Sarah A. Spinier and Simon de Denus
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Define the role of atherosclerotic plaque, platelets, and the coagulation system in an acute coronary syndrome (ACS).
2. List key ECG and clinical features identifying a patient with non-ST-segment elevation (NSTE) ACS who is at high risk of myocardial infarction (Ml) or death.
3. Devise a pharmacotherapy treatment plan for a patient undergoing primary percutaneous coronary intervention (PCI) in ST-segment elevation (STE) Ml given patient-specific data.
4. Devise a pharmacotherapy treatment plan for a patient with STE Ml given patient-specific data.
5. List the quality performance measures of care for Ml.
6. Formulate a monitoring plan for a patient with STE ACS receiving fibrinolytics, aspirin (ASA), clopidogrel, an anticoagulant, IV nitroglycerin, IV β-blockers followed by oral β-blockers, an angiotensin-converting enzyme (ACE) inhibitor, and a statin.
7. Devise a pharmacotherapy treatment and monitoring plan for a patient with NSTE ACS given patient-specific data.
8. Formulate a monitoring plan for a patient with NSTE ACS receiving ASA, clopidogrel, β-blocker, anticoagulant, and glycoprotein llb/llla receptor inhibitor.
9. Devise a pharmacotherapy and risk-factor modification treatment plan for secondary prevention of coronary heart disease events in a patient following Ml.
KEY CONCEPTS
The cause of an acute coronary syndrome (ACS) is the rupture of an atherosclerotic plaque with subsequent platelet adherence, activation, and aggregation, and the activation of the clotting cascade. Ultimately, a clot forms composed of fibrin and platelets.
The American Heart Association (AHA) and the American College of Cardiology (ACC) recommend strategies, or guidelines, for ACS patient care for ST-segment elevation(STE) and non-ST-segment elevation (NSTE) ACS.
Patients with ischemic chest discomfort and suspected ACS are risk-stratified based upon a 12-lead electrocardiogram, past medical history, and results of the creatine kinase (CK) myocardial band (MB) and troponin tests. The diagnosis of myocardial infarction (MI) is confirmed based on the results of the CK MB and troponin tests.
Early reperfusion therapy with primary percutaneous coronary intervention (PCI) within 90 minutes from time of hospital presentation is the reperfusion treatment of choice for patients presenting with STE ACS.
The most recent NSTE ACC/AHA clinical practice guidelines recommend coronary angiography with either PCI or coronary artery bypass graft surgery revascularization as an early treatment (early invasive strategy) for high-risk and moderate-risk NSTE ACS patients.
According to the ACC/AHA Association STE ACS practice guidelines, in addition to reperfusion therapy, early pharmacotherapy of STE should include intranasal oxygen (if oxygen saturation is less than 90%), sublingual (SL) nitroglycerin (NTG) followed by IV NTG in selected patients, ASA, clopidogrel, selective use of β-blockers, an anticoagulant, and fibrinolysis in eligible candidates.
According to the ACC/AHA NSTE ACS practice guidelines, in the absence of contraindications, early pharmacotherapy of NSTE ACS should include intranasal oxygen (if oxygen saturation is low), SL NTG followed by IV NTG in selected patients, ASA, clopidogrel, β-blocker, and anticoagulant. High-risk patients should undergo early coronary angiography and revascularization with PCI or coronary artery bypass graft surgery. Administration of a glycoprotein IIb/IIIa receptor inhibitor may be considered in high-risk patients.
Guidelines from the ACC/AHA suggest that, in the absence of contraindications, following MI from either STE or NSTE ACS, patients should receive indefinite treatment with ASA, aβ-blocker, and an angiotensin-converting enzyme (ACE) inhibitor. For NSTE ACS, most patients should receive clopidogrel, in addition to ASA, for up to 12 months. For STE ACS, clopidogrel is administered during hospitalization and for at least 14 days (unless they undergo PCI where the duration of clopidogrel therapy depends on stent type), and up to 1 year. Most patients will receive a statin to reduce low-density lipoprotein cholesterol to less than 100 mg/dL (2.59mmol/L).
Secondary prevention of death, reinfarction, and stroke is more cost effective than primary prevention of coronary heart disease events.
INTRODUCTION
Cardiovascular disease (CVD) is the leading cause of death in the United States and one of the major causes of death worldwide. Acute coronary syndromes (ACSs), including unstable angina (UA) and myocardial infarction (MI), are a form of coronary heart disease (CHD) that comprises the most common cause of CVD death.1 The cause of an ACS is primarily the rupture of an atherosclerotic plaque with subsequent platelet adherence, activation, and aggregation, and the activation of the clotting cascade. Ultimately, a clot forms composed of fibrin and platelets. The American Heart Association (AHA) and the American College of Cardiology (ACC) recommend strategies, or guidelines, for ACS patient care for ST-segment elevation (STE) and non-ST-segment elevation (NSTE) ACS. These joint practice guidelines are based upon a review of available clinical evidence, have graded recommendations based upon evidence, and are updated periodically. These guidelines form the cornerstone for quality care of the ACS patient.2–4
EPIDEMIOLOGY
Each year, more than one million Americans will experience an ACS and 150,000 will die of an MI.1 In the United States, more than 8 million living persons have survived an MI.1 Chest discomfort is a frequent reason for patient presentation to emergency departments, with up to 6 million, or approximately 5%, of all emergency department visits linked to chest discomfort and possible ACS. Coronary heart disease is the leading cause of premature, chronic disability in the United States. The risks of CHD events, such as death, recurrent MI, and stroke, are higher for patients with established CHD and a history of MI than for patients with no known CHD. The cost of CHD is high, with estimated direct and indirect costs of more than 156 billion dollars.1 The median length of hospital stay for MI in 2005 was approximately 3.3 days.
In patients with STE ACS, in-hospital death rates are approximately 3% in patients receiving primary percutaneous coronary intervention (PCI), 7% for patients who are treated with fibrinolytics and 16% for patients who do not receive reperfusion therapy. In patients with NSTE MI, in-hospital mortality is less than 5%. In-hospital and 1-year mortality rates are higher for women and elderly patients.1 At 1 year, rates of mortality and reinfarction are similar between STE and NSTE MI.
Because reinfarction and death are major outcomes following ACS, therapeutic strategies to reduce morbidity and mortality, particularly utilization of coronary angiography, revascularization, and pharmacotherapy, will have a significant impact on the social and economic burden of CHD in the United States.
ETIOLOGY
Endothelial dysfunction, inflammation, and the formation of fatty streaks contribute to the formation of atherosclerotic coronary artery plaques, the underlying cause of coronary artery disease (CAD). The predominant cause of ACS in more than 90% of patients is atheromatous plaque rupture, fissuring, or erosion of an unstable atherosclerotic plaque that occludes less than 50% of the coronary lumen prior to the event, rather than a more stable 70% to 90% stenosis of the coronary artery?3
Stable stenoses are characteristic of stable angina.
PATHOPHYSIOLOGY
Spectrum of ACSs
ACSs include all clinical syndromes compatible with acute MI resulting from an imbalance between myocardial oxygen demand and supply.3 In contrast to stable angina, an ACS results primarily from diminished myocardial blood flow secondary to an occlusive or partially occlusive coronary artery thrombus. ACSs are classified according to electrocardiogram (ECG) changes into STE ACS (STE MI) or NSTE ACS (NSTE MI and UA) (Fig. 8–1). An STE MI, formerly known as Q-wave or transmural MI, typically results in an injury that transects the thickness of the myocardial wall. Following an STE MI, pathologic Q waves are frequently seen on the ECG, indicating transmural MI, while such an ECG manifestation is seen less commonly in patients with NSTE MI.5 NSTE MI, formerly known as non-Q-wave or nontransmural MI, is limited to the subendocardial myocardium. Patients in this case do not usually develop a pathologic Q wave on the ECG. Moreover, an NSTE MI is smaller and not as extensive as an STE MI. Approximately two-thirds of all MIs are NSTE MI, whereas one-third of patients with MI present with STE. NSTE MI differs from UA in that ischemia is severe enough to produce myocardial necrosis resulting in the release of a detectable amount of biomarkers, mainly troponins T or I, but also creatine kinase (CK) myocardial band (MB), from the necrotic myocytes in the bloodstream.3 The clinical significance of serum markers will be discussed in greater detail in later sections of this chapter.
FIGURE 8–1. Evaluation of the ACS patient. aAs described in Table 8–1. bPositive = above the myocardial infarction decision limit. cNegative = below the myocardial infarction decision limit. (ACSs, acute coronary syndromes; CABG, coronary artery bypass graft; CAD, coronary artery disease; CKMB, creatine kinase myocardial band; ECG, electrocardiogram; min, minute; PCI, percutaneous coronary intervention.) Refer to Figure 9–2 for further details regarding ECG interpretation. (From Spinler SA, de Denus S. Acute Coronary Syndromes. In DiPiro JT, Talbert RL, Yee GC, et al., (eds.) Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008: 251, with permission.)
Plaque Rupture and Clot Formation
Following plaque rupture, a clot (a partially occlusive or completely occlusive thrombus), forms on top of the ruptured plaque. The thrombogenic contents of the plaque are exposed to blood elements. Exposure of collagen and tissue factor induce platelet adhesion and activation, which promote the release of platelet-derived vasoactive substances including adenosine diphosphate (ADP) and thromboxane A2 (TXA2).6 These produce vasoconstriction and potentiate platelet activation. Furthermore, during platelet activation, a change in the conformation in the glycoprotein IIb/IIIa surface receptors of platelets occurs which cross-links platelets to each other through fibrinogen bridges. This is considered the final common pathway of platelet aggregation. Inclusion of platelets gives the clot a white appearance. Simultaneously, the extrinsic coagulation cascade pathway is activated as a result of exposure of blood components to the thrombogenic lipid core and endothelium, which are rich in tissue factor. This leads to the production of thrombin (factor lla), which converts fibrinogen to fibrin through enzymatic activity.6 Fibrin stabilizes the clot and traps red blood cells, which gives the clot a red appearance. Therefore, the clot is composed of cross-linked platelets and fibrin strands.6
Ventricular Remodeling Following an Acute Ml
Ventricular remodeling is a process that occurs in several cardiovascular conditions including heart failure and following an MI. It is characterized by left ventricular dilation and reduced pumping function of the left ventricle, leading to cardiac failure.7 Because heart failure represents one of the principal causes of mortality and morbidity following an MI, preventing ventricular remodeling is an important therapeutic goal.7
Angiotensin-converting enzyme (ACE) inhibitors, angio-tensin receptor blockers (ARBs), β-blockers, and aldosterone antagonists are all agents that slow down or reverse ventricular remodeling through inhibition of the renin-angiotensin aldosterone system and/or through improvement in hemo-dynamics (decreasing preload or afterload).7 These agents also improve survival and will be discussed in more detail in subsequent sections of this chapter.
Complications
This chapter will focus on management of the uncomplicated ACS patient. However, it is important for clinicians to recognize complications of MI, since MI is associated with increased mortality. The most serious complication of MI is cardiogenic shock, occurring in approximately 10% of hospitalized MI patients. Mortality in cardiogenic shock patients with MI is high, approaching 60%.8 Other complications which may result from MI are heart failure, valvular dysfunction, bradycardia, heart block, pericarditis, stroke secondary to left ventricular thrombus embolization, venous thromboembolism, left ventricular free wall rupture, and ventricular and atrial tachyarrhythmias.9 In fact, more than one-quarter of MI patients die, presumably from ventricular fibrillation, prior to reaching the hospital.1
Symptoms and Physical Examination Findings
The classic symptom of an ACS is midline anterior anginal chest discomfort, most often occurring when an individual is at rest, as a severe new onset, or as an increasing angina that is at least 20 minutes in duration. The chest discomfort may radiate to the shoulder, down the left arm, and to the back or to the jaw. Associated symptoms which may accompany the chest discomfort include nausea, vomiting, diaphoresis, or shortness of breath. While similar to stable angina, the duration maybe longer and the intensity greater. On physical examination, no specific features are indicative of ACS.
12-Lead ECG
There are key features of a 12-lead ECG that identify and risk-stratify a patient with an ACS. Within 10 minutes of presentation to an emergency department with symptoms of ischemic chest discomfort, a 12-lead ECG should be obtained and interpreted. When possible, a 12-lead ECG should be performed by emergency medical system providers in order to reduce the delay until myocardial reperfusion. If available, a prior 12-lead ECG should be reviewed to identify whether or not the findings on the current ECG are new or old, with new findings being more indicative of an ACS. Key findings on review of a 12-lead ECG that indicate myocardial ischemia or infarction are STE, ST-segment depression, and T-wave inversion (Fig. 8–1). ST-segment and/or T-wave changes in certain groupings of leads help to identify the location of the coronary artery that is the cause of the ischemia or infarction. In addition, the appearance of a new left bundle-branch block accompanied by chest discomfort is highly specific for acute MI. About one-half of patients diagnosed with MI present with STE on their ECG, with the remainder having ST-segment depression, T-wave inversion, or in some instances, no ECG changes. Some parts of the heart are more “electrically silent” than others, and myocardial ischemia may not be detected on a surface ECG. Therefore, it is important to review findings from the ECG in conjunction with biochemical markers of myocardial necrosis, such as troponin I or T, and other risk factors for CHD to determine the patient’s risk for experiencing a new MI or having other complications.
Biochemical Markers/Cardiac Enzymes
Biochemical markers of myocardial cell death are important for confirming the diagnosis of MI. The diagnosis of MI is confirmed when the following conditions are met in a clinical setting consistent with myocardial ischemia: “Detection of a rise and/or fall of cardiac biomarkers (troponin preferred) with at least one value above the 99th percentile of the upper reference limit together with evidence of myocardial ischemia as recognized by at least one of the following: (a) symptoms of ischemia; (b) ECG changes of new ischemia or development of pathological Q waves; or (c) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.”10 Typically, a blood sample is obtained once in the emergency department, then 6 to 9 hours later, and in patients at a high suspicion of MI but in whom previous measurements did not reveal elevations in biomarkers, 12 to 24 hours after. A single measurement of a biochemical marker is not adequate to exclude a diagnosis of MI, as up to 15% of values which were initially below the level of detection (a “negative” test) rise to the level of detection (a “positive” test) in subsequent hours. While troponins and CK-MB appear in the blood within 6 hours of infarction, troponins stay elevated for up to 10 days while CK-MB returns to normal values within 48 hours. Hence, traditionally, CK-MB was used to detect reinfarction. However, more recent data have suggested that troponins provide similar information to CK-MB in such a situation which has lead to the use of troponins in this setting as well. Current guidelines suggest that, in patients in whom a recurrent MI is suspected, a cardiac biomarker should be immediately measured, followed by a second measurement three to six hours later. A recurrent MI is diagnosed when there is an increase of at least 20% in the second measurement of the biomarker, if this value exceeds the 99th percentile of the upper reference limit.10
Clinical Presentation and Diagnosis of ACSs
General
• The patient is typically in acute distress and may develop or present with heart failure or cardiogenic shock.
Symptoms
• The classic symptom of ACS is midline anterior chest discomfort. Accompanying symptoms may include arm, back, or jaw pain; nausea; vomiting; or shortness of breath.
• Patients less likely to present with classic symptoms include elderly patients, diabetic patients, and women.
Signs
• No signs are classic for ACS.
• However, patients with ACS may present with signs of acute heart failure including jugular venous distention and an S3 sound on auscultation.
• Patients may also present with arrhythmias and therefore may have tachycardia, bradycardia, or heart block.
Laboratory Tests
• Troponin I or T (and creatine kinase myocardial band [CK-MB]) are measured.
• Blood chemistry tests are performed with particular attention given to potassium and magnesium, which may affect heart rhythm.
• The SCr is measured to identify patients who may need dosing adjustments for some medications, as well as those who are at high risk of morbidity and mortality.
• Baseline CBC and coagulation tests (activated partial thromboplastin time and International Normalized Ratio [INR]) should be obtained, as most patients will receive antithrombotic therapy which increases the risk for bleeding.
• Fasting lipid panel. Other Diagnostic Tests
• The 12-lead ECG is the first step in management. Patients are risk-stratified into two groups: ST-segment elevation ACS and suspected non-ST-segment elevation ACS.
• During hospitalization, a measurement of left ventricular function, such as an echocardiogram, is performed to identify patients with low EFs (less than 40%) who are at high risk of death following hospital discharge.
• Selected low-risk patients may undergo early stress testing.
Adapted from Spinler SA, de Denus S. Acute Coronary Syndromes. In: DiPiro JT, Talbert RL, Yee GC, et al., (eds.) Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008: 252, with permission.
Risk Stratification
Patient symptoms, past medical history, ECG, and biomarkers, particularly troponins, are utilized to stratify patients into low, medium, or high risk of death, MI, or likelihood of failing pharmacotherapy and needing urgent coronary angiography and percutaneous coronary intervention (PCI). Initial treatment according to risk stratification is depicted in Figure 8–1. Patients with STE are at the highest risk of death. Initial treatment of STE ACS should proceed without evaluation of the troponins, as these patients have a greater than 97% chance of having an MI subsequently diagnosed with biochemical markers. The ACC/AHA define a target time to initiate reperfusion treatment as within 30 minutes of hospital presentation for fibrinolytics (e.g., streptokinase, alteplase, reteplase, and tenecteplase) and within 90 minutes or less from presentation for primary PCI.3 The sooner the infarct-related coronary artery is opened for these patients, the lower their mortality and the greater the amount of myocardium that is preserved.11,12 While all patients should be evaluated for reperfusion therapy, not all patients may be eligible. Indications and contraindications for fibrinolytic therapy are described in the treatment section of this chapter. Less than 25% of hospitals in the United States are equipped to perform primary PCI. If patients are not eligible for reperfusion therapy, additional pharmacotherapy for STE patients should be initiated in the emergency department and the patient transferred to a coronary intensive care unit. The typical length of stay for a patient with uncomplicated STE MI is less than 4 days.
Risk-stratification of the patient with NSTE ACS is more complex, as in-hospital outcomes for this group of patients varies with reported rates of death of 0% to 12%, reinfarction rates of 0% to 3%, and recurrent severe ischemia rates of 5% to 20%.12 Not all patients presenting with suspected NSTE ACS will even have CAD. Some will eventually be diagnosed with nonischemic chest discomfort. In general, among NSTE patients, those with ST-segment depression (Fig. 8–1) and/or elevated biomarkers are at higher risk of death or recurrent infarction.
TREATMENT
Desired Outcomes
Short-term desired outcomes in a patient with ACS are: (a) early restoration of blood flow to the infarct-related artery to prevent infarct expansion (in the case of MI) or prevent complete occlusion and MI (in UA); (b) prevention of death and other complications; (c) resolve ECG changes; (d) prevention of coronary artery reocclusion; and (e) relief of ischemic chest discomfort.
Patient Encounter 1, Part 1
SD is a 55-year-old, 85 kg (187 lb) male who developed chest tightness while skiing at 20:30 hours. He became short of breath and diaphoretic. Local paramedics were summoned and he was given three 0.4-mg sublingual nitroglycerin tablets by mouth, 325 mg ASA by mouth, and morphine 2-mg IV push without relief of chest discomfort. SD presented to the hospital at 21:15 hours. The hospital does not have a cardiac catheterization laboratory and transport time to the nearest hospital with interventional facilities is more than 1.5 hours away via air transport.
PMH: HTN for 10 years; dyslipidemia for 6 months; two-vessel CAD (60% right coronary artery [RCA] and 80% left anterior descending artery [LAD] occlusion) after intracoronary sirolimus-eluting stent placement to the mid-LAD artery lesion 10 months ago
FH: Father with myocardial infarction at age 65; mother alive and well; one sibling with HTN
SH: Smoked one pack per day for 30 years, quit 10 weeks ago
Allergies: NKDA
Meds: Metoprolol 25 mg by mouth twice daily; ASA 325 mg by mouth once daily; lovastatin 20 mg by mouth once daily at bedtime; enalapril 5 mg by mouth once daily
ROS: 7/10 chest pain/squeezing, diaphoretic
PE:
HEENT: Normocephalic atraumatic
CR: Regular rate and rhythm S1 S2, +S3, +S4, no murmurs or rubs
VS: BP 110/70 mm Hg; HR 98 bpm; T 37°C (98.6°F)
Lungs: Rales bilaterally V4 way up
Abd: Nontender, nondistended
Gl: Normal bowel sounds
GU: Stool guaiac negative
Exts: No bruits, pulses 2+, femoral pulse present, good range of motion
Neuro: Alert and oriented × 3, cranial nerves intact
Labs: Sodium 138 mEq/L (138 mmol/L), potassium 4.2 mEq/L (4.2 mmol/L), chloride 105 mEq/L (105 mmol/L), bicarbonate 24 mEq/L (24 mmol/L), SCr 1.0 mg/dL (88 μmol/L), glucose 95 mg/dL (5.27 mmol/L), WBC 9.9 × 103/mm3 (9.9 × 109L), hemoglobin 15.7 g/dL (157 g/L or 9.7 mmol/L), hematocrit 47%, platelets 220 × 103/mm3 (220 × 109L), brain natriuretic peptide 3,238 pg/mL (3,238 ng/L), troponin I 16 ng/mL (16 mcg/L), oxygen saturation 99% on room air
ECG: Normal sinus rhythm, PR 0.16 seconds, QRS 0.08 seconds, QTc 0.38 seconds, occasional polymorphic premature ventricular contractions, 3 mm ST-segment elevation anterior leads
CXR: Congestive heart failure, borderline upper normal heart size
Echo: Hypocontractile left ventricle, akinesis of anterior apical wall, EF 20%
What information is suggestive of acute MI?
What complications of Ml are present?
Long-term desired outcomes are control of risk factors, prevention of additional cardiovascular events, including reinfarction, stroke and heart failure, and improvement in quality of life.
General Approach to Treatment
General treatment measures for all STE ACS and high-and intermediate-risk NSTE patients include admission to hospital, oxygen administration (if oxygen saturation is low, less than 90%), continuous multi-lead ST-segment monitoring for arrhythmias and ischemia, frequent measurement of vital signs, bed rest for 12 hours in hemodynamically stable patients, avoidance of the Valsalva maneuver (prescribe stool softeners routinely), and pain relief (Figs. 8-2 and 8-3).
Because risk varies and resources are limited, it is important to triage and treat patients according to their risk category. Initial approaches to treatment of STE and NSTE ACS patients are outlined in Figure 8–1. Patients with STE are at high risk of death, and efforts to reestablish coronary perfusion, as well as adjunctive pharmacotherapy, should be initiated immediately.
Features identifying low-, moderate-, and high-risk NSTE ACS patients are described using the thrombolysis in myocardial infarction (TIMI) risk score in Table 8–1.2
Nonpharmacologic Therapy
Primary PCI for STE ACSs
Early reperfusion therapy with primary PCI within 90 minutes from time of hospital presentation is the reperfusion treatment of choice for patients presenting with STE ACS.3,4 (Fig. 8–2) For primary PCI, the patient is taken from the emergency department to the cardiac catheterization laboratory and undergoes coronary angiography with either balloon angioplasty or placement of a bare metal or drug-eluting intracoronary stent. About 62% of patients with STE ACS are treated with primary PCI and 18% are treated with fibrinolytics. Results from a meta-analysis of trials comparing fibrinolysis to primary PCI indicate a lower mortality rate with primary PCI.13 One reason for the superiority of primary PCI compared to fibrinolysis is that more than 90% of occluded infarct-related coronary arteries are opened with primary PCI compared to fewer than 60% of coronary arteries opened with currently available fibrinolytics.9 In addition, intracranial hemorrhage and major bleeding risks from primary PCI are lower than the risks of severe bleeding events following fibrinolysis. An invasive strategy of primary PCI is generally preferred in patients presenting to institutions with skilled interventional cardiologists and a catheterization laboratory immediately available, in patients in cardiogenic shock, those with contraindications to fibrinolytics, and those presenting with symptom onset greater than 3 hours ago.3 A quality performance measure (quality performance measures are measures of quality health care developed from practice guidelines and intended to permit the quality of patient care to be assessed, compared between institutions and over time, and ultimately, improved) in the care of MI patients with STE is the time from hospital presentation to the time that the occluded artery is opened with PCI. This “door-to-primary PCI” time should be equal to or less than 90 minutes.3,14 Currently, the median time for primary PCI is 87 minutes with only 54% of patients being treated within 90 minutes. Hospitals should have policies in place describing triage and catheterization laboratory personnel mobilization for implementing primary PCI for the patient with STE MI.
FIGURE 8–2. Initial pharmacotherapy for ST-segment elevation MI. aFor at least 48 hours. bFor selected patients, see Table 8–2. cFor the duration of hospitalization, up to 8 days. dExact dose not known. (ACSs, acute coronary syndromes; CABG, coronary artery bypass graft surgery; hrs, hours; IV, intravenous; NTG, nitroglycerin; PCI, percutaneous coronary intervention; SC, subcutaneous; SL, sublingual; UFH, unfractionated heparin.) (Adapted from Spinler SA, de Denus S. Acute Coronary Syndromes. In DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008: 256, with permission.) From Refs. 3, 9.
FIGURE 8–3. Initial pharmacotherapy for non-ST-segment elevation ACS. aFor selected patients, see Table 8–2. bEnoxaparin, UFH, fondaparinux plus UFH, or bivalirudin for early invasive strategy; enoxaparin or fondaprinux if no angiography/PCI planned. cln patients unlikely to undergo coronary artery bypass graft surgery. dMay require an IV supplemental dose of enoxaparin, see Table 8–2. eMay require an IV supplemental dose of UFH, see Table 8–2. fFor signs and symptoms of recurrent ischemia. 9SC enoxaparin or UFH can be continued at a lower dose for venous thromboembolism prophylaxis. (ACE, angiotensin-converting enzyme; ACSs, acute coronary syndromes; ARB, angiotensin receptor blocker; hrs, hours; IV, intravenous; NTG, nitroglycerin; PCI, percutaneous coronary intervention; SC, subcutaneous; SL, sublingual; UFH, unfractionated heparin.) (Adapted from Spinler SA, de Denus S. Acute Coronary Syndromes. In DiPiro JT, Talbert RL, Yee GC, et al., (eds.) Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008: 264, with permission.)
Patient Encounter 1, Part 2
Identify your acute treatment goals forSD.
Is reperfusion therapy with fibrinolysis indicated at this time?
What adjunctive pharmacotherapy should be administered to SD in the emergency department?
What additional pharmacotherapy should be initiated on the first day of SD’s hospitalization following successful reperfusion?
PCI during hospitalization for STE MI may also be appropriate in other patients following STE MI, such as those in whom fibrinolysis is not successful, those presenting later in cardiogenic shock, those with life-threatening ventricular arrhythmias, and those with persistent rest ischemia or signs of ischemia on stress testing following MI.3,4
PCI in NSTE ACSs
The most recent NSTE ACC/AHA clinical practice guidelines recommend coronary angiography with either PCI or coronary artery bypass graft (CABG) surgery revascularization as an early treatment (early invasive strategy) for high-risk and moderate-risk NSTE ACS patients2 (Fig. 8–3). Several clinical trials support an “invasive” interventional strategy with early angiography and PCI or CABG versus a “conservative medical management” strategy, whereby coronary angiography with revascularization is reserved for patients with symptoms refractory to pharmacotherapy and patients with signs of ischemia on stress testing.2 An “invasive” approach results in fewer MIs, less need for additional revascularization procedures over the next year following hospitalization, and less cost than the conservative “medical stabilization” approach in patients at moderate to high risk in most trials.2,15 All patients undergoing PCI should receive aspirin (ASA) therapy indefinitely. Clopidogrel is administered (concomitantly with ASA) for at least 30 days following PCI for a patient receiving a bare metal stent and for at least 1 month and ideally up to 12 months following PCI for a patient receiving a drug eluting stent (DES) who is not at high risk for bleeding (Table 8–2).4 Drug-eluting stents reduce the rate of smooth muscle cell growth causing stent restenosis. However, there is a delay in endothelial cell regrowth at the site of the stent which places the patient at higher risk of thrombotic events following PCI. Therefore, dual antiplatelet therapy is indicated for a longer period of time following PCI with a drug-eluting stent.4 Regardless of whether or not a patient with NSTE receives a stent, the preferred duration of clopidogrel therapy is at least a year.2
Table 8–1 TIMI Risk Score for NSTE ACSs
Additional Testing and Risk Stratification
At some point during hospitalization but prior to discharge, patients with MI should have their left ventricular function (LVF) evaluated for risk stratification.2,3 The most common way LVF is measured is using an echocardiogram to calculate the patient’s left ventricular ejection fraction (LVEF). Left ventricular function is the single best predictor of mortality following MI. Patients with LVEFs less than 40% are at highest risk of death. Patients with ventricular fibrillation or sustained ventricular tachycardia occurring more than 2 days following MI and those with LVEF less than 30% (measured at least 1 month after STE MI and 3 months after coronary artery revascularization with either PCI or CABG) benefit from placement of an implantable cardioverter defibrillator (ICD).3,16
Predischarge from the hospital, stress testing (Fig. 8–3) may be indicated in: (a) moderate-or low-risk patients in order to determine who would benefit from coronary angiography to establish the diagnosis of CAD, and (b) patients following MI to predict intermediate-and long-term risk of recurrent MI and death.2 In most cases, patients with a positive stress test indicating coronary ischemia will then undergo coronary angiography and subsequent revascularization of significantly occluded coronary arteries. If a patient has a negative exercise stress test for ischemia, the patient is at lower risk for subsequent CHD events.
Early Pharmacologic Therapy for STE ACSs
Pharmacotherapy for early treatment of ACS is outlined in Figure 8–2. According to the ACC/AHA STE ACS practice guidelines, in addition to reperfusion therapy, early pharmacotherapy of STE should include intranasal oxygen (if oxygen saturation is less than 90%), sublingual (SL) nitroglycerin (NTG) followed by IV NTG in selected patients, ASA, clopidogrel, an anticoagulant, a β-blocker in selected patients, andfibrinolysis in eligible candidates (not undergoing primary PCI). Recent results from two clinical trials in patients with STE ACS indicate that clopidogrel should be administered along with ASA to patients receiving fibrinolytics to reduce mortality and reinfarction as well as to improve the patency of the infarcted artery.17-18 Morphine is administered to patients with refractory angina as an analgesic and a venodilator that lowers preload. These agents should be administered early, while the patient is still in the emergency department. Dosing and contraindications for SL and IV NTG, ASA, clopidogrel, β-blockers, anticoagulants, and fibrinolytics are listed in Table 8–2.2–4
Table 8–2 Evidence-Based Pharmacotherapy for STE and NSTE ACSs
Fibrinolytic Therapy
Administration of a fibrinolytic agent is indicated in patients with STE ACS who present to the hospital within 24 hours of the onset of chest discomfort, have at least a 1 mm STE in two or more contiguous ECG leads, and are not able to undergo primary PCI within 90 minutes of hospital presentation.3 The mortality benefit of fibrinolysis is highest with early administration and diminishes after 12 hours. The use of fibrinolytics between 12 and 24 hours after symptom onset should be limited to patients with ongoing ischemia. Fibrinolytic therapy is preferred over primary PCI where there is no cardiac catheterization laboratory or there would be a delay in “door-to-primary PCI” of more than 90 minutes. Indications and contraindications for fibrinolysis are listed in Table 8–3.9 It is not necessary to obtain the results of biochemical markers before initiating fibrinolytic therapy. Because administration of fibrinolytics result in clot lysis, patients who are at high risk of major bleeding (including intracranial hemorrhage) presenting with an absolute contraindication will likely not receive fibrinolytic therapy, as primary PCI is preferred. In patients who have a contraindication to fibrinolytics and PCI, or who don’t have access to a facility that can perform PCIs, treatment with an anticoagulant (other than unfractionated heparin [UFH]) for up to 8 days can be administered.
In patients with symptoms lasting less than 6 hours, a more fibrin-specific agent such as alteplase, reteplase, or tenecteplase is preferred over a non-fibrin-specific agent such as streptokinase.9,19 Fibrin-specific fibrinolytics open a greater percentage of infarcted arteries. In a large clinical trial, administration of alteplase reduced mortality by 1% (absolute reduction) and cost about $30,000 per year of life saved compared to streptokinase.20 Two other trials compared alteplase to reteplase and alteplase to tenecteplase and found similar mortality between agents.21,22 Therefore, either alteplase, reteplase, or tenecteplase are acceptable as first-line agents. Intracranial hemorrhage and major bleeding are the most serious side effects of fibrinolytic agents. The risk of intracranial hemorrhage is higher with fibrin-specific agents than with streptokinase. However, the risk of systemic bleeding other than intracranial hemorrhage is higher with streptokinase than with other more fibrin-specific agents and was higher with alteplase versus tenecteplase in one study.19,20,22
As mentioned previously, less than 20% of patients with STE ACS receive fibrinolysis compared with more than 60% receiving primary PCI. However, 17% of eligible patients receive neither primary PCI nor fibrinolysis despite being eligible. The primary reason for lack of reperfusion therapy is that most patients present more than 12 hours after the time of symptom onset. The percentage of eligible patients who receive reperfusion therapy is a quality performance measure of care in patients with MI.3,14 The “door-to-needle time,” the time from hospital presentation to start of fibrinolytic therapy, is another quality performance measure.3,14 The ACC/AHA guidelines recommend a “door-to-needle time” of less than 30 minutes from the time of hospital presentation until start of fibrinolytic therapy. The median national average is decreasing and is currently 30 minutes. All hospitals should have protocols addressing fibrinolysis eligibility, dosing and monitoring.
Table 8–3 Indications and Contraindications to Fibrinolytic Therapy per ACC/AHA Guidelines for Management of Patients With STE Ml
|
Indications |
|
1. Ischemic chest discomfort at least 20 minutes in duration but 12 hours or less since symptom onset |
|
and |
|
STE of at least 1 mm in height in two or more contiguous leads, or new or presumed new left bundle-branch block |
|
2. Ongoing ischemic chest discomfort at least 20 minutes in duration 12–24 hours since symptom onset |
|
and |
|
STE of at least 1 mm in height in two or more contiguous leads |
|
Absolute Contraindications |
|
• Active internal bleeding (not including menses) |
|
• Previous intracranial hemorrhage at any time; ischemic stroke within 3 months |
|
• Known intracranial neoplasm |
|
• Known structural vascular lesion (e.g., arteriovenous malformation) |
|
• Suspected aortic dissection |
|
• Significant closed head or facial trauma within 3 months |
ACC, American College of Cardiology; AHA, American Heart Association.
From Ref. 3.
Aspirin
ASA has become the preferred antiplatelet agent in the1 treatment of all ACS.2,3 ASA administration to all patients who do not have contraindications to ASA therapy within 24 hours before or after hospital arrival is a quality performance measure for MI.3,14 The antiplatelet effects of ASA are mediated by inhibiting the synthesis of TXA2 through an irreversible inhibition of platelet cyclooxygenase-1. In patients undergoing PCI, ASA prevents acute thrombotic occlusion during the procedure. In patients receiving fibrinolytics, ASA reduces mortality, and its effects are additive to fibrinolysis alone.23
Although an initial dose of 160 to 325 mg is required to achieve rapid platelet inhibition, long-term therapy with doses of 75 to 150 mg daily are as effective as higher doses. In addition, doses of less than 325 mg daily are associated with a lower rate of bleeding.24,25 The major bleeding rate associated with chronic ASA administration in doses less than 100 mg per day is 1.6%, whereas the rate with doses more than 100 mg per day is 2.3%.25Therefore, a daily maintenance dose of 75 to 162 mg is recommended.2 Although evidence-based data are sparse, a dose of 162 to 325 mg daily is recommended for at least 1 month following intracoronary placement of a bare metal stent, 3 months after a sirolimus stent and 6 months after a paclitaxel stent.3,4
Nonsteroidal anti-inflammatory drugs other than ASA should not be used because they increase the risk of mortality, reinfarction, hypertension (HTN), heart failure and myocar-dial rupture.3 In response to shear stress, endothelial cells produce cyclooxygenase-2 (COX-2). COX-2 inhibition maybe associated with a reduction in prostacyclin synthesis, sodium and water retention and increased blood pressure (BP). During MI, the balance between thrombosis and inhibition of thrombosis may be shifted to a prothrombotic state, increasing infarct size. Other GI disturbances, including dyspepsia and nausea, are infrequent when low-dose ASA is used. ASA therapy should be continued indefinitely.
Thienopyridines
Administration of clopidogrel, in addition to ASA, is recommended for all patients with STE ACS (Table 8–2).3 Clopidogrel blocks adenosine diphosphate receptors on platelets, preventing the expression of glycoprotein IIb/IIIa receptors and thus platelet activation and aggregation.
Clopidogrel reduces death, MI, or stroke in patients with NSTE ACS when combined with ASA.26 Early therapy with clopidogrel 75 mg once daily administered during hospi-talization and up to 28 days (mean 14 days) in patients with STE ACS reduced mortality and reinfarction in patients treated with fibrinolytics without increasing the risk of major bleeding.17,18 Therefore, the combination of clopidogrel and ASA is indicated for all patients with ACS. For PCI, clopidogrel is administered as a 300 to 600 mg loading dose followed by a 75 mg per day maintenance dose, in combination with ASA, to prevent subacute stent thrombosis and long-term events, such as the composite endpoint of death, MI, or need to undergo repeat PCI.3,4 Clopidogrel should be continued for at least 14 days (and up to one year) for patients with STE ACS who do not undergo PCI and a minimum of 4 weeks up to 12 months for patients undergoing primary PCI with a bare metal stent.3,4 In patients receiving a DES, clopidogrel should be administered for at least 12 months.4 For patients not undergoing PCI or early revascularization with CABG surgery, clopidogrel should be administered for 14 days.2,3 If CABG is planned, clopidogrel should be withheld preferably for 5 days, to reduce the risk of postoperative bleeding, unless the need for revascularization outweighs the bleeding risk. The most frequent side effect of clopidogrel is rash or GI events (nausea, vomiting, or diarrhea). Rarely, thrombotic thrombocytopenic purpura has been reported with clopidogrel.
Glycoprotein IIb/IIIa Receptor Inhibitors
Abciximab is a first-line glycoprotein IIb/IIIa receptor inhibitor for patients undergoing primary PCI3,16 who have not received fibrinolytics. It should not be administered for medical management of the STE ACS patient who will not be undergoing PCI. Abciximab, in combination with ASA, a thienopyridine, and UFH (administered as an infusion for the duration of the procedure), is given a higher recommendation in the ACC/AHA guidelines over eptifibatide and tirofiban in this setting because abciximab is the most common glycoprotein IIb/IIIa receptor inhibitor studied in primary PCI trials, and a meta-analysis of trials demonstrated a reduction in short-and long-term mortality.3,19,27
Dosing and contraindications for abciximab are described in Table 8–2. Glycoprotein IIb/IIIa receptor inhibitors block the final common pathway of platelet aggregation; namely, cross-linking of platelets by fibrinogen bridges between the glycoprotein lla and Illa receptors on the platelet surface. Administration of a glycoprotein IIb/IIIa receptor inhibitor increases the risk of bleeding, especially if it is given in the setting of recent (less than 4 hours) administration of fibrinolytic therapy.27 It is important to note that failure to decrease the dose of eptifibatide and tirofiban in patients with renal dysfunction increases bleeding risk. Glycoprotein IIb/IIIa inhibitors are given in addition to ASA, clopidogrel and an anticoagulant, usually UFH or enoxaparin and not bivalirudin. An immune-mediated thrombocytopenia occurs in approximately 5% of patients receiving abciximab.28
Anticoagulants
UFH, administered as a continuous infusion, is a first-line anticoagulant for treatment of patients with STE ACS for patients undergoing PCI.2–4,19,29 In those patients, UFH is initiated in the emergency department and continued until the end of the PCI procedure. For patients undergoing reperfusion with fibrinolytics, newer guidelines have favored the use of enoxaparin.3,19 Anticoagulant therapy should be initiated in the emergency department and continued for at least 48 hours, and up to eight days when fibrinolytics are administered.3 UFH and enoxaparin dosing for STE ACS are described in Table 8–2. The dose of the UFH infusion is adjusted frequently to a target activated partial thromboplastin time (aPTT) (Table 8–2). When coadministered with a fibrinolytic, aPTTs above the target range are associated with an increased rate of bleeding, while aPTTs below the target range are associated with increased mortality and reinfarction.30
A meta-analysis of small randomized studies from the 1970s and 1980s suggests that UFH reduces mortality by approximately 17% compared to no anticoagulant therapy.9 In studies of patients receiving fibrinolytics, both fondaparinux and reviparin have shown mortality reductions compared to placebo (no anticoagulant therapy).31,32 Other beneficial effects of anticoagulation are prevention of cardioembolic stroke, as well as venous thromboembolism in MI patients.3 Besides bleeding, the most frequent adverse effect of UFH is an immune-mediated clotting disorder, heparin-induced thrombocytopenia, which occurs in up to 5% of patients treated with UFH. Heparin-induced thrombocytopenia is less common in patients receiving low-molecular weight heparins (LMWHs), such as enoxaparin or dalteparin.
Low-molecular-weight heparins have not been studied in the setting of primary PCI. Low-molecular-weight heparins, like UFH, bind to antithrombin and inhibit both factor Xa and IIa. However, because their composition contains mostly short saccharide chain lengths, they preferentially inhibit factor Xa over factor IIa, which requires larger chain lengths for binding and inhibition. A large trial comparing enoxaparin administered for up to 8 days or until hospital discharge versus UFH administered for 48 hours in patients who received fibrinolytics found that enoxaparin reduced the rate of death or MI by 17% but also increased the risk of major bleeding (2.1% versus 1.4%).33Fondaparinux, an indirect-acting specific inhibitor of factor Xa, has also been compared to UFH in conjunction with fibrinolytics in the setting of STE MI. The rate of death or MI was similar between fondaparinux (administered as a low-dose for 8 days) and UFH. There was no significant difference in bleeding rates between fondaparinux and UFH.34 Current guidelines by both the AHA/ACC and the American College of Chest Physicians (ACCP) recommend that patients undergoing reperfusion with fibrinolytics receive an anticoagulation treatment with enoxaparin for up to eight days, over a 48-hour regimen of UFH.3,19 Nonetheless, these organizations have provided conflicting recommendations regarding the use of fondaparinux in such patients, illustrating well the more modest results of this agent compared to UFH.3,19
Bivalirudin, an IV direct thrombin inhibitor, may also be a choice of an anticoagulant for patients undergoing primary PCI. Potential advantages of direct thrombin inhibitors over UFH are that they bind to and inhibit clot-bound thrombin in addition to circulating thrombin and have no significant binding to plasma proteins. Thereby, they have a more predictable anticoagulant response. In addition, because thrombin is a potent stimulus for platelet aggregation, direct thrombin inhibitors have antiplatelet as well as anticoagulant activity. Like lepirudin, bivalirudin exhibits bivalent binding to thrombin, that is, it binds to both the active site and exosite-1, while argatroban binds only to the active site. Unlike lepirudin, both argatroban and bivalirudin exhibit reversible binding to thrombin, whereas lepirudin binds irreversibly. After bivalirudin binds to thrombin, thrombin cleaves a bivalirudin Arg3-Pro4 bond, re-exposing the thrombin catalytic site. Thus, bivalirudin provides consistent anticoagulation when administered as an IV bolus and infusion, but its activity is short-lived when discontinued. These potential advantages suggest that bivalirudin may have similar or superior efficacy and fewer bleeding complications compared to traditional anticoagulants. Recently, the results of a clinical trial demonstrated lower mortality at 30 days (34% reduction) and 1 year (31% reduction), with a 40% reduction in bleeding and similar rates of reinfarction with bivalirudin (administered during primary PCI) compared to UFH plus a glycoprotein IIb/IIIa inhibitor (administered during and for 12–18 hours following primary PCI).35
Nitrates
One SL NTG tablet should be administered every 5 minutes for up to three doses in order to relieve myocardial ischemia. If patients have been previously prescribed SL NTG and ischemic chest discomfort persists for more than 5 minutes after the first dose, the patient should be instructed to contact emergency medical services before self-administering subsequent doses in order to activate emergency care sooner. IV NTG should then be initiated in all patients with an ACS who have persistent ischemia, heart failure, or uncontrolled high BP, in the absence of contraindications.9 IV NTG should be continued for approximately 24 hours after ischemia is relieved (Table 8–2). Nitrates promote the release of nitric oxide from the endothelium, which results in venous and arterial vasodilation. Venodilation lowers preload and myocardial oxygen demand. Arterial vasodilation may lower BP, thus reducing myocardial oxygen demand. Arterial vasodilation also relieves coronary artery vasospasm, dilating coronary arteries to improve myocardial blood flow and oxygenation. Although used to treat ACS, nitrates have been suggested to play a limited role in the treatment of ACS patients, as two large, randomized clinical trials failed to show a mortality benefit for IV nitrate therapy followed by oral nitrate therapy in acute MI36,37 The most significant adverse effects of nitrates are tachycardia, flushing, headache, and hypotension. Nitrate administration is contraindicated in patients who have received oral phosphodiesterase 5 inhibitors, such as sildenafil and vardenafil, within the past 24 hours, and tadalafil within the past 48 hours.9
β-Blockers
A β-blocker should be administered early in the care of a patient with STE ACS and continued indefinitely. Early administration of a β-blocker to patients lacking a contraindication within the first 24 hours of hospital arrival as well as prescription at hospital discharge for patients with MI is a quality performance measure.14 In ACS, the benefit of β-blockers mainly results from the competitive blockade of β1-adrenergic receptors located on the myocardium. β1-Blockade produces a reduction in heart rate (HR), myocardial contractility, and BP, decreasing myocardial oxygen demand. As a result of these effects, β-blockers reduce the risk for recurrent ischemia, infarct size and risk of reinfarction, and occurrence of ventricular arrhythmias in the hours and days following MI.38
Landmark clinical trials have established the role of early β-blocker therapy in reducing MI mortality, reinfarction, and arrhythmias. Most of these trials were performed in the 1970s and 1980s before routine use of early reperfusion therapy.39,40 However, data regarding the acute benefit of β-blockers in MI in the reperfusion era is derived mainly from a recently reported large clinical trial, which suggests that there may be an early risk of cardiogenic shock when initiating IV β-blockers followed by oral β-blockers early in the course of STE MI, especially in patients presenting with pulmonary congestion.41 Therefore, a low-dose of an oral β-blocker should be initiated, followed by careful assessment for signs of hypotension and heart failure prior to any dose titration in patients with STE MI. IV β-blockers are reserved for patients presenting with HTN.3
The most serious side effects of β-blocker administration early in ACS are hypotension, bradycardia, and heart block. While initial acute administration of β-blockers is not appropriate for patients who present with decompensated heart failure, initiation of β-blockers may be attempted before hospital discharge in the majority of patients following treatment of acute heart failure.
Calcium Channel Blockers
Calcium channel blockers in the setting of STE ACS are used for relief of ischemic symptoms in patients who have certain contraindications to β-blockers. Current data suggest little benefit on clinical outcomes beyond symptom relief for calcium channel blockers in the setting of ACS.42 Therefore, calcium channel blockers should be avoided in the acute management of MI unless there is a clear symptomatic need or a contraindication to β-blockers. Agent selection is based on HR and left ventricular dysfunction (diltiazem and verapamil are contraindicated in patients with bradycardia, heart block, or systolic heart failure). Dosing and contraindications are described in Table 8–2.
Early Pharmacotherapy for NSTE ACSs
In general, early pharmacotherapy of NSTE ACS (Fig. 8–3) is similar to that of STE ACS with three exceptions: (a) fibri-nolytic therapy is not administered; (b) glycoprotein IIb/IIIa receptor inhibitors are administered to high-risk patients for medical therapy as well as to PCI patients; and (c) at this time, there are no standard quality performance measures for patients with NSTE ACS who are not diagnosed with MI.
According to the ACC/AHA NSTE ACS practice guidelines, in the absence of contraindications, early pharmacotherapy of NSTE ACS should include intranasal oxygen (if oxygen saturation is low), SL NTG followed by IVNTG in selected patients, ASA, clopidogrel, β-blocker, and anticoagulant. High-risk patients should undergo early coronary angiography and revascularization with PCI or CABG. Administration of a glycoprotein IIb/IIIa receptor inhibitor may be considered in high-risk patients. Morphine is also administered to patients with refractory angina as described previously. These agents should be administered early, while the patient is still in the emergency department. Dosing and contraindications for SL and IV NTG (for selected patients), ASA, clopidogrel, β-blockers, and the anticoagulants UFH, LMWHs, bivali-rudin, and fondaparinux are listed in Table 8–2.2,4
Fibrinolytic Therapy
Fibrinolytic therapy is not indicated in any patient with NSTE ACS, as increased mortality has been reported with fibrinolytics compared to controls in clinical trials in which fibrinolytics have been administered to patients with NSTE ACS (patients with normal or ST-segment depression ECGs).
Aspirin
ASA reduces the risk of death or developing MI by about 50% (compared to no antiplatelet therapy) in patients with NSTE ACS.24 Therefore, ASA remains the cornerstone of early treatment for all ACS.43Dosing of ASA for NSTE ACS is the same as that for STE ACS (Table 8–2). ASA is continued indefinitely.
Thienopyridines
For patients with NSTE ACS, clopidogrel added to ASA and started on the first day of hospitalization as a 300 to 600 mg loading dose and followed the next day by 75 mg orally per day is recommended for most patients.2Clopidogrel, administered as a 300 mg loading dose followed by 75 mg once daily for at least 1 month and up to 12 months is recommended in patients who do not undergo a coronary stent placement, because its use reduces the combined risk of death from cardiovascular causes, nonfatal MI, or stroke by 20%.2,26 In patients who undergo a coronary stent placement, it should be used in a similar fashion as described for STEMI.2,4 Because of the potential for increased risk of bleeding, clopidogrel should be discontinued for at least 5 days before elective CABG surgery.2
Glycoprotein IIb/IIIa Receptor Inhibitors
In patients with NSTE ACS scheduled for early PCI, administration of either abciximab or eptifibatide (double bolus) at the time of PCI is recommended. The use of tirofiban in these patients is not recommended, because it has been shown to be inferior to abciximab.2 Medical therapy with either eptifibatide or tirofiban in patients without a planned PCI or as therapy started before PCI is reserved for higher-risk patients, such as those with positive troponin or ST-segment depression, and patients who have continued or recurrent ischemia despite other antithrombotic therapy.2 Abciximab started as medical therapy prior to proceeding to PCI should not be used because it has not been shown to be beneficial in that setting.2
Doses and contraindications to glycoprotein IIb/IIIa receptor inhibitors are described in Table 8–2. Major bleeding and rates of transfusion are increased with administration of a glycoprotein IIb/IIIa receptor inhibitor in combination with ASA and an anticoagulant,25 but there is no increased risk of intracranial hemorrhage in the absence of concomitant fibrinolytic treatment. The risk of thrombocytopenia with tirofiban and eptifibatide is lower than that with abciximab. Bleeding risks appear similar between agents.
Anticoagulants
The choice of anticoagulant for a patient with NSTE ACS is guided by risk stratification, treatment strategy, and the results of recent clinical trials.2,44–46 For patients undergoing an early invasive strategy with early coronary angiography and PCI, either UFH, LMWH, low-dose fondaparinux or bivalirudin should be administered. If fondaparinux is chosen for a patient who undergoes PCI, it should be administered in combination with UFH as the dose of fondaparinux studied appears too low to prevent thrombotic events during PCI. UFH is the preferred anticoagulant following angiography in patients subsequently undergoing CABG during the same hospitalization.2
Patient Encounter 2, Part 1
RR is a 66-year-old, 90-kg (198-lb) male who presents to the emergency department by ambulance complaining of 4 hours of continuous chest pressure that started while mowing the lawn. RR developed substernal chest pressure about 30 minutes after starting to mow his lawn. He stopped and rested but the chest pressure did not resolve. Local paramedics were summoned and he was given three 0.4 mg sublingual nitroglycerin tablets by mouth, 325 mg ASA by mouth, and morphine 2 mg IV push without relief of chest discomfort.
PMH: HTN for 5 years; type 2 DM for 5 years
FH: Father with myocardial infarction at age 75; mother and sister alive with type 2 DM
SH: Nonsmoker
Allergies: NKDA
Meds: Metformin 1,000 mg by mouth twice daily; ASA 325 mg by mouth once daily; lisinopril 20 mg by mouth once daily
ROS: 10/10 chest pain/squeezing
PE:
HEENT: Normocephalic atraumatic
CV: Regular rate and rhythm S1 S2, −S3, −S4, no murmurs or rubs
VS: BP 140/88; HR 88 bpm; T 37°C (98.6°F)
Lungs: Clear to auscultation and percussion
Abd: Nontender, nondistended
Gl: Normal bowel sounds
GU: Stool guaiac negative
Exts: No bruits, pulses 2+, femoral pulse present, good range of motion
Neuro: Alert and oriented × 3, cranial nerves intact
Labs: Sodium 136 mEq/L (136 mmol/L), potassium 4.0 mEq/L (4.0 mmol/L), chloride 105 mEq/L (105 mmol/L), bicarbonate 22 mEq/L (24 mmol/L), SCr 1.0 mg/dL (88 μmol/L), glucose 160 mg/dL (8.9 mmol/L), WBC 6.9 × 103mm3 (6.9 × 109L), hemoglobin 14.7 g/dL (147 g/L or 9.1 mmol/L), hematocrit 42%, platelets 320 × 103/mm3 (320 × 109L), troponin I 10 ng/mL (10 mcg/L), oxygen saturation 99% on room air
ECG: Normal sinus rhythm, PR 0.16 seconds, QRS 0.08 seconds, QTc 0.38 seconds, occasional polymorphic premature ventricular contractions, 2 mm ST-segment depression inferior leads
CXR: Normal
What type of ACS is this?
What information is suggestive of acute MI?
In patients in whom an initial conservative strategy is planned (i.e., are not anticipated to receive angiography and revascularization), either enoxaparin, UFH or low-dose fondaparinux is recommended.2Bivalirudin has not been studied in this setting. Because there are more data supporting the use of enoxaparin,2 it is the preferred LMWH for ACS.
In comparative trials, the rate of bleeding with enoxaparin has been higher than other anticoagulants.2 For patients presenting with NSTE ACS in whom cardiologists suspect a high risk for bleeding while receiving an anticoagulant, fondaparinux (for conservatively managed patients) and bivalirudin (for interventionally managed patients) are the preferred anticoagulants recommended by the ACC/AHA NSTE ACS guidelines.2 Neither fondaparinux or bivalirudin are FDA approved for NSTE ACS despite being recommended by the ACC/AHA NSTE ACS guidelines.
Guideline recommended dosing and contraindications are described in Table 8–2. Because LMWHs are eliminated renally and patients with renal insufficiency generally have been excluded from clinical trials, some practice protocols recommend UFH for patients with creatinine clearance (CrCl) rates of less than 30 mL/min. (CrCl is calculated based on total patient body weight using the Cockroft-Gault equation.2,3) However, while recommendations for dosing adjustment of enoxaparin in patients with CrCl between 10 and 30 mL/min are listed in the product manufacturer’s label, the safety and efficacy of LMWH in this patient population remain vastly understudied. Administration of LMWHs should be avoided in dialysis patients with ACS. It is unclear whether or not bivalirudin requires dose adjustment for patients with significant renal dysfunction. While bivalirudin is eliminated renally, the duration of infusion in recent trials has been short (several hours only), and therefore the actual need for dosing adjustment is unlikely. Patients with serum creatinine (SCr) greater than 3.0 mg/dL (265 μmol/L) were excluded from ACS trials with fondaparinux and the product label states that fondaparinux is contraindicated in patients with CrCl less than 30 mL/min and in patients weighing less than 50 kg (110 lb).
UFH is monitored and the dose adjusted to a target aPTT, whereas LMWHs are administered by a fixed, actual body weight-based dose without routine monitoring of antifactor Xa levels. Some experts recommend antifactor Xa monitoring for LMWHs in patients with renal impairment during prolonged courses of administration of more than several days. No monitoring of coagulation is recommended for bivalirudin and fondaparinux.
Patient Encounter 2, Part 2
Is reperfusion therapy with fibrinolysis indicated at this time for patient RR?
What adjunctive pharmacotherapy should be administered to RR in the emergency department?
What additional pharmacotherapy should be initiated on the first day ofRR’s hospitalization following successful reperfusion?
Nitrates
SL NTG followed by IV NTG should be administered to patients with NSTE ACS and ongoing ischemia (Table 8–2). The mechanism of action, dosing, contraindications, and adverse effects are the same as those described in the section on early pharmacologic therapy for STE ACS. IV NTG is typically continued for approximately 24 hours following ischemia relief.
β-Blockers
The use of β-blockers in NSTE ACS is similar to STE ACS in that oral β-blockers should be initiated within 24 hours of hospital admission to all patients in the absence of contraindications. Benefits of β-blockers in this patient group are assumed to be similar to those seen in patients with STE ACS. β-Blockers are continued indefinitely. The prescription of a β-blocker at hospital discharge used to be reported as a quality measure.
Calcium Channel Blockers
As described in the previous section, calcium channel blockers should not be administered to most patients with ACS. Their role is a second-line treatment for patients with certain contraindications to β-blockers and those with continued ischemia despite β-blocker and nitrate therapy. Administration of either amlodipine, diltiazem, or verapamil is preferred.2
Secondary Prevention Following MI
The long-term goals following MI are to: (a) control modifiable CHD risk-factors; (b) prevent the development of heart failure; (c) prevent recurrent MI and stroke; and (d) prevent death, including sudden cardiac death. Pharmacotherapy, which has been proven to decrease mortality, heart failure, reinfarction, or stroke, should be initiated prior to hospital discharge for secondary prevention. Guidelines from the ACC/AHA suggest that in the absence of contraindications, following MI from either STE ACS or NSTE ACS, patients should receive indefinite treatment with ASA, a β-blocker, and an ACE inhibitor.2,3,47For NSTE ACS, clopidogrel should be added to ASA for at least 1 month and ideally for up to 12 months2 and for STE ACS for at least 2 weeks (unless they undergo PCI where the duration of clopidogrel therapy depends on stent type), and up to 1 year.3 Most patients will receive a statin to reduce low-density lipoprotein cholesterol to less than 100 mg/dL (2.59 mmol/L), and ideally less than 70 mg/dL (1.81 mmol/L). Newer therapies include eplerenone, an aldosterone antagonist. For all ACS patients, treatment and control of modifiable risk factors such as HTN, dyslipidemia, and diabetes mellitus (DM) is essential. Benefits and adverse effects of long-term treatment with these medications are discussed in more detail below.
Because the costs for chronic preventative pharmacotherapy are the same for primary and secondary prevention, while the risk of events is higher with secondary prevention, secondary prevention is more cost effective than primary prevention of CHD. Pharmacotherapy demonstrating cost effectiveness to prevent death in the ACS and post-MI patient includes fibrinolytics ($2,000 to $33,000 cost per year of life saved), ASA, glycoprotein IIb/IIIa receptor inhibitors ($13,700 to $16,500 per year of life added), β-blockers (less than $5,000 to $15,000 cost per year of life saved), ACE inhibitors ($3.000 to $5.000 cost per year of life saved), eplerenone ($15,300 to $32,400 per year of life gained), statins ($4,500 to $9,500 per year of life saved) and gemfibrozil ($17,000 per year of life saved).46–55 Because cost-effectiveness ratios of less than $50,000 per added life-year are considered economically attractive from a societal perspective,48 pharmacotherapy described above for ACS and secondary prevention are standards of care because of their efficacy and cost attractiveness to payors.
Aspirin
ASA decreases the risk of death, recurrent infarction, and stroke following MI. ASA prescription at hospital discharge is a quality care performance measure in MI patients.9,14 All patients should receive ASA indefinitely; those patients with a contraindication to ASA should receive clopidogrel.2,3 The risk of major bleeding from chronic ASA therapy is approximately 2% and is dose-related. ASA doses higher than 75 to 81 mg are no less effective than doses of 160 to 325 mg, but do have lower rates of bleeding. Therefore, chronic doses of ASA should not exceed 81 mg.46 For patients receiving intracoronary stents, the dose of ASA recommended by the ACC/AHA PCI guidelines in combination with clopidogrel is 162–325 mg for the duration specified by type of stent followed by low-dose ASA (see Table 8–2) but this is based upon consensus recommendations and not on randomized trials of ASA dosing.4In contrast, the American College of Chest Physician guidelines recommend low-dose ASA in combination with clopidogrel for all patients, including those with stents.19,29,47
Clopidogrel
For patients with either STE or NSTE ACS, clopidogrel decreases the risk of cardiovascular events.17,18,26 The ACC/AHA guidelines suggest a minimum therapy duration of 1 month in patients following NSTE ACS who are managed conservatively, and ideally up to 12 months.2 In patients receiving clopidogrel for STE MI who do not undergo PCI, clopidogrel should be administered for at least 14 to 28 days.26 Patients who have undergone a PCI with a bare metal stent should receive clopidogrel for at least 1 month, ideally up to 1 year, and for patients receiving a drug-eluting stent for at least 12 months.4
β-Blockers, Nitrates, and Calcium Channel Blockers
Current treatment guidelines recommend that following an ACS, patients should receive a β-blocker indefinitely.2,3 whether they have residual symptoms of angina or not.59 Overwhelming data support the use of β-blockers in patients with a previous MI. Currently, there are no data to support the superiority of one β-blocker over another.
Although β-blockers should be avoided in patients with decompensated heart failure from left ventricular systolic dysfunction complicating an MI, clinical trial data suggest that it is safe to initiate β-blockers prior to hospital discharge in these patients once heart failure symptoms have resolved.49 These patients may actually benefit more than those without left ventricular dysfunction.50 In patients who cannot tolerate or have a contraindication to a β-blocker, a calcium channel blocker can be used to prevent anginal symptoms, but should not be used routinely in the absence of such symptoms.23,51
Finally, all patients should be prescribed short-acting, SL NTG or lingual NTG spray to relieve any anginal symptoms when necessary and instructed on its use.2,3 Chronic long-acting nitrate therapy has not been shown to reduce CHD events following MI. Therefore, IV NTG is not routinely followed by chronic, long-acting oral nitrate therapy in ACS patients who have undergone revascularization, unless the patient has chronic stable angina or significant coronary stenoses that were not revascularized.51
ACE Inhibitors and ARBs
ACE inhibitors should be initiated in all patients following MI to reduce mortality, decrease reinfarction, and prevent the development of heart failure.2,3,9 Dosing and contraindications are described in Table 8–2. The benefit of ACE inhibitors in patients with MI most likely comes from their ability to prevent cardiac remodeling. The largest reduction in mortality is observed in patients with left ventricular dysfunction (low LVEF) or heart failure symptoms. Early initiation (within 24 hours) of an oral ACE inhibitor appears to be crucial during an acute MI, as 40% of the 30-day survival benefit is observed during the first day, 45% from days 2 to 7, and approximately 15% from days 8 to 30.52However, current data do not support the early administration of IV ACE inhibitors in patients experiencing an MI, as mortality may be increased.53 Administration of ACE inhibitors should be continued indefinitely. Hypotension should be avoided, as coronary artery filling may be compromised. Additional trials suggest that most patients with CAD, not just ACS or heart failure patients, benefit from ACE inhibitors. Therefore, ACE inhibitors should be considered in all patients following an ACS in the absence of a contraindication.
Many patients cannot tolerate chronic ACE inhibitor therapy secondary to adverse effects outlined below. The ARBs, candesartan and valsartan, have been documented in trials to improve clinical outcomes in patients with heart failure.54,55 Therefore, either an ACE inhibitor or candesartan or valsartan are acceptable choices for chronic therapy for patients who have a low LVEF and heart failure following MI. Since more than five different ACE inhibitors have proven benefits in MI while only two ARBs have been studied, the benefits of ACE inhibitors are generally considered a class effect while the benefits of ARBs are still under study. More recently, telmisartan has been shown to be equivalent to ramipril for prevention of CVD events or hospitalization for heart failure in patients with CAD or at high risk of CVD events.56 Nevertheless, a subsequent trial in ACE inhibitor intolerant patients produced more modest results.57 ACE inhibitor prescription (or alternatively an ARB) at hospital discharge following MI, in the absence of contraindications, to patients with depressed LVF (EF less than 40%) is currently a quality performance measure for MI.3,14
Besides hypotension, the most frequent adverse reaction to an ACE inhibitor is cough, which may occur in up to 30% of patients. Patients with an ACE inhibitor cough and either clinical signs of heart failure or LVEF less than 40% may be prescribed an ARB.3 Other, less common but more serious adverse effects to ACE inhibitors and ARBs include acute renal failure, hyperkalemia, and angioedema.
Aldosterone Antagonists
To reduce mortality, administration of an aldosterone antagonist, either eplerenone or spironolactone, should be considered within the first 2 weeks following MI in all patients who are already receiving an ACE inhibitor (or ARB) and have an LVEF of equal to or less than 40% and either heart failure symptoms or diagnosis of DM.3 Aldosterone plays an important role in heart failure and in MI because it promotes vascular and myocardial fibrosis, endothelial dysfunction, HTN, left ventricular hypertrophy, sodium retention, potassium and magnesium loss, and arrhythmias. Aldosterone antagonists have been shown in experimental and human studies to attenuate these adverse effects.58Spironolactone decreases all-cause mortality in patients with stable, severe heart failure.59
Eplerenone, like spironolactone, is an aldosterone antagonist that blocks the mineralocorticoid receptor. In contrast to spironolactone, eplerenone has no effect on the progesterone or androgen receptor, thereby minimizing the risk of gyne-comastia, sexual dysfunction, and menstrual irregularities. In a large clinical trial,60 eplerenone significantly reduced mortality, as well as hospitalization for heart failure in post-MI patients with an EF less than 40% and symptoms of heart failure at any time during hospitalization. The risk of hyperkalemia, however, was increased. Therefore, patients with a SCr greater than 2.5 mg/dL (221 μmol/L) or CrCl less than 50 mL/min or serum potassium concentration of greater than 5.0 mmol/L (5.0 mEq/L) should not receive eplerenone (in addition to either an ACE inhibitor or ARB). Currently, there are no data to support that the more selective, more expensive eplerenone is superior to, or should be preferred to, the less expensive generic spironolactone unless a patient has experienced gynecomastia, breast pain, or impotence while receiving spironolactone. Finally, it should be noted that hyperkalemia is just as likely to appear with both of these agents, and is more common in patients receiving concomitant ACE inhibitors.
Lipid-Lowering Agents
There are now overwhelming data supporting the benefits of statins in patients with CAD in prevention of total mortality, cardiovascular mortality, and stroke. According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel recommendations, all patients with CAD should receive dietary counseling and pharmacologic therapy in order to reach a low-density lipoprotein (LDL) cholesterol of less than 100 mg/dL (2.59 mmol/L), with statins being the preferred agents to lower LDL cholesterol.61 Results from landmark clinical trials have unequivocally demonstrated the value of statins in secondary prevention following MI in patients with moderate to high cholesterol.62,63 Although the primary effect of statins is to decrease LDL cholesterol, statins are believed to produce many non-lipid-lowering or “pleiotropic” effects such as anti-inflammatory and antithrombotic properties. Newer recommendations from the NCEP give an optional LDL cholesterol goal of less than 70 mg/dL (1.81 mmol/L).63,64 In patients with an ACS, statin therapy initiation should not be delayed and statins should be prescribed at or prior to discharge in most patients.65 Statin prescription at hospital discharge is currently a quality performance measure for MI.14
A fibrate derivative or niacin should be considered in select patients with a low high-density lipoprotein (HDL) cholesterol less than 40 mg/dL (1.04 mmol/L) and/or a high triglyceride level greater than 200 mg/dL (2.26 mmol/L). In a large randomized trial of men with established CAD and low levels of HDL cholesterol, the use of gemfibrozil (600 mg twice daily) significantly decreased the risk of nonfatal MI or death from coronary causes.66Studies with fenofibrate have produced less definitive results.
Other Modifiable Risk Factors
Smoking cessation, managing HTN, weight loss, and tight glucose control for patients with DM, in addition to treatment of dyslipidemia, are important treatments for secondary prevention of CHD events.3Smoking cessation counseling at the time of discharge following MI is a quality care performance measure.3 The use of nicotine patches or gum, or of bupropion alone or in combination with nicotine patches, should be considered in appropriate patients.3 HTN should be strictly controlled according to published guidelines.67 Patients who are overweight should be educated on the importance of regular exercise, healthy eating habits, and reaching and maintaining an ideal weight.68 Finally, because diabetics have up to a four-fold increased risk of mortality compared to nondiabetics, the importance of tight glucose control, as well as other CHD risk factor modifications, cannot be overstated.69
OUTCOME EVALUATION
• To determine the efficacy of nonpharmacologic and pharmacotherapy for both STE and NSTE ACS, monitor patients for: (a) relief of ischemic discomfort; (b) return of ECG changes to baseline; and (c) absence or resolution of heart failure signs.
• Monitoring parameters for recognition and prevention of adverse effects from ACS pharmacotherapy are described in Table 8–4. In general, the most common adverse reactions from ACS therapies are hypotension and bleeding. To treat for bleeding and hypotension, discontinue the offending agent(s) until symptoms resolve. Severe bleeding resulting in hypotension secondary to hypovolemia may require blood transfusion.
Patient Encounter 1, Part 3
Identify the long-term treatment goals forSD.
What additional pharmacotherapy should be initiated prior to hospital discharge?
Create a care plan for SD for hospital discharge which includes pharmacotherapy, desired treatment outcomes, and monitoring for efficacy and adverse effects.
Patient Encounter 2, Part 3
Patient RR undergoes coronary angiography and PCI with a drug-eluting stent placed for a 90% stenosis in his right coronary artery on hospital day 1.
Identify the long-term treatment goals forRR.
What additional pharmacotherapy should be initiated prior to hospital discharge?
Create a care plan for RR for hospital discharge that includes pharmacotherapy, desired treatment outcomes, and monitoring for efficacy and adverse effects.
Table 8–4 Therapeutic Drug Monitoring for Adverse Effects of Pharmacotherapy for ACSs
Patient Care and Monitoring
For patients in acute distress and ACS is suspected:
• Follow recommendations in Figures 8-1 and 8-2 and Table 8–2. Also incorporate into your plan the recommendations detailed below under “For patients diagnosed with ACS.”
For patients diagnosed with ACS:
1. Review patient’s medical record to determine indications for each medication.
2. Review patient’s medical record to determine contraindications for each medication. For ASA, β-blockers, ACE inhibitors, and ARBs, document contraindications in patient’s medical record.
3. Review doses of medications for appropriateness. Titration toward target doses of ACE inhibitors and β-blockers should be in progress. Evaluate if the dose of ASA may be reduced to less than 100 mg if no recent stent.
4. Interview the patient to assess complementary or alternative medication use. Counsel appropriately based on indications and drug interactions.
5. Evaluate the patient’s medical record and medication history, and conduct a patient interview to assess for the presence of drug allergies, adverse drug reactions, drug interactions, and medication adherence.
6. Educate the patient and evaluate their success with lifestyle modifications, including smoking cessation, diet, weight loss, and exercise. For patients with DM, tight glucose control should be emphasized.
7. Provide patient education with regard to CAD, MI, indications for medications, and potential adverse effects and drug interactions.
• What is CAD?
• How can the progression of CAD and MI be prevented?
• How does each medication benefit the patient?
• Why is adherence important?
• What potential adverse effects may occur?
• What potential drug interactions may occur?
• Warning signs to report to the physician or emergency medical services include chest squeezing, burning, or pain; jaw pain; pain radiation down the arm; bleeding; and loss of consciousness.
• Dial 911 if there is no chest discomfort relief after one SL NTG tablet.
• Important to train caregiver or relative to administer cardiopulmonary resuscitation (CPR).
8. Document smoking cessation counseling and patient receipt of discharge instructions in the patient’s medical record.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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