This chapter describes the management of patients with acute, occlusive
coronary artery thrombosis (acute coronary syndromes, or ACS). The importance of this disorder is shown by the claim that a fatal coronary event occurs once every minute in the United States (1). The focus of this chapter is on the early management of ACS, and not the diagnostic evaluation, and the recommendations are based on clinical practice guidelines from the American Heart Association (2,3). I. PROTECTIVE MEASURES The following measures are aimed at protecting the myocardium from ischemic injury and limiting the extent of myocardial damage. A. Oxygen Therapy 1. INDICATIONS: Oxygen therapy is recommended for an arterial O2 saturation <90%, and for patients with respiratory distress (2,3). 2. COMMENT: Supplemental O2 is no longer recommended as a routine measure in ACS because O2 promotes coronary artery vasoconstriction (4), and toxic O2 metabolites have been implicated in reperfusion injury (5). The potential for harm from O2 therapy was confirmed in a randomized study of patients with acute myocardial infarction in which patients who received supplemental O2 developed larger infarctions and more frequent arrhythmias than patients allowed to breathe room air (6). B. Nitroglycerin 1. INDICATIONS: Sublingual nitroglycerin (NTG) is recommended for immediate relief of ischemic chest pain. NTG is also given by continuous IV infusion for recurrent chest pain, hypertension, or decompensated heart failure associated with ACS. 2. DOSE: The sublingual dose of NTG is 0.4 mg, which can be repeated every 5 minutes for a total of 3 doses, if needed. The IV dose is a continuous infusion, starting at a rate of 5– 10 μg/min, and titrating upward to achieve the desired effect. Dose rates above 100 μg/min are usually not necessary. 3. CONTRAINDICATIONS: NTG is not recommended for right ventricular infarction (because the venodilator effects of NTG are counterproductive), and in patients who have taken a phosphodiesterase inhibitor for erectile dysfunction within the past 24 hours (because of the risk of hypotension) (2,3). 4. NOTE: For more information on NTG, including adverse effects and NTG tolerance, see Chapter 45, Section V. C. Morphine 1. INDICATIONS: Intravenous morphine is the drug of choice for ischemic chest pain that is refractory to nitroglycerin, and is also used for hydrostatic pulmonary edema (because of its venodilating and sedating effects). 2. DOSE: The effective dose of morphine can vary widely in individual patients. The initial dose is usually 4–8 mg as an IV bolus, followed by doses of 2–8 mg IV every 5 or 10 minutes, as needed (2,3). 3. NOTE: For information on the adverse effects of opioids, see Chapter 43, Section I-C. D. Aspirin 1. INDICATIONS: Aspirin is an antiplatelet agent that is recommended for all patients with ACS who are not aspirin-sensitive or intolerant, and should be given as soon as possible (decreases mortality and re-infarction rate) (2,3). 2. DOSE: The initial dose is 162–320 mg, as a chewable tablet (enhances absorption), and the maintenance dose is 81 mg PO daily, using enteric-coated tablets (2,3). 3. NOTE: For patients who are aspirin-sensitive or intolerant, clopidogrel (Plavix) is a suitable alternative (2,3). (The dosing regimen for clopidogrel is presented later in the chapter.) E. β-Receptor Antagonists 1. INDICATIONS: β-receptor blockade is recommended for all patients with ACS who do not have a contraindication, and should be started within 24 hrs after presentation (2,3). Oral therapy is suitable for most cases; IV therapy is reserved for patients with persistent chest pain or troublesome tachycardia or hypertension. 2. CONTRAINDICATIONS: β-blockers are contraindicated in cases of high- grade AV block, decompensated systolic heart failure, hypotension, and reactive airway disease (2,3), and in cases of ACS associated with cocaine or amphetamine intoxication (risk of aggravated coronary vasospasm from unopposed β-receptor activity) (3). 3. DOSING REGIMENS: Metoprolol (a selective β1-antagonist) is a preferred β-blocker for ACS. The oral dosing regimen is 25–50 mg PO every 6 hrs for 48 hrs, then 100 mg PO BID for maintenance therapy. (Longer-acting metoprolol succinate can be used for maintenance therapy at a dose of 200 mg once daily.) The IV dosing regimen is 5 mg as a bolus dose every 5 minutes, as tolerated, to a total of 3 doses (2). F. RAA Inhibitors Drugs that inhibit the renin-angiotensin-aldosterone (RAA) system include angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs). 1. INDICATIONS: ACE inhibitors are recommended for all cases of ACS that do not have a contraindication. They are especially beneficial in patients with anterior infarction or systolic dysfunction (ejection fraction ≤40%), and are recommended in the first 24 hrs after presentation in these patients (2). ARBs are reserved for patients who do not tolerate ACE inhibitors. 2. CONTRAINDICATIONS: These agents are contraindicated in patients with hypotension, bilateral renal artery stenosis, renal failure, or hyperkalemia. 3. DOSING REGIMENS: ACE inhibitors are given orally (risk of hypotension with IV ACE inhibitors post-MI), and several drugs can be used. One of the popular ACE inhibitors is lisinopril, which is started at a dose of 2.5 to 5 mg once daily, and gradually increased to 10 mg daily, as tolerated (2). For ACE inhibitor-intolerant patients the ARB valsartan has equivalent efficacy in acute MI (7). The initial dose is 20 mg PO BID, which is gradually increased to 160 mg PO BID, as tolerated (2). G. Statins 1. INDICATIONS: High-intensity statin therapy is recommended for all cases of ACS that have been stabilized, including those with LDL cholesterol levels <70 mg/dL (2,3). Of the available statins, only high-dose atorvastatin has a proven survival benefit in ACS (8). 2. DOSE: Atorvastatin, 80 mg PO daily (2,3). 3. COMMENT: The troublesome side effects of statins, such as myopathy and hepatotoxicity, occur with chronic therapy, and are not a concern when initiating statin therapy for ACS. There are drug interactions that de-serve mention; i.e., statins are metabolized by the cytochrome P450 system (CYP3A4), and drugs that inhibit this enzyme (e.g., amiodarone, omeprazole) can increase the risk of toxic reactions. II. REPERFUSION A. The Approach 1. The fundamental goal in ACS is to relieve the obstruction and restore flow in the infarct-related coronary artery. There are three methods for achieving this goal: (a) percutaneous coronary intervention or PCI (coronary angiography, angioplasty, and stent placement), (b) thrombolytic therapy, and (c) coronary artery bypass surgery. 2. The approach to reperfusion is determined by the presence or absence of ST elevation on the ECG, as described next. B. ACS with ST Elevation ACS with ST elevation ≥0.1 mv in at least 2 contiguous leads usually indicates a transmural infarction, from complete obstruction of the infarct-related artery. This condition, ST- elevation myocardial infarction or STEMI, requires emergent intervention. FIGURE 14.1 The survival benefit of thrombolytic therapy in relation to the time elapsed from the onset of chest pain. STEMI = ST-elevation myocardial infarction, LBBB = left bundle branch block. Data from Reference 9. 1. Time-Dependence There is convincing evidence that reperfusion with either PCI or thrombolytic therapy can restore flow in occluded arteries and decrease the mortality rate (2). However, the benefit from reperfusion therapy is time-dependent, and diminishes as the time progresses from the onset of chest pain. This is demonstrated in Figure 14.1 for thrombolytic therapy (9); note that the survival benefit is negligible after 12 hours from symptom onset. 2. Indications for Reperfusion Therapy The major indications for reperfusion in patients with STEMI (or a new left bundle branch block) are as follows (2): a. Time from onset of symptoms <12 hrs. b. Evidence of ongoing ischemia 12–24 hours after symptom onset. c. Acute, severe heart failure, or cardiogenic shock, regardless of the time from symptom onset. 3. Percutaneous Coronary Intervention Percutaneous coronary intervention (PCI) is superior to thrombolytic therapy for restoring flow in occluded arteries and improving outcomes (see Figure 14.2) (10-12). Unfortunately, PCI is not available in many hospitals. The recommendations for providing PCI to eligible STEMI patients (i.e., symptom onset <12 hrs, etc.) are as follows (2): a. If the patient is at a PCI-capable hospital, the procedure should be performed within 90 minutes of the first patient contact (in the field). b. If the patient is at a hospital that is not capable of performing PCI, the recommended strategy is transfer to a PCI-capable hospital, with the goal of performing the PCI within 2 hours of the initial patient contact. FIGURE 14.2 Comparative effects of coronary angioplasty and thrombolytic therapy on vascular events (graph on the left) and clinical outcomes (graph on the right) in patients with ST-elevation myocardial infarction. Data from References 10-12. 4. Thrombolytic Therapy Thrombolytic therapy is the alternative to PCI when the latter is not available, or cannot be performed in a timely manner. For optimal results, therapy should begin no later than 30 minutes after the patient arrives at the hospital (2). The major restriction to thrombolytic therapy is a long list of contraindications, as shown in Table 14.1. a. LYTIC AGENTS: Fibrinolytic drugs act by converting plasminogen to plasmin, which then breaks fibrin strands into smaller subunits. The drugs in Table 14.2 act on plasminogen that is bound to fibrin (clot-specific fibrinolysis), which limits the extent of systemic fibrinolysis and reduces the risk of bleeding. The success rate in restoring flow is equivalent (about 85%) for all fibrinolytic drugs (2). b. BLEEDING RISK: The risk of major bleeding, such as intracerebral hemorrhage (0.5–1%), and extracranial hemorrhage that requires blood transfusions (5–15%), is equivalent for all the fibrinolytic drugs (13,14). c. Major bleeding from thrombolysis can be treated with cryoprecipitate (10 to 15 bags) followed by fresh frozen plasma (up to 6 units) if necessary, to achieve a serum fibrinogen ≥100 mg/mL. The use of antifibrinolytic agents such as epsilon-aminocaproic acid (5 grams IV over 15–30 min) is reserved for refractory cases of bleeding (because of the risk of thrombosis) (14). C. ACS without ST Elevation The absence of ST elevation on the ECG indicates less extensive myocardial injury than a transmural MI, or ischemia with threatened myocardial injury(troponin levels can help distinguish between these two). This condition, called non-ST-elevation MI, or nonSTEMI, is the result of partial coronary occlusion, or transient complete occlusion with spontaneous revascularization. As such, it may not require emergent reperfusion. The approach to reperfusion therapy in these cases is summarized below. 1. The timing of PCI in nonSTEMI is determined by the severity of the patient’s clinical condition (3); a. Indications for emergent PCI include refractory or recurrent angina, severe heart failure, hemodynamic instability, and cardiogenic shock. b. In clinically stable patients, clinical scoring systems are used to predict the likelihood of a poor outcome, and the results of these tests are used to determine the need, and timing, of PCI (3). 2. Thrombolytic therapy is not used in nonSTEMI cases. III. ADJUNCTIVE ANTITHROMBOTIC THERAPY Anticoagulation and dual antiplatelet therapy are standard practices for the early management of ACS. The following is a brief summary of the preferred agents and dosing regimens. A. Anticoagulation 1. For STEMI patients who undergo PCI, unfractionated heparin (UFH) is preferred for anticoagulation. a. The dosing regimen involves IV bolus doses of 70–100 Units/kg, or 50–70 Units/kg if a glycoprotein receptor antagonist (described later) is planned, to achieve a therapeutic activated clotting time (250–350 sec) (2). 2. Following PCI and thrombolytic therapy, UFH is recommended for short- term (48 hrs) anticoagulation, using the following regimen (2). a. 60 Units/kg IV bolus (maximum 4,000 Units) followed by an infusion at 12 Units/kg/hr (maximum 1,000 Units/hr), and adjusted to achieve an activated PTT of 1.5 to 2 times control (2). 3. Low-molecular-weight heparin (LMWH) is preferred for long-term (one week) anticoagulation after thrombolytic therapy. The recommended LMWH is enoxaparin, in the following dosing regimen (2). a. For age <75 yrs, 30 mg IV initially, followed in 15 min by 1 mg/kg subQ every 12 hrs (maximum 100 mg for first 2 doses). b. For age ≥75 yrs, the dose is 0.75 mg/kg subQ (maximum 75 mg for first 2 doses) without an IV loading dose. c. Regardless of age, if the creatinine clearance is <30 mL/min, the dose is 1 mg/kg subQ every 24 hrs. 4. For nonSTEMI, enoxaparin (LMWH) can be used for the duration of the hospitalization or until PCI is performed. a. The recommended dose in this setting is 1 mg/kg subQ every 12 hrs, or 1 mg/kg subQ every 24 hrs if the creatinine clearance is <30 mL/min (3). B. P2Y12 Inhibitors 1. The P2Y12 inhibitors are oral antiplatelet agents that block surface receptors involved in ADPinduced platelet aggregation. This mechanism of action differs from that of aspirin, so the antiplatelet effects of aspirin and P2Y12 inhibitors are additive. 2. Three P2Y12 inhibitors are approved for use in ACS: clopidogrel, prasugrel, and ticagrelor. Clopidogrel and prasugrel are prodrugs that require activation in the liver, and their effects are irreversible. Prasugrel has the most potent antiplatelet effects, and the highest risk of bleeding; as a result, prasugrel is not recommended in patients with prior stroke or TIA (2,3). 3. P2Y12 inhibitors are routinely used in combination with aspirin, and their dosing regimens are shown in Table 14.3. When PCI is anticipated, the loading dose of P2Y 12 inhibitors should be given as early as possible, or at the time of the procedure. C. Glycoprotein Receptor Antagonists When platelets are activated, glycoprotein receptors (IIb and IIIa) on the platelet surface begin to bind fibrinogen, and the fibrinogen molecules form bridges between adjacent platelets, which promotes platelet aggregation. 1. Glycoprotein receptor antagonists (also called IIb/IIIa inhibitors) block the binding of fibrinogen to activated platelets, which inhibits platelet aggregation. These drugs are the most potent antiplatelet agents available, and are known as superaspirins. 2. The available IIb/IIIa inhibitors include abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggra-stat). All three are given by IV infusion using the dosing regimens in Table 14.3. 3. These drugs are used in high-risk patients who receive emergent PCI, and are given just before or at the start of the procedure. 4. Abciximab is the most potent, most expensive, and longest-acting IIb/IIIa inhibitor. After discontinuing this drug, bleeding times can take 12 hours to normalize (15). Eptifibatide and tirofiban are short-acting agents; after discontinuing these drugs, bleeding times return to normal in 15 minutes for eptifibatide and 4 hours for tirofiban (15). IV. COMPLICATIONS The complications of ACS can be classified as electrical or mechanical. The former are presented in Chapters 13 and 15, and the latter are briefly described here. A. Structural Defects Structural defects are the result of transmural (ST-elevation) infarctions. They can appear at any time in the first week, but most occur in the first 24 hrs (2). Diagnosis is usually by transthoracic ultrasound. Temporary support with intra-aortic balloon counterpulsation is often necessary, and emergency surgical repair is required in most cases. 1. ACUTE MITRAL REGURGITATION is the result of papillary muscle rupture or postinfarction LV remodeling, and presents with the sudden onset of pulmonary edema and the characteristic holosystolic murmur. Diagnosis is by echocardiography, and should prompt emergent surgical consultation; as delays to surgery diminish the prognosis (16). Temporary support with arterial vasodilators (e.g., hydralazine) and the intra-aortic balloon pump can be used as a bridge to surgery. The mortality rate with mitral valve repair is 20% (2) vs. 70% without surgery (17). 2. RUPTURE OF THE VENTRICULAR SEPTUM often occurs in the first 24 hrs, and is more common following thrombolytic therapy (18). The presentation can mimic acute mitral regurgitation, with acute heart failure and a prominent systolic murmur. Transthoracic ultrasound will identify the problem. Some patients may be hemodynamically stable, but the condition can progress, and emergent surgical repair is required. The reported mortality rate is 20 to 80% with surgery (the higher mortality rates are in patients with shock) (2). 3. LEFT VENTRICULAR FREE-WALL RUPTURE presents with the return of chest pains and new ST-segment abnormalities on the ECG. Accumulation of blood in the pericardium often leads to rapid deterioration from pericardial tamponade. Diagnosis is by cardiac ultrasound, and pericardiocentesis can be life-saving. Immediate surgery is the only course of action, and mortality rates as low as 12% have been reported with a new “patch and glue” surgical technique (19). B. Cardiac Pump Failure 1. About 10% of cases of ST-elevation MI (STEMI) are associated with cardiac pump failure and cardiogenic shock (20). About 15% of cases occur at presentation, and the remainder develop during the hospitalization (2). 2. Management involves emergent PCI (or thrombolysis if PCI is not available) and coronary bypass surgery, if necessary. In one multicenter study, revascularization with PCI or bypass surgery within 6 hours was associated with a 13% absolute decrease in mortality when compared with medical management and delayed surgery (21). 3. The hemodynamic management of cardiogenic shock is described in Chapter 8 (see Sections III-C and IV). An important consideration in postinfarction cardiogenic shock is providing hemodynamic support without producing undesirable increases in myocardial O 2 consumption. Table 14.4 shows the superiority of the intra-aortic balloon pump over pharmacologic support in that regard. V. ACUTE AORTIC DISSECTION Aortic dissection involving the ascending aorta can be mistaken as ACS, and can also be a cause of ACS. However unlike ACS, aortic dissection is a surgical emergency that is often fatal if not managed appropriately. A. Pathophysiology Aortic dissection occurs when a tear in the aortic intima allows blood to dissect between the intimal and medial layers of the aorta, creating a false lumen. When the dissection involves the ascending aorta, retrograde propagation can result in coronary insufficiency, aortic insufficiency, and pericardial tamponade (22). B. Clinical Manifestations 1. The most common complaint is the abrupt onset of chest pain, which is often sharp, and can be substernal (ascending aortic dissection) or in the back (descending aortic dissection). Most importantly, the chest pain can subside spontaneously for hours to days (23,24), and this can be a source of missed diagnoses. About 5% of patients have no pain (22). 2. The most common clinical findings are hypertension (50% of patients) and aortic insufficiency (50% of patients) (23,24). Unequal pulses in the upper extremities (from obstruction of the left subclavian artery in the aortic arch) are found in only 15% of patients (24). 3. The chest x-ray can show mediastinal widening (60% of cases) (24), or can be normal (20% of cases) (22). The ECG can show ischemic changes (15% of cases) or evidence of MI (5% of cases), but the ECG is normal in 30% of cases (22). C. Imaging Studies 1. The diagnosis of aortic dissection requires one of four imaging modalities: magnetic resonance imaging (MRI) (sensitivity and specificity 98%), transesophageal echocardiography (sensitivity 98%, specificity 77%), contrast-enhanced computed tomography (sensitivity 94%, specificity 87%), and aortography (sensitivity 88%, specificity 94%) (25). As indicated MRI is the most sensitive and specific imaging modality for the diagnosis aortic dissection. D. Management The goals of management in aortic dissection are control of hypertension and surgical intervention. 1. Antihypertensive Therapy Antihypertensive therapy should NOT increase cardiac stroke output because increased flow in the aorta will augment the shear forces that promote further dissection. For this reason, β-receptor antagonists are preferred because they decrease the force of ventricular contraction (negative inotropic effect). The drug regimens that are used for blood pressure control in aortic dissection are presented in Table 14.5. a. The β-blocker that is most favored is esmolol (Brevibloc), which has a short duration of action (9 minutes) and can be rapidly titrated to achieve the desired end-point. b. An alternative drug is labetalol, a combined α−β− blocker that can be given in IV bolus doses or by continuous infusion. 2. Outcomes With medical management alone, the mortality in acute aortic dissection increases 1–2% per hour after the onset of symptoms (22). 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