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Non–ST Elevation Acute Coronary Syndromes
Ischemic heart disease may manifest clinically as either chronic stable angina (see Chapter 40) or an acute coronary syndrome (ACS). The spectrum of ACS includes ST-segment elevation myocardial infarction (STEMI) (see Chapters 37 and 38) and the non–ST elevation acute coronary syndromes (NSTE-ACS). The latter consist of non–ST elevation myocardial infarction (NSTEMI) and unstable angina (UA) ( Fig. 39.1 ), which have indistinguishable clinical presentations at the initial evaluation.
Acute coronary syndrome.
Top: Progression of plaque formation and onset and complications of NSTE-ACS. The numbered section of an artery depicts atherogenesis from (1) normal artery to (2) extracellular lipid to (3) fibrofatty stage to (4) procoagulant expression and weakening of the fibrous cap. ACS develops with (5) disruption of the fibrous cap, which is the stimulus for thrombogenesis. (6) Thrombus resorption may be followed by collagen accumulation and smooth muscle cell growth. Thrombus formation reduces blood flow in the affected coronary artery and causes ischemic chest pain. Bottom: The clinical, pathologic, electrocardiographic, and biomarker correlates in ACS and approach to management. Flow reduction may be related to a completely occlusive thrombus or subtotally occlusive thrombus. Most patients with ST elevation (thick white arrow in bottom panel) develop Q wave myocardial infarction (QwMI), and a few (thin white arrow) develop non–Q wave myocardial infarction (NQMI). Those without ST elevation have either UA or NSTEMI (thick red arrows), a distinction based on cardiac biomarkers. Most patients presenting with NSTEMI develop NQMI; a few may develop QwMI. CPG, Clinical practice guideline; Dx, diagnosis.
From Amsterdam E, et al. 2014 ACC/AHA Non-ST-Segment Elevation ACS Guideline. J Am Coll Cardiol. 2014;64(24):e139–e228; and Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001;104:365–372.
Several features help to differentiate ACS from chronic stable angina, including (1) sudden onset of symptoms at rest (or with minimal exertion) that last at least 10 minutes unless treated promptly; (2) severe pain, pressure, or discomfort in the chest; and (3) an accelerating pattern of angina that develops more frequently, with greater severity, or that awakens the patient from sleep. The 12-lead electrocardiogram (ECG) and markers of myocardial necrosis are essential tools in distinguishing between the three types of ACS mentioned previously. Patients with typical symptoms without persistent (>20 minutes) ST-segment elevation in at least two contiguous electrocardiographic leads, but with elevation of myocardial biomarkers (>99% of the normal range), are classified as having NSTEMI. Patients with typical symptoms and serial negative markers of myocardial necrosis are classified as having UA, a diagnosis that carries a better prognosis.
Epidemiology
Despite the decline in age-adjusted cardiovascular disease (CVD) mortality over the past three decades, ischemic heart disease remains the leading cause of death worldwide, affecting 197 million individuals and is responsible for 9.14 million deaths annually with more disability life-years lost (182 million) than any other cause worldwide in 2019. In the United States in 2020, it is estimated that more than 1 million patients will experience a coronary heart disease event, of whom 76% will have an MI. The fraction of ACS attributed to NSTEMI continues to increase, while that for STEMI is declining, for several reasons: (1) wider use of preventive measures such as aspirin, statins, and smoking cessation; (2) aging of the population, with greater prevalence of diabetes and chronic kidney disease (CKD); (3) wider use of cardiac troponin (cTn) (see later) assays with higher sensitivity for myocardial necrosis, which shifts the diagnosis from UA to NSTEMI; and (4) wider implementation of the universal definition of MI.
Pathophysiology
The pathogenesis of NSTE-ACS involves five processes operating singly or in various combinations: (1) disruption of an unstable atheromatous plaque, (2) erosion of an atheromatous plaque ( Fig. 39.2 ; Table 39.1 ), (3) coronary arterial vasoconstriction, (4) gradual intraluminal narrowing of an epicardial coronary artery caused by progressive atherosclerosis or restenosis after percutaneous coronary intervention (PCI), and (5) oxygen supply-demand mismatch (see Chapter 36 ). Our understanding of the complex interactions between these pathways continues to evolve. For example, studies have implicated a role for matrix metalloproteinase-9 (MMP-9) in T-cell hyperactivity and dysregulation during the acute phase of ACS by its cleavage of the transmembrane glycoprotein adhesion molecule CD31 leading to lymphocyte activation. In addition to serving as useful biomarkers in ACS, better understanding of the pathophysiology of ACS could identify molecular targets for anti-inflammatory therapies in patients with this condition.
TABLE 39.1
Main Characteristics of Plaque Rupture and Superficial Erosion
Modified from Libby P, Pasterkamp G. Requiem for the “vulnerable plaque.” Eur Heart J 2015;36:2984–2987.
| PLAQUE RUPTURE | PLAQUE EROSION |
|---|---|
| Lipid rich | Lipid poor |
| Collagen poor, thin fibrous cap | Proteoglycan and glycosaminoglycan rich |
| Interstitial collagen breakdown | Nonfibrillar collagen breakdown |
| Abundant inflammation | Few inflammatory cells |
| Smooth muscle cell apoptosis | Endothelial cell apoptosis |
| Macrophage predominance | Secondary neutrophil involvement |
| Less expression of hyaluronidase-2 and of the hyaluronan-receptor CD44 | Profound alteration of hyaluronan metabolism resulting in hyaluronan accumulation |
| Larger number of nonculprit plaques and greater panvascular instability | Smaller number of nonculprit plaques and less panvascular instability |
| Male predominance | Female predominance |
| High level of low-density lipoprotein cholesterol | High level of triglycerides |
Three mechanisms may lead to plaque disruption: plaque fissure with inflammation, plaque fissure without inflammation, or plaque erosion. Although plaque rupture remains the most common mechanism of ACS, plaque erosion is increasing in frequency and is present in up to 40% of ACS cases ( Fig. 39.3 ). Plaques that rupture characteristically have large lipid pools with foam cells and a thin fibrous cap. Increasing use of high-intensity lipid-lowering therapies that can deplete intimal lipid collections can halt progression or even cause regression of plaques. Plaques that are lipid poor with few macrophages but rich in matrix are more prone to erosion and are increasingly common. In addition, plaque rupture leads to fibrin-rich red thrombi; plaque erosion is associated with white platelet-rich thrombi. Whether this distinction has therapeutic implications is an area of ongoing investigation. Vasoconstriction causing dynamic obstruction of coronary arterial flow may result from spasm of epicardial coronary arteries (Prinzmetal’s vasospastic angina [see later]) or from constriction of small, intramural muscular coronary arteries. The latter may result from vasoconstrictors released by platelets, from endothelial dysfunction, adrenergic stimuli, cold temperature, cocaine, or amphetamines (see later). More than one of these mechanisms may operate simultaneously.
Activation of the coagulation cascade and of platelets play central roles in the formation of thrombus following plaque disruption or erosion (see Chapter 95 ). The key steps in thrombus formation include (1) adhesion of platelets to the arterial wall, (2) platelet activation , (3) platelet degranulation and further activation , and (4) parallel expression of tissue factor with activation of the coagulation cascade .
Four observations support the central role of coronary artery thrombosis in the pathogenesis of NSTE-ACS: (1) autopsy findings of thrombi in the coronary arteries typically localized to a ruptured or eroded atherosclerotic plaque; (2) visualization by optical coherence tomography (OCT), invasive coronary arteriography, or coronary computed tomographic angiography (CCTA) of plaque ulceration and/or irregularities in the fibrous cap of atherosclerotic plaque, consistent with plaque rupture and thrombus formation; (3) elevation of serum markers of platelet activity, thrombin generation, and fibrin formation; and (4) improvement in clinical outcome with antiplatelet and anticoagulant therapies.
Clinical Assessment
History
NSTE-ACS resulting from atherosclerosis is relatively uncommon in men <40 years and women <50 in the absence of genetic disorders such as familial hypercholesterolemia, but the incidence rises steadily thereafter. Patients with ACS frequently have traditional risk factors for coronary artery disease (CAD) (see Chapters 25 and 27 ). However, while coronary risk factors reliably assess risk in populations, they are less helpful in the assessment of individual patients.
The initial symptom of NSTE-ACS is typically described as retrosternal pressure, heaviness, or frank pain, and although it resembles stable exertional angina, it is usually more intense and lasts longer (>10 minutes). Radiation to the ulnar aspect of the upper left arm, either shoulder, the neck, or the jaw is common, but symptoms may localize anywhere between the ear and epigastrium. Diaphoresis, nausea, abdominal pain, dyspnea, and syncope may accompany the discomfort. Features that support the diagnosis include exacerbation of symptoms by physical exertion and precipitation by severe anemia, infection, inflammation, fever, or metabolic or endocrinologic (e.g., thyroid) disorders. Atypical manifestations, such as dyspnea without chest discomfort and pain limited to the epigastrium or indigestion, represent “anginal equivalents.” These atypical findings are more prevalent in women, older adults, and patients with diabetes mellitus (DM), CKD, or dementia and can lead to under recognition, undertreatment, and worse outcomes. Chest pain that is pleuritic, positional, or described as “stabbing” is generally not caused by myocardial ischemia. The clinical manifestations may appear suddenly, with severe, new-onset symptoms occurring during minimal exertion (Canadian Cardiovascular Society Class [CCSC] III) or at rest (CCSC IV), an accelerating pattern of angina (more frequent, more intense, longer lasting), or angina occurring shortly after a completed MI.
Physical Examination
The physical examination may be normal, although patients with large territories of myocardial ischemia may have audible third and/or fourth heart sounds or pulmonary rales. Rarely, hypotension, pale cool skin, sinus tachycardia, or frank cardiogenic shock can occur; these findings are much more common with STEMI than with NSTE-ACS. Potential precipitating causes of ACS, such as fever, resistant or inadequately treated hypertension, tachycardia, profound bradycardia, thyroid disease, and gastrointestinal (GI) bleeding, can sometimes be identified. Pulse deficits, tachypnea, and tachycardia in the presence of clear lung fields and pulsus paradoxus with jugular venous distention may lead to alternative life-threatening diagnoses, such as aortic dissection, pulmonary embolism, or cardiac tamponade.
Electrocardiography
The most common abnormalities on the 12-lead ECG are ST-segment depression and T wave inversion, which are more likely to be present while the patient is symptomatic. If possible, comparison with a recent ECG is important because dynamic ST-segment depression as little as 0.05 mV is a sensitive (but not specific) marker for NSTE-ACS. Deep (>0.2 mV) T wave inversions are compatible with, but not necessarily diagnostic of, NSTE-ACS, whereas isolated T wave inversions of lesser magnitude are not particularly helpful given their low specificity. When present in patients with established NSTE-ACS, new T wave abnormalities are strongly associated with myocardial edema on T2-weighted images on MRI. Dynamic ST and T wave changes that are associated with clinical symptoms in patients with an elevated cTn may be helpful in identifying acute MI, although myocardial injury due to myocarditis or Takotsubo cardiomyopathy may mimic these changes (see later). Greater degrees of ST-segment depression predict poorer outcomes. Transient ST-segment elevation lasting less than 20 minutes occurs in up to 10% of patients and suggests either UA or coronary vasospasm.
More than half of patients with NSTE-ACS may have normal or nondiagnostic ECGs. Because ischemia may occur in a territory that is not well represented on the standard 12-lead ECG (see later), or because the patient may have episodic ischemia that is missed on the initial ECG, tracings should be repeated every 20 to 30 minutes until the symptoms resolve, or the diagnosis of MI is established or excluded.
Patients with baseline conduction disturbances and paced rhythms represent particular challenges for diagnosing myocardial ischemia by ECG. Comparison with a prior tracing when the patient was asymptomatic and recording an ECG with the pacing function temporarily switched off (in patients who are not pacemaker dependent) may be helpful.
Coronary angiography identifies a culprit lesion in the circumflex coronary artery in one-third of patients with high-risk NSTE-ACS. Because the standard 12-lead ECG does not represent the territory supplied by the circumflex coronary artery well, assessment of posterior leads V 7 through V 9 (with the gain increased to 20 mm/mV) should be considered in patients with a history suggestive of ACS and a nondiagnostic initial ECG. Similarly, ACS caused by isolated involvement of an acute marginal branch of the right coronary artery is often not apparent on the standard 12-lead ECG but may be suspected from leads V 3 R and V 4 R. Therefore, it is useful to obtain these extra leads in patients suspected of having ACS but with normal findings on a 12-lead ECG. Continuous monitoring of the ECG in the days following NSTE-ACS can identify patients at higher risk for recurrent events. ST-segment depressions noted on such monitoring within the first week after NSTE-ACS are associated with an increased risk for reinfarction and death.
Laboratory Testing: Biomarkers
A number of biomarkers reflecting the diverse causes of NSTE-ACS are useful for prognostication. These include markers of myocyte necrosis, hemodynamic stress, vascular damage (particularly renovascular), acceleration of atherosclerosis, and inflammation ( Fig. 39.4 ). Cardiac-specific troponins I (cTnI) and T (cTnT) are the biomarkers of choice to identify myocardial injury, thus distinguishing between NSTE-ACS and UA. Because the sensitivities of different Tn assays in clinical practice vary, the consensus recommendation is to define injury by an elevation in cTnI or cTnT >99th percentile of the normal range of the specific assay used, , with a typical temporal rise and fall indicating acute injury ( Fig. 39.5 ). The diagnosis of acute MI is appropriate in patients with acute MI and a clinical presentation and/or ECG findings consistent with ACS. However, a number of other cardiac and systemic causes may lead to myocardial injury ( Table 39.2 ); these can be distinguished from acute MI depending on the clinical context and information from imaging studies.
TABLE 39.2
Reasons for the Elevation of Cardiac Troponin Values Because of Myocardial Injury
From Thygesen K, et al. Fourth universal definition of myocardial infarction. J Am Coll Cardiol 2018;72:2231–2264; and Collet J-P, et al. 2020 ESC Guideline for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2020;42(14):1289–1367.
| Myocardial Injury Related to Acute Myocardial Ischemia |
| Atherosclerotic plaque disruption with thrombosis |
| Myocardial Injury Related to Acute Myocardial Ischemia Because of Oxygen Supply/Demand Imbalance |
Reduced myocardial perfusion:
|
Increased myocardial oxygen demand:
|
| Other Causes of Myocardial Injury |
|
Systemic conditions:
|
As high-sensitivity troponin (hsTn) assays that can detect ultralow concentrations of troponin in approximately >90% of healthy individuals become increasingly available, consideration of the clinical context of a troponin elevation will become even more important in avoiding misdiagnosis and improper triage in patient management. Noncardiac factors such as anemia, hypoxemia, kidney disease, shock, and CV conditions (e.g., heart failure [HF], tachyarrhythmia) may lead to myocardial injury in the absence of acute MI (see Chapter 36 ).
The assessment of patients with suspected ACS begins with integration of the cTn results at presentation with the clinical assessment and ECG findings. New hsTn assays can permit exclusion of acute MI with a single measurement in patients with symptom onset >3 hours before presentation or with two measurements performed at presentation and 1 hour later (the so-called “0/1” approach) in patients who present within 3 hours of symptom onset. In such patients both the absolute and the change in hsTn concentration from hour 0 to hour 1 should be considered. In both scenarios, the cut points for absolute and change in cTn used are assay specific.
With serial measurements of hsTn at 0/1 hours, 60% of patients presenting to the emergency department (ED) with acute chest pain were ruled out MI with 100% sensitivity and negative predictive value (NPV). This allows for more rapid discharge from the ED and high specificity and positive predictive value for MI (97% and 84%, respectively). Large independent validation studies in patients presenting to the ED demonstrated NPVs of 99.1% to 100% with a 0/1 hour approach using hsTn. Some patients with intermediate absolute and/or change in hsTn at 1 hour may require an additional hsTn at 3 hours. A comparison of accelerated diagnostic protocols to rule-in or rule-out MI are shown in Table 39.3 .
TABLE 39.3
Summary of hsTn Rapid Rule-Out and Rule-In Accelerated Diagnostic Panels
From Januzzi JL Jr, et al. Recommendations for Institutions Transitioning to High-Sensitivity Troponin Testing: JACC Scientific Expert Panel. J Am Coll Cardiol 2019;73:1059–1077.
| 0/3 h | High STEACS | 0/2 h | 0/1 h | |
|---|---|---|---|---|
| Rule-Out Criteria | ||||
| hs-cTnT | <14 ng/L at 0 and 3 h ∗ and GRACE score <140 | NA | <14 ng/L at 0 and 2 h and Δ <4 ng/L | <12 ng/L at 0 and 1 h Δ <3 ng/L |
| hs-cTnI † | <26 ng/L at 0 and 3 h ∗ and GRACE score <140 | <5 ng/L at 0 h or a 3-h value: <16 ng/L in women <34 ng/L in men and Δ <3 ng/L |
<6 ng/L at 0 and 2 h and Δ <2 ng/L | <5 ng/L at 0 and 1 h Δ <2 ng/L |
| NPV for MI | 98.3%–100% | 99.5% | 99.4%–99.9% | 98.9%–100% |
| Sensitivity for MI | 98.9%–100% | 97.7% | 96.0%–99.6% | 96.7%–100% |
| Proportion ruled out | 39.8%–49.1% | 74.2% | 56.0%–77.8% | 47.9%–64.2% |
| Rule-In Criteria | ||||
| hs-cTnT | >14 ng/L at 0 or 3 h | NA | ≥53 ng/L at 0 h or ≥10 ng/L Δ at 2 h | ≥52 ng/L at 0 h or 1 h Δ ≥ 5 ng/L |
| hs-cTnI | >26 ng/L at 0 or 3 h | >16 ng/L in women >34 ng/L in men at 0 or 3 h |
≥64 ng/L at 0 h or ≥15 ng/L Δ at 2 h | ≥52 ng/L at 0 h or 1 h Δ ≥ 6 ng/L |
| PPV for MI | 72.0%–83.5% | 59.5% | 75.8%–85.0% | 63.4%–84.0% |
| Specificity for MI | 96.7%–98.2% | 87.6% | 95.2%–99.0% | 93.8%–97% |
| Proportion ruled-in | 9.7%–38.2% | 22.0% | 7.7%–16.7% | 13.1%–23.0% |
0/1h, accelerated diagnostic protocol to rule out MI in patients presenting >3 h from symptoms using a single hs-cTn measurement at presentation, whereas for other patients, an absolute hs-cTn at presentation and 1-h Δ are used to rule out or rule in MI or to place patients in an observational zone; 0/2h, accelerated diagnostic protocol that uses maximal levels and absolute Δ hs-cTnI or T concentrations at 0 and 2 h to rule out or rule in MI or place patients in an observational zone; 0/3h, accelerated diagnostic protocol that incorporates hs-cTn at 0 and 3 h, hs-cTn change, and time since pain onset to determine which patients are appropriate for discharge or stress testing versus invasive management; GRACE, Global Registry of Acute Coronary Events; High STEACS, High-Sensitivity Troponin in the Evaluation of Patients with Acute Coronary Syndrome; hs-cTnI, high-sensitivity cardiac troponin I; hs-cTnT, high-sensitivity cardiac troponin T, NA, not applicable; NPV, negative predictive value; PPV, positive predictive value.
∗ In patients with ≥6 h of pain, only a single value below this threshold is required.
Studies comparing a 0/1 with 0/3 hour algorithms concluded that the 0/1 hour was preferable as it provided a more favorable combination of safety (NPV) with diagnostic accuracy. , In some high-risk subgroups (e.g., elderly, CKD) the specificity of hsTn is substantially lower, and thus slightly higher cutoff concentrations may be needed. , The HEART ( H istory, E CG, A ge, R isk factors, and T roponin) pathway is an algorithm that combines a clinical score with a serial troponin and identified 31% of patients as low risk with an NPV of 99.6% for 30-day death or MI. Prognostication can be improved by use of a multimarker approach or coronary imaging with CCTA for patients at low-intermediate likelihood, or by invasive coronary angiography in patients with high clinical suspicion for MI. It is not recommended to measure additional biomarkers of necrosis (creatine kinase, creatine kinase myocardial band, fatty acid binding protein, or copeptin) in addition to hsTn.
Several other biomarkers may be useful in estimating prognosis and helping to guide care. Of these, the natriuretic peptides (NPs; i.e., brain natriuretic peptide [BNP] and N-terminal pro-BNP) have been most widely used and endorsed by guidelines. NPs rise in proportion to the degree of ventricular distention (strain) and correlate with the risk of adverse events, including death, HF, and MI, in a graded fashion. More importantly, elevation of a baseline NP identifies patients who are more likely to benefit from more intensive anti-ischemic and lipid-lowering regimens as well as early coronary revascularization.
Similarly, high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, is elevated following NSTE-ACS, and the degree of elevation correlates with long-term CV outcomes. In addition, serials increases in hs-CRP may identify patients with NSTE-ACS who require more intensive management of risk factors (e.g., lipids, glucose, blood pressure (BP), and weight) and/or targeted anti-inflammatory therapy. Growth differentiation factor (GDF)-15 independently predicted death and CV events when added to a model that included clinical risk factors and left ventricular ejection fraction (EF), both early and late (5 years median follow-up) after ACS ( eTable 39.1 ).
eTABLE 39.1
Novel Biomarkers in Acute Coronary Syndromes
| Marker Name | Description | Reference |
|---|---|---|
| Markers Predicting Death and/or Ischemic Events | ||
| Cardiac myosin-binding protein C | Structural myocardial protein with discriminatory power similar to hsTn to diagnosis MI; may be particularly useful in early presentation after symptom onset | |
| Chemokine ligand-5, -18, and -21 | Mediators of monocyte recruitment induced by ischemia | |
| Cysteine-rich angiogenic inducer 61 | Matricellular protein involved in angiogenesis, inflammation, and fibrotic tissue repair; serves as a ligand for activated platelets binding to integrin a IIb β 3 | |
| Fibrin clot properties (clot lysis time, maximum turbidity) | Functional measures of clot resistance to lysis | |
| Fibroblast growth factor 23 | Multiple pleotropic effects of cardiovascular structure and function | X |
| Growth differentiation factor-15 | Member of the transforming growth factor-beta cytokine superfamily that is released from cardiomyocytes after ischemia and reperfusion injury | |
| Heart-type fatty acid-binding protein | Cytoplasmic protein involved in intracellular uptake and buffering of free fatty acids in the myocardium | |
| Interleukin-6 | Stimulator of hepatic synthesis of C-reactive protein | |
| Interleukin-17 | Produced by CD4 + T cells, it plays a role in host immunity and development of an unstable plaque | |
| Membrane attack complex | Ischemia leads to changes in myocardial cell surface molecule expression, rendering the cell membrane a target for the complement system, ultimately leading to cell lysis | |
| Myeloperoxidase | Hemeprotein released during degranulation of neutrophils and some monocytes | |
| Pentraxin-3 | Inflammatory marker associated with thin-cap vulnerable plaques | |
| Placental growth factor | Member of the vascular endothelial growth factor family that is strongly upregulated in atherosclerotic lesions and acts as a primary inflammatory instigator of atherosclerotic plaque instability | |
| Pregnancy-associated plasma protein A | Zinc-binding metalloproteinase found in vulnerable plaques that cause destabilization of the fibrous plaque | |
| Progenitor cells | Mononuclear cells mobilized from the bone marrow into the circulation in response to tissue injury and contribute to repair and regeneration | |
| Secretory phospholipase A 2 | Hydrolyzes phospholipids to generate lysophospholipids and fatty acids, thereby enhancing susceptibility of the vessel atherosclerosis | |
| Soluble suppression of tumorigenicity-2 | Member of the interleukin-1 receptor family that is a biomarker of myocardial fibrosis and remodeling | |
| Triggering receptor expressed on myeloid cells-1 | Immune receptor and member of the immunoglobulin superfamily that amplifies innate immune response | |
| Trimethyllysine | Nutrient precursor of the gut microbiota-derived metabolite trimethylamine N-oxide | |
| Markers Predicting Heart Failure | ||
| Copeptin | Peptide fragment of provasopressin | |
| Galectin-3 | A galactoside-binding lectin mainly secreted by activated macrophages | |
| Midregional proadrenomedullin | Peptide fragment of the vasodilatory peptide adrenomedullin | |
| Midregional proatrial natriuretic peptide | Peptide fragment of atrial natriuretic peptide | |
| Neopterin | Marker of monocyte activation | |
| Osteoprotegerin ∗ | Modulator of immune function and inflammation | |
Multimarker approaches (e.g., simultaneous assessment of hsTn, hs-CRP, BNP, GDF-15, and cystatin-C) as well as serial assessments of hsTn and hs-CRP can improve risk stratification of patients with NSTE-ACS. While lipid measurements are less helpful for individual prognostication, assessment of the low-density lipoprotein cholesterol (LDL-C) and triglycerides, along with glucose or hemoglobin (Hb) A 1c , can identify uncontrolled risk factors that, with proper management, could reduce the risk of future CV events. Assessments of arterial oxygenation, hematocrit, and thyroid function may identify treatable conditions that can cause secondary ACS.
Imaging
Noninvasive Testing
Noninvasive testing in patients with established or suspected NSTE-ACS has been shown to play several important roles: (1) establishing the presence (or absence) of significant CAD, (2) diagnosing CAD as the cause of cTn elevation in patients who may have other explanations (see previous section), (3) evaluating the extent of residual ischemia after initiation of medical therapy to guide management, (4) localizing the territory of ischemia before revascularization in patients with multivessel disease, and (5) assessing left ventricular (LV) function.
The safety of early stress testing in patients with NSTE-ACS has been debated, but symptom-limited or pharmacologic stress testing appears to be safe after at least 24 hours of stabilization without symptoms of active ischemia or other signs of hemodynamic or electrical instability. For most patients, electrocardiographic exercise stress testing is recommended if the ECG at rest lacks significant baseline abnormalities (e.g., ST depressions, bundle-branch block, electronic pacing) (see Chapter 69 ). If significant baseline ECG abnormalities are present, stress perfusion or echocardiographic imaging should be performed before and immediately after exercise. In patients who cannot achieve a significant workload during exercise, pharmacologic stress testing with imaging is recommended. Exercise stress myocardial perfusion imaging with nuclear isotopes and stress echocardiography with dobutamine have greater sensitivity than electrocardiographic exercise stress testing without imaging (see Chapters 14, 16 and 18 ). High-risk findings on the stress test (e.g., severe ischemia as reflected by ST-segment depression ≥0.2 mV before stage 3, hypotension with exercise, ventricular tachyarrhythmia, new or worsening LV dysfunction) are indications to proceed rapidly with coronary angiography with the intent to perform coronary revascularization, if possible.
Echocardiography (see Chapters 14 and 16 ) is useful in the assessment of LV systolic and diastolic function and can also identify left atrial dilation, functional mitral regurgitation, tricuspid annular plane systolic excursion, diastolic dysfunction, ventricular mechanical dyssynchrony, and ultrasound “lung comets” (extravascular lung fluid observed on thoracic ultrasound scanning). Each of these is associated with an adverse prognosis in patients with NSTE-ACS.
CCTA in patients with or suspected of having NSTE-ACS can help to (1) recognize or exclude the presence of epicardial CAD, (2) identify which vessel(s) have obstruction, and (3) assist in risk stratification and prognosis (see Chapter 20 ). Three large randomized trials have shown that CCTA compared with standard evaluation (which could include functional and imaging studies other than CCTA) expedites the triage of patients presenting with chest discomfort in the ED, thereby shortening length of stay. Additional benefits include reductions in costs and of return visits to the ED. A randomized trial comparing standard of care with or without CCTA in patients with suspected angina demonstrated that CCTA better clarified the diagnosis of angina due to CAD, reduced the need for stress testing, but increased the use of coronary angiography. These studies and others led to Class 1 recommendations to use of CCTA in the ED in patients with chest discomfort and suspected ACS who are at low risk at presentation , ( Table 39.4 ). Some studies have suggested that CCTA may improve risk stratification in patients in whom hsTn levels do not conclusively rule MI in or out.
TABLE 39.4
Appropriateness of Coronary Computed Tomographic Angiography in Patients with Acute Chest Pain Syndromes
Modified from Hollander JE, et al. State-of-the-art evaluation of emergency department patients presenting with potential acute coronary syndromes. Circulation 2016;134:547–564.
| Appropriate Indications |
| Electrocardiogram negative or indeterminate for myocardial ischemia Low-intermediate pretest likelihood by risk stratification tools TIMI risk score of 0-2 (low risk) ideal or TIMI score of 3-4 (intermediate) in some cases HEART score <3 ≥1 negative troponin value, including point-of-care assays Equivocal or inadequate previous functional testing during index ED or within previous 6 months |
| Equivocal Indications |
| High clinical likelihood of ACS by clinical assessment and standard risk criteria (e.g., TIMI score >4) Previously known coronary artery disease Known calcium score ≥400 |
| Relative Contraindications |
| History of allergic reaction to iodinated contrast eGFR 30 to <60 mL/min/1.73 m2 Factors likely to lead to nondiagnostic scans; specific will vary with scanner technology and site capabilities Heart rate greater than site maximum for reliably diagnostic scans after beta blockers (usually 70-80 beats/min) Contraindications to beta blockers and heart rate not controlled Atrial fibrillation or other markedly irregular rhythm Body mass index >39 kg/m 2 |
| Absolute Contraindications |
| Known acute coronary syndromes eGFR <30 unless on long-term dialysis Previous anaphylaxis after iodinated contrast administration Previous episode of contrast allergy after adequate steroid/antihistamine preparation Pregnancy or uncertain pregnancy status in premenopausal women |
TIMI, Thrombolysis in myocardial infarction.
The benefits of CCTA may extend beyond the ED, permitting more rapid and accurate identification of high-risk patients who may benefit from early, intensive therapies, including invasive coronary angiography and revascularization.
Cardiac magnetic resonance (CMR) imaging using a rapid-scan protocol can provide precise measurements of ventricular volumes and function, detect and assess ventricular wall edema, identify areas of infarcted versus viable hibernating myocardium, establish the presence of myocardial perfusion, quantify wall motion, and identify myocardium at risk in patients with NSTE-ACS (see Chapter 19 ). Addition of high-resolution late gadolinium enhanced imaging can help provide this information when CMR alone is inconclusive. Detailed assessments by noninvasive cardiac imaging can help guide coronary revascularization in several common clinical scenarios, such as when the stenosis is of borderline significance, the culprit lesion is uncertain because of multivessel disease, or when myocardial viability in a territory at risk requires clarification.
Invasive Imaging
Invasive coronary angiography has been the standard technique for imaging the coronary arterial tree for nearly six decades. The culprit lesion in NSTE-ACS typically exhibits an eccentric stenosis with scalloped or overhanging edges and a narrow neck (see Chapter 21 ). These angiographic findings may represent disrupted atherosclerotic plaque or thrombus. Features suggesting thrombus include globular intraluminal masses with a rounded or polypoid shape; “haziness” of a lesion suggests the presence of thrombus, but this finding is not specific.
Approximately 90% of patients with a clinical diagnosis of NSTE-ACS have significant coronary obstruction, i.e., >50% stenosis of luminal diameter in at least one major coronary artery. Most have obstructive disease in multiple epicardial arteries (approximately 10% have left main [LM] CAD) often accompanied by multivessel CAD. Among patients without LM disease, about 35% have three-vessel disease, and 25% two-vessel disease, whereas only approximately 20% have single-vessel disease. The remaining 10% have no significant coronary obstruction, a finding that is more common in women and minorities than in white men. In such patients, NSTE-ACS may be related to microvascular coronary obstruction, endothelial dysfunction, or coronary artery spasm and may have a more favorable prognosis. In 37,101 patients enrolled in eight clinical trials of NSTE-ACS, the 30-day rate of death or MI was 2.2% in those with no obstructive CAD compared with 13.3% in patients with obstructive disease.
Intravascular ultrasound (IVUS) and OCT are two invasive cross-sectional imaging techniques that can provide details regarding plaque morphology (see Fig. 39.3 ). In the clinical setting, IVUS or OCT are used most commonly to guide coronary stent placement (see Chapter 41 ). These techniques and others (e.g., near-infrared spectroscopy, intravascular CMR, angioscopy) can provide detailed plaque morphology and establish the pathophysiologic etiology of ACS, although the clinical utility of such additional information is uncertain.
Risk Assessment
Residual Risk
The risk for recurrent ischemic events following an episode of ACS depends as much on the presence and stability of multifocal lesions as on the culprit lesion responsible for the initial event. A new broad conceptual framework to address residual risk from atherosclerotic disease has been proposed that includes five domains: lipoproteins, inflammation, obesity and glucose metabolism, platelets, and coagulation. Aggressive medical management targeting the domains that have not been optimized is required to treat the remaining plaques and prevent new ones, thus reducing the risk of recurrent events.
Natural History
Patients with UA have lower short-term mortality (<2.0% at 30 days) than do those with NSTEMI or STEMI. However, with the increasing use of hsTn, the fraction of patients with NSTE-ACS diagnosed with UA is declining. , The early mortality risk with NSTEMI is related to the extent of myocardial damage and resulting hemodynamic compromise and is lower than in patients with STEMI, who usually have larger infarcts. In an analysis of 66,252 patients with NSTEMI enrolled in 14 Thrombolysis in Myocardial Ischemia (TIMI) trials, 85% of the deaths in the first 30 days were CV, of which recurrent MI and HF were the most common causes. After 30 days, sudden cardiac death (SCD) was the most common mode of CV death.
In contrast, patients with STEMI have higher rates of early mortality, while long-term outcomes with respect to both mortality and nonfatal events are worse in patients with NSTE-ACS. This finding probably results from the greater age, extent of CAD, history of a previous MI, comorbid condition (e.g., diabetes, impaired renal function), and likelihood of recurrence of ACS in patients with NSTE-ACS than in those with STEMI. In the aforementioned analysis of the TIMI trials, an analysis of causes of death after 30 days showed that CV deaths represented 70% of the total; sudden death (46%) was more than twice as common as any other CV cause.
Risk Assessment Scores
Several risk scores that integrate clinical variables and findings on the ECG and from serum biomarkers have been developed for patients with NSTE-ACS. The TIMI risk score for UA/NSTEMI identifies seven independent risk factors; their sum correlates directly with death or recurrent ischemic events ( Fig. 39.6A ). This simple, rapid assessment at the initial evaluation identifies high-risk patients who can derive benefit from an early invasive strategy and more intensive antithrombotic therapy. The Global Registry of Acute Coronary Events (GRACE) risk score uses a larger number of weighted risk factors to predict mortality after NSTE-ACS; however, it is more complex than the TIMI risk score and is not easily calculated by hand. For longer-term prognostication in patients following ACS, a risk score based on nine independent clinical predictors identifies a gradient of risk for recurrent atherothrombotic events called the TIMI stable ischemic CAD risk score (see Fig. 39.6B ). It distinguishes patients with greater absolute benefit with more intensive antithrombotic and lipid-lowering therapies. A risk score evaluated in 23,489 patients who survived hospitalization for ACS had excellent discrimination (c-statistic 0.80) to predict 2-year mortality using 17 variables, including quality-of-life, educational level, and geographic region in addition to typical CV risk factors. This score may be helpful for the identification of patients at higher risk and tailor secondary prevention measures.
Management
Management of patients with NSTE-ACS consists of an acute phase focused on relief of the clinical symptoms and stabilization of the culprit lesion(s) and a long-term phase that involves therapies directed at the prevention of disease progression and future plaque rupture/erosion. Retrospective angiographic studies and a prospective natural history study of patients with NSTE-ACS managed with PCI have shown that plaques that cause more severe stenosis have a higher risk of rupture leading to an ACS event. However, since plaques with less severe stenosis are more prevalent, these less obstructive lesions are responsible for about half of the future ACS events.
General Measures
Patients with new or worsening chest discomfort or an anginal equivalent symptom suggestive of ACS should be transported rapidly to the ED by ambulance, if possible, and evaluated immediately. The initial evaluation should include a directed history and physical examination and ECG performed within 10 minutes of arrival. If possible, the ECG should be recorded in the ambulance. Blood specimens for cTn or, if possible, hsTn assay should be obtained immediately with expedited assessment through either a point-of-care device or laboratory measurement that can provide results within 60 minutes. Additional laboratory studies, such as a complete blood count, serum electrolytes, creatinine, and glucose, can help guide early management treatments and strategy.
Patients with elevated cTn or new ST-segment abnormalities or are deemed to be at moderate or high risk based on a validated risk score (e.g., TIMI, GRACE, see earlier) should be admitted to a specialized cardiovascular care unit. Patients with UA but without elevated cTn and ischemic electrocardiographic changes should be admitted to a monitored bed, preferably in a CV step-down unit. In these settings, continuous ECG monitoring with telemetry is recommended for 24 hours or until revascularization to detect tachyarrhythmias, alterations in atrioventricular (AV) and intraventricular conduction, and changes in ST-segment deviation. Patients should be placed on bed rest and inhaled oxygen in those patients with arterial oxygen saturation (Sa o 2 ) less than 90% and/or those with HF and pulmonary rales. Routine oxygen in patients with suspected ACS without hypoxemia or HF is of unclear benefit. Ambulation, as tolerated, is permitted if the patient has been stable without recurrent chest discomfort or ECG changes for at least 12 to 24 hours.
Anti-Ischemic Therapy
Guidelines emphasize the early use of anti-ischemic therapies to improve the balance between oxygen supply and demand. , The goals of anti-ischemic therapy include relief of symptoms and prevention of early sequelae of ACS, including recurrent MI, HF, arrhythmias, and death. Table 39.5 summarizes traditional and newer/experimental pharmacologic anti-ischemic therapies.
TABLE 39.5
Pharmacologic Anti-Ischemic Therapies in Non–ST Elevation Acute Coronary Syndromes
From Soukoulis V, et al. Nonantithrombotic medical options in acute coronary syndromes: old agents and new lines on the horizon. Circ Res 2014;114:1944–1958.
| Class Of Medication | Mechanism of Action | Clinical Effects In Nste-Acs |
|---|---|---|
| Traditional Therapies | ||
| Beta blockers | Decrease heart rate, blood pressure, and contractility through antagonism of beta 1 receptors | Decrease mortality |
| Nitrates | Decrease preload through venodilation; vasodilate coronary arteries | No benefit on mortality |
| Calcium channel blockers | May vasodilate, reduce heart rate, or decrease contractility depending on specific drug | No clear benefit on mortality or reinfarction Increased reinfarction rate when short-acting nifedipine is used alone |
| Newer and Experimental Therapies | ||
| Ranolazine | Inhibits late inward sodium current | Decreases recurrent ischemia and arrhythmias |
| Trimetazidine | Shifts myocardial metabolism from fatty acid to glucose use | Decreases short-term mortality |
| Nicorandil | Activates ATP-sensitive K + channels and dilates arterioles; may have ischemic precondition-like effect | Decreases arrhythmias and transient ischemia |
Nitrates
Nitrates are vasodilators that increase myocardial blood flow and reduce myocardial oxygen requirements by lowering cardiac preload (systemic venodilation) and afterload (systemic arterial dilation), thereby diminishing ventricular wall stress, and they may have a mild antiplatelet effect. Reflex increases in heart rate and myocardial contractility by nitrates that increase myocardial O 2 demand can be mitigated by concomitant use of a beta blocker. Well-controlled clinical trials have not shown a reduction in cardiac events with nitrates; however, the rationale for nitrate use in NSTE-ACS is extrapolated from pathophysiologic principles and extensive clinical observations demonstrating their clinical effectiveness in relief of pain or other discomfort caused by myocardial ischemia.
In symptomatic patients without hypotension, the initial administration of rapidly acting nitroglycerin (sublingual [SL]or buccal, 0.3 to 0.6 mg at 5-minute intervals), beginning before hospital arrival whenever possible, is recommended. Intravenous (IV) nitroglycerin (5 to 10 μg/min, titrated to a maximum of 200 μg/min as needed) should be initiated in patients with hypertension and in patients with persistent or recurrent ischemic symptoms or HF, provided that the systolic blood pressure (SBP) is at least 90 to 100 mm Hg. Tolerance to nitrates may develop within 12 to 24 hours and can be mitigated by nitrate-free intervals or increasing the dose if symptoms persist. Abrupt discontinuation of high doses of IV nitrates is not advised because it may precipitate recurrent ischemia and/or rebound hypertension; instead, IV nitrates should be weaned over several hours.
Important contraindications to nitrates include hypotension and use within 24 hours of a phosphodiesterase type 5 (PDE-5) inhibitor, sildenafil or vardenafil, or tadalafil within 48 hours. Since the catalytic site of PDE-5 normally degrades cyclic guanosine monophosphate, inhibitors of PDE-5 potentiate the endogenous levels of cyclic guanosine monophosphate, possibly resulting in exaggerated, prolonged, and dangerous vasodilatory effects of nitrates. Relative contraindications to nitrates include hypotension (SBP <90 mm Hg), severe obstruction to LV outflow, large right ventricular infarction, or hemodynamically significant pulmonary embolism. In such patients, nitrates should be used with caution, if at all.
Beta-Adrenergic Receptor–Blocking Agents
Beta blockers inhibit the O 2 oxygen consumption by lowering heart rate, BP, and myocardial contractility (see Chapters 38 and 40 ). They may be initiated intravenously for rapid onset, followed by long-term oral use. The evidence supporting beta blockers derives largely from older studies of patients with acute MI (generally STEMI) or new left bundle branch block, before the current era of reperfusion therapy. In clinical trials of patients with acute MI, both early IV administration and long-term oral beta blockers have been shown to reduce reinfarction, ventricular arrhythmias, and death. The findings from these trials, most on patients with STEMI (see Chapter 38 ), have been extrapolated to patients with UA and NSTEMI.
A systematic review that pooled data on approximately 4700 patients with UA from five trials performed before 1986 showed that beta blockers reduced the risk for progression to MI. Whether beta blockers would have similar efficacy in the modern era of intensive pharmacologic management with an early invasive strategy is unclear.
Intravenous Beta Blockers
If ischemia persists despite IV nitrate therapy, IV beta blockers (e.g., metoprolol 5 mg over 1 to 2 min, repeated every 5 min for a total initial dose of 15 mg) may be used cautiously, and generally followed by initiation of oral administration. Beta blockers should be avoided in patients with (1) acute or severe HF, (2) low cardiac output, (3) hypotension, (4) contraindications to beta blocker therapy (e.g., high-degree AV block, active bronchospasm), and (5) coronary vasospasm or acute intoxication with cocaine or methamphetamine because unopposed alpha-mediated coronary vasoconstriction may occur, worsening coronary spasm. IV beta blockers have been shown to increase mortality in patients with or at high risk for developing cardiogenic shock.
Oral Beta Blockers
Oral beta blockers in doses used for chronic stable angina (e.g., metoprolol tartrate 25 mg every 6 hours; see Chapter 40 ) should be initiated within the first 24 hours in the absence of the previously mentioned scenarios. , Patients with initial contraindications to beta blockers should be reevaluated to determine subsequent eligibility to receive one of these agents. Beta blockers with intrinsic sympathomimetic activity (e.g., acebutolol, pindolol) should be avoided because they may increase the risk of ventricular tachycardia and fibrillation.
Morphine
If there is ongoing ischemic discomfort or pain despite treatment with maximally tolerated anti-ischemic medications (nitrates, beta blockers), in the absence of contraindications (e.g., hypotension, allergy, history of opiate addiction), it is reasonable to administer IV morphine (1 to 5 mg), with the caveat that morphine may slow intestinal absorption of oral platelet inhibitors. Data suggest that coadministration of morphine and clopidogrel may blunt the antiplatelet effect of clopidogrel and is associated with an increase short-term risk of ischemic events. The morphine dose may be repeated every 5 to 30 minutes to relieve symptoms and maintain the patient’s comfort. Morphine may act as both an analgesic and an anxiolytic; its venodilator effects may be beneficial by reducing preload (particularly in patients who have experienced acute pulmonary edema), and mildly reduces heart rate and BP by increasing vagal tone. Morphine may cause hypotension; supine positioning and IV saline may be used to restore BP. Naloxone (0.4 to 2.0 mg IV) may be administered for morphine overdose with respiratory or circulatory depression. In patients with morphine allergy, meperidine can be substituted.
Calcium Channel Blockers
Calcium channel blockers (CCBs) have vasodilatory effects and reduce arterial pressure. Some CCBs, such as verapamil and diltiazem, also slow heart rate, reduce myocardial contractility, thereby reducing myocardial oxygen requirements. CCBs have been effective in reducing ischemia in patients with NSTE-ACS and persistent ischemia despite treatment with full-dose nitrates and beta blockers, as well as in patients with contraindications to beta blockers and in patients with hypertension. , Such patients should receive nondihydropyridine CCBs that lower heart rate. The short-acting formulation of the dihydropyridine nifedipine, which accelerates heart rate, can cause harm in patients with ACS when not co-administered with a beta blocker and should be avoided. No harm has been observed with long-term treatment with the long-acting dihydropyridines, amlodipine and felodipine, in patients with documented LV dysfunction and CAD, suggesting that these agents may be safe in patients with NSTE-ACS and LV dysfunction. However, use of dihydropyridines in the absence of beta blocker remains controversial in ACS. Contraindications to nondihydropyridine CCBs include significant LV dysfunction, increased risk of cardiogenic shock, PR interval longer than 0.24 second, and high-degree AV block.
Antiplatelet Therapy (see Chapter 95 )
See Fig. 39.7 , Table 39.6 , and eTable 39.G2 .
TABLE 39.6
Antithrombotic Therapy in Patients on Chronic Oral Anticoagulation Who Present with an NSTE-ACS
|
Oral Antiplatelet Drugs
Aspirin (acetylsalicylic acid [ASA]) acetylates platelet cyclooxygenase 1 (COX-1), thereby blocking the synthesis and release of thromboxane A 2 (TxA 2 ), a platelet activator, and reducing platelet aggregation and arterial thrombus formation. Because the inhibition of COX-1 by ASA is irreversible, the antiplatelet effects last for the lifetime of the platelets, approximately 7 to 10 days. Several placebo-controlled trials have demonstrated the benefit of ASA in patients with NSTE-ACS. In addition to reducing adverse clinical events in the first months of treatment, ASA also reduces the frequency of ischemic events in secondary prevention. It is a cornerstone of antiplatelet therapy in patients with all forms of ACS, as well as those with chronic CAD.
Even though doses of ASA have ranged from 50 to 1300 mg/day in randomized trials, there does not appear to be a dose-response effect on efficacy, but GI bleeding is increased at higher doses. The CURRENT OASIS-7 trial randomized patients with ACS to high-dose (300 to 325 mg/day) or low-dose (75 to 100 mg/day) ASA for 30 days (and to high-dose versus regular-dose clopidogrel; see later). No difference in the risk for CV death, MI, or stroke was observed between the two doses of ASA, but GI bleeding increased with the higher dose. Guidelines recommend that in patients with NSTE-ACS who have not been taking ASA, the initial loading dose should be 162 to 325 mg of non–enteric-coated ASA, followed by a maintenance dose of 75 to 100 mg daily. Enteric-coated ASA should be avoided initially because it delays and reduces absorption. Most nonsteroidal anti-inflammatory drugs (NSAIDs) bind reversibly to COX-1, preventing this enzyme’s inhibition by ASA, and may cause prothrombotic effects; thus NSAIDs should be avoided.
So-called ASA resistance may occur during chronic therapy, with 2% to 8% of patients exhibiting a limited antiplatelet effect resulting in a greater risk of recurrent cardiac events. Causes of ASA resistance are varied and include poor compliance (pseudoresistance), use of enteric-coated forms, reduced absorption, interaction with ibuprofen or other NSAIDs, and overexpression of COX-2 mRNA.
Contraindications to ASA include documented allergy (e.g., ASA-induced asthma), nasal polyps, active bleeding, or a known platelet disorder. Dyspepsia or other GI symptoms with long-term ASA therapy (i.e., ASA intolerance) do not usually preclude therapy in the short term. In patients who have an allergy to ASA, desensitization or substituting clopidogrel, prasugrel, or ticagrelor is recommended. Clopidogrel may be substituted in place of ASA in patients who cannot tolerate ASA because of GI bleeding.
P2Y 12 Inhibitors (see eTable 39.G3 )
Management of ACS now routinely includes dual-antiplatelet therapy (DAPT) consisting of both ASA and a P2Y 12 inhibitor, which blocks the P2Y 12 receptor and blocks adenosine diphosphate (ADP) binding to the surface of the platelets (see Table 39.6 ). The latter includes the oral thienopyridines (clopidogrel, prasugrel), which are irreversible blockers, as well as a cyclopentyltriazolopyrimidine (ticagrelor), which is a reversible P2Y 12 inhibitor. Thienopyridines are prodrugs that require oxidation by the hepatic cytochrome P-450 (CYP) system to form the active metabolites. Thus drugs that inhibit the CYP system reduce the formation of the active form of thienopyridines, unlike ticagrelor, which does not depend on the CYP system. In addition to inhibition of platelet activation and aggregation, thienopyridines also reduce fibrinogen, blood viscosity, and erythrocyte deformability and aggregability through mechanisms that appear to be independent of ADP.
Clopidogrel
Clopidogrel was the first thienopyridine to be widely studied in patients with CAD, NSTE-ACS, and patients undergoing PCI. For over a decade, clopidogrel, used in combination with ASA, was the preferred oral antiplatelet drug combination in multiple guidelines. With the development of more potent antiplatelet drugs (prasugrel, ticagrelor), clopidogrel has been in part supplanted, although it is still frequently used in patients who are at very high risk of bleeding and in patients with contraindications or difficulty accessing the newer agents.
In the CURE trial, patients with NSTE-ACS who were treated with ASA, were randomized to either clopidogrel or placebo. The addition of clopidogrel to ASA reduced CV death, MI, or stroke by 20% in both low- and high-risk patients, regardless of whether they were managed with medical therapy, PCI, or coronary artery bypass grafting (CABG). Benefit was seen as early as 24 hours, with Kaplan-Meier curves beginning to diverge after just 2 hours. Moreover, the reduction in MI or CV death was similar before and after PCI. Clopidogrel was associated with an increase in bleeding, including nonsignificant increases in both life-threatening and fatal bleeding.
Current guidelines recommend clopidogrel (600 mg loading dose, 75 mg daily maintenance dose) in addition to aspirin in patients with NSTE-ACS who cannot receive ticagrelor or prasugrel (e.g., due to intolerance or very high risk of bleeding due to a prior intracranial hemorrhage or indication for full-dose oral anticoagulation or cost). Use of a 600-mg loading dose achieves a steady-state level of platelet inhibition after 2 hours, more rapidly than the 300-mg dose. Two strategies for initiating clopidogrel therapy in patients with NSTE-ACS have evolved: (1) starting clopidogrel at arrival or hospital admission or (2) delaying treatment with clopidogrel until after coronary angiography and then administering the drug on the catheterization table if PCI is to be performed. The early treatment strategy is preferred because it affords the benefits of reducing early ischemic events, but at the cost of an increase in bleeding in the minority of patients who undergo CABG instead of PCI, and thus is no longer recommended in patients in whom the coronary anatomy is not known and an early invasive approach is planned. In patients undergoing CABG, those who had received clopidogrel within 5 days of surgery had an increased risk for major bleeding and the need for reoperation, which led to the recommendation that clopidogrel be discontinued at least 5 days before major surgery, if possible.
Although DAPT reduces recurrent ischemic events in patients with NSTE-ACS compared with ASA alone, up to 10% of patients treated with ASA and clopidogrel have events within the first year of ACS, including stent thrombosis in up to 2% of patients at 1 year.
As with ASA, hyporesponders to clopidogrel have been identified and are at higher risk for recurrent cardiac events, including stent thrombosis, MI, and death. The incidence of patients not achieving the expected pharmacologic response to clopidogrel ranges from 5% to 30%, depending on the population and the definition used to assess response. Hyporesponsiveness to clopidogrel is more common in patients with DM, obesity, advanced age, and certain genetic polymorphisms of the CYP system. Patients with a minimal antiplatelet response to clopidogrel have lower concentrations of the active metabolite, thus indicating failure of necessary conversion of the prodrug to the active drug.
Several polymorphisms of the gene encoding for the CYP2C19 enzyme have been associated with reduced production of the active metabolite of clopidogrel (see Chapter 9 ). These polymorphisms (especially the reduced-function ∗C2 allele) occur in approximately one-third of white individuals and up to half of Asians and have been associated with increased adverse clinical outcomes in patients treated with clopidogrel. In other studies, reduced-function alleles are associated with increased stent thrombosis. Testing for these polymorphisms in patients who are candidates for thienopyridine treatment can identify those who are likely to be unresponsive or hyporesponsive to the standard dose of clopidogrel and are candidates for alternative antiplatelet regimens. Proton pump inhibitors (PPIs) modestly reduce the antiplatelet effect of clopidogrel because of competition for metabolism by the CYP3A4 enzyme. The clinical significance of this interaction remains uncertain as the addition of omeprazole to clopidogrel did not increase CV events compared with placebo plus clopidogrel, but omeprazole did decrease adverse GI outcomes in a randomized, double-blind trial.
Prasugrel
Like clopidogrel, prasugrel is a prodrug requiring hepatic oxidation to form an active metabolite that irreversibly inhibits the platelet P2Y 12 receptor. However, unlike clopidogrel, formation of the active metabolite of prasugrel requires only one step and is generated within 30 minutes of ingestion. While the active metabolites of clopidogrel and prasugrel exert equal antiplatelet effects in vitro, the generation of the prasugrel metabolite is approximately 10 times as great as the clopidogrel metabolite.
Prasugrel (60-mg loading dose, 10-mg daily maintenance dose) was compared with clopidogrel in patients with NSTE-ACS with known coronary anatomy in the TRITON-TIMI 38 trial. The primary composite of CV death, MI, or stroke was reduced significantly by 19% in the patients randomized to prasugrel through 15 months of follow-up ( Fig. 39.8 ). This benefit was driven by a significant 24% reduction in MI and was particularly striking in patients with diabetes (30% reduction). In addition, prasugrel markedly reduced the rate of definite or probable stent thrombosis (by 52%), particularly in patients with drug-eluting stents (DESs) (64%) ; thus prasugrel should be considered in patients who present with stent thrombosis despite compliance with clopidogrel therapy.
Severe bleeding complications were more common with prasugrel than clopidogrel, including non-CABG major (see Fig. 39.8 ), spontaneous, and fatal bleeding. Prasugrel is contraindicated in patients with prior stroke or transient ischemic attack due to evidence of net harm in this group in TRITON-TIMI 38. Bleeding rates were especially high in elderly patients (≥75 years) and those with reduced body weight (<60 kg [132 lb]). Thus prasugrel should be avoided in such patients unless they are at high risk for thrombosis, in which case a 5-mg maintenance dose is preferred. In patients younger than 75 years who weighed at least 60 kg and had no prior stroke or transient ischemic attack, the “core” group of patients for whom the U.S. Food and Drug Administration (FDA) approved its use, prasugrel was associated with a 26% reduction in the primary end point. Prasugrel should be discontinued at least 7 days before cardiac surgery whenever possible.
Prasugrel (10-mg daily) was compared with clopidogrel (75 mg daily) on a background of ASA and other standard therapies in patients with NSTE-ACS managed with an ischemia-guided strategy in the TRILOGY ACS randomized trial. There was no benefit of treatment with prasugrel over clopidogrel, and bleeding rates were similar. The ACCOAST trial of high-risk patients with NSTE-ACS managed with an early invasive strategy was randomized to prasugrel or clopidogrel prior to angiography . There was no significant difference in the composite primary efficacy endpoint, but prasugrel did increase bleeding compared with clopidogrel. Given the totality of the evidence from these three randomized trials, prasugrel (60-mg loading dose, 10-mg daily maintenance) in addition to ASA is most suitable in patients with NSTE-ACS <75 years without a prior stroke or transient ischemic attack who have had coronary angiography and in whom PCI is planned. Prasugrel is not recommended for use in patients with NSTE-ACS before the coronary anatomy is known.
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