- CONDITION CENTERS
Ms. Dang, Mr. Chang, Ms. Mai, and Ms. Xie are PharmD candidates from Western University of Health Sciences, College of Pharmacy, in Pomona, California. Dr. Pham is assistant professor of pharmacy practice at Western University of Health Sciences, College of Pharmacy.
AMI diagnosis requires at minimum 2 of the following 3 criteria: (1) clinical history of ischemic-type chest discomfort; (2) serial electrocardiographic tracings indicative of AMI; (3) a rise and fall in serum cardiac markers. If chest pain presents together with ST segment elevation, the likelihood that the patient has an AMI is greater than 90%.2
Heaviness, pressure, squeezing, or tightness in the chest, persisting 30 minutes or longer and radiating to the arms, neck, or jaw, often describe an AMI. Many patients also present with dyspnea, diaphoresis, nausea, and emesis; however, about one fourth experience mild to no symptoms.1
The rate of morbidity and mortality is decreased when pharmacotherapy is aimed at restoring coronary blood flow in the occluded artery in a time-specific manner. The administration of oxygen via nasal prongs, intravenous (IV) analgesia with morphine sulfate, oral aspirin, and sublingual nitroglycerin should be administered early to achieve hemodynamic stability. Aspirin should be maintained indefinitely, as it is associated with a 25% reduction in death, nonfatal reinfarction, and stroke.3
Reperfusion through thrombolysis or percutaneous coronary angioplasty is a standard treatment in impending AMI. Early reperfusion can reduce myocardial damage and preserve left ventricular function, leading to decreased mortality. Thrombolytic agents available include serine proteases that convert plasminogen to plasmin, which breaks down fibrinogen and fibrin contained in a clot.
Streptokinase is the least expensive fibrinolytic agent, but it is highly antigenic with unfavorable adverse reactions resulting in limited clinical use. Urokinase-like plasminogen activators are produced in renal cells, circulate in the blood, and are excreted in the urine. Their ability to catalyze the conversion of plasminogen to plasmin is affected only slightly by the presence or absence of local fibrin clot.
Alteplase (tPA, Activase) was the first recombinant tissue-type plasminogen activator (tPA) most often used to treat coronary artery thrombosis, pulmonary embolism, and acute ischemic stroke. Reteplase (r-PA, Retavase) is a second-generation recombinant tPA with fast onset, low bleeding risk, and low antigenic property, compared with alteplase. Tenectaplase (TNKase), pharmacologically similar to alteplase, was approved by the FDA as a fibrinolytic agent and is the latest thrombolytic agent approved for managing AMI.
The major complication of fibrinolysis is intracranial hemorrhage, but serious hemorrhagic complications can occur from bleeding at any site in the body. Common hemorrhagic problems seen after thrombolytic therapy include reperfusion arrhythmia, hypertension, gastrointestinal bleeding, retroperitoneal bleeding, pericardial bleeding, genitourinary bleeding, epistaxis, ecchymosis, gingival bleeding, and bleeding from puncture sites. Large hematomas at peripheral arterial puncture sites occasionally can cause a compartment syndrome. Risk factors for hemorrhagic complications include increasing age, elevated pulse pressure, uncontrolled hypertension, recent stroke, recent injury and recent surgery, the presence of a bleeding diathesis, severe chronic heart failure, and recent vascular puncture.
The use of percutaneous coronary intervention (PCI) to abort a myocardial infarction (MI) is known as primary PCI. Primary PCI is superior to fibrinolytic therapy when performed rapidly by expert teams. The goal of primary PCI is to open the artery, preferably within 90 minutes upon the patient's arrival at the emergency department, also referred to as the "door-to-balloon" time. Primary PCI is often performed with a coronary angiogram to determine the location of the infarcted vessel, followed by balloon angioplasty at the thrombosed arterial segment. An extraction catheter may be used in an attempt to aspirate the thrombus prior to balloon angioplasty. More frequently, an intracoronary stent is deployed to decrease the rate of restenosis, although stent placement does not improve the short-term outcomes of primary PCI, compared with balloon angioplasty.
Adjuvant therapy during primary PCI includes IV heparin, oral aspirin, and oral clopidogrel. The glycoprotein IIb/IIIa inhibitors are often used in primary PCI to reduce the risk of ischemic complications. Due to the number of antiplatelet agents and anticoagulants used during primary PCI, the risk of bleeding associated with the procedure is high. Anticoagulants such as heparins, fondaparinux, or direct antithrombin inhibitors are indicated for acute coronary syndrome (ACS) patients undergoing reperfusion therapy due to reduction of mortality, reinfarction rates, and recurrent ischemic events.4
Heparin, an indirect thrombin inhibitor, interacts with antithrombin to rapidly inactivate thrombin (factor Xa) along with factors XIIa, XIa, and IXa. In patients with non?ST-segment elevation myocardial infarction (NSTEMI) who were given aspirin, unfractionated heparin (UFH), and low-molecular-weight heparin (LMWH) have been shown to decrease the risk of MI or death by 50%.5 Enoxaparin, an LMWH, has demonstrated comparable or superior benefit to UFH in reducing death and cardiac ischemic episodes in NSTEMI patients and possesses several advantages over UFH, such as a more predictable anticoagulant effect requiring less monitoring, easy administration, and lowered risk of heparin-induced thrombocytopenia (HIT).6,7 Furthermore, a meta-analysis of trials that compared UFH and enoxaparin in ST-segment elevation myocardial infarction (STEMI) patients receiving fibrinolysis suggested that enoxaparin significantly reduced death and MI, compared with UFH at 30 days, which compensated for the increased incidence of major bleed.8 Thus, enoxaparin has an indication for the management of patients with acute STEMI undergoing reperfusion therapy.
Fondaparinux, a synthetic heparin pentasaccharide, is preferred in NSTEMI patients with increased risk of bleeding and also recommended in favor of UFH in patients with NSTEMI undergoing conservative procedures unless a coronary artery bypass graft is planned within 24 hours.4 Unlike heparin-antithrombin complexes, which cannot bind or inactivate thrombin inside a clot, direct thrombin inhibitors are another class used in ACS that can inactivate thrombin in blood clots. Bivalirudin is recommended in patients with NSTEMI undergoing invasive therapy and can also be used as an alternative for STEMI patients receiving fibrinolytics who develop HIT from UFH.9 Evidence supports the use of anticoagulants in ACS, but the choice of anticoagulant depends on overall treatment regimen and should be patient-specific.
Along with reperfusion therapy, the American College of Cardiology/American Heart Association (ACC/AHA) recommends acute management of ACS patients with medications such as aspirin, nitrates, morphine sulfate, and beta-blockers. Oxygen also should be administered to all patients presenting with ischemic-type chest discomfort to limit myocardial injury and decrease the amount of ST-segment elevation. Aspirin is the initial line of drug therapy for patients with suspected ACS—the recommended dose is 162 to 325 mg chewed to allow rapid buccal absorption.9 Aspirin will have an immediate antithrombotic effect by irreversibly binding to cyclooxygenase and inhibiting thromboxane A2 production. Evidence suggests that chronic aspirin use significantly decreases mortality, nonfatal reinfarction, and stroke in ACS patients.10
Nitroglycerin produces venous and modest arterial dilation to decrease preload and some afterload, ultimately allowing increased perfusion of blood to ischemic zones, and reduces myocardial oxygen demand.11 Although no mortality benefit exists, nitroglycerin is effective in relieving chest pain.12
Morphine sulfate also alleviates chest pain through its analgesic properties, lowering circulating catecholamines, decreasing myocardial oxygen consumption, and decreasing preload through venodilation and arterial vasodilation. It also lowers the heart rate by increasing vagal tone and thus decreases the cardiac workload.9,13
A cardioselective beta-blocker is crucial for the management of ACS, because it reduces heart rate, blood pressure, and contractility, which in turn decreases oxygen demand and relieves ischemic chest pain. IV administrations of cardioselective beta-blockers such as atenolol and metoprolol have been well studied and shown to reduce morbidity and mortality.14
Chronic management is indicated for ACS patients with comorbidities such as, but not limited to, hypertension, diabetes, and hyperlipidemia. The ACC/AHA guidelines recommend starting an oral angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker within the first 24 hours in stable STEMI patients, but not IV ACE inhibitors in patients categorized as class III due to the possibility of hypotension.9 ACE inhibitors act as vasodilators to reduce preload and afterload and inhibit activation of aldosterone to reduce volume retention and to prevent cardiac remodeling. The GISSI-3 and ISIS-4 studies have shown reduction in morbidity and mortality with ACE inhibitors.15 The ACC/AHA also recommends assessing the patient's fasting lipid profile within 24 hours of an ACS event and initiating chronic statin therapy to lower the low-density lipoprotein level to <100 mg/dL in an attempt to prevent another ACS episode.9
Patients presenting with ACS should be stabilized through acute management and, to prevent another ACS event, chronic pharmacologic management. Patients with persistent ACS symptoms, despite taking the first dose of sublingual nitroglycerin, should be transported by ambulance to the emergency department. Upon confirmation of STEMI with onset of symptoms less than 12 hours, patients should receive immediate reperfusion therapy with either PCI or fibrinolytics to restore blood flow. Anticoagulation and antiplatelet therapy should be administered before reperfusion therapy. Aspirin, nitrates, morphine sulfate, cardioselective beta-blockers, and oxygen are also indicated for acute management, unless contraindicated.9 Chronic management should be initiated once the patient's condition is stable, and therapy should be based on coexisting medical conditions.
Formulary considerations must take into account all agents used in the management of AMI. Drug selection should be guided by evidence-based medicine.