Coronary artery disease (CAD) is the leading cause of death in the United States. Unstable angina (UA) and the closely related condition of non–ST-segment elevation myocardial infarction (NSTEMI) are common manifestations of this disease. Knowledge of disease pathophysiology, diagnostic approaches, management strategies, and preventive measures continue to evolve. Accordingly, the American College of Cardiology (ACC) and the American Heart Association (AHA) organized a committee to revise and update (2007) the previous guidelines published in 2000 and updated in 2002.
Overview of Changes
The writing committee considered evidence published since 2002 and drafted revised recommendations to incorporate results from major clinical trials. , In the 2007 revision, greater emphasis is placed on earlier access to medical evaluation. New imaging modalities (coronary computed tomographic angiography [CTA] and cardiac magnetic resonance imaging) are recognized as diagnostic options in selected patients. Troponins are highlighted as the dominant cardiac biomarker of necrosis. B-type natriuretic peptide (BNP) has been added to the list of biomarkers potentially useful in risk assessment. Supplemental posterior electrocardiograph (ECG) leads V 7 to V 9 are noted to be a reasonable diagnostic tool to assess the possibility of ST-segment elevation myocardial infarction (STEMI) caused by left circumflex occlusion.
Clinical trials data are noted overall to continue to support an initial invasive strategy for higher-risk and clinically unstable UA/NSTEMI patients ; nevertheless, other data (ICTUS) also were reviewed that allowed an initial conservative strategy to be considered in initially stabilized patients, and an initial conservative strategy is now specifically recognized as the preferred strategy in those at low risk of acute coronary syndromes (ACS), particularly low-risk women, as supported by a growing body of evidence.
The recommendation for beta blockade is now counterbalanced with a statement on the potential for harm, especially with acute intravenous administration in those at risk of heart failure or cardiogenic shock (COMMIT). Nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin should be avoided in UA/NSTEMI patients because of the recent recognition of potential harm. ,
Two new anticoagulants, fondaparinux and bivalirudin, have undergone testing and are recommended as alternatives to unfractionated heparin (UFH) and low–molecular-weight heparins (LMWHs) for specific applications in UA/NSTEMI. Support for thienopyridine use (primarily with clopidogrel in 2007) continues to grow, including higher loading-dose options, earlier (upstream) administration, and longer administration (especially after drug-eluting stent [DES] placement). Evidence still supports glycoprotein (GP) IIb/IIIa receptor antagonists as providing incremental benefit in higher risk patients. Special emphasis is placed on dosing adjustment (e.g., for anticoagulants and antiplatelet agents) based on creatinine clearance, especially in the elderly, in women, and in others with baseline renal insufficiency, to prevent dosing errors leading to increased bleeding risk. The guidelines also incorporate recent updates for secondary and primary prevention. An expanded section recognizes special diagnostic and therapeutic considerations in special patient groups, and care processes are highlighted as an area important to short- and long-term patient outcomes.
Nearly simultaneously, the European Society of Cardiology (ESC) also published guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. These complementary guidelines are recommended for additional reading and insights into the evaluation and management of this condition.
Classification of Recommendations
The schema for classification and level of evidence of recommendations follow that of the previous version of these and other recent ACC/AHA guidelines. These can be summarized briefly as follows:
Class I: Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective (i.e., the procedure/treatment SHOULD be performed/administered).
Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment.
Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy (i.e., IT IS REASONABLE to perform procedure/administer treatment).
Class IIb: Usefulness/efficacy is less well established by evidence/opinion (i.e., the procedure/treatment MAY BE CONSIDERED).
Class III: Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful/effective and in some cases may be harmful (i.e., the procedure/treatment should NOT be performed/administered).
The weight of evidence is ranked separately from the class recommendation as (A), highest, if data were derived from multiple randomized clinical trials or meta-analyses that involved sufficiently large numbers of patients and multiple population risk strata, and (B), intermediate, if data were derived from a single randomized trial or nonrandomized studies with limited population risk strata evaluated. The lowest rank (C) was given when expert opinion, case studies, or standard-of-care formed the primary basis for the recommendation.
Overview of Acute Coronary Syndromes
Acute coronary syndromes (ACS) represent a major health problem. The National Center for Health Statistics report for 2007 indicates that 1,565,000 hospitalizations occurred in 2004 for a primary or secondary diagnosis of an acute coronary syndrome: 669,000 for UA and 896,000 for myocardial infarction (MI). In the spectrum of ACS, UA/NSTEMI is defined by ECG ST-segment depression or prominent T wave inversion and/or positive biomarkers of necrosis (e.g., troponin) in the absence of ST-segment elevation and in an appropriate clinical setting (i.e., chest discomfort or anginal equivalent). The importance of this syndrome is emphasized by the fact that approximately three-quarters (1.24 million) of ACS hospitalizations annually are for UA/NSTEMI and the other quarter (0.33 million) for ST-segment elevation MI (STEMI). UA/NSTEMI is usually, but not always, a complication of atherothrombotic coronary artery disease (CAD) leading to a marked reduction in oxygen supply to the myocardium and an increased risk of subsequent MI and cardiac death.
Initial Evaluation and Management
Delays in recognition of the symptoms of UA/NSTEMI and presentation to the medical care system remain a challenge for optimal medical care. There is a continued need to stress earlier recognition and presentation for care, which can reduce morbidity and mortality. Currently, the average delay after symptom onset is approximately 2 hours. Reasons for delay include a mismatch between expectation and actual symptoms, an impression that symptoms are self-limited, or attribution of symptoms to other conditions. Also, ACS/MI may be clinically silent, unrecognized, or associated with symptoms other than chest discomfort (such as dyspnea) in one third to one half of cases. , Older patients, women, and diabetics are more likely to have a silent or atypical presentation.
When first contacted, health care providers should advise patients with possible ACS that evaluation cannot be performed solely via the telephone, and they should especially target those with known coronary heart disease (CHD) or equivalents. Instructions to administer aspirin may be given. When symptoms are moderate to severe or sustained (e.g., >20 min), unresponsive to 1 nitroglycerin (NTG) dose (if available and administered), and MI is suspected, patients should be instructed to access the emergency medical system (EMS) by dialing 911 and be transported to hospital by ambulance. On arrival, these patients should be considered high priority and evaluated by a predetermined algorithm ( Fig. 34-1 ) aimed at addressing two specific questions: what is the likelihood that symptoms represent ACS, and what is the likelihood of an adverse clinical outcome?
Early Risk Stratification
An estimation of risk is useful in selection of the level of initial medical care and initial medical and interventional therapies. This risk is assessed by integrating features of the initial medical history, physical examination, ECG (goal, within 10 min of emergency department [ED] arrival), renal function, and cardiac biomarker measurements. The application of quantitative risk scores developed in recent years (e.g., TIMI, GRACE, and PURSUIT risk scores) is expected to assist with short- as well as longer-term risk assessment ( Table 34-1 ). Overall, risk is highest at presentation then declines but remains elevated above baseline for at least 1 to 3 months beyond the acute stage.
| TIMI Risk Score | All-Cause Mortality, New or Recurrent Myocardial Infarction, or Severe Recurrent Ischemia Requiring Urgent Revascularization Through 14 Days after Randomization |
|---|---|
| 0-1 | 4.7% |
| 2 | 8.3% |
| 3 | 13.2% |
| 4 | 19.9% |
| 5 | 26.2% |
| 6-7 | 40.9% |
- •
Age 65 years or older
- •
At least 3 risk factors for CAD
- •
Prior coronary stenosis of 50% or more *
- •
ST segment deviation on ECG presentation
- •
At least 2 anginal events in prior 24 hours
- •
Use of aspirin in prior 7 days
- •
Elevated serum cardiac biomarkers
* Variable remained relatively insensitive to missing information and remained a significant predictor of events. The TIMI risk tool can be accessed at www.timi.org .
It should be recognized that three fourths of patients evaluated in the ED for suspected ACS will be found not to have acute ischemia and require further evaluation, triage, and treatment as indicated by their underlying symptoms and condition.
Cardiac Biomarkers of Necrosis
The sensitivity and specificity of the cardiac troponins I and T have made them the diagnostic biomarkers of choice and inspired the redefinition of acute myocardial infarction (AMI). Further, they may identify high-risk patients who will benefit from aggressive medical and interventional therapies. Myocardial necrosis now is defined as an elevation of troponin above the 99th percentile of normal, and MI is defined as necrosis related to ischemia. The diagnosis of AMI must be based on troponin elevation supplemented with other clinical and laboratory features, because detectable elevations of troponin are commonly observed with other conditions using the newer, highly sensitive troponin assays.
Troponins can be detected in blood as early as 2 to 4 hours after symptom onset, but elevation can be delayed for up to 8 to 12 hours. The timing of initial elevation is similar to that of creatine kinase (CK)-MB but persists longer, that is, for 5 to 14 days ( Fig. 34-2 ). CK-MB remains useful for the diagnosis of early infarct extension (reinfarction) and for periprocedural MI because its short half-life is well suited to detecting secondary marker increases. A newer method aims to identify MI earlier by relying on changes in serum marker levels (delta values) over an abbreviated time interval (e.g., 2 hours) when markers may be still in the normal or indeterminate range.
Other Biomarkers
Biomarkers of other pathophysiologic mechanisms implicated in ACS and multimarker approaches are currently under investigation. B-type natriuretic peptides have been shown to provide incremental prognostic value in patient cohorts with STEMI and UA/NSTEMI and now may be used to supplement risk assessment.
Initial Triage and Immediate Management
Based on initial clinical risk assessment, patients can be assigned and managed according to one of four categories: noncardiac diagnosis, chronic stable angina, possible ACS, and definite ACS, which is further divided into UA/NSTEMI and STEMI, based on the initial ECG (see Fig. 34-1 ). Emergency department–based chest pain evaluation units have been found to be helpful to avoid both unnecessary hospital admissions as well as inappropriate ED discharges. Patients at low ACS risk (see Fig. 34-1 , box F1) may be considered for a predischarge stress test or coronary CT angiogram. Alternatively, they may be discharged with appropriate medications and instructions and return for testing within 72 hours. Patients with definite or probable ACS, including those with ongoing ischemic symptoms, positive cardiac biomarkers, new ST-segment deviations, new deep T wave inversions, hemodynamic abnormalities, or a positive stress test are admitted to the hospital for further management.
Selected Recommendations for Initial Evaluation and Management
- A
Clinical Assessment
Class I
- 1
Patients with definite symptoms of ACS (chest discomfort with or without radiation to the arm[s], back, neck, jaw, or epigastrium; shortness of breath; weakness; diaphoresis; nausea; lightheadedness) should be instructed to call 911 and should be transported to the hospital by ambulance rather than by friends or relatives. ( Level of Evidence [ LOE ] : B )
- 2
Prehospital EMS providers should administer 162 to 325 mg of aspirin (chewed) to chest pain patients suspected of having ACS unless contraindicated or already taken by the patient. Although some trials have used enteric-coated aspirin for initial dosing, more rapid buccal absorption occurs with non–enteric-coated formulations. ( LOE: C )
- 3
Health care providers should instruct patients with suspected ACS for whom NTG has been prescribed previously to take not more than 1 dose of NTG sublingually in response to chest discomfort or pain. If chest discomfort or pain is unimproved or is worsening 5 min after 1 NTG dose has been taken, it is recommended that the patient or family member, friend, or caregiver call 911 immediately to access EMS before taking additional NTG. In patients with chronic stable angina, if symptoms are significantly improved by 1 dose of NTG, it is appropriate to instruct the patient or family member, friend, or caregiver to repeat NTG every 5 min for a maximum of 3 doses and call 911 if symptoms have not resolved completely. ( LOE: C )
- 4
Patients with a suspected ACS with chest discomfort or other ischemic symptoms at rest for greater than 20 minutes, hemodynamic instability, or recent syncope or presyncope should be referred immediately to an ED. Other patients with a suspected ACS who are experiencing less severe symptoms and who have none of the above high-risk features, including those who respond to an NTG dose, may be seen initially in an ED or an outpatient facility able to provide an acute evaluation. ( LOE: C )
- 1
- B
Early Risk Stratification
Class I
- 1
A rapid clinical determination of the likelihood risk of obstructive CAD (i.e., high, intermediate, or low) should be made in all patients with chest discomfort or other symptoms suggestive of an ACS and considered in patient management. ( LOE: C )
- 2
A 12-lead ECG should be performed and shown to an experienced emergency physician as soon as possible after ED arrival, with a goal of within 10 minutes of ED arrival for all patients with chest discomfort (or anginal equivalent) or other symptoms suggestive of ACS. ( LOE: B )
- 3
A cardiac-specific troponin is the preferred biomarker, and, if available, should be measured in all patients who present with chest discomfort consistent with ACS. CK-MB by mass assay is acceptable but not preferred. ( LOE: B )
- 4
Patients with negative cardiac biomarkers within 6 hours of the onset of symptoms consistent with ACS should have biomarkers remeasured in the time frame of 8 to 12 hours after symptom onset. ( LOE: B )
- 1
Class IIa
- 1
Use of risk-stratification models, such as the Thrombolysis In Myocardial Infarction (TIMI) or Global Registry of Acute Coronary Events (GRACE) risk score or the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) risk model, can be useful to assist in decision making regarding treatment options in patients with suspected ACS. ( LOE: B )
- 2
It is reasonable to obtain supplemental ECG leads V 7 through V 9 in patients whose initial ECG is nondiagnostic to rule out MI due to left circumflex occlusion. ( LOE: B )
- 1
Class IIb
- 1
For patients who present within 6 hours of symptoms suggestive of ACS, a 2-hour delta CK-MB mass in conjunction with 2-hour delta troponin may be considered. ( LOE: B )
- 2
Measurement of BNP or NT terminal (NT)-proBNP may be considered to supplement assessment of global risk in patients with suspected ACS. ( LOE: B )
- 1
- C
Immediate Management
Class I
- 1
The history, physical examination, 12-lead ECG, and initial cardiac biomarker tests should be integrated to assign patients with chest pain into one of four categories: a noncardiac diagnosis, chronic stable angina, possible ACS, and definite ACS. ( LOE: C )
- 2
In patients with suspected ACS in whom ischemic heart disease is present or suspected, if the follow-up 12-lead ECG and cardiac biomarkers measurements are normal, a stress test (exercise or pharmacologic) to provoke ischemia or a noninvasive coronary imaging test should be performed in the ED, in a chest pain unit, or on an outpatient basis in a timely fashion (within 72 h) as an alternative to inpatient admission. Low-risk patients with a negative diagnostic test can be managed as outpatients. ( LOE: C )
- 3
Patients with definite ACS and ongoing ischemic symptoms, positive cardiac biomarkers, new ST-segment deviations, new deep T wave inversions, hemodynamic abnormalities, or a positive stress test should be admitted to the hospital for further management. Admission to the critical care unit is recommended for those with active, ongoing ischemia or injury, hemodynamic or electrical instability. Otherwise, a telemetry step-down unit is reasonable. ( LOE: C )
- 1
Class IIa
- 1
In patients with suspected ACS with a low or intermediate probability of CAD, in whom the follow-up 12-lead ECG and cardiac biomarker measurements are normal, performance of a noninvasive coronary imaging test (i.e., coronary CT angiography) is reasonable as an alternative to stress testing. ( LOE: B )
- 1
Early Hospital Care
General and Anti-Ischemic Therapy
Patients with definite or probable UA/NSTEMI are admitted for inpatient care. High-risk patients, including those with continuing discomfort, hemodynamic instability, or both should be hospitalized initially in a coronary care unit. After admission, standard medical therapy is indicated to relieve ischemia and prevent serious adverse outcomes. Unless contraindicated, general treatment for UA/STEMI patients should include aspirin, a beta blocker (preferably orally, in titrated doses), anticoagulant therapy, a GP IIb/IIIa receptor antagonist, and a thienopyridine (initiation may be deferred until a revascularization decision is made). Nitroglycerin (NTG) is indicated for treatment of persistent ischemia, heart failure, or hypertension. Supplemental oxygen is given to relieve or prevent desaturation. A critical early decision, which influences the choice of antithrombotic and other therapies, is the choice of an angiographic (invasive) or an initial conservative strategy.
Selected Recommendations: Anti-Ischemic and Analgesic Therapy
Class I
- 1
Bed or chair rest with continuous ECG monitoring is recommended for all UA/NSTEMI patients during the early hospital phase. ( LOE: C )
- 2
Supplemental oxygen should be administered to patients with UA/NSTEMI with an arterial saturation less than 90%, respiratory distress, or other high-risk features for hypoxemia. Pulse oximetry is useful for continuous measurement of Sa o 2 . ( LOE: B )
- 3
Patients with UA/NSTEMI with ongoing ischemic discomfort should receive sublingual NTG (0.4 mg) every 5 min for a total of 3 doses, after which assessment should be made about the need for intravenous NTG, if not contraindicated. ( LOE: C )
- 4
Intravenous NTG is indicated in the first 48 hours after UA/NSTEMI for treatment of persistent ischemia, heart failure (HF), or hypertension. The decision to administer intravenous NTG and the dose used should not preclude therapy with other proven mortality-reducing interventions such as beta blockers or angiotensin-converting enzyme (ACE) inhibitors. ( LOE: B )
- 5
Oral beta-blocker therapy should be initiated within the first 24 hours for patients without contraindications who do not have one or more of the following: (1) signs of HF; (2) evidence of a low-output state; (3) increased risk * for cardiogenic shock; or (4) relative contraindication to beta blockade (PR interval greater than or equal to 0.24 second, second- or third-degree heart block, active asthma, or reactive airway disease). ( LOE: B )
- 6
In UA/NSTEMI patients with continuing or frequently recurring ischemia and in whom beta blockers are contraindicated, a nondihydropyridine calcium channel blocker (e.g., verapamil or diltiazem) should be given as initial therapy in the absence of clinically significant left ventricular (LV) dysfunction or other contraindications. ( LOE: B )
- 7
An ACE inhibitor should be administered orally within the first 24 hours to UA/NSTEMI patients with pulmonary congestion or LV ejection fraction (LVEF) less than or equal to 0.40, in the absence of hypotension (systolic blood pressure less than 100 mm Hg or less than 30 mm Hg below baseline) or known contraindications to that class of medications. ( LOE: A )
- 8
An angiotensin receptor blocker should be administered to UA/NSTEMI patients who are intolerant of ACE inhibitors and have either clinical or radiologic signs of HF or LVEF less than or equal to 0.40. ( LOE: A )
- 9
Because of the increased risks of mortality, reinfarction, hypertension, HF, and myocardial rupture associated with their use, NSAIDS, except for aspirin, whether nonselective or cyclooxygenase (COX)-2-selective agents, should be discontinued at the time a patient presents with UA/NSTEMI. ( LOE: C )
- 1
Class IIa
- 1
It is reasonable to administer supplemental oxygen to all patients with UA/NSTEMI during the first 6 hours after presentation. ( LOE: C )
- 2
In the absence of contradictions to its use, it is reasonable to administer morphine sulfate intravenously to UA/NSTEMI patients if there is uncontrolled ischemic chest discomfort despite NTG, provided that additional therapy is used to manage the underlying ischemia. ( LOE: B )
- 3
It is reasonable to administer intravenous beta blockers at the time of presentation for hypertension to UA/NSTEMI patients who do not have one or more of the following: (1) signs of HF; (2) evidence of a low-output state; (3) increased risk * for cardiogenic shock; or (4) relative contraindication to beta blockade (PR interval greater than or equal to 0.24 second, second- or third-degree heart block, active asthma, or reactive airway disease). ( LOE: B )
- 4
Oral long-acting nondihydropyridine calcium channel blockers are reasonable for use in UA/NSTEMI patients for recurrent ischemia in the absence of contraindications after beta blockers and nitrates have been fully used. ( LOE: C )
- 5
An ACE inhibitor administered orally within the first 24 hours of UA/NSTEMI can be useful in patients without pulmonary congestion or LVEF less than or equal to 0.40 in the absence of hypotension (systolic blood pressure less than 100 mm Hg or less than 30 mm Hg below baseline) or known contraindications to that class of medications. ( LOE: B )
- 6
Intra-aortic balloon pump counterpulsation is reasonable in UA/NSTEMI patients for severe ischemia that is continuing or recurs frequently despite intensive medical therapy, for hemodynamic instability in patients before or after coronary angiography, and for mechanical complications of MI. ( LOE: C )
- 1
Class III
- 1
Nitrates should not be administered to UA/NSTEMI patients with systolic blood pressure less than 90 mm Hg or greater than or equal to 30 mm Hg below baseline, severe bradycardia (less than 50 beats/min), tachycardia (more than 100 beats/min) in the absence of symptomatic HF, or right ventricular infarction. ( LOE: C )
- 2
Nitroglycerin or other nitrates should not be administered to patients with UA/NSTEMI who had received a phosphodiesterase inhibitor for erectile dysfunction within 24 hours of sildenafil or 48 hours of tadalafil use. The suitable time for the administration of nitrates after vardenafil has not been determined. ( LOE: C )
- 3
Immediate-release dihydropyridine calcium channel blockers should not be administered to patients with UA/NSTEMI in the absence of a beta blocker. ( LOE: A )
- 4
It may be harmful to administer intravenous beta blockers to UA/NSTEMI patients who have contraindications to beta blockade, signs of HF or low-output state, or other risk factors * for cardiogenic shock ( LOE: A )
- 5
Nonsteroidal antiinflammatory drugs (except for aspirin), whether nonselective or COX-2-selective agents, should not be administered during hospitalization for UA/NSTEMI because of the increased risks of mortality, reinfarction, hypertension, HF, and myocardial rupture associated with their use. ( LOE: C )
- 1
* Age greater than 70 years, systolic blood pressure less than 120 mm Hg, heart rate greater than 110 or less than 60, increased time since onset of symptoms of UA/STEMI.
Choice of Strategy: Initial Conservative Versus Early Invasive
Two general pathways have emerged for treating UA/NSTEMI patients: the early invasive strategy ( Fig. 34-3 ) and the initial conservative strategy ( Fig. 34-4 ).
The initial conservative strategy calls for invasive evaluation only with symptomatic failure of medical therapy or other objective evidence of recurrent or latent ischemia (i.e., “selective invasive” management). For stabilized patients, noninvasive stress testing (treadmill, echo, or nuclear) or coronary imaging (multislice coronary CTA) before or shortly after discharge then is used for estimating residual risk as low, intermediate, or high, and to determine the need for angiography (see Fig. 34-4 ). In the absence of conclusive comparative data, test selection may be based primarily on patient characteristics, physician judgment, and local availability and expertise.
In contrast, the invasive strategy calls for routine angiography, generally early during hospitalization. The initial invasive strategy can be subdivided into two groups: patients who fail to stabilize on presentation with initial medical therapy and require urgent angiography/revascularization because of ongoing ischemic/hemodynamic/rhythm instability, and a second, larger group of patients who initially stabilize but are believed to benefit from “early” (generally, within 4 to 24 hours) but nonurgent angiography/intervention. For this second invasive group, two alternatives have been studied: earlier, or more delayed, angiography (i.e., within, or after, a 12- to 48-hour window from admission). To address this, the ISAR-COOL trial randomized 410 patients to very early angiography (median time 2.4 hours) or delayed angiography (median 86 hours) during “cooling off” with intensive medical therapy. Earlier angiography resulted in fewer deaths or MIs at 30 days (5.9% vs. 11.6%; P = .04). Additional data assessing the timing of angiography are needed.
Prior meta-analyses have suggested that routine invasive therapy yields better long-term clinical outcomes in higher-risk patients. In contrast, a relatively recent trial, ICTUS, has reported equivalent outcomes (and fewer biomarker MIs) with selective invasive therapy in stabilized but troponin-positive patients. , Proposed explanations for this result have included more aggressive medical therapy (statins, clopidogrel) than in previous studies, a high rate of revascularization in the selective invasive arm (47%), limited power for low event rates, and the counting of minor, clinically questionable troponin elevations as recurrent MIs. Longer-term (5 year) outcomes from two other, larger randomized trials: RITA-3 and FRISC-II, published contemporaneously with ICTUS, favored the invasive strategy for the endpoint of death or nonfatal MI. A contemporary meta-analysis of 7 randomized trials, including ICTUS, continues to support the long-term benefit of an early invasive strategy, with a relative risk of all-cause mortality of 0.75 (95% confidence interval [CI], 0.63-0.90) and recurrent nonfatal MI of 0.83 (CI, 0.72-0.96). Nevertheless, these guidelines recognize that an initially conservative (selective invasive) strategy may be considered (Class IIb, LOE B) as an alternative treatment option in stabilized UA/NSTEMI patients based on physician judgment and patient preference.
In contrast to these results for higher-risk patients, for those at lower risk, especially lower-risk women, accumulating evidence favors an initial conservative strategy. For example, in TACTICS TIMI-18, there was a reduction in the composite risk of death, nonfatal MI, or rehospitalization for UA in women with intermediate (3 to 4) or high (5 to 7) TIMI risk scores undergoing an early invasive strategy that was similar to that in men. In contrast, women with a low TIMI risk score had an increased risk of events (odds ratio [OR], 1.59; 95% CI, 0.69-3.67) with the invasive versus the conservative strategy, whereas low-risk men had similar outcomes with the two strategies. Similarly, women with an elevated troponin T benefited from an invasive strategy (adjusted OR, 0.47; 95% CI, 0.26-0.83), whereas the primary endpoint was significantly more frequent in women (but not men) treated invasively with a negative troponin (OR, 1.46; 95% CI, 0.78-2.72). The FRISC-II and RITA-3 , randomized trials reported improved outcomes with an invasive strategy only in men, but a high percentage of women were low risk, and an assessment of outcomes by risk or troponin status was not reported. A more recently published meta-analysis also supports the recommendation favoring a conservative approach in low-risk women.
Several criteria to consider in choosing between an invasive or conservative strategy are summarized in Table 34-2 .
| Preferred Strategy | Patient Characteristics |
|---|---|
| Invasive * | Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy |
| Elevated cardiac biomarkers (TnT or TnI) | |
| New or presumably new ST-segment depression | |
| Signs or symptoms of HF or new or worsening mitral regurgitation | |
| High-risk findings from noninvasive testing | |
| Hemodynamic instability | |
| Sustained ventricular tachycardia | |
| PCI within 6 months | |
| Prior CABG | |
| High-risk score (e.g., TIMI, GRACE) | |
| Reduced left ventricular function (LVEF less than 40%) | |
| Conservative | |
| Low-risk score (e.g., TIMI, GRACE) | |
| Patient or physician preference in the absence of high-risk features |
* The European guidelines 21 also recognize diabetes and renal dysfunction.
Selected Recommendations: Initial Conservative Versus Initial Invasive Strategies
Class I
- 1
An early invasive strategy (i.e., angiography with intent to perform revascularization) is indicated in patients with UA/NSTEMI who have refractory angina or hemodynamic or electrical instability (without serious comorbidities or contraindications to such procedures). ( LOE: B )
- 2
An early invasive strategy (i.e., angiography with intent to perform revascularization) is indicated in initially stabilized UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events. ( LOE: A )
- 3
In women with low-risk features, a conservative strategy is recommended. ( LOE: B ) (see also section on Women )
- 4
Because of the many anatomic possibilities that might be responsible for recurrent ischemia, there should be a low threshold for angiography in post-coronary artery bypass graft (CABG) patients with UA/NSTEMI. ( LOE: C ) (see also section on Post-CABG Patients )
- 1
Class IIb
- 1
In initially stabilized patients, an initial conservative (i.e., selectively invasive) strategy may be considered for UA/NSTEMI patients who have an elevated risk for clinical events including those who are troponin positive. ( LOE: B ) The decision to implement an initial conservative (vs. initial invasive) strategy in these patients may be made considering physician and patient preference. ( LOE: C )
- 2
An invasive strategy may be reasonable in patients with chronic renal insufficiency. ( LOE: C )
- 1
Class III
- 1
An early invasive strategy (i.e., angiography with intent to perform revascularization) is not recommended in patients with acute chest pain and a low likelihood of ACS. ( LOE: C )
- 1
Antiplatelet Therapy
Platelets represent a principal component of thrombus formation after plaque disruption precipitating ACS, and inhibition of platelet aggregation represents an essential element in UA/NSTEMI therapy.
Aspirin
Aspirin acts to inhibit cyclooxygenase (COX)-1 within platelets, prevent thromboxane A 2 formation, and diminish platelet aggregation associated with that pathway. Early trials of aspirin in UA/NSTEMI consistently documented benefit and established aspirin as a standard element of initial and chronic care. Higher doses are given for initiation of therapy and after stent placement followed by lower doses for long-term maintenance.
Platelet Glycoprotein (GP) IIb/IIIa Antagonists
Activation of platelets by a number of mechanisms leads to expression of GP IIb/IIIa receptors on their cell membranes that have high affinity for fibrinogen. The GP IIb/IIIa receptor antagonists (inhibitors) act by occupying these receptors, preventing fibrinogen binding, preventing platelet aggregation, and thereby reducing thrombus propagation. The three approved GP IIb/IIIa antagonists have differing properties. Abciximab, a humanized murine Fab antibody fragment, has strong receptor affinity and a short plasma half-life but a more prolonged (1 to 2 day) pharmacodynamic effect. Eptifibatide, a cyclic heptapeptide, and tirofiban, a nonpeptide fibrinogen mimetic, have high receptor specificity but short half-lives (2 to 3 hours) and short durations of antiplatelet effect (4 to 8 hours).
The efficacy of GP IIb/IIIa inhibitors for prevention of percutaneous coronary intervention (PCI)-related complications has been documented in several trials. The three trials most relevant to UA/NSTEMI are CAPTURE (abciximab), PRISM-PLUS (tirofiban), and PURSUIT (eptifibatide). Each showed a significant reduction in rate of MI or death during the phase of medical management preceding intervention and an augmented benefit after PCI (each receives a Class I indication with an invasive strategy). In contrast, GP IIb/IIIa antagonist trials of patients with UA/NSTEMI not routinely scheduled to undergo coronary revascularization have suggested a more modest benefit (greater among patients with elevated troponin or ECG changes) for tirofiban and eptifibatide, which receive a Class IIb indication, and no benefit or a suggestion of harm for abciximab (GUSTO-IV), which receives a class III (contraindication) in conservatively (non-invasively) managed UA/NSTEMI patients.
Adenosine Diphosphate Receptor Antagonists
Ticlopidine and clopidogrel are adenosine diphosphate (ADP) purinergic G protein–coupled P2Y 12 (P2Y12) receptor antagonists currently approved for antiplatelet therapy. Their platelet effects are irreversible but take several hours to days to achieve maximal therapeutic effect, depending on whether and how large a loading dose is given. Because of a better safety profile, clopidogrel is generally preferred.
The CURE trial randomized 12,562 patients with UA/NSTEMI to clopidogrel (300 mg, then 75 mg/day) or placebo (plus aspirin) and followed them for 3 to 12 months. Cardiovascular death, MI, or stroke occurred in 9.3% of clopidogrel and 11.5% of placebo patients (relative risk [RR] 0.80; P < .001). Benefit was observed across all subgroups and began within a few hours. A small bleeding excess was noted, which was increased in patients undergoing bypass surgery within 5 days of stopping clopidogrel. The 2658 patients undergoing PCI within the CURE trial (PCI-CURE substudy) experienced a 30% reduction in cardiovascular death, MI, or urgent target-vessel revascularization within 30 days of PCI ( P = .03) and a 31% reduction in cardiovascular death or MI ( P = .002). Therefore, clopidogrel is indicated in UA/NSTEMI patients treated with either a conservative or an invasive strategy.
Combination and Timing of Antiplatelet Therapy
A challenge for current guidelines is the integration of the GP IIb/IIIa antagonist studies from the 1990s with more recent studies using clopidogrel and newer anticoagulants. The ISAR-REACT-2 trial tested whether patients undergoing PCI and preloaded with clopidogrel 600 mg at least 2 hours before the procedure would derive additional benefit from GP IIb/IIIa receptor antagonist therapy with abciximab, given at angiography. The study randomized 2022 patients with UA/NSTEMI to abciximab or placebo. The primary ischemic endpoint was reduced from 11.9% to 8.9% (RR, 0.75; CI, 0.58-0.97; P = .03). Benefit was limited to patients with an elevated troponin level. Thus, it appears that addition of a GP IIb/IIIa receptor antagonist to thienopyridine therapy is beneficial in patients undergoing an invasive strategy with high-risk features.
The timing of initiating clopidogrel and GP IIb/IIIa inhibitors in patients undergoing an invasive evaluation, however, is currently controversial. An argument for “upstream” initiation before angiography is that it may have incremental benefit to GP IIb/IIIa inhibition, with earlier initiation providing optimal benefit. An argument for delayed initiation of clopidogrel until the time of angiography is that patients with advanced CAD requiring bypass surgery are placed at higher bleeding risk for early surgery or must experience a 5- to 7-day delay to surgery to allow for elimination of antiplatelet effect, that intravenous (IV) GP IIb/IIIa inhibitor therapy is sufficiently protective until the time of early angiography, and that clopidogrel’s effect is delayed for several hours after oral dosing. Clinical trials data are not definitive as to which strategy provides the better benefit-risk ratio, and the current guidelines allow for either approach, both of which are in current widespread use. The future availability of short-acting, rapidly reversible and intravenously administered ADP receptor antagonists (e.g., cangrelor) may allow resolution of these two divergent approaches. Another potent oral ADP receptor antagonist, prasugrel, has undergone favorable phase III clinical trials testing in comparison with clopidogrel in UA/NSTEMI and may need to be integrated into therapeutic algorithms in the near future.
The guidelines currently specify the administration of at least one (Class I, LOE A) or both (Class IIa, LOE B) of these two classes of antiplatelet agents prior to angiography, with both upstream GP IIb/IIIa inhibitor and clopidogrel therapy being favored when there are delays to angiography, high-risk features, or early recurrent ischemic discomfort in invasively treated patients (see Fig. 34-3 ). In conservatively treated patients, early clopidogrel (Class I, LOE B) is recommended, with the consideration of adding eptifibatide or tirofiban (Class IIb, LOE B) in those with high-risk features (e.g., troponin elevation, ECG changes, recurrent ischemia) (see Fig. 34-4 ).
Selected Recommendations: Early Antiplatelet Therapy
Class I
- 1
Aspirin should be administered to UA/NSTEMI patients as soon as possible after hospital presentation and continued indefinitely in patients not known to be intolerant to that medication ( LOE: A ) (see Figs. 34-3 and 34-4 , box A).
- 2
Clopidogrel (loading dose followed by daily maintenance dose) * should be administered to UA/NSTEMI patients who are unable to take aspirin because of hypersensitivity or major gastrointestinal intolerance ( LOE: A ) (see Figs. 34-3 and 34-4 , box A).
- 3
In UA/NSTEMI patients with a history of gastrointestinal bleeding, when ASA and clopidogrel are administered alone or in combination, drugs to minimize the risk of recurrent gastrointestinal bleeding (e.g., proton-pump inhibitors) should be prescribed concomitantly. ( LOE: B )
- 4
For UA/NSTEMI patients in whom an initial invasive strategy is selected, antiplatelet therapy in addition to aspirin should be initiated before diagnostic angiography (upstream) with either clopidogrel (loading dose followed by daily maintenance dose) *
* Randomized trials establishing its efficacy and providing data on bleeding risks used a loading dose of 300 mg orally followed by a daily oral dose of 75 mg. Higher oral loading doses such as 600 or 900 mg of clopidogrel may more rapidly inhibit platelet aggregation and achieve a higher absolute level of inhibition of platelet aggregation, but additive efficacy and safety of higher oral loading doses have not been rigorously established.
or an IV GP IIb/IIIa inhibitor ( LOE: A ) (see Fig. 34-3 ).
Abciximab as the choice for upstream GP IIb/IIIa therapy is indicated only if there is no appreciable delay to angiography and PCI is likely to be performed; otherwise, IV eptifibatide or tirofiban is the preferred GP IIb/IIIa inhibitor. ( LOE: B )
- 5
For UA/NSTEMI patients in whom an initial conservative (i.e., noninvasive) strategy is selected, clopidogrel (loading dose followed by daily maintenance dose) * should be added to aspirin and anticoagulant therapy as soon as possible after admission and administered for at least 1 month ( LOE: A ) and ideally up to 1 year ( LOE: B ) (see Fig. 34-4 , box C2).
- 6
For UA/NSTEMI patients in whom an initial conservative strategy is selected, if recurrent symptoms, ischemia, HF, or serious arrhythmias subsequently appear, diagnostic angiography should be performed ( LOE: A ) (see Fig. 34-4 , box D). Either an IV GP IIb/IIIa inhibitor (eptifibatide or tirofiban; LOE: A ) or clopidogrel (loading dose followed by daily maintenance dose; LOE: A ) * should be added to aspirin and anticoagulant therapy before diagnostic angiography (upstream). ( LOE: C )
- 1
Class IIa
- 1
For UA/NSTEMI patients in whom an initial conservative strategy is selected and who have recurrent ischemic discomfort with clopidogrel, aspirin, and anticoagulant therapy, it is reasonable to add a GP IIb/IIIa antagonist before diagnostic angiography. ( LOE: C )
- 2
For UA/NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to initiate antiplatelet therapy with both clopidogrel (loading dose followed by daily maintenance dose) *
* Randomized trials establishing its efficacy and providing data on bleeding risks used a loading dose of 300 mg orally followed by a daily oral dose of 75 mg. Higher oral loading doses such as 600 or 900 mg of clopidogrel may more rapidly inhibit platelet aggregation and achieve a higher absolute level of inhibition of platelet aggregation, but additive efficacy and safety of higher oral loading doses have not been rigorously established.
and an IV GP IIb/IIIa inhibitor ( LOE: B ) †
† Factors favoring the administration of both clopidogrel and a GP IIb/IIIa inhibitor include: delay to angiography, high-risk features, and early recurrent ischemic discomfort.
.
Abciximab as the choice for upstream GP IIb/IIIa therapy is indicated only if there is no appreciable delay to angiography and PCI is likely to be performed; otherwise, IV eptifibatide or tirofiban is the preferred choice of a GP IIb/IIIa inhibitor. ( LOE: B )
- 3
For UA/NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to omit upstream administration of an IV GP IIb/IIIa antagonist before diagnostic angiography if bivalirudin is selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 hours earlier. ( LOE: B )
- 1
Class IIb
For UA/NSTEMI patients in whom an initial conservative (i.e., noninvasive) strategy is selected, it may be reasonable to add eptifibatide or tirofiban to anticoagulant and oral antiplatelet therapy. ( LOE: B ) (see Fig. 34-4 , box C2)
Class III
Abciximab should not be administered to patients in whom PCI is not planned. ( LOE: A )
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