Gus Theodos, Anthony A. Bavry, and A. Michael Lincoff
TERMINOLOGY AND OVERVIEW
The current approach to unstable or acute coronary syndromes (ACSs) recognizes a heterogeneous clinical spectrum that ranges from unstable angina (UA) and non–ST-elevation myocardial infarction (NSTEMI) to ST-elevation myocardial infarction (STEMI). ACS is one manifestation of atherothrombotic disease. Other clinical manifestations of vascular disease include ischemic/embolic stroke, transient ischemic attack, renal insufficiency/failure, and limb ischemia/claudication. There is considerable overlap in the burden of vascular disease, so the presence of atherothrombosis in one vascular bed should raise the suspicion for disease in another vascular bed. As an example, an individual who has limb claudication is also likely to have coronary artery disease and should undergo equally aggressive atherothrombotic risk factor modification.
Various classifications have been used to describe the syndrome of UA. The Braunwald classification of UA is a widely used mechanism for providing diagnostic and prognostic information about the patient. In this system, angina is divided into acute rest (class III), subacute rest (class II), or exertional angina (class I). Acute rest angina is chest pain that occurred at rest within 48 hours of presentation, while subacute rest angina is chest pain that occurred at rest within the previous month, although more than 48 hours prior to presentation. Exertional angina is chest pain that has been present for <2 months’ duration that is described as new onset, severe, or accelerating in nature. This type of angina occurs with any exertion or less exertion than would normally bring about chest pain, with no rest angina for the previous 2 months. The Braunwald classification system also describes the clinical circumstances in which the angina is occurring. For example, secondary UA is caused by a clinical process that causes demand ischemia, such as gastrointestinal bleeding resulting in tachycardia. This process is in contrast to primary UA, in which supply ischemia results from plaque rupture with partial or total coronary occlusion. Postinfarction angina is a special clinical circumstance to consider, as these patients are at higher risk for adverse cardiac outcomes.
The classification for ACS focuses on electrocardiographic (ECG) findings in the first minutes to hours of an event. This approach ensures that the most appropriate management (i.e., early invasive therapy with appropriate coronary revascularization vs. a more conservative approach) occurs as rapidly as possible. Older ACS terminology is inefficient, as it focused on the ECG findings after the completion of the coronary event. Historical terms such as Q-wave and non–Q-wave myocardial infarction (MI) should therefore be avoided.
This chapter discusses the spectrum that encompasses UA and NSTEMI, while another chapter focuses on STEMI. Other causes of chest pain syndromes such as aortic dissection, acute pericarditis, or pulmonary embolus are not discussed here. These chapters follow the American College of Cardiology/American Heart Association (ACC/AHA) guidelines (Table 40.1).
TABLE
40.1 ACC/AHA Classification for Recommendations
From Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007;50(7):e1–e157, with permission from Elsevier.
EPIDEMIOLOGY AND PROGNOSIS
There are over 5 million annual visits to emergency departments in this country for the evaluation of chest pain, with approximately 1.5 million hospitalizations for UA/NSTEMI. This number is expected to increase over the next decade. Atherothrombotic disease, especially ACS, significantly shortens an individual’s life span. A survived acute MI shortens the expected life expectancy for a 60-year-old individual by approximately 9 years, whereas a cerebrovascular accident shortens an individual’s expected life span by about 12 years. Coronary disease is the single largest cause of mortality worldwide. This translates into approximately one of every five deaths in the United States being attributable to atherothrombotic disease. The shift in the epidemiology of coronary disease in this country, with improved overall mortality, is due to effective prevention and treatment of cardiovascular disease over the last several decades.
Most ACSs occur in individuals >65 years old, and nearly 50% occur in women. When women present with chest pain, the etiology is less likely to be secondary to obstructive coronary disease, and when coronary disease is present, it tends to be less severe than in men. In-hospital mortality of UA and NSTEMI patients is less than that of STEMI patients, although because the former are at risk for recurrent events, their long-term risk is equivalent or worse compared to STEMI patients.
CLINICAL PRESENTATION
UA and NSTEMI patients typically present with substernal chest discomfort, described as a pressure or a heavy sensation. This more accurately describes angina than terminology such as “pain.” Symptoms typically last <30 minutes, although they may recur frequently throughout the day or evening upon minimal exertion. Symptoms may occur at rest. Angina that occurs with minimal exertion is usually relieved promptly with rest or nitroglycerin. Anginal equivalents include neck and jaw discomfort, although the most common anginal equivalent is worsening dyspnea upon exertion. Atypical findings such as nausea, vomiting, and fatigue are easily overlooked, although these symptoms should be considered as angina in diabetics, women, and the elderly. Findings that are typically not characteristic of myocardial ischemia include sharp/pleuritic pain, pain that has been present for several hours, and brief pain that lasts only a few seconds. Up to 20% of MI s are “silent” and occur without any appreciable symptoms.
ECG findings include transient ST elevations, ST depressions (horizontal or downsloping), T-wave inversions, or nonspecific changes. The ECG may also appear normal. Deep symmetric T-wave inversions predict higher risk than small T-wave inversions. Ischemic T waves may also have a biphasic appearance. Dynamic ECG changes that are obtained during an episode of chest pain are particularly valuable, especially if the changes resolve in the absence of symptoms. It is important to repeat the ECG frequently, as a non–ST-elevation ACS may progress to a STEMI. Conversely, initial ST elevations may resolve quickly, thus changing the focus of early management.
PATHOPHYSIOLOGY FOR PRIMARY AND SECONDARY CAUSES OF ANGINA
The above discussion assumes a primary coronary etiology for an unstable coronary syndrome. The corresponding pathophysiology for a primary ACS is most commonly felt to be rupture of a vulnerable plaque, and less commonly due to plaque erosion or calcific nodules. Vulnerable plaques overlie lipid-rich cores that are surrounded by thin fibrous caps. Exposure of the underlying plaque to blood is a potent activator of platelets and thrombus formation. This subsequently results in microembolization of platelet aggregates and intermittent coronary vasoconstriction. The fibrous cap can become unstable as a result of fissures caused by proteinases secreted by neighboring macrophages. As a plaque matures, the fibrous cap becomes thicker and more stable. Conversely, plaque erosion occurs over lesions rich in smooth muscle cells and proteoglycans. These areas have minimal amounts of inflammatory substrate. The calcific nodule refers to rupture of a dense, calcified matrix through a fibrous cap. These are commonly associated with healed plaques. An important observation has been that acute MIs do not occur at sites of severe coronary narrowing. Two-thirds of events that are caused by an acutely occluded coronary vessel are in the location of a previous mild stenosis (i.e., stenosis <50%).
Secondary causes of ACS that are responsible for demand ischemia should be screened for and corrected if present before proceeding down the appropriate ACS management algorithm. Secondary causes include hypertensive crises, anemia/hypovolemia, worsened chronic obstructive pulmonary disease/hypoxia, hyperthyroidism, arteriovenous fistula in dialysis patients, and systemic infection. Aortic stenosis and hypertrophic obstructive cardiomyopathy are cardiac diseases that may cause demand myocardial ischemia. Cocaine use is a special condition to consider, as it can produce both demand ischemia (increased heart rate and blood pressure) as well as supply ischemia (coronary vasospasm and thrombus formation).
RISK STRATIFICATION
ECG
Risk stratification is a necessary component in the initial management of coronary disease patients. The ECG is a first-line test that provides not only diagnostic but also prognostic information. Data from the Global Use Of Strategies To Open Occluded Arteries In Acute Coronary Syndromes (GUSTO IIb) trial revealed a lower 6-month survival among patients with ST depressions treated conservatively compared to STEMI patients treated with fibrinolysis. The lowest-risk ACS patients (among those with any ECG changes) were those with T-wave inversions. Patients with a completely normal ECG had the lowest overall risk. A similar analysis from the relationship between insulin sensitivity and cardiovascular disease risk (RISC) Study Group found the highest risk to be among those with ST elevations and reciprocal changes (ST depressions). The lowest risk was among those with no ST changes or nonspecific ST-T changes.
Biomarkers
While the ECG is being performed and interpreted, blood work should be sent for analysis of complete blood count (CBC), chemistry, cardiac biomarkers, markers of inflammation and volume overload, and a lipid profile. Although it is not usually thought of for this purpose, information available from the CBC can be helpful in providing a crude measure of risk stratification. An elevated white blood cell (WBC) count has been shown to predict worse cardiac outcomes in ACS patients.
High-sensitivity C-reactive protein (hs-CRP) as a marker of inflammation provides prognostic information in unstable coronary syndromes. An elevated hs-CRP predicts a three- to fourfold increased risk for future cardiac events. This increased risk for MI can be attenuated by the use of aspirin. An hs-CRP level >3 mg/L is considered high risk, while a level >10 mg/L is considered an acute-phase response and should be repeated in 3 weeks. An elevated CRP predicts future cardiac events better than elevated cholesterol or presence of the metabolic syndrome.
An elevated troponin I or T also carries independent prognostic information. A meta-analysis showed that troponin-positive ACS patients have a fourfold increased risk for death compared to troponin-negative patients. Similarly, an analysis of the thrombolysis in myocardial infarction (TIMI) IIIb trial documented an eightfold increased risk of death at 42 days for patients with an elevated troponin I (>9 ng/mL) compared to troponinnegative patients. The 42-day mortality in patients with an elevated troponin was 7.5%, compared to 1% in those with a negative troponin.
An elevated brain natriuretic peptide (BNP) predicts increased risk for adverse cardiac events across the spectrum of ACS, although the predictive effect is greatest for UA and NSTEMI. BNP is a cardiac neurohormone synthesized in the ventricles and released as a larger peptide which is then cleaved into smaller portions including BNP and inactive N-terminal proBNP peptide (NT-proBNP). The release of BNP reflects the decompensated state of the ventricles, and it causes vasodilatation, natriuresis, and diuresis, leading to some improvement of the loading conditions of the failing heart. Even though BNP is the active hormone, both forms can be measured and serve as markers of congestive heart failure (CHF).
The combination of multiple biomarkers has incremental value. An hs-CRP combined with cardiac biomarkers (i.e., troponin I or T) and markers of pressure/volume overload (i.e., BNP) predict an increased risk for major cardiac events. In the OPUS-TIMI 16 trial there was a sixfold increased risk for 30-day cardiac events when all three markers were elevated. Similarly, in the TACTICS-TIMI 18 trial there was a 13-fold increased risk in 30-day cardiac events. So hs-CRP, troponin I or T, and BNP provide prognostic information in ACS patients. Other inflammatory markers such as CD-40 ligand are experimental, although they may have a role in the future in predicting the overall risk for cardiac events in ACS.
Risk Scores
The TIMI risk score incorporates data derived from the TIMI 11B trial and has been validated by three additional trials. The TIMI risk score is an easily used model that has important prognostic and therapeutic implications. It incorporates seven variables that are readily available from the history, ECG, and cardiac biomarkers (Fig. 40.1). The presence of six or seven risk factors predicts a 40% incidence of death, MI, or ischemia requiring repeat revascularization by 30 days. This is in contrast to zero or one risk factor, where the 30-day cardiac event rate is <5%. The seven variables used to calculate the TIMI risk score are age ≥65 years, ≥3 coronary disease risk factors (defined as diabetes, hypertension, hyperlipidemia, use of tobacco, and family history of premature coronary disease), a known coronary stenosis of >50%, ST deviation (transient ST elevations, ST depressions, or T-wave inversions), ≥2 anginal events in the past 24 hours, aspirin use in the last 7 days, and elevated cardiac biomarkers (i.e., elevated CK-MB or troponin).
FIGURE 40.1 TIMI risk model for prediction of short-term adverse cardiac events in UA/NSTEMI patients. (Adapted from Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA.2000;284:835–842.)
Another risk score which has been utilized extensively is the global registry of acute coronary events (GRACE) score. This score is the composite of nine variables, which, when added together, can be plotted on a nomogram to determine mortality risk from discharge to 6 months. The variables included in the score include age, history of CHF, history of MI, heart rate and blood pressure on presentation, presence of ST-segment depression on initial ECG, serum creatinine and elevated cardiac biomarkers during hospitalization, and no percutaneous coronary intervention (PCI) performed during hospitalization.
With either scoring system in patients presenting with UA/NSTEMI, there is progressively greater benefit of more aggressive therapies as the risk score rises.
MANAGEMENT
Initial Approach
The initial assessment of UA/NSTEMI coronary syndromes includes establishing intravenous access and starting supplemental oxygen in patients who are hypoxic or who show signs of respiratory distress. Simultaneously, an ECG must be interpreted, a targeted history and physical exam taken, and cardiac biomarkers measured. Preferred cardiac biomarkers include troponin I or T and CK-MB. Total CK (without MB) should not be used to evaluate an ACS (class III recommendation).
The primary management focus during an ACS, while antithrombotic and anti-ischemic medicines are administered (Table 40.2), is to determine a patient’s suitability for early invasive therapy versus conservative therapy. While fibrinolytic therapy plays an invaluable role in STEMI patients, it should not be used for the management of UA/NSTEMI unstable coronary syndromes (class III recommendation).
TABLE
40.2 Class I Anti-ischemic Recommendations
aIntravenous beta-blockers class IIa.
bNondihydropyridine calcium channel blockers may be used when beta-blockers are not successful, or there is a contraindication to their use.
cACE-I are continued when ischemia is controlled, especially for LV dysfunction or diabetes.
dClopidogrel can be substituted in patients who cannot take aspirin due to hypersensitivity or major gastrointestinal intolerance.
ePrasugrel can be substituted if planning for PCI with risk of bleeding is low and CABG considered unlikely—class IIb recommendation.
From Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007;50(7):e1–e157, with permission from Elsevier.
Invasive Therapy
Early trials failed to show a benefit from an invasive approach in UA/NSTEMI patients. A meta-analysis performed in the current PCI era analyzed all available studies that randomized patients to early invasive therapy versus conservative management. In those studies, patients who were treated conservatively could have an angiogram performed if they had recurrent chest pain, ischemic ECG changes, a large reversible defect with noninvasive stress testing, or elevated cardiac biomarkers. Only contemporary trials that used glycoprotein (GP) IIb/IIIa inhibitors and intracoronary stents were included. Five studies, involving nearly 7,000 UA/NSTEMI patients, were analyzed. This analysis revealed a 6- to 12-month survival advantage from early invasive therapy compared to conservative management (RR = 0.80, 95% CI 0.63 to 1.03). In contrast, studies that enrolled patients before the routine use of stents and GP IIb/IIIa inhibitors revealed a harmful association from early invasive therapy (RR 1.31, 95% CI 0.98 to 1.75).
The most contemporary large-scale data on this topic derive from the Invasive versus Conservative Treatment in Unstable coronary Syndromes (ICTUS) trial, which randomized 1,200 UA/NSTEMI patients to routine invasive or selective invasive management. Patients in the selective invasive arm were treated medically and only in cases of refractory angina or a positive exercise stress test underwent coronary angiography with or without revascularization. Results at the end of 1 year and after 3 years follow-up showed there was no significant difference in the composite ischemic end point. The investigators postulate that due to the high rate of revascularization in the selective invasive therapy arm (47%), use of aggressive medical therapy in both arms (including routine use of clopidogrel in the conservative arm) and low event rate, there was little incremental benefit to be observed with an early invasive strategy. Given the results of ICTUS, the ACC/AHA guidelines recognize that an initially conservative (selective invasive) strategy may be considered as a treatment option in stabilized UA/NSTEMI patients.
Earlier trials comparing early invasive versus conservative management include third randomized intervention treatment of angina (RITA-3) and FRagmin and fast revascularization during InStability in Coronary artery disease (FRISC II). In the RITA-3 trial, 1,810 UA/NSTEMI patients were randomized to interventional versus conservative treatment. Like ICTUS, at 1 year, death and MI rates were similar, but at 5 years, a significant reduction in death or MI emerged in the early invasive treatment arm. Benefits were seen mainly in high-risk patients. Similarly, an invasive strategy was favored at 5 years in the FRISC II trial for the primary end point of death or nonfatal MI (HR 0.81, p = 0.009). Here, the benefit was confined to males, nonsmokers, and patients with two or more cardiac risk factors.
A meta-analysis of seven randomized trials of management strategies in UA/NSTEMI, including ICTUS, supports the long-term benefit of an early invasive strategy. Among 8,375 patients, the incidence of all-cause mortality at 2 years was 4.9% in the early invasive group compared with 6.5% in the conservative groups (RR 0.75, 95% CI 0.63 to 0.90, p = 0.001), while also showing a significant reduction in nonfatal MI and hospitalization
Data from the ABOARD, TIMACS, and ISAR-COOL studies helped to determine the optimal timing of the invasive strategy. These three trials, taken together with earlier studies, do provide support for a strategy of early angiography and intervention to reduce ischemic complications in patients who have been selected for an initial invasive strategy, particularly among those at high risk (defined by GRACE score >140), whereas a more delayed approach is reasonable in low- to intermediate-risk patients. The “early” time period in this context is considered to be within the first 24 hours after hospital presentation, although there is no evidence that incremental benefit is derived by angiography and intervention performed within the first few hours of hospital admission. The advantage of early intervention was achieved in the context of intensive background antithrombotic therapy.
Therefore, current ACC/AHA guidelines recommend (class I) an early invasive approach to patients with angina in the presence of heart failure symptoms (pulmonary edema, an S3 gallop, or new mitral regurgitation), known left ventricular dysfunction, hemodynamic instability, positive noninvasive stress test (large area of ischemia), sustained ventricular tachycardia, or prior revascularization (prior coronary artery bypass grafting [CABG], or PCI within the last 6 months). The updated guidelines additionally recommend that individuals with rest angina despite intensive anti-ischemic therapy or with new ST depressions or elevated cardiac biomarkers be directed to early invasive therapy. Routine invasive therapy is discouraged in low-risk patients and those with extensive comorbidities (class III recommendation).
Intermediate-risk patients can initially be treated by either an early invasive or a conservative approach with careful monitoring for the development of high-risk features. High-risk features include refractory pain, angina with dynamic ECG changes, or elevated cardiac biomarkers. Such a change in clinical status should advance therapy to a more invasive approach along with adjunctive GP IIb/IIIa inhibitor use.
Low-risk patients can often be treated as outpatients or screened for MI with serial cardiac enzymes in a chest pain unit with a goal of early discharge. Invasive therapy is discouraged in these patients. Risk-factor modification is emphasized to all patients regardless of their risk at presentation.
Once the decision is made to perform coronary angiography, the patient’s suitability for coronary revascularization is determined. Two options for revascularization are PCI (i.e., percutaneous transluminal coronary angioplasty [PTCA] and intracoronary stents) or CABG. The choice of which revascularization to perform is beyond the scope of this chapter, although several general guidelines exist. Severe left main trunk disease is usually an indication for CABG, although left main PCI can be performed in select cases (i.e., the patient is not a candidate for open heart surgery). Severe three-vessel disease or severe two-vessel disease involving the left anterior descending artery, along with left ventricular dysfunction or diabetes, also favor CABG (Fig. 40.2).
FIGURE 40.2 Revascularization strategy in UA/NSTEMI. *There is conflicting information about these patients. Most consider CABG to be preferable to PCI. CABG, coronary artery bypass graft; LAD, left anterior descending coronary artery; PCI, percutaneous coronary intervention; UA/NSTEMI, unstable angina/non–ST-elevation myocardial infarction. (From Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007;50(7):e1–e157, with permission from Elsevier.)
Antiplatelet Agents
Aspirin
Aspirin is the cornerstone of treatment for all unstable coronary syndromes unless there is a serious contraindication to its use (class I recommendation). Aspirin blocks the conversion of arachidonic acid to thromboxane A2 by irreversibly acetylating cyclooxygenase (Fig. 40.3). Full-dose aspirin exerts maximal antiplatelet effects within 30 minutes of absorption; therefore an initial 325 mg of aspirin orally (or by rectal suppository if necessary) is given during an ACS (see Table 40.2). Low-dose aspirin (75 to 150 mg daily) is effective in primary prevention by reducing the incidence of MI. Optimal dosing of aspirin has been debated for some time, and the recently published CURRENT-OASIS 7 trial demonstrated no difference in outcome between patients treated with low-dose and high-dose aspirin, in all patients and in the PCI subgroup. This indicates that either dose can be used provided a 300-mg loading dose is used before initiation of a maintenance dose. There was an increase in minor bleeding events with high-dose aspirin, and therefore lower doses of aspirin should be used unless there is concern for recurrent ischemia. In secondary prevention, aspirin improves survival. Bleeding complications increase with increasing dosage; therefore ongoing aspirin therapy is typically an 81-mg tablet daily unless there is a compelling reason for using a higher dosage, such as mitigating the cutaneous side effects of niacin.
FIGURE 40.3 Schema for platelet aggregation and inhibition of platelet aggregation by GP Iib/IIIa inhibitors. Platelets are activated by adenosine diphosphate, thrombin, epinephrine, collagen, and thromboxane A2. Aspirin blocks the conversion of arachidonic acid to thromboxane A2. Clopidogrel blocks adenosine diphosphate-mediated platelet activation. GP IIb/IIIa inhibitors cause a conformational change in the GP IIib/IIIa receptor that prevents fibrinogenmediated platelet aggregation. (From Yeghiazarians Y, Braunstein JB, Askari A, Stone PH. Unstable angina pectoris. N Engl J Med. 2000;342:101-114, with permission from the Massachusetts Medical Society.)
Thienopyridines and ADP Inhibitors
Despite aspirin’s proven benefit in reducing MI and death, it does not fully block platelet aggregation, especially when aggregation is induced by adenosine diphosphate (ADP). Other agents such as thienopyridines play a valuable role in the management of UA/NSTEMI patients because they complement the actions of aspirin. Thienopyridines are represented by ticlopidine, clopidogrel, and prasugrel. These agents act by inhibiting ADP receptor–mediated platelet activation. Ticagrelor has also recently been approved for use in the United States. In contrast to the other thienopyridines, ticagrelor has a binding site different from ADP, making it an allosteric antagonist, and the blockage is reversible. Newer agents, cangrelor and elinogrel, which are direct inhibitors of the ADP receptor P2Y12, are also on the horizon. Thienopyridines may be used alone if a patient has a hypersensitivity to aspirin, but they are ideally used adjunctively with aspirin. Clopidogrel is preferred over ticlopidine, given its lower incidence of neutropenia and thrombocytopenia and its rapid onset of action. A loading dose of 300 to 600 mg of clopidogrel produces maximal antiplatelet effects in 4 to 6 hours. The important studies that document the benefit of clopidogrel in unstable coronary syndromes are the CAPRIE and CURE trials.
The CAPRIE trial randomized over 19,000 vascular disease patients to receive aspirin or clopidogrel. Vascular disease was manifested as a history of ischemic stroke, MI, or symptomatic peripheral arterial disease. After nearly 2 years of follow-up, clopidogrel reduced a composite endpoint of ischemic stroke, MI, or death from vascular causes (5.3% vs. 5.8%, p = 0.04).
The CURE trial tested protection from ischemic events beyond that of aspirin by the addition of clopidogrel to aspirin and standard medical therapy in patients with ACS. This trial randomized over 12,000 non–ST-elevation ACS patients within 24 hours of their onset of chest pain to clopidogrel plus aspirin versus aspirin alone. Patients were eligible if they had ischemic ECG changes or elevated cardiac biomarkers. Individuals who were randomized to clopidogrel received a loading dose of 300 mg, followed by 75 mg/d for 3 to 12 months. Aspirin could be given at a dose of 75 to 325 mg/d. This was largely a conservatively treated population, as <50% of the patients underwent angiography. Among enrolled patients, <20% underwent CABG, and <25% had percutaneous coronary revascularization. Also, <10% of individuals were treated with a GP IIb/IIIa inhibitor in addition to the other antithrombotic agents. The mean duration of treatment with clopidogrel was 9 months. A composite of cardiac outcomes was significantly reduced at 30 days (RR = 0.79, 95% CI 0.67 to 0.92) and 1 year by the regimen of clopidogrel plus aspirin versus aspirin alone (RR = 0.8, 95% CI 0.72 to 0.9, p < 0.001). There were trends toward reduction in each of the individual components, with the most effect on MI. The primary outcome was reduced across a range of patients regardless of whether or not they were revascularized.
Important safety data also came from the CURE trial. Major bleeding was significantly increased by the use of clopidogrel, although this did not include hemorrhagic strokes. Patients who had clopidogrel discontinued more than 5 days before CABG did not have an increase in major postoperative bleeding, while individuals whose clopidogrel was stopped within 5 days of CABG appeared to have an increase in major bleeding (9.6% in clopidogrel vs. 6.3% in placebo, RR 1.53, p = 0.06). Additionally, patients on clopidogrel who were treated with high-dose aspirin (325 mg/d) suffered more bleeding than individuals on approximately 81 mg/d.
The recent CURRENT-OASIS 7 trial examined dosing strategies of aspirin and clopidogrel, and determined equivalent short-term efficacy with both low and high-dose aspirin. Double-dose clopidogrel for 6 days (after a 600 mg loading dose) was associated with a significant reduction in both the primary endpoint (30 day mortality, MI, or stroke) (0.7 vs. 1.3%; HR = 0.54, 95% CI 0.39 to 0.74, p = 0.0001) and the secondary outcome of stent thrombosis (1.6% vs. 2.3%; HR = 0.68; 95% CI, 0.55 to 0.85; p = 0.001) among the 17,263 patients who underwent PCI.
Prasugrel is another drug in the thienopyridine class, and it is metabolized by the intestine and liver into its active metabolite. It is nearly completely converted to the active metabolite rapidly after ingestion and therefore inhibits ADP-induced platelet aggregation more rapidly, more consistently, and to a greater extent than do standard and higher doses of clopidogrel. The clinical benefit of this intense platelet inhibition with prasugrel was demonstrated in the TRITON-TIMI 38 study. This randomized trial compared clopidogrel and prasugrel, in addition to aspirin, in 13,608 patients with ACSs scheduled to undergo PCI. There was a significant reduction in the composite endpoint of cardiovascular death, myocardial infraction, or stroke in patients who received prasugrel versus clopidogrel (9.9% vs. 12.1%, p < 0.001) over 15 months. This decrease in cardiovascular outcomes was associated with a higher risk of bleeding, both TIMI major (2.4% vs. 1.8%, p = 0.03) and life-threatening bleeding (1.4% vs. 0.9%, p = 0.01). The increase in bleeding was particularly marked in certain subgroups, including patients >75 years old, patients with history of transient ischemic attack (TIA) or stroke, and those with body weight <60 kg. For this reason caution should be taken in older patients and those with low body weight, and is contraindicated in those with prior TIA or stroke. Prasugrel was also associated with a particular benefit in diabetic patients.
Clopidogrel should be considered in addition to aspirin (or alone when there is hypersensitivity to aspirin) for all UA/NSTEMI patients when PCI is planned or for those managed conservatively (class I recommendation) (see Table 40.2). Patients with UA/NSTEMI at medium/high risk should receive dual-antiplatelet therapy on presentation. The decision on which adjunctive medication to use depends on whether it is being started before PCI (then choose clopidogrel or a GP IIb/IIIa inhibitor) or at the time of PCI (then choose clopidogrel, prasugrel, or a GP IIb/IIIa inhibitor). Prasugrel may be considered for administration on presentation, but only if PCI is planned and the perceived need for CABG is low (class IIb recommendation).
Duration of therapy with either clopidogrel or prasugrel is at least 1 month and ideally 1 year or longer. Those patients in whom a stent is placed should be treated with dual antiplatelet therapy for at least 1 month (with bare metal stents) and ideally at least 1 year (with drug-eluting stents). An important caveat with clopidogrel and prasugrel is that they likely increase the risk for major bleeding during surgery and so they should be held for at least 5 days before cardiac surgery is performed. For this reason, clopidogrel or prasugrel is often first administered on the catheterization table (loading dose) after coronary anatomy is defined and it is clear that cardiac surgery will not be required. A loading dose of clopidogrel is 300 to 600 mg, followed by a daily dose of 75 mg. A loading dose of prasugrel is 60 mg, and a daily dose is 10 mg daily. When a significant aspirin allergy exists, clopidogrel should be used in its place (class I recommendation).
Ticagrelor is a reversible nonthienopyridine direct P2Y12 receptor antagonist, and unlike clopidogrel and prasugrel, does not require metabolic activation. The platelet inhibition and patient outcomes (PLATO) study in mid-2009 found that ticagrelor reduced the incidence of the composite ischemic endpoint compared with clopidogrel (9.8% vs. 11.7%, p < 0.001) when used in addition to aspirin in patients with ACS. Patients given ticagrelor were less likely to die from vascular causes, heart attack, or stroke. Unlike the experience with the nonreversible prasugrel, ticagrelor therapy was associated with little increase in bleeding complications. This agent was recently approved by the United States Food and Drug Administration, but optimal time to discontinue before CABG is still under review.
Overall, ADP inhibition with thienopyridines adds to aspirin in protecting patients against ischemic events. This benefit is tempered by an increased risk of bleeding. More inhibition of ADP receptors (with higher doses of clopidogrel, prasugrel, or ticagrelor) produces better inhibition of ischemic endpoints, but the risk–benefit ratio becomes narrower with nonreversible intense agents like prasugrel. Ticagrelor may be a nearly optimal combination with aspirin, as it provides the benefit of more intense inhibition without a substantial excess of bleeding complications.
Glycoprotein IIb/IIIa Inhibitors
GP IIb/IIIa inhibitors have been shown to be effective in the management of high-risk UA/NSTEMI patients managed by early invasive therapy, particularly those who undergo PCI. GP IIb/IIIa inhibitors further complement the actions of aspirin and clopidogrel by blocking the final pathway involved in platelet activation and aggregation. Medicines in this class include eptifibatide, abciximab, and tirofiban. In individuals for whom an invasive strategy is planned, the use of a GP IIb/IIIa inhibitor reduces mortality and MI rates, albeit with an increased risk of bleeding. Accordingly, it is a class I recommendation to use a GP IIb/IIIa inhibitor as one of the potential second antiplatelet therapies that can be administered on presentation in high-risk UA/NSTEMI patients.
This information comes principally from studies that were performed prior to the widespread use of dual antiplatelet therapy with aspirin and thienopyridines. Therefore, more contemporary trials were performed to determine the use of GP IIb/IIIa inhibitors as a third antiplatelet therapy.
Prior to the widespread use of dual antiplatelet therapy with oral thienopyridines, there was more “upstream” (upon presentation and prior to angiography) use of GP IIb/IIIa inhibitors. In the more contemporary era, the EARLY ACS trial tested a strategy of routine upstream usage of eptifibatide versus delayed provisional usage in 9,492 UA/NSTEMI patients. “Upfront” clopidogrel was used in 70% of patients. The primary composite endpoint of death, MI, need for urgent revascularization or thrombotic bailout were similar between the groups, but routine upstream usage of eptifibatide was associated with increased risk of TIMI major bleeding (2.6% vs. 1.8%, p = 0.02).
Further evidence supporting a more selective usage of GP IIb/IIIa inhibitors comes from the ACUITY trial. Patients with moderate- or high-risk unstable coronary syndromes were randomized to receive adjunctive anticoagulation with strategies including heparin, bivalirudin, or GP IIb/IIIa inhibitors. Clopidogrel was used in 63% of patients before angiography. Patients within either of the two strategies using GP IIb/IIIa inhibitors were further randomized to routine upstream administration (upon randomization) versus deferred selective usage (in the cardiac catheterization laboratory at the time of PCI). Results again showed similar rates of ischemic endpoints with more bleeding in the routine upstream usage groups (6.1% vs. 4.9%, p < 0.001). See “Direct Thrombin Inhibitors” for further discussion of the ACUITY trial as it relates to bivalirudin.
The benefits of GP IIb/IIIa inhibitors in patients during (as compared with prior to) PCI were confirmed in the ISAR-REACT 2 trial. 2,022 patients with UA/NSTEMI who had been treated with a 600 mg clopidogrel bolus previously were randomized to receive abciximab versus placebo (and additional heparin) at the time of PCI. Patients who received abciximab had a reduced rate of the composite endpoint of death, MI, or urgent revascularization at 30 days (8.9% vs. 11.9%, p < 0.05). There were also reduced rates of the individual outcomes, with no difference in bleeding outcomes.
These studies highlight the benefit of GP IIb/IIIa inhibitors, especially in those undergoing PCI. Early upstream usage of GP IIb/IIIa inhibitors is associated with more bleeding risk than a delayed provisional approach, and should only be used when the risk–benefit ratio is appropriate. Routine use of GP IIb/IIIa inhibitors in addition to dual antiplatelet therapy should therefore be reserved for patients at particularly high risk for ischemic complications or with recurrent or refractory symptoms.
Antithrombin Therapy
Unfractionated Heparin and Low-Molecular-Weight Heparin
Heparins have been used in the management of coronary syndromes and during PCI for the last several decades. Unfractionated heparin is a glycosaminoglycan composed of polysaccharide chains which inhibit platelet aggregation and fibrin formation by causing a conformational change in antithrombin III that inhibits the activity of thrombin (factor IIa) and factor Xa. Low-molecular-weight heparins are easy to administer and do not require monitoring, and the various low-molecular-weight heparins have different ratios of anti-Xa to IIa.
Heparin and aspirin reduce death and MI in non–ST-elevation ACSs compared to treatment with aspirin alone. Therapy with unfractionated heparin is a class I recommendation in the care of intermediate- or higher-risk ACS patients. Low-molecular-weight heparin may have marginal benefit over unfractionated heparin in conservatively treated patients, and can be considered in patients who do not have renal insufficiency or when surgical revascularization is not planned within 24 hours (class IIa recommendation). For invasively treated patients, there is no clear advantage of low-molecular-weight heparin over unfractionated heparin, and institutional preference should govern the choice of a particular agent.
The dose of unfractionated heparin in conservatively treated patients is 80 U/kg bolus followed by 18 U/kg/h infusion. Heparin dosage is lowered if a patient will be managed invasively with a GP IIb/IIIa inhibitor and will be at higher risk for bleeding. The heparin dose in this case is 60 U/kg bolus (maximum 5,000 U) followed by 12 U/kg/h infusion (maximum 1,000 U/h) for a goal partial thromboplastin time (pTT) of 45 to 65. Conservative dosing for enoxaparin is 1 mg/kg subcutaneously twice a day, while the dose used in conjunction with invasive therapy is 0.75 mg/kg subcutaneously twice a day.
The large meta-analysis on GP IIb/IIIa inhibition in the setting of PCI revealed an increase in major bleeding when heparin was continued after PCI, although major adverse cardiac outcomes (MI, stroke, urgent revascularization) were not increased by stopping heparin at the time of completion of PCI. Accordingly, heparin or coumadin should not be continued post-PCI, unless there is a specific indication for their use. The routine use of coumadin in stabilized UA/NSTEMI patients is a class IIb recommendation. An indication for continuing antithrombin therapy after PCI would be a patient with atrial fibrillation or a mechanical valve. The optimal duration of heparin in conservatively treated patients is unknown, although if patients are asymptomatic, the duration of heparin therapy usually should not exceed 48 hours. If conservatively treated patients continue to have signs of ischemia, then longer duration of heparin therapy may be indicated.
Direct Thrombin Inhibitors
In contrast to heparins, direct thrombin inhibitors (DTIs) block only factor IIa via a mechanism that does not require the action of antithrombin III. These agents overcome important limitations of heparin, including unpredictable pharmacokinetics, increased bleeding, and the potential to cause heparin-induced thrombocytopenia (HIT). Representative agents in this class of medicines include hirudin, argatroban, and bivalirudin. Older studies suggested improved cardiac outcomes and reduced bleeding risk with bivalirudin, although an increased risk of major bleeding with hirudin.
The REPLACE-2 trial expanded on these findings by examining the role of bivalirudin during contemporary PCI. Although the patients in this trial were relatively stable, some lower-risk UA patients were enrolled. This trial documented the noninferiority of bivalirudin and a provisional GP IIb/IIIa inhibitor (in ~5% of patients) compared to unfractionated heparin and a planned GP IIb/IIIa inhibitor. Additionally, bivalirudin was shown to significantly reduce the risk for major bleeding (2.4% in the bivalirudin group vs. 4.1% in the heparin group, p < 0.001).
In the ACUITY trial, 13,819 patients with UA/NSTEMI were randomized to one of three strategies: heparin plus GP IIb/IIIa inhibitor, bivalirudin plus GP IIb/IIIa inhibitor, or bivalirudin alone. The groups with bivalirudin plus GP IIb/IIIa inhibitor and heparin plus GP IIb/IIIa inhibitor had similar outcomes. Importantly, though, bivalirudin alone, in comparison to heparin plus GP IIb/IIIa, was associated with similar cardiac ischemic outcomes, but significantly reduced rates of major bleeding (3.0% vs. 5.7%; p < 0.001). These results have led to an increase in the usage of bivalirudin as alternative antithrombotic to heparin plus GP IIb/IIIa during PCI.
These trials highlight the utility of bivalirudin across in patients at different levels of risk, and confirm that it provides equal protection against ischemic events, with a significantly reduced risk of bleeding, as does heparin plus GP IIb/IIIa inhibition. Therefore, in patients with UA/NSTEMI in whom PCI is planned as a postangiography management strategy, it is a class IIa recommendation to administer bivalirudin instead of GP IIB/IIIa inhibitors. This is particularly true for patients at high bleeding risk.
Anti-Ischemic Agents
Regardless of whether a patient will be directed to an early invasive approach versus a conservative approach, anti-ischemic medications are a priority. Nitroglycerin and beta-blockers are the first-line agents to consider (see Table 40.2). Nitroglycerin is initiated by a 0.4-mg sublingual tablet (repeated several times every 5 minutes if symptoms persist and hypotension does not develop), followed by intravenous infusion started at 10 to 20 µg/min (titrated up until resolution of symptoms or hypotension develops). An intravenous dose of 200 µg/min is considered a ceiling, although doses as high as 400 µg/min are occasionally used if needed. Sildenafil use within 24 hours of presentation is a class III recommendation to the use of nitroglycerin.
Beta-blockers are administered along with nitroglycerin and help to blunt the reflex tachycardia that may occur from its use. Beta-blockade is initiated intravenously (i.e., 5 mg metoprolol intravenously, repeated several times every 5 minutes), followed by oral administration (i.e., 25 mg metoprolol orally twice to three times per day and titrated up to effect) if there are no contraindications to its use. Contraindications include significant conduction abnormalities (marked first-degree AV block, or second/third-degree block), asthma, or decompensated heart failure. If beta-blockers are used at maximal dose or there are contraindications to their use, a nondihydropyridine (i.e., diltiazem or verapamil) may be considered to control symptoms. Morphine (1 to 5 mg intravenously) is also considered a class I anti-ischemic medication and is particularly helpful for anxious patients. Care must be taken, however, not to obscure symptoms and confound treatment of ongoing myocardial ischemia with excessive morphine doses.
If hemodynamics are well controlled with anti-ischemic medications (i.e., heart rate is 50 to 60 beats/min and systolic blood pressure is 90 to 100 mm Hg) but ischemia persists, an intra-aortic balloon pump (IABP) should be considered (class IIa recommendation). Hemodynamic instability is another class IIa indication for using an IABP in the management of UA/NSTEMI. In either scenario, the device is used as a bridge to coronary angiography or until stabilization occurs after invasive therapy has been performed.
Miscellaneous Agents
Angiotensin-converting enzyme inhibitors (ACE-I) should be considered in patients after an unstable coronary syndrome (class IIa recommendation) (Table 14.5). An ACE-I is usually not given in the first hours of an ACS, to ensure that the patient is hemodynamically stable. The presence of diabetes or left ventricular dysfunction strengthens the recommendation for an ACE-I after UA/NSTEMI (class I recommendation).
Early statin trials excluded ACS patients, although more recent studies have addressed this high-risk population. The PROVE IT-TIMI 22 trial randomized >4,000 patients within 10 days of an ACS to intensive lipid lowering (80 mg/d atorvastatin) versus moderate lipid lowering (40 mg/d pravastatin). The outcome was a composite of death, MI, ACS requiring rehospitalization, revascularization, and stroke. Follow-up was 18 to 36 months, with a mean follow-up of 24 months. Atorvastatin was more effective in lowering cholesterol (median low-density lipoprotein [LDL] 62 mg/dL) than pravastatin (median LDL 95 mg/dL). The primary outcome was reached in 22% of the atorvastatin group and 26% of the pravastatin group, representing a 16% reduction in the hazard ratio (95% CI 5 to 26%, p = 0.005). Intensive lipid-lowering therapy appeared to beneficially lower the primary outcome as early as 30 days after enrollment. Both medications were well tolerated, with 23% of the atorvastatin group discontinuing therapy at 1 year because of an adverse event, compared to 21% for pravastatin (p = 0.3). Atorvastatin was associated with more elevations in liver enzymes (defined as alanine aminotransferase more than three times the upper limit of normal) (3.3% of the atorvastatin group, 1.1% of the pravastatin group).
DISCHARGE PLANNING AND NONINVASIVE STRESS TESTING
All stabilized UA/NSTEMI patients need aggressive riskfactor modification (including smoking cessation) and must have their discharge medicines reviewed. For intermediate- and low-risk patients managed conservatively (either hospitalized or observed in a chest pain unit), a noninvasive stress test provides important additional risk stratification (Table 40.3). A noninvasive stress test should be performed in intermediate-risk patients who have been free of chest pain and without heart failure symptoms for 2 to 3 days and in low-risk patients who have been free of chest pain and without heart failure symptoms for 12 to 24 hours. Patients who have an interpretable baseline ECG and are able to exercise should have an exercise ECG performed. Radionuclide or echocardiographic imaging should be used if there is a noninterpretable ECG (i.e., the presence of a left bundle branch block or left ventricular hypertrophy with repolarization changes). Patients who are unable to exercise should have a pharmacologic stress test.
TABLE
40.3 Noninvasive Risk Stratification
From Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007',50(7):e1–e157, with permission from Elsevier.
SUMMARY
Patients with unstable coronary syndromes are a heterogeneous group that includes UA and NSTEMI. These patients have a high burden of atherothrombotic disease in other vascular beds and are at high risk for future adverse cardiac events. Risk stratification helps to guide therapy and should take place by one of several mechanisms during the initial assessment of the patient. The ECG is one simple and readily available diagnostic test that should be performed in all ACS patients that provides important prognostic information.
High-risk patients presenting with UA/NSTEMI benefit from early therapy with aspirin, heparin, and a thienopyridine or ADP inhibitor. Among patients receiving dual antiplatelet therapy with aspirin and a thienopyridine, routine use of upstream GP IIb/IIIa inhibitors is not advised, and should be used in a delayed, provisional manner. Alternatively, in patients with ACS for whom a thienopyridine is not employed prior to revascularization (i.e., in anticipation of possible need for cardiac surgery), GP IIb/IIIa inhibitors as a component of dual antiplatelet therapy are indicated. “Triple” antiplatelet therapy with aspirin, thienopyridine, and GP IIb/IIIa inhibition is best reserved for highest-risk patients or those with recurrent ischemia. Bivalirudin is useful as an adjunctive anticoagulant during PCI, with similar ischemic outcomes and significantly reduced bleeding risks. Lowest-risk patients can be treated with aspirin and managed expeditiously in a chest pain unit or discharged home with noninvasive stress testing performed on an outpatient basis. In addition to antiplatelet and antithrombin agents, anti-ischemic agents should be used judiciously, with the goal of relieving ischemic symptoms and improving hemodynamics. Nitroglycerin and beta-blockers are first-line anti-ischemic medications, unless there is a contraindication to their use. Calcium channel blockers are considered second-line anti-ischemic agents. Intensive statin therapy and possibly an ACE-I (especially if the patient is diabetic or there is left ventricular dysfunction) should be part of the discharge regimen. Once ACS patients are risk stratified, stabilized, and possibly revascularized, discharge planning goals are centered on aggressive risk factor modification. Lower-risk patients who were not revascularized should have plans made for a future noninvasive stress test.
SUGGESTED READINGS
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Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000;284:835–842.
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Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med. 2001;344:1879–1887.
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QUESTIONS AND ANSWERS
Questions
1. All of the following are recommended mechanisms to decrease bleeding complications in the management of unstable coronary syndromes, except:
a. Decreasing the maintenance dose of aspirin from 325 to 81 mg daily
b. Stopping clopidogrel a minimum of 5 days prior to a major surgical procedure
c. Stopping the routine use of heparin after percutaneous coronary intervention
d. Withholding the loading dose of clopidogrel
e. Reducing the dose of heparin for patients who are also on aspirin and a glycoprotein IIb/IIIa inhibitor
2. All of the following are high-risk features of the thrombolysis in myocardial infarction (TIMI) risk score for stratifying patients with unstable coronary syndromes, except:
a. Elevated cardiac biomarkers
b. Age >65 years
c. Tachycardia
d. Ischemic electrocardiographic (ECG) changes
e. A known coronary stenosis of more than 50%
3. All of the following therapies are class I recommendations for conservatively treated patients with unstable coronary syndromes, except:
a. Angiotensin-converting enzyme inhibitor (ACE-I) therapy
b. Nitrate therapy
c. Aspirin therapy
d. Beta-blocker therapy
e. Clopidogrel therapy
4. All of the following are class III recommendations in: the treatment of unstable coronary syndromes, except
a. Use of fibrinolytic therapy for non–ST-elevation acute coronary syndromes (ACSs)
b. Use of abciximab for conservatively managed high-risk patients who continue to have ischemic symptoms
c. The use of a low-molecular-weight heparin instead of unfractionated heparin for conservatively managed unstable coronary syndromes
d. Use of nitroglycerin within 24 hours of sildenafil (Viagra)
e. Invasive therapy in low-risk patients who present with a chest pain syndrome
5. Which of the following are causes of secondary angina?
a. An anemic patient from a gastrointestinal bleed
b. A dialysis patient with an arteriovenous fistula
c. A dyspneic patient with underlying emphysema
d. a and c
e. a, b, and c
6. A 47-year-old female without known coronary artery disease (CAD) presents with two episodes of exertional angina over the past 2 weeks, and one episode of rest angina. Her cardiac risk factors include hypertension (HTN) and hyperlipidemia. Her examination and ECG are normal. Her troponin is negative.
What is the most appropriate course of action?
a. Discharge home with follow-up in 7 days.
b. Immediate stress echocardiography
c. Observe with serial cardiac biomarkers, with exercise testing before discharge.
d. Proceed with coronary angiography and percutaneous coronary intervention (PCI) if indicated.
7. An 87-year-old male without known CAD presents with several anginal episodes at rest. ECG and examination are normal. Troponin is slightly elevated at 0.10. After discussion with the patient, you decide on an initial conservative approach. His hemoglobin is normal and his serum creatinine is 2.8 mg/dL. Which of the following is the most appropriate antiplatelet and anticoagulant strategy?
a. ASA, clopidogrel, LMWH
b. ASA, fondaparinux
c. ASA, clopidogrel, UFH
d. ASA, abciximab
8. Which of the following is an absolute contraindication to the use of prasugrel in a patient presenting with ACS?
a. Systemic HTN with BP >160/100
b. Prior history of transient ischemic attack (TIA) or cerebrovascular accident (CVA)
c. Concomitant use of glycoprotein IIb/IIIa inhibitor
d. Weight < 60 kg
e. Age >75 years old
9. Which of the following is the most common cause of unstable angina (UA)?
a. Plaque rupture and thrombosis
b. Secondary causes (i.e., HTN)
c. Coronary vasospasm
d. Embolization of thrombus
Answers
1. Answer D: When clopidogrel is used for either invasively or conservatively managed unstable coronary syndromes, a loading dose of 300 to 600 mg should be used. Giving 75 mg of clopidogrel daily without a loading dose would require up to 7 days to reach full antiplatelet effect. All of the other listed strategies may be effective in reducing bleeding complications.
2. Answer C: Although tachycardia (and hypotension) have been identified through the PURSUIT trial to be markers of high risk, they are not part of the formal TIMI risk model. All the other variables are components of the TIMI risk score.
3. Answer A: All of the listed therapies are class I recommendations for stabilized patients with unstable coronary syndromes except ACE-I, which are a class IIa recommendation. ACE-I are strengthened to a class I recommendation if patients have diabetes or left ventricular dysfunction. Clopidogrel is a class I recommendation for both invasive and conservatively managed patients with unstable coronary syndromes.
4. Answer C: There may be a marginal benefit of low-molecular-weight heparin over unfractionated heparin for conservatively managed patients, and this strategy is a class IIa recommendation. Nitroglycerin should not be used within 24 hours from the last dose of sildenafil. Fibrinolytics should only be used for ST-elevation myocardial infarctions (STEMIs). Ideally, high-risk patients should be managed invasively, but for high-risk individuals who defer invasive therapy or who have extensive comorbidities and continue to have ischemic symptoms, the use of a glycoprotein IIb/IIIa inhibitor is a class IIa recommendation. However, eptifibatide or tirofiban should be used in this setting, while abciximab should be used only during invasive management.
5. Answer E: Anemia, arteriovenous shunting, and hypoxemia can all cause demand ischemia. Note that a left-arm arteriovenous fistula can produce shunting as well as subclavian steal in patients with a previous left internal mammary artery graft.
6. Answer C: She has UA, but class III recommendation to perform cardiac catheterization in patients with acute chest pain and low likelihood of ACS.
7. Answer C: LMWH should not be used due to the elevated creatinine. Abciximab is not indicated in early conservative strategies.
8. Answer B: Prasugrel is contraindicated in patients with prior history of TIA or CVA.
9. Answer A: Vulnerable plaques overlie lipid-rich cores that are surrounded by thin fibrous caps. Exposure of the underlying plaque to blood is a potent activator of platelets and thrombus formation