Sarah A. Spinler and Simon de Denus
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 College of Cardiology Foundation (ACCF), American Heart Association (AHA), and Society for Cardiovascular Angiography and Interventions (SCAI) recommend strategies, or guidelines, for ACS patient care for ST-segment elevation (STE) myocardial infarction (MI) and non–ST-segment elevation (NSTE) ACS, including guidelines for patients undergoing percutaneous coronary intervention (PCI).
Patients with ischemic chest discomfort and suspected ACS are risk-stratified based on a 12-lead electrocardiogram (ECG), past medical history, and results of the troponin and creatine kinase (CK)–myocardial band (MB) tests. The diagnosis of MI is confirmed based on the results of the CK-MB and troponin biochemical marker tests.
Early reperfusion therapy with primary PCI of the infarct artery is the recommended therapy for patients presenting with STE MI within 12 hours of symptom onset.
The most recent PCI ACCF/AHA/SCAI 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 patients with NSTE ACS at an elevated risk for death or MI, including those with a high risk score or patients with refractory angina, acute heart failure, other symptoms of cardiogenic shock, or arrhythmias.
In addition to reperfusion therapy, other early pharmacotherapy that all patients with STE MI and without contraindications should receive within the first day of hospitalization, and preferably in the emergency department, are intranasal oxygen (if oxygen saturation is low), sublingual (SL) nitroglycerin (NTG), aspirin (ASA), a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor depending on reperfusion strategy), and anticoagulation with bivalirudin, unfractionated heparin (UFH), enoxaparin, (agent dependent on reperfusion strategy), or fondaparinux. A glycoprotein (GP) IIb/IIIa inhibitor should be administered if UFH is selected as the anticoagulant for patients undergoing primary PCI. A statin should be administered prior to PCI. IV β-blockers and IV NTG should be given in selected patients. Oral β-blockers should be initiated within the first day in patients without contraindications.
In the absence of contraindications, all patients with NSTE ACS should be treated in the emergency department with intranasal oxygen (if oxygen saturation is low), SL NTG, ASA, and an anticoagulant (UFH, enoxaparin, fondaparinux, or bivalirudin). High-risk patients should proceed to early angiography, and may receive a GP IIb/IIIa inhibitor. A P2Y12 inhibitor (selection of agent and timing of initiation dependent on selection of an interventional approach involving PCI or CABG surgery vs. a noninterventional approach with medical management alone) should be administered to all patients. A statin should be administered prior to PCI. IV β-blockers and IV NTG should be given in selected patients. Oral β-blockers should be initiated within the first day in patients without contraindications.
Secondary prevention guidelines from the ACCF/AHA suggest that following MI from either STE MI or NSTE ACS, all patients, in the absence of contraindications, should receive indefinite treatment with ASA, a β-blocker, a statin, and an angiotensin-converting enzyme (ACE) inhibitor for secondary prevention of death, stroke, or recurrent infarction. The goal low-density lipoprotein cholesterol is less than 100 mg/dL (2.59 mmol/L) and ideally less than 70 mg/dL (1.81 mmol/L). A P2Y12 inhibitor should be continued for at least 12 months for patients undergoing PCI and for patients with NSTE ACS receiving a medical management strategy of treatment. Clopidogrel should be continued for at least 14 days in patients with STE MI in patients not undergoing PCI. An angiotensin II receptor blocker and a mineralocorticoid receptor antagonist should be given to selected patients. For all patients with ACS, treatment and control of modifiable risk factors such as hypertension (HTN), dyslipidemia, obesity, smoking, and diabetes mellitus are essential.
To determine the efficacy of nonpharmacologic treatments and pharmacotherapy, monitor patients for relief of ischemic discomfort, return of ECG changes to baseline, and absence or resolution of heart failure signs and symptoms. The most common adverse effects from pharmacotherapy of ACS are bleeding and hypotension.
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 Foundation (ACCF) recommend strategies, or guidelines, for ACS patient care for ST-segment elevation (STE) and non–ST-segment elevation (NSTE) ACS. In collaboration with the Society for Cardiovascular Angiography and Interventions (SCAI), the ACCF and AHA issue joint guidelines for percutaneous coronary intervention (PCI), including PCI in the setting of ACS. These practice guidelines are based on a review of available clinical evidence, have graded recommendations based on evidence and expert opinion, and are updated periodically. These guidelines form the cornerstone for quality care of the ACS patient.2–7
Each year, more than 1.1 million Americans will experience an ACS, and 150,000 die of an MI.1 In the United States, more than 7 million living persons have survived an MI.1
CVDs are the leading cause of hospitalization in the United States, resulting in about 6.2 million hospital discharges per year. Each year, there are more than 1.3 million MIs, and one in six deaths is secondary to CHD.1
The proportion of patients with MI presenting with STE MI compared with those presenting with NSTE MI decreased from approximately 80% in the early 1990s to between 25% and 30% currently.1 This may be secondary to the use of the more sensitive biomarker troponin (increasing the diagnosis of MI in the NSTE ACS group), greater use of antecedent revascularization procedures, decreased reinfarction from enhanced medical therapy after an initial event, or prevention of progression of UA to MI through more effective anticoagulant and antiplatelet therapy.
According to data from the National Registry of Myocardial Infarction, in-hospital mortality has decreased by more than 20% during the last 20 years. Improvements in care that may have contributed to this mortality reduction include greater use of guideline-recommended drugs (e.g., aspirin [ASA], β-blockers, angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs], statins, clopidogrel), reductions in the door-to-needle time for administering fibrinolytics and in the corresponding first medical contact time to primary PCI, treatments for heart failure (HF), and increased use of early coronary angiography and PCI for high-risk patients with NSTE ACS.1
In patients with STE MI, in-hospital death rates are approximately 3% in patients receiving primary 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%. At 6 months and 1 year, mortality and reinfarction rates are similar between STE and NSTE MI.1 Other than persistent ST-segment changes and troponin, other predictors of in-hospital mortality include older age, elevated serum creatinine (SCr), tachycardia, and HF.1,2,8 One-year mortality following STE MI ranges from 7% to 18%.2
CHD 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 $195 billion.1 The estimated cost of hospitalization for MI is $14,000, and the median length of hospital stay is 3.2 days.1,2 Risk-standardized hospital mortality for MI and 30-day hospital readmission rates following MI and PCI are quality performance measures and Outcome of Care Measures that are publically reportable by the Center for Medicare and Medicaid Services.6 The Patient Protection and Affordable Care Act of 2010 links quality performance measures to hospital reimbursement.
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).7 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.9 Stable stenoses are characteristic of stable angina.
Spectrum of ACSs
ACSs include all clinical syndromes compatible with acute MI resulting from an imbalance between myocardial oxygen demand and supply. 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 MI or NSTE ACS (NSTE MI and UA) (Fig. 7-1).10 An STE MI occurs when symptoms of myocardial ischemia occur in conjunction with new STE with subsequent release of biomarkers of myocardial necrosis, mainly troponins T or I, but also creatine kinase (CK)–myocardial band (MB).2 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, whereas such an ECG manifestation is seen less commonly in patients with NSTE MI.3NSTE 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. 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 CK MB, from the necrotic myocytes in the bloodstream. The clinical significance of serum markers will be discussed in greater detail in later sections of this chapter.
FIGURE 7-1 Evaluation of the acute coronary syndrome patient. aAs described in Table 7-1. b“Positive”: Above the myocardial infarction decision limit. c“Negative”: Below the myocardial infarction decision limit. (ACS, acute coronary syndrome; CABG, coronary artery bypass graft; CAD, coronary artery disease; CK-MB, creatine kinase myocardial band; ECG, electrocardiogram; PCI, percutaneous coronary intervention.) (Modified with permission from Spinler SA. Evolution of antithrombotic therapy used in acute coronary syndromes. In: Richardson MM, Chant C, Cheng JWM, et al., eds. Pharmacotherapy Self-Assessment Program. Book 1: Cardiology, 7th ed. Lenexa, KS: American College of Clinical Pharmacy, 2010.)
Plaque Rupture and Clot Formation
Following plaque rupture, a clot (a partially 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 induces platelet adhesion and activation, which promote the release of platelet-derived vasoactive substances including adenosine diphosphate (ADP) and thromboxane A2 (TXA2).7These produce vasoconstriction and potentiate platelet activation. Furthermore, during platelet activation, a change in the conformation in the glycoprotein (GP) IIb/IIIa surface receptors of platelets occurs that 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 disrupted endothelium, which are rich in tissue factor. This leads to the production of thrombin (factor IIa), which converts fibrinogen to fibrin through enzymatic activity. 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.9,11
Ventricular Remodeling Following an Acute MI
Ventricular remodeling is a process that occurs in several cardiovascular (CV) conditions including HF and following an MI. It is characterized by left ventricular dilation and reduced pumping function of the left ventricle, leading to cardiac failure.12 Because HF represents one of the principal causes of mortality and morbidity following an MI, preventing ventricular remodeling is an important therapeutic goal.
ACE inhibitors, ARBs, β-blockers, and mineralocorticoid receptor antagonists (MRAs) are all agents that slow down or reverse ventricular remodeling through inhibition of the renin–angiotensin–aldosterone system and/or through improvement in hemodynamics (decreasing preload or afterload).12 These agents also improve survival and will be discussed in more detail in subsequent sections of this chapter.
This chapter focuses on management of the uncomplicated ACS patient. However, it is important for clinicians to recognize complications of MI, because MI is associated with increased mortality. The most serious complication of MI is cardiogenic shock, occurring in approximately 5% to 6% of hospitalized patients presenting with STE MI.13 Mortality complicated by cardiogenic shock with MI is high, approaching 60%.14 Other complications that may result from MI are HF, valvular dysfunction, bradycardia, heart block, pericarditis, stroke secondary to left ventricular thrombus embolization, venous thromboembolism, left ventricular free wall or ventricular septal rupture, left ventricular aneurysm formation, and ventricular and atrial tachyarrhythmias.2 In fact, more than one quarter of MI patients die, presumably from ventricular fibrillation, prior to reaching the hospital.1
CLINICAL PRESENTATION Diagnosis of ACSs
• The patient is typically in acute distress and may develop or present with acute HF, cardiogenic shock, or cardiac arrest.
• 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.
• No signs are classic for ACS.
• Patients with ACS may present with signs of acute HF 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.
• Troponin I or T and CK-MB are measured at the time of first assessment and repeated at least once, 6 to 9 hours later to ascertain heart muscle damage, confirmatory for the diagnosis of infarction. For patients with NSTE ACS, an elevated troponin is diagnostic for MI, defining a NSTE MI. Patients presenting with suspected NSTE ACS who do not have an MI undergo further diagnostic testing to determine whether or not they have UA or ACS.
• Blood chemistry tests are performed with particular attention given to potassium and magnesium, which may affect heart rhythm.
• SCr is measured and CrCl is used 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 complete blood count (CBC) and coagulation tests (aPTT and INR) should be obtained, as most patients will receive antithrombotic therapy that increases the risk for bleeding.
• Fasting lipid panel (optional).
Other Diagnostic Tests
• The 12-lead ECG is the first step in management. Patients are risk-stratified into two groups: STE ACS and suspected NSTE ACS.
• High-risk ACS patients and those with recurrent chest discomfort will undergo coronary angiography via a left heart catheterization and injection of contrast dye into the coronary arteries to determine the presence and extent of coronary artery stenosis.
• During hospitalization, a measurement of LVF, 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.
With permission from reference 10.
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 that may accompany the chest discomfort include nausea, vomiting, diaphoresis, or shortness of breath. Although similar to stable angina, the duration may be longer and the intensity greater. All healthcare professionals should review these warning symptoms with patients at high risk for CHD. On physical examination, no specific features are indicative of ACS.
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. 7-1).10 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 acute 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 (cardiac troponin preferred) with at least one value above the 99th percentile of the upper reference limit with at least one of the following: (a) symptoms of ischemia; (b) new or presumed new significant ST-segment–T wave changes or new left bundle-branch block; (c) development of pathologic Q waves; or (d) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.”15 Typically, a blood sample is obtained once in the emergency department, and 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 that 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 that has led 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 3 to 6 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.15
Patient symptoms, past medical history, ECG, and biomarkers, particularly cardiac 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 PCI (Table 7-1).3,5,16 Initial treatment according to risk stratification is depicted in Figure 7-1.2–5,8,10 Patients with STE MI are at the highest risk of death. Initial treatment of STE MI should proceed without evaluation of the troponins because these patients have a greater than 97% chance of having an MI subsequently diagnosed with biochemical markers. The ACCF/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 first medical contact for primary PCI.2,5 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.17,18 Although all patients should be evaluated for reperfusion therapy, not all patients may be eligible. Indications and contraindications for fibrinolytic therapy are described in Treatment below. 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.19
TABLE 7-1 Risk Stratification for Acute Coronary Syndromes (ACS)3,4,16,23,24
Risk stratification of the patient with NSTE ACS is more complex because in-hospital outcomes for this group of patients vary with reported rates of death of 0% to 12%, reinfarction rates of 0% to 3%, and recurrent severe ischemia rates of 5% to 20%.17 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. 7-1) and/or elevated biomarkers are at higher risk of death or recurrent infarction.
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 MI complications; (c) prevention of coronary artery reocclusion; and as evidence of restoration of coronary artery blood flow; (d) relief of ischemic chest discomfort; and (e) resolution of ST-segment and T-wave changes on the ECG.
Long-term desired outcomes are control of CV risk factors, prevention of additional CV events, including reinfarction, stroke, and HF, and improvement in quality of life.
General Approach to Treatment
Selecting evidence-based therapies described in the ACCF/AHA guidelines for patients without contraindications results in lower mortality.20–22 General treatment measures for all STE MI and high- and intermediate-risk NSTE ACS patients include admission to hospital, oxygen administration (if oxygen saturation is low, less than 90%), continuous multilead ST-segment monitoring for arrhythmias and ischemia, frequent measurement of vital signs, bedrest for 12 hours in hemodynamically stable patients, avoidance of the Valsalva maneuver (prescribe stool softeners routinely), and pain relief (Figs. 7-2 and 7-3).2–4,8,10,16
FIGURE 7-2 Initial pharmacotherapy for ST-segment elevation myocardial infarction. aFor at least 48 hours. bSee Table 7-2 for dosing and specific types of patients who should not receive enoxaparin.c For the duration of hospitalization, up to 8 days. dFor selected patients, see Table 7-2. eIf pretreated with UFH, stop UFH infusion for 30 minutes prior to administration of bivalirudin (bolus plus infusion). fIncreased risk of major bleeding and intracranial hemorrhage if a GP IIb/IIIa inhibitor is added to an anticoagulant for PCI following fibrinolysis, especially in the elderly; weight risk versus benefit. (ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CABG, coronary artery bypass graft; GP, glycoprotein; NTG, nitroglycerin; PCI, percutaneous coronary intervention; Subcut, subcutaneous; SL, sublingual; UFH, unfractionated heparin.) (Modified with permission from Spinler SA. Evolution of antithrombotic therapy used in acute coronary syndromes. In: Richardson MM, Chant C, Cheng JWM, et al., eds. Pharmacotherapy Self-Assessment Program. Book 1: Cardiology, 7th ed. Lenexa, KS: American College of Clinical Pharmacy, 2010.)
FIGURE 7-3 Initial pharmacotherapy for non–ST-segment elevation ACS. aFor selected patients, see Table 7-2. bPreferred in patients at high risk for bleeding. cIf pretreated with UFH, stop UFH infusion for 30 minutes prior to administration of bivalirudin bolus plus infusion. dMay require IV supplemental dose of enoxaparin; see Table 7-2. eDo not use if prior history of stroke/transient ischemic attack (TIA), age older than 75 years, or body weight less than or equal to 60 kg. fSubcut enoxaparin or UFH can be continued at a lower dose for venous thromboembolism prophylaxis. (ACE, angiotensin-converting enzyme; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHD, coronary heart disease; GP, glycoprotein; NTG, nitroglycerin; PCI, percutaneous coronary intervention; Subcut, subcutaneous; SL, sublingual; UFH, unfractionated heparin.) (Modified with permission from reference 16.)
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 MI and NSTE ACS patients are outlined in Figures 7-2 and 7-3. 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 in Table 7-1.16,23,24
Primary PCI for STE MIs
Early reperfusion therapy with primary PCI of the infarct artery within 90 minutes of first medical contact is the reperfusion treatment of choice for patients presenting with STE MI who present within 12 hours of symptom onset2 (Fig. 7-2). First, emergency medical services are activated for a patient complaining of ischemic symptoms. Paramedics arrive to care for the patient out of the hospital and they perform a 12-lead ECG that demonstrates STE. Sometimes, the 12-lead ECG is transmitted electronically or via telephone to an emergency department where a physician reviews the ECG and may “activate” the cardiac catheterization medical team to alert them that a patient with STE MI will be arriving at the hospital shortly. The patient is transported to the emergency department. 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 in the artery associated with the infarct. In order to meet the quality of care metric of less than 90 minutes from first medical contact to primary PCI, many transitions of care occur and care coordination between paramedics, emergency department staff, and cardiac catheterization is vital. Every minute delay results in additional myocardial cell damage that may be irreversible.
About 62% of patients with STE MI are treated with primary PCI; 18% are treated with fibrinolytics. Results from a meta-analysis of trials comparing fibrinolysis with primary PCI indicate a lower mortality rate with primary PCI.25 One reason for the superiority of primary PCI compared with fibrinolysis is that more than 90% of occluded infarct-related coronary arteries are opened with primary PCI compared with fewer than 60% of coronary arteries opened with currently available fibrinolytics.2 In addition, intracranial hemorrhage (ICH) 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, patients in cardiogenic shock, those with contraindications to fibrinolytics, and those with continuing symptoms 12 to 24 hours after symptom onset.2
A quality performance measure (quality performance measures are measures of quality healthcare 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 MI is the time from first medical contact to the time the occluded artery is opened with PCI. This “first medical contact-to-primary PCI” time should be equal to or less than 90 minutes.2 Efforts to improve system-wide rapid triage of patients with STE MI such as participation in the Door to Balloon Time Alliance and Get with the Guidelines (GWTG) educational programs within health systems have resulted in shorter primary PCI times in the United States. In 2010, the median door-to-primary PCI time (meaning the time from hospital arrival to primary PCI) was 64 minutes, decreasing from a median of 96 minutes in 2005.26 In 2005, 44% of patients treated with primary PCI had door-to-primary PCI times of less than 90 minutes, while in 2010 this percentage had increased to 94%.26 Unfortunately, most hospitals do not have interventional cardiology services capable of performing primary PCI 24 hours a day. Patients presenting to facilities that do not have interventional cardiology services can be transferred to such facilities when a transfer protocol that minimizes transfer delays has been established between the institutions and if primary PCI can be performed within the first 120 minutes of medical contact.2
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.2
PCI in NSTE ACSs
The most recent PCI ACCF/AHA/SCAI 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 patients with NSTE ACS at an elevated risk for death or MI, including those with a high risk score (Table 7-1) or patients with refractory angina, acute HF, other symptoms of cardiogenic shock, or arrhythmias (Fig. 7-3).5,8 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.5,27 An early invasive approach results in a lower rate of refractory angina during hospital admission and over the first year, as well as a lower frequency of MI at 5 years, but an increased frequency of minor bleeding related to the procedure.27 An early invasive strategy is also less costly than the conservative medical stabilization approach.28Mortality is not reduced by an early invasive approach in patients with NSTE ACS.27
All patients undergoing PCI should receive low-dose ASA therapy indefinitely. A P2Y12 inhibitor antiplatelet (clopidogrel, prasugrel, or ticagrelor) should be administered concomitantly with ASA for at least 12 months following PCI for a patient with ACS (Table 7-2).2,5 Earlier discontinuation of the P2Y12 inhibitor should be considered if the risk of bleeding outweighs the anticipated benefit in reduction in risk of death, MI, or stroke as well as stent thrombosis.2,5 A longer duration of P2Y12 inhibitor therapy may be considered for patients receiving a drug-eluting stent, as the risk of stent thrombosis is greater on cessation of dual antiplatelet therapy.2,5 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 that 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. Trials are ongoing evaluating the need for an extended duration in patients without ACS undergoing PCI (greater than 12 months) of P2Y12 inhibitor therapy following PCI. Regardless of whether or not a patient with NSTE ACS receives a stent, the preferred duration of P2Y12 therapy is at least a year.2,5
TABLE 7-2 Evidence-Based Pharmacotherapy for ST-Segment Elevation Myocardial Infarction and Non–ST-Segment Elevation Acute Coronary Syndrome2–5,8
Additional Testing and Risk Stratification
For patients with NSTE ACS, an initial conservative strategy is recommended for patients with a low risk score, normal ECGs, and negative troponin tests who are without recurrence of chest discomfort (Fig. 7-3).3,4
Within the first 3 days of hospital admission patients with MI should have their left ventricular function (LVF) evaluated for risk stratification.2 The most common way LVF is measured is using an echocardiogram to calculate the patient’s left ventricular ejection fraction (LVEF). LVF is the single best predictor of mortality following MI. Patients with LVEFs less than 40% (0.40) 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 or equal to 30% (0.30, measured at least 40 days after MI) (and have a New York Heart Association functional class I) or who have nonsustained ventricular tachycardia secondary to a prior MI and a LVEF of less than or equal to 40% (0.40) with inducible ventricular fibrillation or ventricular tachycardia at electrophysiology study benefit from placement of an implantable cardioverter-defibrillator (ICD) for sudden cardiac death prevention.29
Predischarge from the hospital, stress testing (Fig. 7-3) is indicated in patients with NSTE ACS where an initial conservative strategy is selected and for patients with STE MI where coronary angiography was not performed and there has been no recurrent ischemia.2–4 Following the stress test, patients deemed not at low risk should undergo left heart catheterization with coronary angiography and revascularization as indicated by the results.3
Early Pharmacotherapy for STE MIs
Pharmacotherapy for early treatment of ACS is outlined in Figure 7-2 and Table 7-2.2–5,8 According to the ACCF/AHA STE MI practice guidelines, in addition to reperfusion therapy, other early pharmacotherapy that all patients with STE MI and without contraindications should receive within the first day of hospitalization, and preferably in the emergency department, are intranasal oxygen (if oxygen saturation is low), sublingual (SL) nitroglycerin (NTG), ASA, a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor depending on reperfusion strategy), and anticoagulation with bivalirudin, unfractionated heparin (UFH), enoxaparin, or fondaparinux (agent dependent on reperfusion strategy; see Table 7-2). A GP IIb/IIIa inhibitor should be administered with UFH for patients undergoing primary PCI. IV β-blockers and IV NTG should be given in selected patients. Oral β-blockers should be initiated within the first day in patients without cardiogenic shock.2–4,8 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. An ACE inhibitor is recommended to be administered within the first 24 hours in patients with STE MI who have either an anterior wall MI or an LVEF less than or equal to 40% (0.40) and no contraindications. Dosing and contraindications for SL and IV NTG, ASA, clopidogrel, β-blockers, ACE inhibitors, anticoagulants, and fibrinolytics are listed in Table 7-2.2–5,8
Administration of a fibrinolytic agent is indicated in patients with STE MI who present to the hospital within 12 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 120 minutes of medical contact.2 The mortality benefit of fibrinolysis is highest with early administration and diminishes after 12 hours.30 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 (of first medical contact) within the institution or 120 minutes (of first medical contact) if the patient is transferred. Indications and contraindications for fibrinolysis are listed in Table 7-3.2 It is not necessary to obtain the results of biochemical markers before initiating fibrinolytic therapy. Because administration of fibrinolytics results in clot lysis, patients who are at high risk of major bleeding (including ICH) presenting with an absolute contraindication should not receive fibrinolytic therapy, as primary PCI is preferred. In patients who have a contraindication to fibrinolytics and PCI, or who do not have access to a facility that can perform PCIs, treatment with an anticoagulant (other than UFH) for up to 8 days can be administered.
TABLE 7-3 Indications and Contraindications to Fibrinolytic Therapy Per ACC/AHA Guidelines for Management of Patients with ST-Segment Elevation Myocardial Infarction2
A fibrin-specific agent, such as alteplase, reteplase, or tenecteplase, is preferred over a non–fibrin-specific agent such as streptokinase.2 Fibrin-specific fibrinolytics open a greater percentage of infarcted arteries. Two trials compared alteplase with reteplase and alteplase with tenecteplase and found similar mortality between agents.31,32 Therefore, alteplase, reteplase, and tenecteplase are acceptable as first-line agents. ICH and major bleeding are the most serious side effects of fibrinolytic agents. The risk of ICH is higher with fibrin-specific agents than with streptokinase.17 However, the risk of systemic bleeding other than ICH is higher with streptokinase than with other more fibrin-specific agents and was higher with alteplase versus tenecteplase in one study.17,30–32
As mentioned previously, less than 20% of patients with STE MI 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.33 The “door-to-needle time,” the time from hospital presentation to start of fibrinolytic therapy, is another quality performance measure.33 The ACCF/AHA guidelines recommend a “door-to-needle time” of less than 30 minutes from the time of hospital presentation until start of fibrinolytic therapy.8 The median administration time in the United States in 2006 was 29 minutes, with only 50% of patients meeting the quality performance target of less than 30 minutes.34 All hospitals should have protocols addressing fibrinolysis eligibility, dosing, and monitoring.
ASA is the preferred antiplatelet agent in the treatment of all ACSs.2–5,8 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.33 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.2,8,35 Additionally, in patients undergoing PCI, ASA, in addition to a P2Y12 inhibitor, reduces the risk of stent thrombosis.5
In patients experiencing an ACS, an initial dose equal to or greater than 160 mg nonenteric ASA is necessary to achieve a rapid platelet inhibition.36,37 Current guidelines for STE MI recommend an initial ASA dose of 162 to 325 mg (Table 7-2).2 This first dose can be chewed in order to achieve high blood concentrations and platelet inhibition rapidly. Preferably, patients undergoing PCI not previously taking ASA should receive 325 mg nonenteric-coated ASA.5 The notion of chewing ASA came from the use of an enteric-coated formulation of ASA in the Second International Study of Infarct Survival (ISIS-2) trial in order to break the enteric coating to ensure more rapid effect.35Current data suggest that although an initial dose of 162 to 325 mg is required, long-term therapy with doses of 75 to 150 mg daily is as effective as higher doses, and therefore a daily maintenance dose of 75 to 162 mg is recommended in most patients to inhibit the 10% of the total platelet pool that is regenerated daily.37,38 In a large (n = 25,086) randomized trial, high-dose ASA, 300 to 325 mg daily, had similar frequency of CV death, MI, or stroke as well as major bleeding compared with low-dose ASA in the first 30 days following ACS presentation.39,40 Minor bleeding and GI bleeding were less frequent with low-dose ASA. In this trial, patients undergoing PCI during hospitalization had a lower frequency of death, MI, or stroke, but major bleeding was increased with high-dose ASA.43 Post hoc analysis from the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial compared outcomes in patients treated with ASA doses of less than or equal to 200 mg with doses of greater than 200 mg daily and found that higher doses were a predictor of major bleeding but demonstrated similar 3-year risk of CV events.41 In the Study of Platelet Inhibition and Patient Outcomes (PLATO), a randomized, double-blind clinical trial comparing ticagrelor with clopidogrel in patients receiving ASA, a post hoc analysis suggested that maintenance doses of ASA above 100 mg daily reduced the effectiveness of ticagrelor.42 Because of increased bleeding risk in patients receiving ASA plus a P2Y12 inhibitor compared with ASA alone, low-dose ASA (81 mg daily) is preferred following PCI.5,43 Low-dose ASA should be continued indefinitely.43
Nonsteroidal antiinflammatory agents other than ASA, as well as cyclooxygenase-2 (COX-2) selective antiinflammatory agents, should be discontinued at the time of STE MI secondary to increased risk of death, reinfarction, HF, and myocardial rupture.8
The most frequent side effects of ASA are dyspepsia and nausea. Patients should be counseled about the risk of bleeding, especially GI bleeding, with ASA.
Platelet P2Y12 Inhibitors
Clopidogrel, prasugrel, and ticagrelor block a subtype of ADP receptor, the P2Y12 receptor, on platelets, preventing the binding of ADP to the receptor and subsequent expression of platelet GP IIb/IIIa receptors, reducing platelet activation and aggregation. Both clopidogrel and prasugrel are thienopyridines and prodrugs that are converted to an active metabolite by a variety of cytochrome P450 (CYP) isoenzymes (Table 7-4).44–46
TABLE 7-4 Pharmacokinetics of Clopidogrel, Prasugrel, and Ticagrelor 44–46
Both of these agents bind irreversibly to P2Y12 receptor. Ticagrelor, which is not a thienopyridine, is a reversible, noncompetitive P2Y12 receptor inhibitor. Ticagrelor parent compound has antiplatelet effects and is also metabolized primarily by CYP3A to an active metabolite producing its antiplatelet effects.
Both prasugrel and ticagrelor are more potent ADP inhibitors than clopidogrel. Prasugrel has the fewest significant drug–drug interactions. The production of clopidogrel’s active metabolite and consequently its antiplatelet effect is reduced by moderate and strong inhibitors of CYP2C19, while ticagrelor’s concentration is reduced by strong inhibitors of CYP3A. Labeled drug interactions are described in Table 7-4. A more detailed discussion of the interaction between clopidogrel and proton pump inhibitors may be found in Chapter 6.
A considerable amount of data support that genetic variations in the gene coding for CYP2C19 significantly modulate the antiplatelet effects of clopidogrel. Specifically, carriers of reduced-function allele (i.e., *2 or *3) are not able to convert clopidogrel to its active metabolite in comparison to carriers of the wild-type allele. This results in decreased antiplatelet effects,47 as well as higher rates of CV events, especially stent thrombosis and MI around the time of PCI.48 Prasugrel is not as dependent on CYP2C19 genotype for its conversion to the active metabolite and has a lower frequency of poor antiplatelet responsiveness.49 Moreover, current data suggest that the benefit of prasugrel compared with clopidogrel may only be apparent in carriers of these reduced-function alleles,49 whereas the benefits of ticagrelor over clopidogrel may be unrelated to CYP2C19.50 Hence, ticagrelor or prasugrel may be considered preferred agents in carriers of CYP2C19 reduced-function alleles.
Although the product labeling for clopidogrel suggests that genetic testing and alternative therapy should be selected for patients who are CYP2C19 poor metabolizers,44 the most recent clinical practice guidelines of the ACCF/AHA/SCAI have not endorsed routine genotyping to guide the prescription of P2Y12 inhibitors because no prospective randomized clinical study has demonstrated the benefit of such a genotype-based prescribing approach.5
Administration of a P2Y12 receptor inhibitor, in addition to ASA, is recommended for all patients with STE MI.2,8 For STE MI undergoing primary PCI, clopidogrel, prasugrel, or ticagrelor, in addition to ASA, should be administered to prevent subacute stent thrombosis and longer-term CV events (Table 7-2).2,5 Although not FDA approved, a clopidogrel loading dose of 600 mg is recommended over administration of 300 mg for patients undergoing PCI.5 A systematic review and meta-analysis of randomized and nonrandomized trials in more than 25,000 patients demonstrated a reduction in CV ischemic events with a loading dose of 600 mg compared with 300 mg in patients undergoing PCI.51
In the most recent ACCF/AHA/SCAI PCI practice guidelines, no preference is given for one agent over the other. Nevertheless, clinical trials comparing these agents have highlighted distinct clinical differences between these antiplatelet agents.
A large randomized, double-blind study demonstrated that, compared with clopidogrel, the addition of prasugrel to ASA for patients undergoing PCI in the setting of STE MI or NSTE ACS significantly reduced risk of CV death or MI by 19% (9.9% vs. 12.1%), as well as MI and stent thrombosis, but increased the risk of major bleeding (not ICH) by 32% (2.4% vs. 1.8%).52 Patients with a history of prior stroke or transient ischemic attack (TIA) had an increased risk of ICH and no net clinical benefit from prasugrel, and the product label lists prior stroke or TIA as a contraindication to prasugrel.45,52 Patients older than 75 years and those weighing less than 60 kg (132 lb) are at increased risk of bleeding with prasugrel compared with clopidogrel.52 Two subgroups of patients do not have an increased bleeding risk with prasugrel compared with clopidogrel and have even greater benefit, namely, patients undergoing primary PCI for STE MI and patients with a history of diabetes mellitus (DM).53,54
PLATO compared ticagrelor with clopidogrel in patients receiving ASA and presenting with either STE MI or NSTE ACS and undergoing an intended interventional management strategy with PCI or conservative noninterventional management strategy with medical therapy alone. In this trial, ticagrelor significantly reduced the rate of the CV death, MI, stroke, and stent thrombosis compared with clopidogrel.55 Although no increase in study-defined major bleeding was noted with ticagrelor, the frequency of non-CABG major bleeding was increased compared with clopidogrel. As with the prasugrel trial described, several subgroups of patients enrolled in this trial had particular benefit with ticagrelor, including those with an intended invasive approach, those with an intended noninvasive approach, patients with STE MI primary PCI, and patients with DM.56–59 Therefore, both of the more potent P2Y12 inhibitors are more efficacious than clopidogrel but may also be associated with an increased risk of bleeding. No large randomized trial has directly compared ticagrelor and prasugrel. Figure 7-4 outlines the role of the newer P2Y12 inhibitors in ACS compared with clopidogrel.60
FIGURE 7-4 Proposed use of P2Y12 inhibitors. aDo not use clopidogrel in patients with active pathologic bleeding; consider alternative P2Y12 receptor inhibitor if documented clopidogrel ineffectiveness (e.g., poor metabolism, stent thrombosis during clopidogrel therapy) or drug–drug interactions (e.g., avoid moderate and strong CYP2C19 inhibitors); clopidogrel should be held for at least 5 days before CABG surgery, if the surgery can be delayed. bDo not use prasugrel in patients with active pathologic bleeding or a history of transient ischemic attack or stroke; if a patient subsequently goes on to receive CABG surgery, the drug should be held for at least 7 days if the surgery can be delayed. cDo not use ticagrelor in patients with active pathologic bleeding or a history of intracranial hemorrhage, or in patients planned to undergo urgent CABG surgery; concomitant maintenance aspirin dose above 100 mg should be avoided; dose of ticagrelor should be held for 5 days before CABG surgery, if the surgery can be delayed; when selecting this agent, consider patient compliance (dosed twice daily), unique adverse effects (e.g., dyspnea), and potential drug–drug interactions (e.g., avoid strong CYP3A inhibitors/inducers). dPrior to diagnostic angiography, it is difficult to determine the likelihood that an individual patient will receive CABG surgery; notable variables that predict this occurrence include previous CABG, male gender, previous heart failure, presence of diabetes, and previous percutaneous coronary intervention, among others. eRecommendation based on subgroup analysis. fAt this time, there are insufficient data to support ticagrelor or prasugrel in the “fibrinolytic or nonprimary PCI” patient group. (ACS, acute coronary syndrome; CABG, coronary artery bypass graft; MI, myocardial infarction; NSTE, non–ST-segment elevation; PCI, percutaneous coronary intervention; STE, ST-segment elevation; TIA, transient ischemic attack.) (Adapted from Crouch MA, Colucci VJ, Howard PA, Spinler SA. P2Y12 receptor inhibitors: Integrating ticagrelor into management of acute coronary syndrome. Ann Pharmacother 2011;45:1151–1156. Reprinted by Permission of SAGE Publications.)
The recommended duration of P2Y12 inhibitors for a patient undergoing PCI for ACS, either STE MI or NSTE ACS, is at least 12 months for patients receiving either a bare metal or a drug-eluting stent.2,5The benefit of prolonging treatment beyond 12 months is uncertain.2,5 Nonadherence to P2Y12 inhibitors is a major risk factor for stent thrombosis, and hence the likelihood of adherence to dual antiplatelet therapy (ASA and a P2Y12 inhibitor) should be assessed prior to angiography.5 The use of a bare metal stent over a drug-eluting stent should be considered in patients who are anticipated to be nonadherent to 12 months of dual antiplatelet therapy.5
To minimize the risk of CV events, elective noncardiac surgery should be delayed to more than 4 to 6 weeks after angioplasty or bare metal stent implantation, or 12 months after drug-eluting stent implantation if the discontinuation of the P2Y12 inhibitor is required.5 If CABG surgery is planned, clopidogrel and ticagrelor should be withheld preferably for 5 days, and prasugrel at least 7 days, to reduce the risk of postoperative bleeding, unless the need for revascularization outweighs the bleeding risk.2
Although a variety of blood tests can assess functional platelet aggregation inhibition to P2Y12 inhibitors, especially clopidogrel, there is no one gold standard test. Moreover, despite using a higher maintenance dose of clopidogrel (150 mg daily) in patients with a high level of on-treatment platelet aggregation (low platelet aggregation inhibition) that resulted in improved platelet aggregation inhibition, dosing of clopidogrel via platelet aggregation testing does not result in improved clinical outcomes.61 Therefore, the most recent PCI practice guidelines (2011) do not recommend routine platelet aggregation testing to determine P2Y12 inhibitor strategy.5
The most frequent side effects of clopidogrel and prasugrel are nausea, vomiting, and diarrhea, which occur in approximately 2% to 5% of patients.44,45 Rarely, thrombotic thrombocytopenic purpura (TTP) has been reported with clopidogrel.44 In addition to nausea (4%) and diarrhea (3%), use of ticagrelor is associated with dyspnea (14%) and, rarely, ventricular pauses and bradyarrhythmias. Patients at risk of bradycardia were excluded from PLATO.46Small nonclinically significant increases in SCr and serum uric acid have also been reported with ticagrelor.46
In patients receiving fibrinolysis, early therapy with clopidogrel 75 mg once daily administered during hospitalization and up to 28 days (mean: 14 days) in patients with STE MI reduced mortality and reinfarction in patients treated with fibrinolytics without increasing the risk of major bleeding.8,62,63 In adult patients younger than 75 years of age receiving fibrinolytics, the first dose of clopidogrel can be a 300 mg loading dose.8,63 Although prasugrel and ticagrelor have been studied in the setting of PCI, no studies have evaluated their use when added to both ASA and a fibrinolytic.
Clopidogrel is currently the ACCF/AHA guideline–preferred P2Y12 inhibitor added to ASA and should be continued for at least 14 days (and up to 1 year) for patients presenting with STE MI who do not undergo reperfusion therapy with either primary PCI or fibrinolysis.2,62 However, recent subgroup analysis from PLATO suggests that ticagrelor may also be an option in medically managed patients with ACS not receiving fibrinolysis because the frequency of CV death, MI, or stroke as well as mortality was lower in ticagrelor-treated patients compared with those receiving clopidogrel (Fig. 7-4).56,60 Ticagrelor use was not associated with a higher bleeding rate compared with clopidogrel.56
PERSONALIZED MEDICINE OF P2Y12 INHIBITORS
In the last decade, a significant amount of information has been published with regard to the association of genetic factors with the antiplatelet response to clopidogrel.47,64,65 Specifically, a great amount of evidence indicates that patients carrying a reduced or loss-of-function allele of the gene coding for CYP2C19, one of the isoenzymes implicated in the conversion of clopidogrel to its active metabolite, have a higher risk of CV events following an ACS, particularly those undergoing PCI. These data do not extend to other populations of patients receiving clopidogrel. Nevertheless, despite these extensive data, the most recent AHA/ACCF guideline does not endorse routine genotyping in patients receiving an ADP P2Y12 inhibitor.7 On the other hand, guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) recommend the use of genotyping in all patients with an ACS or undergoing PCI for whom clopidogrel is being prescribed.66 The guideline specifically stressed that clopidogrel should not be given to intermediate or poor metabolizers (those carrying one or two CYP2C19*2 alleles) and should be replaced by an alternative such as prasugrel. These inconsistencies between two professional organizations reflect differences in their level of evidence to evaluate the data. The AHA/ACCF guideline is primarily based on results from large, randomized controlled trials demonstrating a superiority of an approach before it can be strongly endorsed, whereas CPIC focused more on consistent results from well-designed clinical studies to give strong recommendations.
In the past, pharmacogenetic testing often involved lengthy waits for results to become available and thus lacked utility for clinical decision making at the time a patient was experiencing an ACS event. More recently, a simple rapid point-of-care assay demonstrated 100% sensitivity and 99% specificity for identifying patients with the CYP2C19*2 allele demonstrating high on-treatment platelet reactivity.65 This test utilizes a buccal swab and takes no longer than 8 minutes for results to become available. A recent randomized controlled study using this rapid pharmacogenetic assay suggested that a genotype-guided approach may be useful to select between antiplatelet agents, but was limited by a small sample size, and the use of surrogate CV end points.65 Many have argued that the level of evidence to use these pharmacogenomic markers in clinical practice constitutes genetic exceptionalism as the level of evidence required to use these markers in clinical practice to guide therapy is considerably higher than the data used to adjust medication doses based on renal function or drug–drug interactions, for example.67,68
Glycoprotein IIb/IIIa Receptor Inhibitors
GP IIb/IIIa receptor inhibitors block the final common pathway of platelet aggregation, namely, cross-linking of platelets by fibrinogen bridges between the GP IIb and IIIa receptors on the platelet surface. In patients with STE MI undergoing primary PCI who are treated with UFH, abciximab (IV or intracoronary administration), eptifibatide, or tirofiban may be administered.5 Routine use of a GP IIb/IIIa receptor inhibitor is not recommended in patients who have received fibrinolytics or in those receiving bivalirudin secondary to increased bleeding risk. GP IIb/IIIa inhibitors should not be administered for medical management of the patient with STE MI who will not be undergoing PCI.2,8 A meta-analysis of STE MI primary PCI trials demonstrated no reduction in mortality or 30-day reinfarction but increased risk of major bleeding with GP IIb/IIIa inhibitors compared with control.69 Although there are more clinical trial data with abciximab for primary PCI compared with the small-molecule GP IIb/IIIa inhibitors eptifibatide and tirofiban, the small-molecule agents are used more commonly in clinical practice. A meta-analysis found no difference in efficacy and safety between abciximab and the small-molecule GP IIb/IIIa inhibitors.70
Dosing and contraindications for GP IIb/IIIa inhibitors are described in Table 7-2. Bleeding is the most significant adverse effect associated with administration of GP IIb/IIIa inhibitors. GP IIb/IIIa inhibitors should not be administered to patients with a prior history of hemorrhagic stroke or recent ischemic stroke. The risk of bleeding is increased in patients with chronic kidney disease. Eptifibatide is contraindicated in patients dependent on dialysis and requires a reduced infusion dose in patients with creatinine clearance (CrCl) less than 50 mL/min (0.83 mL/s).71 The STE MI PCI guideline–recommended dosing for tirofiban is not a FDA-approved regimen but one that has been studied in more contemporary clinical trials.5,72 The dose of tirofiban should be halved in patients with CrCl less than 30 mL/min (0.50 mL/s).73 No dosage adjustment for renal function is necessary for abciximab. An immune-mediated thrombocytopenia occurs in approximately 5% of patients with abciximab and less than 1% of patients receiving eptifibatide or tirofiban.74
Options for anticoagulant therapy for patients with STE MI are outlined in Figure 7-2 and Table 7-2.2,5 For patients undergoing primary PCI, either UFH or bivalirudin is preferred, whereas for fibrinolysis, UFH, enoxaparin, or fondaparinux may be administered.2 For patients undergoing PCI, anticoagulation is discontinued immediately following the PCI procedures. In patients receiving an anticoagulant plus a fibrinolytic, UFH is continued for a minimum of 48 hours and if either enoxaparin or fondaparinux is selected, those agents are continued for the duration of hospitalization, up to 8 days.8 In patients who do not undergo reperfusion therapy, it is reasonable to administer anticoagulant therapy for up to 48 hours for UFH or for the duration of hospitalization for enoxaparin or fondaparinux.2
UFH has been the traditional anticoagulant administered to patients with STE MI to prevent reocclusion of an infarct artery for more than 50 years. The results of a meta-analysis of more than 7,500 patients suggest that low-molecular-weight heparins (LMWHs) reduce both mortality and reinfarction compared with placebo in patients treated with fibrinolytics and ASA.75 In a randomized open-label clinical trial of primary PCI for STE MI, bivalirudin, a direct thrombin inhibitor, significantly reduced the frequency of CV mortality by 45% (2.9% vs. 5.1%) and all-cause mortality by 25% (5.9% vs. 7.7%) at 3 years of followup while lowering the risk of in-hospital major bleeding events by 40% (4.9% vs. 8.3%) compared with UFH plus a GP IIb/IIIa inhibitor (abciximab, eptifibatide, or tirofiban).76,77 Therefore, bivalirudin has similar or greater efficacy but better safety than UFH in the setting of primary PCI.
In patients with STE MI treated with fibrinolytics, enoxaparin, administered for a median of 7 days, has shown a reduction in the risk of death or nonfatal MI but increased bleeding risk compared with UFH administered for a median of 2 days in a large randomized clinical trial.78 Enoxaparin dosing is adjusted for body weight and renal function, and when administered in combination with fibrinolysis, it has special dosing requirements for older patients and those weighing more than 100 kg (Table 7-2).
Besides bleeding, the most serious adverse effect of UFH and enoxaparin is heparin-induced thrombocytopenia. ACS registry data indicate, however, that the frequency of heparin-induced thrombocytopenia is rare (less than 0.5%).79 Bivalirudin would be a preferred anticoagulant for patients with a history of heparin-induced thrombocytopenia undergoing PCI.2,5
A β-blocker should be administered early in the care of patients with STE MI and continued indefinitely. In ACS, the benefit of β-blockers results mainly from the competitive blockade of β1-adrenergic receptors located on the myocardium. β1-Blockade produces a reduction in heart rate (HR), myocardial contractility, and blood pressure (BP), decreasing myocardial oxygen demand. In addition, the reduction in HR increases diastolic time, thus improving ventricular filling and coronary artery perfusion. As a result of these effects, β-blockers reduce the risk for recurrent ischemia, infarct size, risk of reinfarction, and occurrence of ventricular arrhythmias in the hours and days following MI.
Landmark clinical trials have established the role of early β-blocker therapy in reducing MI mortality. Most of these trials were performed in the 1970s and 1980s before routine use of early reperfusion therapy.80,81 However, data regarding the acute benefit of β-blockers in MI in the reperfusion era are derived mainly from a single large clinical trial that suggests that although initiating IV followed by oral β-blockers early in the course of STE MI was associated with a lower risk of reinfarction or ventricular fibrillation, there may be an early risk of cardiogenic shock, especially in patients presenting with pulmonary congestion or systolic BP less than 120 mm Hg.82 Therefore, initiation of β-blockers, particularly when administered IV, should be limited to patients who present with hypertension (HTN) and/or have ongoing signs of myocardial ischemia and do not demonstrate any signs or symptoms of acute HF.2 Careful assessment for signs of hypotension and HF should be performed following β-blocker initiation and prior to any dose titration. Patients already taking β-blockers can continue taking them.8 The Joint Commission and Centers for Medicare & Medicaid Services retired the “Beta Blocker at Hospital Arrival” (acute myocardial infarction [AMI]-6 Core Measure) in 2009 and is no longer requiring hospital reporting of this measure.83
The most serious side effects of β-blocker administration early in ACSs are hypotension, acute HF, bradycardia, and heart block. Although initial acute administration of β-blockers is not appropriate for patients who present with acute HF, initiation of β-blockers may be attempted before hospital discharge in most patients following treatment of acute HF. β-Blockers should be continued for at least 3 years in patients with normal LV function and indefinitely in patients with LV systolic dysfunction and an LVEF less than or equal to 40% (0.40).43
A high-intensity statin (either atorvastatin 80 mg or rosuvastatin 40 mg) should be administered to all patients prior to PCI (regardless of prior lipid-lowering therapy) to reduce the frequency of periprocedural MI (a Type IVa MI) following PCI.5,15
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 to activate emergency care sooner. IV NTG should then be initiated in all patients with an ACS who have persistent ischemia, HF, or uncontrolled high BP in the absence of contraindications.2 IV NTG should be continued for approximately 24 hours after ischemia is relieved (Table 7-2). 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 because two large randomized clinical trials failed to show a mortality benefit for IV nitrate therapy followed by oral nitrate therapy in acute MI.84,85 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 last 24 hours, and tadalafil within the last 48 hours.2
Calcium Channel Blockers
Calcium channel blockers in the setting of STE MI 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.2 Therefore, calcium channel blockers should be avoided in the acute management of all ACSs unless there is a clear symptomatic need or a contraindication to β-blockers. Agent selection is based on presenting HR and LVF. Administration of an agent that lowers HRs, either diltiazem or verapamil, is preferred unless the patient has LV systolic dysfunction, bradycardia, or heart block, and then either amlodipine or felodipine is preferred.8 Nifedipine should be avoided because it has demonstrated reflex sympathetic activation, tachycardia, and worsened myocardial ischemia.2 Dosing and contraindications are described in Table 7-2.
Early Pharmacotherapy for NSTE ACSs
In general, early pharmacotherapy of NSTE ACS (Fig. 7-3) is similar to that of STE MI. In the absence of contraindications, all patients with NSTE ACS should be treated in the emergency department with intranasal oxygen (if oxygen saturation is low), SL NTG, ASA, and an anticoagulant: UFH, enoxaparin, fondaparinux, or bivalirudin. High-risk patients should proceed to early angiography and may receive a GP IIb/IIIa inhibitor (optional with either UFH or enoxaparin but should be avoided with bivalirudin). A P2Y12 inhibitor (selection of agent and timing of initiation dependent on selection of an interventional approach involving PCI or CABG surgery vs. a noninterventional approach with medical management alone) should be administered to all patients. IV β-blockers and IV NTG should be given in selected patients. Oral β-blockers should be initiated within the first 24 hours in patients without cardiogenic shock.2–4 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. Fibrinolytic therapy is never administered. Dosing and contraindications for SL and IV NTG (for selected patients), ASA, P2Y12 inhibitors, β-blockers, and anticoagulants are listed in Table 7-2.
Fibrinolytic therapy is not indicated in any patient with NSTE ACS because increased mortality has been reported with fibrinolytics compared with controls in clinical trials in which fibrinolytics have been administered to patients with NSTE ACS (patients with normal or ST-segment depression ECGs).4
ASA reduces the risk of death or developing MI by about 50% (compared with no antiplatelet therapy) in patients with NSTE ACS.38 Therefore, ASA remains the cornerstone of early treatment for all ACS. Dosing of ASA for NSTE ACS is the same as that for STE MI (Table 7-2). Low-dose ASA is continued indefinitely.
The choice of anticoagulant for a patient with NSTE ACS is guided by risk stratification and initial treatment strategy, either an early invasive approach with early coronary angiography and PCI or an early conservative strategy with angiography in selected patients guided by relief of symptoms and stress testing (Fig. 7-3). For patients treated by an early invasive strategy, UFH, enoxaparin, or bivalirudin should be administered.4,5 In a large open-label randomized clinical trial evaluating bivalirudin versus UFH or enoxaparin plus a GP IIb/IIIa inhibitor (abciximab, eptifibatide, or tirofiban) in moderate- and high-risk patients with NSTE ACS undergoing an early invasive strategy, bivalirudin demonstrated similar efficacy in preventing CV ischemic events but a lower bleeding rate.86 Similarly, in a smaller randomized trial specifically comparing abciximab plus UFH with bivalirudin for patients with NSTE MI undergoing PCI, bivalirudin demonstrated no differences in clinical outcomes but a lower bleeding risk.87
In patients in whom an initial conservative strategy is planned (i.e., they are not anticipated to receive coronary angiography and revascularization), enoxaparin, UFH, or low-dose fondaparinux is recommended.3,4 UFH and LMWH when added to ASA reduce the frequency of death or MI in patients presenting with NSTE ACS compared with control/placebo in patients primarily managed with a conservative strategy.88,89 Compared with enoxaparin, fondaparinux showed similar ischemic outcomes with a lower bleeding rate in a large randomized trial of patients with NSTE ACS primarily managed with a conservative strategy.90 If fondaparinux is chosen for a patient initially receiving a conservative strategy who subsequently undergoes angiography and PCI, it should be administered in combination with UFH (and not as the sole anticoagulant) because the dose of fondaparinux studied appears too low to prevent thrombotic events during PCI.5 Neither fondaparinux nor bivalirudin is FDA approved for NSTE ACS despite being recommended by the ACCF/AHA NSTE ACS guidelines. Bivalirudin has not been studied for initial therapy in patients intended to receive a conservative management strategy. Guideline-recommended dosing and contraindications are described in Table 7-2.
Therapy should be continued for up at least 48 hours for UFH, until the patient is discharged from the hospital (or 8 days, whichever is shorter) for either enoxaparin or fondaparinux, or until the end of PCI or angiography procedure (or up to 72 hours following PCI for bivalirudin).4,5 UFH is the preferred anticoagulant following angiography in patients subsequently undergoing CABG during the same hospitalization because it has a short duration of action following discontinuation when the patient is proceeding to surgery.2,4 Because enoxaparin is eliminated renally and patients with renal insufficiency generally have been excluded from clinical trials, some practice protocols recommend UFH for patients with CrCl rates of less than 30 mL/min (0.50 mL/s) based on total patient body weight using the Cockroft-Gault equation.3 Although recommendations for dosing adjustment of enoxaparin in patients with CrCl between 10 and 30 mL/min (0.27 and 0.50 mL/s) are listed in the product manufacturer’s label, the safety and efficacy of enoxaparin in this patient population remain vastly understudied. Administration of enoxaparin should be avoided in dialysis patients with ACS. It is unclear whether or not bivalirudin requires dose adjustment for patients with significant renal dysfunction. Although 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. Practice guidelines recommend manufacturer’s suggested dosing adjustment for patients with chronic kidney disease.5Patients with SCr greater than 3 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 (0.50 mL/s) and in patients weighing less than 50 kg (110 lb).
UFH is monitored and the dose adjusted to a target activated partial thromboplastin time (aPTT), whereas enoxaparin is administered by a fixed actual body weight–based dose without routine monitoring of anti–factor Xa levels. Some experts recommend anti–factor 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.
Figure 7-4 delineates the role of different P2Y12 inhibitors in ACS. For patients with NSTE ACS where an initial invasive management strategy is selected, two initial options for dual antiplatelet therapy are described by the practice guidelines depending on choice of P2Y12 inhibitor. In addition to ASA administered either prehospital or in the emergency department, either of the following is recommended:
1. Early use of clopidogrel or ticagrelor (in the emergency department)4
2. Double-bolus dose eptifibatide plus an eptifibatide infusion or high-dose tirofiban bolus plus infusion administered at the time of PCI.4 (Bivalirudin should not be administered as the anticoagulant in this option.)4
Subsequent antiplatelet therapy following PCI is selected based on the coronary anatomy at the time of angiography. For patients undergoing PCI initially treated with regimen 1 above, a GP IIb/IIIa inhibitor (abciximab, eptifibatide, or high-dose tirofiban) can be added, and then clopidogrel or ticagrelor continued with low-dose ASA. For patients undergoing PCI initially treated with option 2, clopidogrel, prasugrel, or ticagrelor can be selected following PCI (within 1 hour following PCI) and the P2Y12 inhibitor continued with low-dose ASA. In a subgroup of patients undergoing PCI enrolled in a large clinical trial evaluating clopidogrel versus placebo added to ASA in patients with NSTE ACS, clopidogrel reduced the frequency of death or MI by 30%.91 In the large pivotal trials of prasugrel versus clopidogrel and ticagrelor versus clopidogrel (PLATO), no added benefit of the newer P2Y12inhibitors was observed in the subgroup of patients with NSTE ACS undergoing PCI.52,55 Following PCI in ACS, dual oral antiplatelet therapy is continued for at least 12 months.2,5
For patients receiving an initial conservative treatment strategy, the 2012 ACCF/AHA NSTE ACS guidelines recommend early administration of either clopidogrel or ticagrelor in addition to ASA.4 The subgroup of medically managed patients in a large trial of clopidogrel in patients with NSTE ACS demonstrated a 20% reduction in the risk of CV death, MI, or stroke compared with ASA alone, a benefit similar to that seen in patients undergoing PCI.92Ticagrelor is an alternative in medically managed patients as described in the section Early Pharmacotherapy for STE MIs above.56,60 Dual antiplatelet therapy is continued for at least 12 months.5
Specific dosing and contraindications of the P2Y12 inhibitors are described in Table 7-2.
Glycoprotein IIb/IIIa Receptor Inhibitors
The role of GP IIb/IIIa inhibitors in NSTE ACS is diminishing as P2Y12 inhibitors are used earlier in therapy, and bivalirudin is selected more commonly as the anticoagulant in patients receiving an early intervention approach. See P2Y12 Inhibitors above, which includes the selection and timing of GP IIb/IIIa inhibitors in patients with NSTE ACS undergoing PCI.4,5 Routine administration of eptifibatide (added to ASA and clopidogrel) prior to angiography and PCI (i.e., “upstream” use) in NSTE ACS does not reduce ischemic events and increases bleeding risk compared to placebo.93 Therefore, the two antiplatelet initial therapy options, described in the previous section, are preferred.4,5
For low-risk patients where a conservative management strategy is selected, there is no role for routine GP IIb/IIIa inhibitors as the bleeding risk exceeds the benefit.4 For patients in whom an initial conservative strategy was selected but who experience recurrent ischemia (chest discomfort and ECG changes), HF, or arrhythmias after initial medical therapy necessitating a change in strategy to angiography and revascularization, a GP IIb/IIIa inhibitor may be added to ASA and clopidogrel prior to the angiogram.4,93
Doses and contraindications to GP IIb/IIIa receptor inhibitors are described in Table 7-2.
SL NTG followed by IV NTG should be administered to patients with NSTE ACS and ongoing ischemia, HF, or uncontrolled high BP (Table 7-2). The mechanism of action, dosing, contraindications, and adverse effects are the same as those described in Early Pharmacotherapy for STE MIs above. IV NTG is typically continued for approximately 24 hours following ischemia relief.
The use of β-blockers in NSTE ACS is similar to that in STE MI 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 MI. β-Blockers are continued indefinitely in patients with LVEF less than or equal to 40% (0.40) and for at least 3 years in patients with normal LV function.43
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. Agent selection for NSTE ACS is identical to that for STE MI with either diltiazem or verapamil preferred unless the patient has LV systolic dysfunction, bradycardia, or heart block, and then either amlodipine or felodipine is preferred. Nifedipine is contraindicated.4
Secondary Prevention Following MI
The long-term goals following MI are to (a) control modifiable CHD risk factors; (b) prevent the development of systolic HF; (c) prevent recurrent MI and stroke; (d) prevent death, including sudden cardiac death; and (e) prevent stent thrombosis following PCI. Pharmacotherapy, which has been proven to decrease mortality, HF, reinfarction or stroke, and stent thrombosis, should be initiated prior to hospital discharge for secondary prevention. Secondary prevention guidelines from the ACCF/AHA suggest that following MI, from either STE MI or NSTE ACS, all patients, in the absence of contraindications, should receive indefinite treatment with ASA, an ACE inhibitor, and a “high-intensity” statin for secondary prevention of death, stroke, or recurrent infarction.43 A β-blocker should be continued for at least 3 years in patients without HF or an ejection fraction (EF) of less than or equal to 40% (0.40) and indefinitely in patients with LV systolic dysfunction or HF symptoms.43 A P2Y12 inhibitor should be continued for at least 12 months for patients undergoing PCI and for patients with NSTE ACS receiving a medical management strategy of treatment.2,5 Clopidogrel should be continued for at least 14 days in patients with STE MI not undergoing PCI.8 An ARB and a MRA should be given to selected patients as discussed in greater detail later in the chapter.2,43 For all patients with ACS, treatment and control of modifiable risk factors such as HTN, dyslipidemia, obesity, smoking, and DM are essential.43 Dosing and contraindications are described in detail in Table 7-2. Benefits and adverse effects of long-term treatment with these medications are discussed in more detail later. Use of ICDs for the prevention of sudden cardiac death following MI in patients with diminished LVF and nonsustained ventricular arrhythmias is discussed in more detail in Chapter 8.
ASA decreases the risk of death, recurrent infarction, and stroke following MI. All patients should receive ASA indefinitely; those patients with a contraindication to ASA should receive clopidogrel.43 The risk of major bleeding from chronic ASA therapy is approximately 2% and is dose related. Higher doses of ASA, 160 to 325 mg, are not more effective than ASA doses of 75 to 81 mg but have higher rates of bleeding.94 Even in the setting of PCI, low-dose ASA (75 to 100 mg daily) was found to be equally safe and efficacious compared with higher doses of ASA (300 to 325 mg daily) in a prespecified subgroup analysis of 30-day outcomes in a large randomized, double-blind clinical trial of patients with ACS who underwent PCI.42 (All patients received an initial dose on presentation to hospital of at least 300 mg.) Therefore, chronic doses of ASA should not exceed 81 mg.2,5,43
For patients with either STE MI or NSTE ACS, clopidogrel decreases the risk of CV events and stent thrombosis compared with placebo. Compared with clopidogrel, either prasugrel or ticagrelor lowers the risk of CV death, MI, or stroke by an additional 20% to 30% depending on the patient population studied. The frequency of stent thrombosis following PCI is also lower with prasugrel or ticagrelor compared with clopidogrel. However, the rate of non-CABG surgery-associated bleeding is higher with both prasugrel and ticagrelor compared with clopidogrel. For all patients with ACS, a P2Y12 inhibitor should be continued for at least 1 year.2–5,8 The ACCF/AHA/SCAI PCI guidelines recommend that for patients with ACS, a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) should be continued for at least 1 year following PCI.5 For medically managed patients with STE MI, clopidogrel should be continued for at least 14 days and up to 1 year.8 For medically managed NSTE ACS patients, clopidogrel or ticagrelor should be continued for up to 1 year.4
The combination of clopidogrel and ASA increases the risk of major bleeding by approximately 50% and minor bleeding by approximately 40% but not fatal bleeding compared with single agent alone.95Compared with clopidogrel, ticagrelor increased the risk of major bleeding not related to CABG surgery by 18% in a large randomized comparative trial of patients presenting with ACS and undergoing either PCI or medical management while prasugrel increased major bleeding by 33% compared with clopidogrel in a pivotal trial of patients with ACS undergoing PCI.52,55 Oral antiplatelet agents are the third leading cause of adverse drug reaction–associated hospital admissions after emergency department visits among senior citizens.96 Therefore, patients should be counseled on the risks and sites of potential bleeding and should be told to seek medical care immediately if significant bleeding is noticed. Lower-weight patients (less than or equal to 60 kg) and elderly patients are at higher risk of bleeding with prasugrel or ticagrelor compared with clopidogrel.97,98 Prasugrel is contraindicated in patients with a prior history of stroke as the risk of ICH is increased with prasugrel compared with clopidogrel.52,98
TRIPLE ORAL ANTITHROMBOTIC THERAPY
Patients with ACS undergoing PCI and intracoronary stent placement with either a bare metal stent or a drug-eluting stent are managed with dual antiplatelet therapy that reduces stent thrombosis risk and reinfarction risk.5 But what antithrombotic therapy is best for patients with a chronic or new indication for longer-term anticoagulant therapy following hospital discharge such as atrial fibrillation, the presence of a mechanical heart valve, venous thromboembolism, or left ventricular thrombus? Which combination of antithrombotic agents is best to maximize efficacy while decreasing bleeding risk? A meta-analysis of nonrandomized controlled clinical trials suggests a significant reduction in all-cause mortality at a cost of increased major bleeding with triple antithrombotic therapy (ASA, clopidogrel, and an oral vitamin K antagonist) compared with dual antiplatelet therapy alone (ASA plus clopidogrel).99 Current practice guidelines, a North American consensus statement, recommend triple antithrombotic therapy (warfarin, low-dose ASA, and clopidogrel) for 1 to 6 months for patients following PCI with a bare metal stent placement and between 6 and 12 months for patients following PCI with a drug-eluting stent placement, depending on bleeding risk. Thereafter, a single antiplatelet agent, either clopidogrel or low-dose ASA, is recommended in addition to warfarin.100
Only one randomized trial, the What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting (WOEST) trial, has been published.101 In this open-label study, patients undergoing PCI who were chronically treated with an oral vitamin K antagonist were randomized to receive clopidogrel alone or clopidogrel plus low-dose ASA 80 to 100 mg/day. The target international normalized ratio (INR) of anticoagulation was that recommended based on the indication. At 1-year followup, the primary end point, any bleeding episode was increased more than twofold in patients randomized to triple therapy compared with clopidogrel plus anticoagulation (44.4% vs. 19.4%, P < 0.0001). GI bleeding was the most common type of bleeding and was increased threefold by ASA (2.9% in patients receiving anticoagulation plus clopidogrel vs. 8.8% in patients receiving triple therapy). Therefore, consideration should be given to stopping ASA in patients receiving triple therapy as is an option in the practice guidelines recommended above.
The manufacturers of prasugrel and ticagrelor recommend against combining those P2Y12 inhibitors with an oral anticoagulant due to a lack of data as well as clinical experience. Therefore, when triple therapy is needed, clopidogrel should be selected as the P2Y12 inhibitor. Also, both rivaroxaban and apixaban have increased bleeding risk, including increased ICH risk when combined with ASA plus clopidogrel in patients with ACS, and there is no information on long-term treatment with dabigatran, ASA, and clopidogrel, and therefore warfarin should be selected as the anticoagulant of choice when triple antithrombotic therapy is needed.102,103 While both the North American Consensus Document and the ACCF/AHA practice guidelines recommend a tighter warfarin INR range goal of 2 to 2.5 in patients receiving triple antithrombotic therapy, no clinical trial has prospectively tested this more stringent goal.2,100
In summary, triple antithrombotic therapy, when needed, should consist of warfarin (INR target 2 to 2.5), low-dose ASA 81 mg orally daily, and clopidogrel 75 mg orally daily. The anticoagulant should be discontinued if possible (such as in 3 to 6 months post-MI in patients at risk of left ventricular thrombus but without actual thrombi present), and then either clopidogrel or preferably ASA, discontinued after at least 1 month in a patient with a bare metal stent and after at least 6 months in a patient with a drug-eluting stent. Concomitant use of a proton pump inhibitor is recommended in patients receiving triple therapy undergoing PCI.5
β-Blockers, Nitrates, and Calcium Channel Blockers
Current treatment guidelines recommend that following an ACS, patients should receive a β-blocker for at least 3 years following MI in the absence of left ventricular dysfunction and regardless of whether they have residual symptoms of angina or not.2,43 Patients with or without HF and LVEF less than or equal to 40% should receive a β-blocker indefinitely. Overwhelming data support the use of β-blockers in patients with a previous MI.104 Currently, there are no data to support the superiority of one β-blocker over another in the absence of HF.
Although β-blockers should be avoided in patients with decompensated HF from left ventricular systolic dysfunction complicating an MI, clinical trial data suggest it is safe to initiate β-blockers prior to hospital discharge in these patients once HF symptoms have resolved.105 These patients may actually benefit more than those without left ventricular dysfunction.106 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.2,4,107
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.107 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.107
ACE Inhibitors and ARBs
ACE inhibitors should be initiated in all patients following MI to reduce mortality, decrease reinfarction, and prevent the development of HF.2–5,8,43 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 HF symptoms. Early initiation (within 24 hours) of an oral ACE inhibitor appears to be crucial during an acute MI because 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 30.108 However, current data do not support the early administration of IV ACE inhibitors in patients experiencing an MI because mortality may be increased.109 Administration of ACE inhibitors should be continued indefinitely. Hypotension should be avoided because coronary artery filling may be compromised. Additional trials suggest that most patients with CAD, not just ACS or HF 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. The ARBs, candesartan, valsartan, and losartan, have been documented in trials to improve clinical outcomes in patients with HF.110,111Therefore, either an ACE inhibitor or candesartan, valsartan, or losartan is an acceptable choice for chronic therapy for patients who have a low LVEF and HF following MI. 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 HF or LVEF less than 40% (0.40) may be prescribed an ARB.43 Other, less common but more serious adverse effects to ACE inhibitors and ARBs include acute renal failure, hyperkalemia, and angioedema.
Mineralocorticoid Receptor Antagonists
To reduce mortality, administration of a MRA, either eplerenone or spironolactone, should be considered within the first 7 days following MI in all patients who are already receiving an ACE inhibitor (or ARB) and a β-blocker and have an LVEF of equal to or less than 40% (0.40) and either HF symptoms or DM.2,43 Aldosterone plays an important role in HF and in MI because it promotes vascular and myocardial fibrosis, endothelial dysfunction, HTN, left ventricular hypertrophy, sodium retention, potassium and magnesium loss, and arrhythmias. MRAs have been shown in experimental and human studies to attenuate these adverse effects.112 Spironolactone decreases all-cause mortality in patients with stable, severe HF.113
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 gynecomastia, sexual dysfunction, and menstrual irregularities. In a large clinical trial,114 eplerenone significantly reduced mortality as well as hospitalization for HF in post-MI patients with an LVEF less than 40% (0.40) and symptoms of HF at any time during hospitalization. Eplerenone has also been demonstrated to reduce mortality in patients with mild systolic HF.115 The risk of hyperkalemia, however, was increased in both these studies. Patients with a SCr greater than 2.5 mg/dL (221 μmol/L) or CrCl less than 30 mL/min or serum potassium concentration of greater than 5 mmol/L (5 mEq/L) should not receive an MRA. 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.
Following MI, statins reduce total mortality, CV mortality, and stroke. According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel and the AHA secondary prevention of MI guidelines, all patients with CAD should receive dietary counseling and a statin in order to reach a low-density lipoprotein (LDL) cholesterol of less than 100 mg/dL (2.59 mmol/L) at a dose to reduce LDL cholesterol by 30%.43,116 Results from landmark clinical trials have unequivocally demonstrated the value of statins in secondary prevention following MI. A meta-analysis of randomized controlled clinical trials in almost 18,000 patients with recent ACS (less than 14 days) found that statin therapy reduces mortality by 19%, with benefits observed after approximately 4 months of treatment.117 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 antiinflammatory and antithrombotic properties. Additional recommendations from the NCEP and AHA give an optional LDL cholesterol goal of less than 70 mg/dL (1.81 mmol/L).118 The current evidence indicates that higher-dose statin therapy, such as atorvastatin 40 to 80 mg daily and rosuvastatin 10 to 20 mg daily, produces greater reduction in CV events such as MI, ischemic stroke, and revascularization than less intensive statin regimens (such as simvastatin 20 to 40 mg daily).119 Moreover, the administration of high-dose statins prior to PCI reduces the risk of periprocedural MI and, hence, statins should be initiated as early as possible in ACS.2,5
Whether or not additional therapies such as ezetimibe, a fibrate derivative, niacin, or fish oil should be added to a statin in patients with an elevated non–high-density lipoprotein (non-HDL) cholesterol level or LDL cholesterol level despite maximally tolerated statin therapy or maximally dosed statin remains controversial as the benefits of this management strategy remain largely unproven.43,120 In a large randomized trial of men with established CAD and low levels of HDL cholesterol, the use of gemfibrozil (600 mg twice daily, alone and not added to a statin) significantly decreased the risk of nonfatal MI or death from coronary causes.121 Studies with fenofibrate and niacin have produced less definitive results.122,123
Other Modifiable Risk Factors
Smoking cessation, managing HTN, weight loss, exercise, and tight glucose control for patients with DM, in addition to treatment of dyslipidemia, are important treatments for secondary prevention of CHD events.43 Referral to a comprehensive CV risk reduction program for cardiac rehabilitation is recommended.43 The use of nicotine patches or gum, or of bupropion alone or in combination with nicotine patches, should be considered in appropriate patients.8,43 HTN should be strictly controlled according to published guidelines.43 Patients who are overweight should be educated on the importance of regular exercise, healthy eating habits, and reaching and maintaining an ideal weight. Moderate-intensity aerobic exercise for at least 30 minutes, 7 days/wk (minimum 5 days/wk) is recommended.43 The goal body mass index is less than 25 kg/m2. Finally, because patients with DM have up to a fourfold increased mortality risk compared with patients without DM, the importance of blood glucose control, as well as other CHD risk factor modifications, cannot be overstated.43
To determine the efficacy of nonpharmacologic therapy 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 HF signs and symptoms.
Monitoring parameters for recognition and prevention of adverse effects from ACS pharmacotherapy are described in Table 7-5. 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.
TABLE 7-5 Therapeutic Drug Monitoring for Adverse Effects of Pharmacotherapy for Acute Coronary Syndromes
Because poor medication adherence of secondary prevention medications following MI leads to worsened CV outcomes, patients should receive medication counseling (including counseling prior to hospital discharge) and be monitored for medication persistence.2,5,124 Counseling should include assessment of health literacy level, assessment of barriers to adherence, assessment of access to medications, written and verbal instructions about the purpose of each medication, changes to previous medication regimen, optimal time to take each medication, new allergies or medication intolerances, need for timely prescription fill after discharge, anticipated duration of therapy, consequences of nonadherence, common and/or serious adverse reactions that may develop, drug–drug and drug–food interactions, and an assessment of instruction understanding.
Process of care quality performance measures for MI endorsed by the AHA and Centers for Medicare and Medicaid Services is described in Table 7-6.33,83
TABLE 7-6 Process of Care Quality Performance Measures for Myocardial Infarction 33,83
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