcified and noncalcified coronary plaques and has a very high negative predictive value (91% to 100%) of ruling out the presence of CAD. Excellent images may be obtained within five minutes, thereby facilitating rapid triage from the emergency department. Its primary use in acute chest pain should be reserved for patients with an intermediate pretest probability of CAD or for those patients at increased risk for aortic dissection and segmental pulmonary embolism that can be visualized at the same time. Patients with a low pretest probability should not be subjected to the risk of radiation; patients with a high pretest probability of CAD and suspected NSTEMI or UA would not benefit because a negative CCT would not alter the pretest probability.
Cardiac magnetic resonance (CMR) with late gadolinium enhancement may identify specific myocardial regions at risk and thereby provide additive information pertinent not only to risk stratification but also for targeting revascularization in patients with UA/NSTEMI. CMR is a rapidly evolving technology and the reported specificity, positive predictive value, and overall accuracy are likely to improve. The disadvantages of CMR include cost, long time required for scanning, the use of gadolinium in patients with reduced renal function, and contraindications (implanted pacemakers and defibrillators).