Acute coronary syndrome (ACS) is an

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1 OVERVIEW OF MEDICAL MANAGEMENT OF ACUTE CORONARY SYNDROMES Robert B. Parker, PharmD * Acute coronary syndrome (ACS) is an umbrella term used to describe any group of symptoms of acute myocardial ischemia (ie, chest pain caused by insufficient blood supply to the heart muscle) that are often caused by atherosclerotic coronary artery disease. Patients experiencing ACS include those patients with disorders that are based on whether ST-segment elevation is present on the electrocardiogram (ECG); patients with ST-elevation are thought to have ST-elevation myocardial infarction (STEMI), whereas patients without ST-elevation may have non ST-segment elevation myocardial infarction (NSTEMI) or unstable angina (UA). Although these are 3 distinct disorders, they share a common pathophysiologic origin characterized by disruption or rupture of the fibrous cap of a vulnerable atherosclerotic plaque. This plaque disruption exposes substances within the plaque that promote thrombus formation. The resultant thrombus then occludes the coronary artery and decreases blood flow to the heart muscle downstream from the thrombus. Patients with STEMI typically have complete thrombotic occlusion of a coronary artery, whereas patients with NSTEMI or UA often have incomplete occlusion of the infarct-related vessel. Unstable angina/non ST-segment elevation myocardial infarction are often considered to be closely related conditions, but of differing severity. The level of severity is determined by whether ischemia is sufficient to cause myocardial damage, as determined by the presence of biomarkers of myocardial injury, such as troponin I, troponin T, or creatine phosphokinase-mb (CK-MB). Patients presenting with clinical symptoms of ACS with *Associate Professor, Department of Pharmacy, University of Tennessee College of Pharmacy, Memphis, Tennessee. Address correspondence to: Robert B. Parker, PharmD, Associate Professor, Department of Pharmacy, University of Tennessee College of Pharmacy, 26 South Dunlap Street, Memphis, TN rparker@utmem.edu. no measurable increase in these biomarkers are thought to have UA; any increase in cardiac biomarkers is NSTE- MI. These markers are detectable in the bloodstream for hours after the onset of ischemic chest pain. The presence of these biomarkers is often the only finding that enables the clinician to distinguish UA (no detectable biomarkers) from NSTEMI (increased biomarkers). Unstable angina/non ST-segment elevation myocardial infarction is associated with an increased risk of cardiac death and MI. With heart disease as the number one cause of death in the United States and UA/NSTEMI a very common manifestation of this disease, it is not surprising that UA/NSTEMI is a major cause of emergency medical care and hospitalizations. The prevalence of UA/NSTEMI is increasing; one study found that the prevalence of non Q-wave infarctions increased from 45% in 1994 to 63% in 1999 (P =.0001). 1 Therefore, UA/NSTE- MI may also be encountered in outpatient/non-emergency department settings. Of those patients who experience a fatal MI, more than 50% will die within the first hour without receiving medical attention. 2 In 2002, the American Heart Association (AHA) and the American College of Cardiology (ACC) updated their guidelines on the management of patients with UA/NSTEMI. 3 The updated guidelines recommend stratifying the patient by risk of death or nonfatal MI and the likelihood that the presenting symptoms are caused by ACS secondary to coronary artery disease. Stratification is based on the patient s history, physical examination, character of chest pain, ECG findings, and cardiac biomarkers. Once a patient is documented as being high risk, the patient should be hospitalized and standard medical therapy initiated. The recommendations on hospitalization for lowerrisk patients are outlined in detail in the guideline. 3 Patients who have acute ischemia (ie, recurrent ischemia and ST-segment shift, deep T-wave inversion, Advanced Studies in Pharmacy 7

2 or positive cardiac markers) should begin receiving the appropriate anti-ischemic therapies: aspirin, β blockers, nitrates, antithrombin regimen, and glycoprotein (GP) IIb/IIIa receptor antagonist/inhibitors, along with proper monitoring. These patients are thought to be medically managed. During this time, the clinician will determine if the patient will continue with an early conservative strategy (ie, evaluation of left ventricular function and possibly a stress test) or an early invasive strategy (the angiographic strategy) involving a percutaneous coronary intervention (PCI) possibly or coronary artery bypass surgery. PCI refers to a family of percutaneous techniques that often involves balloon angioplasty and intracoronary stenting. THE COAGULATION CASCADE In ACS, the coagulation cascade is typically activated by exposure of tissue factor after rupture of an atherosclerotic plaque. Tissue factor, in combination with factor VIIa, activates factor X to Xa, which leads to thrombin formation, fibrin deposition, platelet activation, and development of a clot in the coronary artery. This activation of the coagulation cascade serves as the basis for the use of anticoagulant drugs in the pharmacotherapy of ACS (Figure 1). 4 Unfractionated heparin consists of oligosaccharide chains of varying length; it is not a molecularly consistent product, thus dosing is in units of activity rather than in weight. UFH is delivered by continuous intravenous infusion, initiated with a bolus injection. Its activity and therapeutic levels should be monitored every 6 hours through the activated partial thromboplastin time, a measure of the time to clot formation. Unfractionated heparin has a short half-life, ranging from 1 to 5 hours, depending on the dose administered. Because of this relatively short halflife, the drug is quickly cleared from the plasma. Thus, if severe bleeding occurs, the anticoagulant effect of UFH does not persist for long periods after Figure 1. Schematic of the Coagulation Cascade and the Targets of UFH and LMWH THERAPEUTIC OPTIONS The 2 anticoagulant therapies available are unfractionated heparin (UFH) and low-molecular weight heparin (LMWH). Heparin is a glycosaminoglycan found in mast cells. It consists of a core protein attached to several long polysaccharide chains of varying length. During its synthesis in the cell, the polysaccharide units undergo a series of modifications, including N-deacetylation, N- and O-sulfation, and epimerization. There is no set pattern to these modifications, thus the oligosaccharide chains vary widely. However, there is a pentasaccharide sequence that is known to be the active site of heparin in anticoagulation (Figure 2); it occurs in approximately 30% of heparin molecules. 5 Heparin s anticoagulant activity is mediated by binding to antithrombin III, accelerating the effect of antithrombin III on thrombin by at least 1000-fold. As shown in Figure 1, antithrombin inhibits factor Xa and thrombin, thus preventing coagulation. In acute coronary syndromes, thrombosis is typically initiated through exposure of tissue factor at the site of a disrupted plaque. In the coagulation cascade, unfractionated heparin and low-molecular weight heparin act by complexing with antithrombin III. LMWH = low-molecular weight heparin; UFH = unfractionated heparin. Reproduced with permission from Wong et al. JAMA. 2003;289: November 2004

3 discontinuation of the infusion. In addition, its anticoagulant effect can be completely reversed by protamine, which is often done after cardiac surgery or other vascular procedures. Therefore, cardiologists Figure 2. Antithrombin-Binding Pentasaccharide of Heparin Reproduced with permission from Majerus et al. Anticoagulant, thrombolytic, and antiplatelet drugs. In: Hardman JG, Limbird LE, eds. Goodman & Gilman s The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996: have traditionally had a greater comfort level with UFH because its anticoagulant effect can be readily monitored and reversed. However, UFH also has several limitations that are important to consider, especially with the LMWHs that are available. Table 1 summarizes the limitations of UFH and their pharmacologic and clinical consequences, in addition to the potential pharmacologic advantages of LMWH. 4 Those limitations include a narrow therapeutic window, poorly predictable kinetics, risk of platelet activation/thrombocytopenia, and inability to inhibit clot-bound thrombin. As the name suggests, LMWHs consist of shorter heparin chains. They also inhibit clot formation by their effects on factor Xa and antithrombin III; however, the polysaccharide chains that are of Table 1. Limitations of Unfractionated Heparin Unfractionated Heparin Potential Pharmacologic Advantage Properties Pharmacologic Consequences Clinical Consequences of LMWH over UFH Thrombin-dependent properties Nonspecific protein binding Less drug binding to thrombin; Variable level of anticoagulation Less nonspecific protein binding sensitivity to inactivation by requiring monitoring of activated platelet factor 4 and histidine- PTT rich glycoprotein Short plasma half-life Poor bioavailability with a single Requires continuous IV infusion Long plasma half-life relative to UFH IV or SC dose enables intermittent IV or SC injections without concomitant infusions Relative inability to inhibit Increased thrombin generation Rebound thrombosis during and Decreased new thrombin generation clot-bound thrombin after clot lysis in presence of after UFH treatment because of superior proximal Xa therapeutic levels of UFH inhibition Depletion of TFPI Decreased attenuation of tissue Rebound hypercoagulability Relatively less TFPI depletion factor/factor VIIa complex Thrombin-independent properties Increased binding to platelets Increased immunogenicity; Increased potential for bleeding, Relatively less platelet activation and increased platelet activation HITTS, or thrombosis platelet-endothelial interactions and adhesion to endothelium Inability to blunt increase of Elevations of vwf in ACS Increased potential for thrombosis Superior attenuation of the increase vwf in ACS in vwf in ACS ACS = acute coronary syndrome; HITTS = heparin-induced thrombocytopenia and thrombosis syndrome; IV = intravenous; LMWH = low-molecular weight heparin; PTT = partial thromboplastin time; SC = subcutaneous; TFPI = tissue factor pathway inhibitor; UFH = unfractionated heparin; vwf = von Willebrand factor. Adapted with permission from Wong et al. JAMA. 2003;289: Advanced Studies in Pharmacy 9

4 insufficient length to activate antithrombin III exert most of their effect through factor Xa. 5 There are 2 LMWH preparations available in the United States: enoxaparin and dalteparin. However, enoxaparin has a larger amount of data to support its use and appears to be more effective compared to dalteparin in UA, although direct head-to-head studies have not yet been performed (Figure 3). 3,6-9 Enoxaparin is named in the ACC/AHA guidelines as an equivalent option to UFH. It is also considered to be possibly preferable to UFH based on class IIa evidence (Table 2). 3 Enoxaparin is administered in a fixed or weightadjusted dosage once or twice daily through subcutaneous injection. The limitations associated with enoxaparin revolve primarily around dosing. In those patients with renal insufficiency, dosing adjustments are required, and optimal dosing during invasive cardiac procedures has not been prospectively defined. However, these limitations can be solved with experience. It has a longer halflife ( hours, depending on dosing and renal function) than UFH, thus its antithrombotic effect may persist much longer than UFH. Also, enoxaparin's anticoagulant effect can only be partially reversed with protamine. Antiplatelet therapy (aspirin, ticlopidine, or clopidogrel) and GP IIb/IIIa inhibitors are also recommended in the guideline for immediate administration (Table 3). 3 The GP IIb/IIIa receptor is found on platelets and is involved in binding to fibrinogen and other ligands upon activation. GP IIb/IIIa antagonists bind to the receptor and prevent fibrinogen binding. Their role in ACS management has been evolving since the 2002 guidelines were published, in part because enoxaparin is used more frequently in these patients. The current guideline recommends an early invasive strategy (ie, PCI) in patients with UA/NSTEMI without serious comorbidity and who have any of the listed high-risk indicators. 3 Since the guideline was published, management of ACS has continued to support earlier and more aggressive interventions and increased use of GP IIb/IIIa inhibitors. The benefits of enoxaparin compared to UFH are well documented in patients with UA/NSTEMI undergoing medical therapy. However, many patients with UA/NSTEMI are now managed with an early invasive strategy that often includes PCI. Compared to UFH, there is lit- Figure 3. Low-Molecular Weight Heparin in Unstable Angina: Effects on Triple Endpoints Nadroparin is currently only available in Canada. Reprinted with permission from Braunwald et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-st-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Patients with Unstable Angina). Available at: Accessed October 1, Table 2. Recommendations for Heparin Use for Unstable Angina/Non ST-Segment Elevation Myocardial Infarction Class I Anticoagulation with subcutaneous LMWH or intravenous UFH should be added to antiplatelet therapy with ASA and/or clopidogrel. Level of evidence: A Class IIa Enoxaparin is preferable to UFH as an anticoagulant in patients with UA/NSTEMI, in the absence of renal failure and unless CABG is planned within 24 hours. Level of evidence: A ASA = acetylsalicylic acid; CABG = coronary artery bypass grafting; LMWH = lowmolecular weight heparin; NSTEMI = non ST-segment elevation myocardial infarction; UA = unstable angina; UFH = unfractionated heparin. Adapted with permission from Braunwald et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Patients with Unstable Angina). Available at: Accessed October 1, Table 3. Class I Recommendations for Antithrombotic Therapy Definite ACS with Continuing Ischemia or Other High-Risk Possible ACS Likely/Definite ACS Features or Planned Intervention Aspirin Aspirin + SC LMWH Aspirin + IV heparin + IV or IV heparin platelet GP IIb/IIIa inhibitor ACS = acute coronary syndrome; GP = glycoprotein; IV = intravenous; LMWH = lowmolecular weight heparin; SC = subcutaneous. Adapted with permission from Braunwald et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Patients with Unstable Angina). Available at: Accessed October 1, November 2004

5 tle information on the safety and efficacy of enoxaparin use in patients undergoing early invasive management. Therefore, it is imperative to evaluate enoxaparin in this setting. The SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) study has recently been published. 10 It was designed to assess the safety and efficacy of enoxaparin in high-risk patients with ACS managed with an early invasive strategy. This issue of Advanced Studies in Pharmacy provides a reprint of that study and important information regarding the study rationale, design, and clinical implications by one of the study s Executive Committee members, Dr Marc Cohen. Dr Cohen has been an investigator in several clinical studies of UFH and enoxaparin; he explains some of the clinical trial history with the heparins that led to the SYNERGY study, and discusses the study s strengths and weaknesses. Dr Sarah Spinler, a clinical pharmacist with extensive experience in cardiology and the clinical trials of UFH and enoxaparin in UA/NSTEMI, offers her insights into the SYNERGY results and how they will affect clinical pharmacy practice. She provides practical commentary on the issues faced by pharmacists in managing patients with ACS. As pharmacists continue to work to optimize the pharmacotherapy of patients with ACS, it is important that we keep abreast of issues surrounding use of anticoagulant and other therapies used in the treatment of these patients. REFERENCES 1. Rogers WJ, Canto JG, Lambrew CT, et al. Temporal trends in the treatment of over 1.5 million patients with myocardial infarction in the US from 1990 through 1999: the National Registry of Myocardial Infarction 1, 2, and 3. J Am Coll Cardiol. 2000;36: Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction. J Am Coll Cardiol. 1996;28: Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Patients with Unstable Angina). Available at: unstable/unstable.pdf. Accessed October 1, Wong GC, Giugliano RP, Antman EM. Use of low-molecular-weight heparins in the management of acute coronary artery syndromes and percutaneous coronary intervention. JAMA. 2003;289: Majerus PW, Broze GJ Jr, Miletich JP, Tollefsen DM. Anticoagulant, thrombolytic, and antiplatelet drugs. In: Hardman JG, Limbird LE, eds. Goodman & Gilman s The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996: Klein W, Buchwald A, Hillis SE, et al. Comparison of lowmolecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in unstable coronary artery disease study (FRIC) [published correction appears in Circulation. 1998;97:413]. Circulation. 1997;96: Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-q-wave myocardial infarction: FRAX.I.S. (FRAxiparine in Ischaemic Syndrome). Eur Heart J. 1999;20: Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med. 1997;337: Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation. 1999;100: Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-st-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYN- ERGY randomized trial. JAMA. 2004;292: Advanced Studies in Pharmacy 11