Each day, nearly 2,500 Americans die of cardiovascular disease--representing an average of one death every 35 seconds. Cardiovascular disease claims more lives per year than the next four leading causes of death combined (cancer, chronic lower respiratory diseases, accidents, and diabetes mellitus). It is estimated that in 2003, there were 879,000 patient discharges with acute coronary syndromes (ACS). When including secondary discharge diagnosis, the corresponding number of hospital discharges was 1,550,000 unique hospitalizations for ACS; 946,000 for myocardial infarction (MI); and 650,000 for unstable angina (UA).1

The term ACS is used to describe a spectrum of myocardial ischemia or injury.2 ACS results primarily from diminished myocardial blood flow secondary to an occlusive or partially occlusive coronary artery thrombus.3 Patients with ACS include those with clinical presentations that cover the following range of diagnoses: UA, non–ST-segment elevation MI (NSTEMI), and ST-segment elevation MI (STEMI). 2 Risk factors for the development of ACS include smoking, family history of premature coronary events, adverse lipid profiles, elevated blood pressure, diabetes, physical inactivity, and obesity.4  

The purpose of this article is to familiarize pharmacists with the pathophysiology, clinical presentation, and treatment of ACS. Secondary prevention of cardiovascular disease in patients post ACS will also be covered briefly. The recommendations for treatment of ACS provided in this article are based on Class I recommendations from the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for UA/NSTEMI and STEMI.2,3 The classification scheme is further defined in Table 1.

Disruption of vulnerable or high-risk plaques is a common pathophysiologic cause of ACS.2 These plaques are formed during a process termed atherothrombosis. Atherothrombosis is a systemic disease involving the large and medium-size arteries, including the aorta and the carotid, coronary, and peripheral arteries. Atherothrombotic plaques are composed mainly of connective tissue extracellular matrix, lipids, inflammatory cells, smooth muscle cells, thrombi, and calcium deposits.5-7 Plaque characteristics that are related to high likelihood of disruption and rupture include high lipid content, inflammation (including macrophage and T-lymphocyte activity at the plaque shoulder), metalloproteinase activity, and thinning of the fibrous cap. Growing plaques appear to be more vulnerable than well-established, more severely stenotic lesions.8 Following plaque disruption, substances that promote platelet activation, adhesion, and aggregation, thrombin generation, and ultimately thrombus formation are exposed. The resultant thrombus can completely oc­clude the epicardial infarct artery.2,9-11 The decrease in perfusion leads to varying degrees of myocardial injury. Angiographic evidence of coronary thrombus formation may be seen in more than 90% of patients with STEMI and in 35% to 75% of patients with unstable angina or NSTEMI.2,12-16 Although ACS is used collectively to describe unstable angina, NSTEMI, and STEMI, the pathophysiology and clinical presentations of each differ, and, therefore, so do their treatments.

Clinical Presentation
UA/NSTEMI: UA and NSTEMI are closely related conditions whose clinical presentations are similar but of differing severity; they differ primarily in whether the ischemia is severe enough to cause sufficient myocardial damage to release detectable quantities of troponin or creatine kinase–myocardial band.3 Markers of myocardial injury may be detected in the bloodstream hours after the onset of ischemic chest pain, which allows the differentiation between UA (i.e., no markers in circulation and usually transient, if any, ECG changes of ischemia) and NSTEMI (i.e., elevated biochemical markers and electrocardiogram [ECG] changes of ischemia).3 Patients with UA/NSTEMI may have discomfort that has all the qualities of typical angina except that the episodes are more severe and prolonged, may occur at rest, or may be precipitated by less exertion than previously seen. Patients may also present with jaw, neck, ear, arm, or epigastric discomfort. Nausea, vomiting, diaphoresis, dyspnea, and unexplained fatigue may also be presenting symptoms. 3

STEMI: It is estimated that 30% to 45% of patients with ACS have a diagnosis of STEMI.1,17 STEMI patients present similarly to UA/NSTEMI patients with chest pain, diaphoresis, nausea, vomiting, numbness, dyspnea, and syncope. They differ in presentation of UA/NSTEMI with persistent ST-segment elevation on ECG and positive biomarkers such as troponin and creatine kinase–myocardial band. Patients with STEMI generally have a higher in-hospital mortality rate; timely diagnosis and pharmacologic and nonpharmacologic interventions to restore perfusion are of the utmost importance.8

Management of ACS
UA/NSTEMI Management: The optimal management of UA/NSTEMI has the dual goals of immediate relief of ischemia and the prevention of serious adverse outcomes (i.e., death or MI or reinfarction). This is best accomplished with an approach that includes anti-ischemic therapy, antiplatelet and antithrombotic therapy, continuing risk stratification, and the use of catheter-based interventions. All patients presenting with UA/NSTEMI should be considered for treatment with symptomatic and supportive therapies such as oxygen, nitroglycerin, morphine, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors for persistent hypertension.3 Recommendations for standard treatment of care for continuing ischemia and other high-risk clinical features in UA/NSTEMI patients can be found in Table 2. Antiplatelet and anticoagulation strategies should include the use of aspirin and/or clopidogrel, low-molecular-weight heparins or unfractionated heparin, and a platelet glycoprotein (GP) IIb/IIIa antagonist.3 Specific treatment recommendations are located in Table 3 and are based on the certainty of the ACS diagnosis. A meta-analysis of fibrinolytics in UA and NSTEMI patients showed no benefit and an increased risk of MI in UA patients.3,18 Consequently, fibrinolytic agents are reserved for patients with STEMI or its equivalent (e.g., patients with new onset left bundle branch block).2

Coronary revascularization, percutaneous coronary intervention (PCI), or coronary artery bypass grafting is carried out to improve prognosis, relieve symptoms, prevent ischemic complications, and improve functional capacity. 

Although beyond the scope of this article, the decision to proceed to diagnostic angiography and revascularization is influenced by many factors and has been described in great detail in the ACC/AHA Guideline Update for the Management of Patients with Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction and the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention.6,19

STEMI Management: The routine management for STEMI patients should consist of symptomatic treatment with oxygen, nitroglycerin, morphine, aspirin, and a beta-blocker. All STEMI patients should undergo rapid evaluation for reperfusion therapy and have a reperfusion strategy implemented promptly after contact with the medical system. Prompt and complete restoration of perfusion in the infarct artery can be achieved by pharmacologic means (fibrinolysis), PCI (balloon angioplasty with or without deployment of an intracoronary stent under the support of pharmacologic measures to prevent thrombosis), or surgical means. 2 Evidence exists that expeditious restoration of flow in the obstructed infarct artery after the onset of symptoms in patients with STEMI is a key determinant of short- and long-term outcomes regardless of whether reperfusion is accomplished by fibrinolysis or PCI.2,16,20,21 The current recommendations are door-to-needle time of 30 minutes for fibrinolysis and door-to-balloon time of 90 minutes for PCI.2 The ACC/AHA guidelines recommend that STEMI patients presenting to a facility without the capability for expert, prompt intervention with primary PCI within 90 minutes of first medical contact should undergo fibrinolysis--unless contraindications exist--if (1) symptom onset was within the last 12 hours and ST-segment elevation is greater than 0.1 mV in at least two contiguous precordial leads or at least two adjacent limb leads, or (2) patients present within 12 hours of symptom onset with a new, or presumably new, left bundle branch block.2 Absolute contraindications are listed in Table 4.

PCI is a very effective method for reestablishing coronary perfusion and is suitable for at least 90% of patients. It is recommended that if immediately available, primary PCI should be performed in patients with STEMI or MI with new or presumably new left bundle branch block who can undergo PCI of the infarct artery within 12 hours of symptom onset, provided a door-to-balloon time of 90 minutes is attainable. 2

Antithrombin and antiplatelet therapy is indicated in STEMI patients regardless of reperfusion strategy. Unfractionated heparins are indicated in patients receiving either PCI or fibrinolytics. Low-molecular-weight heparin could be considered an alternative to unfractionated heparin in patients younger than 75 years without renal dysfunction. Aspirin should be given indefinitely after STEMI to all patients without a true aspirin allergy. Clopidogrel is indicated for patients with a planned PCI and should be continued for one month after bare-metal stent implantation, three months after drug-eluting (sirolimus) stents, six months after drug-eluting (paclitaxel) stents, and up to 12 months in patients who are not at high risk for bleeding. If coronary artery bypass grafting is planned, patients should have their clopidogrel withheld for at least five days, preferably for seven days, unless the urgency for revascularization outweighs the risk of excess bleeding.2 It is also reasonable to start treatment with a GP IIb/IIIa antagonist if PCI is planned.19

Medications for ACS Management
Nitroglycerin: Nitroglycerin's physiological effects would potentially create a more favorable subendocardial-to-epicardial flow ratio by reducing preload and afterload through peripheral arterial and venous dilation, relaxation of epicardial coronary arteries to improve coronary flow, and dilation of collateral vessels.2,22-24 Nitrates in all forms should be avoided in patients with initial systolic blood pressure of less than 90 mmHg or of 33 mmHg or more below baseline, marked bradycardia or tachycardia,2,25 or known or suspected right ventricular infarction.2,26 Nitrates should not be administered to patients who have received a phosphodiesterase inhibitor for erectile dysfunction in the previous 24 hours (48 hours for tadalafil). Sublingual nitroglycerin is usually given at a dose of 0.4 mg up to three doses. A useful intravenous (IV) nitroglycerin regimen employs an initial infusion rate of 5 to 10 mcg/min with increases of 5 to 20 mcg/min until symptoms are relieved or mean arterial blood pressure is reduced by 10% of its baseline level in normotensive patients and by up to 30% for hypertensive patients, but in no case below a systolic blood pressure of 90 mmHg or a drop greater than 30 mmHg below baseline.2

Morphine Sulfate: Morphine sulfate remains the analgesic agent of choice for the management of pain associated with ACS.2 Morphine administration for patients with pulmonary edema is clearly beneficial and may promote peripheral arterial and venous dilation, reducing the work of breathing and slowing the heart rate secondary to combined withdrawal of sympathetic tone and augmentation of vagal tone.2,27,28 Side effects of morphine administration include urticaria, hypotension, respiratory depression, and constipation. A suggested analgesic regimen in ACS is 2 to 4 mg of IV morphine sulfate with increments of 2 to 8 mg repeated at five- to 15-minute intervals until adequate symptom control is achieved.2

Beta-Blockers: During the first few hours after the onset of ACS, use of beta-blockers may diminish myocardial oxygen demand by reducing heart rate, systemic arterial pressure, and myocardial contractility. Immediate beta-blocker therapy appears to reduce the magnitude of infarction, the incidence of associated complications in individuals not receiving fibrinolytic therapy, the rate of reinfarction in patients receiving fibrinolytic therapy, and the frequency of life-threatening ventricular tachyarrhythmias.2 Beta-blockers should not be administered to patients with ACS brought on by cocaine use--because of the risk of exacerbating coronary spasm--or to patients with acute decompensated heart failure.2,29 Relative contraindications to beta-blockers include a heart rate of less than 60 beats per minute (bpm), a systolic blood pressure of less than 100 mmHg, moderate or severe left ventricular failure, signs of peripheral hypoperfusion, shock, PR interval greater than 0.24 seconds, second- or third-degree arterioventricular block, active asthma, or reactive airway disease.2 A suggested beta-blocker regimen consists of metoprolol in 5-mg increments by slow IV administration (5 mg over one to two minutes), repeated every five minutes for a total IV dose of 15 mg. Oral therapy should be initiated 15 minutes after the last IV dose at 25 to 50 mg every six hours for 48 hours. Thereafter, patients should receive a maintenance dose of 100 mg orally twice a day.3

ACE Inhibitors: These agents inhibit ACE, which is responsible for the conversion of angiotensin I to the vasoconstrictor substance angiotensin II. This conversion leads to decreased vasopressor activity and aldosterone secretion.30 ACE inhibitors have been shown to reduce mortality rates in patients with acute MI, patients with a recent MI and left ventricular systolic dysfunction, patients with diabetes and left ventricular dysfunction, and a broad spectrum of patients with high-risk chronic coronary artery disease, including patients with normal left ventricular function.3,31-35 ACE inhibitors have a black box warning against use in pregnancy. A dry, nonproductive cough is a common side effect. The potential for azotemia at the time of initiation and angioedema are serious side effects for pharmacists and patients to monitor.

Aspirin: At a dosage of 162 mg or more, aspirin produces a rapid clinical antithrombotic effect caused by immediate and near-total inhibition of thromboxane A2 production. Unlike the case with fibrinolytic agents, there is little evidence for a time-dependent effect of aspirin on early mortality. The use of aspirin is contraindicated in those with a hypersensitivity to salicylate. An initial dose of 162 to 325 mg of aspirin should be chewed by patients, and a dosage of 75 to 162 mg daily should be continued indefinitely. 2

Clopidogrel: Clopidogrel selectively inhibits the binding of adenosine diphosphate to its platelet receptor and the subsequent adenosine diphosphate–mediated activation of the GP IIb/IIIa complex, thereby inhibiting platelet aggregation. Clopidogrel is contraindicated in patients with hypersensitivity to the product or with active pathologic bleeding, as from a peptic ulcer or intracranial hemorrhage. For patients undergoing coronary artery bypass grafting, it is recommended to discontinue use of clopidogrel five to seven days prior to surgery.36 According to the ACC/AHA guidelines, a 75 mg/day regimen of clopidogrel is recommended, but a loading dose of 300 to 600 mg can be used if rapid onset of action is desired.3

Unfractionated Heparin: At low doses, unfractionated heparin combines with antithrombin III (heparin cofactor). This complex then inactivates activated factor X, thereby inhibiting the conversion of prothrombin to thrombin. With larger doses, heparin combines with antithrombin III to inactivate factors IX, X, XI, and XII as well as thrombin and to prevent the conversion of fi­ brinogen to fibrin. Heparin also inhibits the activation of factor XIII (fibrin-stabilizing factor) and prevents the formation of a stable fibrin clot. It has no fibrinolytic activity (i.e., does not increase clot dissolution), but it can prevent extension of existing clots.37 Heparin can decrease thrombin-induced platelet agglutination as well. The risk of bleeding is increased in patients with ACS who are receiving heparin. Therefore, the activated partial thromboplastin time (aPTT) should be monitored closely, along with signs of active bleeding. Due to a 3% risk of heparin-induced thrombocytopenia, platelet counts should be monitored daily. 2 There is also concern about an increased risk of recurrent ischemic events within the first few days after cessation of unfractionated heparin. No specific recommendations exist, but studies are ongoing.38  

Heparin doses for UA/NSTEMI are recommended at a bolus IV dose of 60 to 70 U/kg (maximum, 5,000 U), followed by an infusion of 12 to 15 U/kg/h titrated to an aPTT of 1.5 to 2.5 times control.3

Heparin doses for STEMI patients differ from those for UA/NSTEMI patients. If PCI is planned, then 70 to 100 U/kg is the recommended bolus dose. If GP IIb/IIIa antagonists are administered to STEMI patients, then the dose should be reduced to 50 to 70 U/kg. For fibrin-specific fibrinolytic agents used in STEMI patients, the bolus dose should be 60 U/kg followed by a maintenance infusion of 12 U/kg/h. 2

Low-Molecular-Weight Heparins: Low-molecular-weight heparins are derived from heparin by chemical or enzymatic depolymerization, yielding fragments approximately one third the size of heparin.39 Like unfractionated heparin, low-molecular-weight heparins produce their major anticoagulant effect by activating antithrombin. The interaction with antithrombin is mediated by a unique pentasaccharide sequence.38-41 All low-molecular-weight heparin chains containing high-affinity pentasaccharide catalyze the inactivation of factor Xa.38 Patients who have renal failure should receive a lower dose due to decreased renal clearance.38

A suggested dose for enoxaparin is 1 mg/kg subcutaneously every 12 hours; clinicians may choose to precede the first dose with a 30 mg IV bolus dose.3

GP IIb/IIIa Antagonists: GP IIb/IIIa antagonists prevent the binding of fibrinogen, von Willebrand's factor, and other adhesive ligands to GP IIb/IIIa receptors, resulting in inhibition of platelet aggregation. This inhibition of platelet aggregation is reversible following discontinuation of GP IIb/IIIa receptor antagonist therapy and is thought to be due to dissociation of the receptor antagonist from the platelet.42-44

Recommended doses for IV GP IIb/IIIa antagonists are as follows:
• Tirofiban: 0.4 mcg/kg/min for 30 minutes, followed by an infusion of 0.1 mcg/kg/min for up to 24 hours42
• Eptifibatide: 180 mcg/kg bolus (maximum, 22.6 mg) over one to two minutes, followed by continuous IV infusion of 2 mcg/kg/min (maximum, 15 mg/h) for up to 72 hours 43
• Abciximab: 0.25 mg/kg bolus, followed by an IV infusion of 0.125 mcg/kg/min (maximum, 10 mcg/min) for up to 24 hours44

Fibrinolytics: These agents have a high specificity for the substrate plasminogen, hydrolyzing a peptide bond to yield the active enzyme plasmin. Free plasmin is rapidly neutralized by the serine proteinase inhibitor alpha-antiplasmin, whereas fibrin-bound plasmin is protected from rapid inhibition, thereby promoting clot lysis.30 There are, however, the following limitations to fibrinolytic therapy: (1) failure to achieve patency in 15% to 20% of patients; (2) failure to achieve normal TIMI (thrombolysis in myocardial infarction) flow in 40% to 50% of patients; and (3) a 10% to 15% rate of reocclusion.45,46 There is also a 0.5% to 1% risk of intracranial hemorrhage.45,47,48 Absolute contraindications are listed in Table 4.

Recommended doses for fibrinolytic agents are as follows:
• Streptokinase: 1.5 million U over 60 minutes.49
• Alteplase: >67 kg: total dose, 100 mg over 1.5 hours; infuse 15 mg over one to two minutes; then infuse 50 mg over 30 minutes. 67 kg: total dose, 1.25mg/kg; infuse 15 mg IV bolus over one to two minutes, then infuse 0.75 mg/kg (maximum, 50 mg) over next 30 minutes, followed by 0.5 mg/kg over next 60 minutes (maximum, 35 mg). 50
• Reteplase: 10 U IV over two minutes, followed by a second dose 30 minutes later of 10 U IV over two minutes.51
• Tenecteplase: total dose should not exceed 50 mg and is based on weight. Administer as a bolus over five seconds. <60 kg = 30 mg dose; 60 to <70 kg = 35 mg dose; 70 to <80 kg = 40 mg dose; 80 to <90 kg = 45 mg dose; 90 kg = 50 mg dose. 52

The Pharmacist's Role
A recent publication addressing patterns of adherence to nine ACC/AHA guidelines for class I recommendations for ACS medications revealed that 74% of treatment decisions were consistent with guideline recommendations.53 Also, patients who are discharged after ACS will most likely be on four or more medications. Several studies have revealed that medication adherence for ACS patients is poor and is associated with increased mortality and rehospitalization.54-57 Eight percent to 20% of patients who have had ACS discontinue cardiac protective medications within six months of hospital discharge.54,56 It has also been reported that one in three patients with ACS experiences depressive symptoms during hospitalization. 54,58 Poor medication adherence has been proposed as a mechanism to explain why depressed patients, compared with nondepressed patients, are at an increased risk for mortality and other adverse outcomes after ACS.54,59,60

Considering these recent findings, pharmacists have a unique role in the management of both acutely diagnosed and ambulatory patients with ACS. In a recent study, the most influential variables for medication adherence are the beliefs and attitudes that patients hold about their illness, about taking drugs in general, and about specific agents they are prescribed.49,61 Pharmacists' are able to address many of the issues related to medication adherence because of their unique knowledge and easy access to patients. They should encourage a healthy lifestyle that focuses on proper diet and exercise, smoking cessation, and the management of hypertension, diabetes, and hypercholesterolemia. They should engage their patients in a dialogue about their medications and help them to understand the importance of each medication and how it benefits their disease state. Pharmacists should be aware of current guidelines, such as those described in this article, to ensure that patients are receiving the most current and appropriate medical therapy.

1. Thom T, Haase N, et al. Heart disease and stroke statistics--2006 update: a report from the American Heart Association Statistics Committee and stroke statistics subcommittee. Circulation. 2006;113:e85-e151.
2. Antman EM, Anbe DT, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction. Circulation. 2004;110:82-292.
3. Braunwald E, Antman EM, 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 the management of patients with unstable angina) 2002. Available at: www.acc.org/clinical/guidelines/unstable/ unstable.pdf.
4. Smith SC, Allen J, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113:2363-2372.
5. Corti R, Fuster V, Badimon JJ. Pathogenetic concepts of acute coronary syndromes. J Am Coll Cardiol. 2003;41(4 suppl S);4S:7S-14S.
6. Stary HC. Composition and classification of human atherosclerotic lesions. Virchows Arch A Pathol Anat Histopathol. 1992;421:277-290.
7. Davies MJ. Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lecture 1995. Circulation. 1996;94:2013-2020.
8. Granger CB, Weaver WD. Reducing cardiac events after acute coronary syndromes. Rev Cardiovasc Med. 2004;5 Suppl 5:S39-S46.
9. Dahlback B. Blood coagulation. Lancet. 2000;355:1627-1632.
10. Rosenberg RD, Aird WC. Vascular-bed: specific hemostasis and hypercoagulable states. N Engl J Med. 1999;340:1555-1564.
11. Reimer KA, Lowe JE, et al. The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation. 1977;56:786-794.
12. DeWood MA, Spores J, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med. 1980;303:897-902.
13. de Feyter PJ, van den Brand M, et al. Early angiography after myocardial infarction: what have we learned? Am Heart J. 1985;109:194-199.
14. DeWood MA, Stifter WF, et al. Coronary ateriographic findings soon after non-Q-wave myocardial infarction. N Engl J Med. 1986;315:417-423.
15. Early effects of tissue-type plasminogen activator added to conventional therapy on the culprit coronary lesion in patients presenting with ischemic cardiac pain at rest. Results of the Thrombolysis in Myocardial Ischemia (TIMI IIIA) trial. Circulation. 1993;87:38-52.
16. Boersma E, Mercado N, et al. Acute myocardial infarction. Lancet. 2003;361:847-858.
17. Morrow DA, et al. Performance of the thrombolysis in myocardial infarction risk index for early acute coronary syndrome in the national registry of myocardial infarction: a simple risk index predicts mortality in both ST and non-ST elevation myocardial infarction. J Am Coll Cardiol. 2003;41SA:365A-366A.
18. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Results of the TIMI IIIB trial. Thrombolysis In Myocardial Ischemia. Circulation. 1994;89:1545-1556.
19. Smith SC, Feldman TE, et al. ACC/AHA/SCAI 2005 guidelines update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (ACC/AHASCAI writing committee to update the 2001 guidelines for percutaneous coronary intervention). Available at: www.americanheart.org.
20. De Luca G, Suryapranata H, et al; ZWOLLE Myocardial Infarction Study Group. Symptom-onset-to-balloon time and mortality in patients with acute myocardial infarction treated by primary angioplasty. J Am Coll Cardiol. 2003;42:991-997.
21. De Luca G, Suryapranata H, et al. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: every minute of delay counts. Circulation. 2004;109:1223-1225.
22. Abrams J. Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J . 1985;110:216-224.
23. Winbury MM. Redistribution of left ventricular blood flow produced by nitroglycerin. An example of integration of the macro-and microcirculation. Circ Res. 1971;28(Suppl 1):140-147.
24. Gorman MW, Sparks HV Jr. Nitroglycerin causes vasodilation within ischeamic myocardium. Cardiovasc Res. 1980;14:515-521.
25. Come PC, Pitt B. Nitroglycerin-induced severe hypotension and bradycardia in patients with acute myocardial infarction. Circulation. 1976;54:624-628.
26. Kinch JW, Ryan TJ. Right ventricular infarction. N Engl J Med. 1994;330:1211-1217.
27. Antman EM, Braunwald E. Acute myocardial infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, Pa: WB Saunders Co Ltd; 2001:1114-1251.
28.Hochman JS, Califf RM. Acute myocardial infarction In: Smith TW. Cardiovascular Therapeutics: A Companion to Braunwald's Heart Disease. 2nd ed. Philadelphia, Pa: WB Saunders Co Ltd; 2001:235-291.
29. Kloner RA, Hale S. Unraveling the complex effects of cocaine on the heart. Circulation. 1993;87:1046-1047.
30. Product Information: ALTACE oral capsules, ramipril oral capsules. Monarch Pharmaceutical, Bristol, Tennessee, 2004.
31. Yusuf S, Pepine CJ, et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet. 1992;340:1173-1178.
32. Rutherford JD, Pfeffer MA, et al. Effects of captopril on ischemic events after myocardial infarction. Results from the Survival and Ventricular Enlargement trial. SAVE Investigators. Circulation. 1994;90:1731-1738.
33. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group. Circulation. 1998;97:2202-2212.
34. Gustafsson I, Torp-Pedersen C, et al. Effect of the angiotensin-converting enzyme inhibitor trandolapril on mortality and morbidity in diabetic patients with left ventricular dysfunction after acute myocardial infarction. Trace Study Group. J Am Coll Cardiol. 1999;34:83-89.
35. Yusuf S, Sleight P, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153.
36. Product Information. PLAVIX oral tablets, clopidogrel bisulfate oral tablets. Sanofi-Synthelabo, New York, NY, 2006.
37. Ellenhorn MJ, Barceloux DG. Medical Toxicology: Diagnosis and Treatment of Human Poisoning . New York, NY: Elsevier; 1988.
38. Bijsterveld NR, Peters RJ, et al. Recurrent cardiac ischemic events early after discontinuation of short-term heparin treatment in acute coronary syndromes: results from the Thrombolysis in Myocardial Infarction (TIMI) 11B and Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) studies. J Am Coll Cardiol. 2003;42:2083-2089.
39. Hirsch J, Warkentin TE, et al. Heparin and low-molecular weight heparin. Mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy and safety. Chest. 2001;119:64S-94S.
40. Casu B, Oreste P, et al. The structure of heparin oligosaccharide fragments with high anti-(factor Xa) activity containing the minimal antithrombin III-binding sequence. Chemical and 13C nuclear-magnetic-resonance studies. Biochem J. 1981;197:599-609.
41. Choay J, Petitou M, et al. Structure-activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin and eliciting high anti-factor Xa activity. Biochem Biophys Res Commun. 1983;116:492-499.
42. Product Information. Aggrastat, tirofiban hydrochloride. Merck & Co, Inc, West Point, PA, 2000.
43. Product Information. Integrilin injection, eptifibatide. COR Therapeutics, Inc, South San Francisco, CA, 2001.
44. Product Information. ReoPro vials, abciximab. Centocor B.V, Leiden, The Netherlands, 2001.
45. Sura AC, Kelemen MD. Early management of ST-segment elevation myocardial infarction. Cardiol Clin. 2006;24:37-51.
46. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N Engl J Med. 1993;329:673-682.
47. Gore JM, Granger CB, et al. Stroke after thrombolysis. Mortality and functional outcomes in the GUSTO-I trial. Global Use of Strategies to Open Occluded Coronary Arteries. Circulation. 1995;92:2811-2818.
48. Berkowitz SD, Granger CB, et al. Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. The Global Utilization of Streptokinase and Tissue Plasminogen activator for Occluded coronary arteries (GUSTO) I Investigators. Circulation. 1997;95:2508-2516.
49. Product Information. Streptase, streptokinase. Hoechst-Roussel Pharmaceuticals, Inc, Philadelphia, PA, 1998.
50. Product Information. Activase alteplase, recombinant. Genentech, Inc, San Francisco, CA, 1999.
51. Product Information. Retavase, reteplase recombinant. Centocor, Inc, Malvern, PA, 2001.
52. Product Information. TNKase, tenecteplase. Genentech, Inc, South San Francisco, CA, 2000.
53. Tricoci P, Peterson ED, et al. Patterns of guideline adherence and care delivery for patients with unstable angina and non-ST-segment elevation myocardial infarction (from the CRUSADE Quality Improvement Initiative). Am J Cardiol. 2006;98:30Q-35Q.
54. Rieckmann N, Gerin W, et al. Course of depressive symptoms and medication adherence after acute coronary syndromes: an electronic medication monitoring study. J Am Coll Cardiol. 2006;48:2218-2222.
55. DiMatteo MR, Giordani PJ, et al. Patient adherence and medical treatment outcomes: a meta-analysis. Med Care. 2002;40:794-811.
56. Eagle KA, Kline-Rogers E, et al. Adherence to evidence-based therapies after discharge for acute coronary syndromes: an ongoing prospective, observational study. Am J Med. 2004;117:73-81.
57. Sud A, Kline-Rogers EM, et al. Adherence to medications by patients after acute coronary syndromes. Ann Pharmacother. 2005;39:1792-1797.
58. Thombs BD, Bass EB, et al. Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med. 2006;21:30-38.
59. Zellweger MJ, Osterwalder RH, et al. Coronary artery disease and depression. Eur Heart J . 2004;25:3-9.
60. Ziegelstein RC, Fauerbach JA, et al. Patients with depression are less likely to follow recommendations to reduce cardiac risk during recovery from a myocardial infarction. Arch Intern Med. 2000;160:1818-1823.
61. Horne R. Representations of medication and treatment advances in theory and measurement. In: Petrie KJ, Weinman J, eds. Perceptions of Health and Illness: Current Research and Applications. London, England: Harwood Academic; 1997:155-187.

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