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Acute Coronary Syndromes: Making Best Use of Cardiac Drugs

Acute Coronary Syndromes: Making Best Use of Cardiac Drugs

Acute coronary syndromes are characterized by myocardial ischemia and include unstable angina, sudden cardiac death, myocardial infarction (MI) with ST-segment elevation (Q wave MI), non-Q wave MI, and the complications associated with percutaneous coronary artery interventions. The goal of treatment is to prevent or minimize myocardial injury and necrosis. Depending on the clinical circumstances, interventions may include fibrinolytic drugs, antiplatelet drugs, standard unfractionated heparin or low molecular weight heparin (LMWH), or percutaneous transluminal coronary angioplasty (PTCA) with or without stenting.

Here, I review recent recommendations for the use of cardiac drugs in emergency settings.1-5 The specific recommendations are highlighted in red. In a coming issue, I will focus on fibrinolytic and antiplatelet drugs.

The American Heart Association guidelines for drug therapy in the resuscitation of patients with cardiac arrest have been revised.1 The evidence supporting the use of most traditional antiarrhythmic drugs is not particularly strong, primarily because of methodologic problems inherent in the design of studies of out-of-hospital cases of ventricular fibrillation (VF) or ventricular tachycardia (VT).2

Lidocaine. Although there are no placebo-controlled, randomized studies supporting the effectiveness of lidocaine for various cardiac arrhythmias, it has been a standard first-line antiarrhythmic drug since the late 1960s.3 For the treatment of VF, lidocaine has been reclassified as "class indeterminate." It is acceptable for the management of VF that is refractory to electrical defibrillation and for the management of pulseless VT. However, the evidence supporting such use is weak.2,3 Lidocaine is not recommended for prophylaxis of ventricular arrhythmias.

In a study reported more than 10 years ago, patients who had out-of-hospital cardiac arrest and VF that persisted after a first defibrillation attempt were randomized to receive either lidocaine or epinephrine before the next 2 defibrillating shocks.6 Asystole occurred after defibrillation in 25% of patients who received lidocaine, compared with 7% of those who received epinephrine. The percentages of patients who had return of spontaneous circulation and survived were similar in the 2 groups.

The outcomes in patients who received either lidocaine or epinephrine were compared with outcomes in patients who received sodium bicarbonate during cardiac resuscitation in the 2 years before the lidocaine-epinephrine study.6 The rate of successful resuscitation was higher in patients who had received a continuous infusion of sodium bicarbonate during defibrillation attempts. However, the survival rates were similar.

Bretylium. For 2 to 3 years, the supply of bretylium has been tenuous because of difficulty in obtaining the raw material needed for its manufacture. Therefore, although the use of bretylium remains acceptable, it is no longer recommended for VF or pulseless VT.2,3 Moreover, the efficacy of bretylium has been questioned.7-9

In a randomized, clinical trial, bretylium was compared with lidocaine in 146 patients who had out-of-hospital VF.9 The rate of return of spontaneous circulation was virtually identical in the 2 groups (bretylium, 58%; lidocaine, 60%). Survival to hospital discharge was also similar (bretylium, 34%; lidocaine, 26%). No differences were noted in the average number of defibrillatory shocks (bretylium, 2.8; lidocaine, 2.4) or in the average time after initiation of advanced cardiac life support required to establish an organized rhythm (bretylium, 10.4 minutes; lidocaine, 10.6 minutes). The authors concluded that neither drug provided "chemical defibrillation."9

A second randomized, prospective study failed to show an advantage of bretylium over lidocaine in out-of-hospital patients with refractory VF.10 The resuscitation rate (defined as survival with a pulse until admission to the emergency department) was 23% in each group.

Magnesium sulfate. This is effective and is still recommended for tachyarrhythmias secondary to hypomagnesemia and for torsades de pointes.2,3 However, the routine use of magnesium sulfate in cardiac arrest is not supported. One case-control study of magnesium sulfate administered after 1 dose of epinephrine to patients with VF showed no significant difference in survival.11

In a randomized in-hospital study, 158 patients who had cardiac arrest were given intravenous magnesium sulfate or placebo.12 No significant differences were noted between the 2 groups in return of spontaneous circulation, survival at 24 hours, or survival to hospital discharge.

Procainamide. Usually, procainamide should not be used during resuscitation of a patient who has VF or pulseless VT because of the time required to obtain therapeutic blood and tissue levels. Moreover, because procainamide can decrease cardiac contractility-thereby causing hypotension-it has to be administered slowly.

Amiodarone. Intravenous amiodarone is emerging as the preferred antiarrhythmic agent for shock-refractory VF or pulseless VT.2,3,13 It was originally thought that the onset of action of amiodarone was too slow for the drug to be of value in managing life-threatening arrhythmias. However, it has been shown that if the initial intravenous dose of amiodarone is large enough, the onset of action is within minutes. One study demonstrated that intravenous administration of amiodarone in a dose designed to achieve a serum concentration between 2 and 3 µg/mL reduced episodes of VT by 85% and paired premature ventricular complexes by 74%.14

The results of other studies have led to the approval of intravenous amiodarone for the treatment of refractory ventricular tachyarrhythmias.15-17 More recently, the results of the clinical study known by the acronym ARREST were reported.13 This randomized, double-blind, placebo-controlled study included 504 patients who had out-of-hospital cardiac arrest with either VF or pulseless VT. Patients were given standard advanced cardiovascular life support (ACLS) plus a placebo or standard ACLS plus a single dose of amiodarone (300 mg by rapid IV infusion) at the time of the first injection of epinephrine.

The patients who received the single dose of amiodarone were more likely to survive to be admitted to the hospital (44%) than those who received placebo (34%). Although the rate of survival to hospital discharge was not different between the 2 groups, the study did not have the statistical power to rule out a difference (which would require at least several thousand subjects).13

There appeared to be a consistent trend toward improved short-term outcome among the patients who received amiodarone, particularly among those who had a return of spontaneous circulation during the resuscitation sequence. Patients who revert to VF or VT after being resuscitated appear to be the most appropriate candidates for amiodarone, because the drug appears to stabilize cardiac rhythm best in this subgroup of patients.13

The principal adverse effects of intravenous amiodarone are hypotension and bradycardia. Hypotension usually responds to administration of intravenous fluids but may require the use of dopamine. Bradycardia usually responds to atropine, but a short period of external pacing may be needed.

The single intravenous dose of amiodarone (300 mg) that was used in the ARREST study is higher than the recommended dose for patients who are not receiving cardiopulmonary resuscitation (CPR) but who have either sustained or intermittent ventricular tachyarrhythmias. In these patients, who have retained some degree of peripheral perfusion, the initial intravenous dose of amiodarone is 150 mg given over 10 minutes. This is followed by an infusion of 360 mg administered over 6 hours, followed by 540 mg given over 18 hours.

Recurrent episodes of ventricular tachyarrhythmias usually are managed with a rapid infusion of amiodarone, 150 mg.

Epinephrine. An increased incidence of postresuscitation complications has been reported in patients who received epinephrine in high doses (0.1 mg/kg).2,3,18,19 Also, research has not shown improved survival rates following cardiac arrest in patients who were given escalating doses of epinephrine.20-22

Vasopressin. Based on data obtained in various studies in Europe, vasopressin appears to be an acceptable alternative to epinephrine as a pressor agent during CPR. The recommended dose is 40 U IV, not to be repeated.

The renewed interest in vasopressin began with a study devised by Lindner and associates.23 Blood samples were drawn from patients requiring CPR by emergency medical technicians at the time of placement of an intravenous line and before any medications were given. Additional blood samples were obtained at 5, 15, 30, and 60 minutes after the restoration of spontaneous circulation. These blood samples were assayed for various endogenous vasopressor agents, such as vasopressin, epinephrine, and norepinephrine, and so-called stress hormones, such as adrenocorticotropic hormone (ACTH) and cortisol.

Both the baseline and the resuscitation levels of epinephrine and norepinephrine were significantly higher in patients who could not be resuscitated. Despite the increased sympathetic response during CPR, the levels of both ACTH and vasopressin were lower in patients who could not be resuscitated than in those who were successfully resuscitated (Table 1). Even after epinephrine had been administered as part of the resuscitation protocol, the levels of both ACTH and vasopressin were significantly lower in the patients who could not be resuscitated.

The increased level of ACTH in the patients who were resuscitated successfully was not surprising because ACTH is a stress-related hormone. However, the significantly higher levels of vasopressin in patients who were resuscitated raised many questions.

Because vasopressin is a potent vasoconstrictor, did patients with higher levels have better coronary artery perfusion before cardiac arrest and therefore have a greater likelihood of return of spontaneous circulation? Alternatively, did the higher levels of vasopressin indicate more effective CPR?

A preliminary, randomized, clinical study compared a single dose of vasopressin (40 U IV as a bolus injection) with epinephrine (1 mg IV) in 40 patients who had VF that was resistant to electrical defibrillation.24 The results showed a trend toward improved survival with vasopressin. Specifically, 70% of patients who received vasopressin survived to hospital admission, compared with 35% of those who received epinephrine. In the vasopressin group, more patients (60%) survived for 24 hours than in the epinephrine group (20%). Also, 40% of patients who received vasopressin survived to hospital discharge, compared with 15% of those who received epinephrine.25

The unpublished results of a larger, in-hospital, clinical study involving 200 patients were reviewed at the Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Conference.4 This study showed no differences between vasopressin and epinephrine in 1-hour survival and survival to hospital discharge among patients who had cardiac arrest of short duration.

Currently, vasopressin is considered to be an effective vasopressor agent that may be used as an alternative to epinephrine in adults who have VF that is resistant to electrical defibrillation. Vasopressin may be used also for the management of hypotension in patients who have shock associated with vasodilation (septic shock).

Because vasopressin is a potent stimulator of smooth muscle, a potential adverse effect is severe vasoconstriction of visceral blood vessels, leading to mesenteric ischemia and infarction of the bowel. Theoretically, this effect is more likely with prolonged infusion of vasopressin, particularly in patients who are in shock.

No basic changes have been recommended in the immediate care of a patient who has evidence of an acute MI or unstable angina. Morphine, oxygen, nitroglycerin, and aspirin (known by the acronym MONA) along with a β-adrenergic blocking agent should be considered as basic therapy for such patients unless there are specific contraindications to any of the agents.

Aspirin is the most cost-effective medication for use in emergency cardiovascular care. Unless contraindicated, every patient who has unstable angina or evidence of an impending MI should receive 325 mg of aspirin immediately.5 Numerous clinical trials have shown that β-adrenergic blockade reduces the incidence of MI in patients who have acute myocardial ischemia; infarct size, the incidence of nonfatal MI, and mortality rates are reduced also.26-33

Unless the patient's systolic blood pressure is less than 90 mm Hg, administer nitroglycerin sublingually or by aerosol. The initial dose may be repeated twice at 5-minute intervals until pain is relieved or hypotension limits its use. Nitroglycerin should not be used in patients who have right ventricular (RV) infarction because it can lower the RV preload and cause hypotension.5

In cases of suspected acute coronary syndrome, supplemental oxygen administered by nasal cannula may limit ischemic myocardial injury in patients who do not have a normal arterial oxygen saturation at baseline. This is reflected in the fact that oxygen often decreases ST-segment elevation in such patients.5

Because of its favorable hemodynamic actions, morphine may be an effective adjunct in patients who have vascular congestion.5

According to the Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care, "The 12-lead ECG is central to triage of ACS [acute coronary syndrome] in the Emergency Department."1 An initial assessment of the 12-lead ECG permits classification of the patient into 1 of 3 categories, which are listed in Table 2.

Reperfusion therapy using medications, as opposed to PTCA, generally involves the use of tissue plasminogen activator (tPA) or one of its derivatives. These agents have varying degrees of fibrin specificity. Arranged in increasing order of specificity, the available drugs are streptokinase, reteplase, tPA, and tenecteplase. If a fibrin-specific drug is used, standard heparin or LMWH also should be administered because of its antithrombin activity.5

Standard heparin and LMWH. Heparin works as an antithrombin agent by acting in concert with antithrombin III to inhibit the formation of thrombin from prothrombin. To reduce the risk of intracranial hemorrhage, the recommended dose of heparin has been reduced as follows5:

  • Bolus dose of 60 U/kg (maximum of 4000 U).
  • Infusion rate of 12 U/kg/h (maximum of 1000 U/h).

The goal is to achieve an activated partial thromboplastin time (aPTT) of between 50 and 70 seconds. The lower dose of heparin is based on the results of the first Global Utilization of Streptokinase and TPA for Occluded Arteries (GUSTO-I) trial.34 The data from this trial showed that an aPTT of more than 70 seconds was associated with a greater likelihood of death, stroke, bleeding, and reinfarction.

In general, the LMWHs have greater bioavailability, longer plasma half-lives, and more predictable anticoagulant responses than regular heparin. The results of studies of the available agents indicate that the LMWHs reduce mortality rate, incidence of MI, and risk of recurrent angina more effectively in patients who have either unstable angina or non-Q wave MI.5

Either standard heparin or LMWH is indicated in patients with suspected MI who have ST-segment elevation of 1 mm or more or new-onset left bundle branch block if a fibrin-specific fibrinolytic agent is given or if PTCA is performed. Treatment with standard heparin or LMWH also is indicated in patients who have symptoms of myocardial ischemia and who have ST-segment depression of 1 mm or more, suggesting either an impending non-Q wave MI or unstable angina.

Glycoprotein IIb/IIIa receptor inhibitors. The glycoprotein (GP) IIb/IIIa receptor inhibitors are recommended in patients who have ST-segment depression of 1 mm or more and clinical evidence of myocardial ischemia, particularly patients in high-risk groups.5 Patients considered to be at high risk are those who have unstable angina accompanied by any of the following:

  • Persistent symptoms of recurrent ischemia.
  • Diffuse or widespread abnormalities on ECG.
  • Depressed left ventricular function.
  • Congestive heart failure.
  • Positive serum markers for myocardial injury (particularly troponin).

GP IIb/IIIa receptor inhibitors are used also in patients who have had PTCA with or without placement of a stent. Several clinical trials of these agents either are in progress or have been reported.35,36

Currently, 3 GP IIb/IIIa receptor inhibitors are available: abciximab, tirofiban, and eptifibatide. All 3 drugs are given by intravenous infusion.

In terms of reduction in either death or MI, most of the benefit from these drugs has occurred in patients who also underwent PTCA or coronary artery bypass grafting. However, it is not always possible to know which patients will need such an intervention. The current recommendation is to use a GP IIb/IIIa receptor inhibitor in patients who have non-Q wave MI or high-risk unstable angina.37

The currently available GP IIb/ IIIa receptor inhibitors provide an incremental benefit to therapy with heparin and aspirin. Although LMWHs are considered to be equivalent to heparin, until the appropriate safety and efficacy studies have been completed, GP IIb/IIIa receptor inhibitors should be used with standard heparin and not with LMWH.5


1. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 1: introduction to the International Guidelines 2000 for CPR and ECC. Circulation. 2000;102(suppl):I1-I11.
2. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Section 5: pharmacology I: agents for arrhythmias. Circulation. 2000;102(suppl):I112-I128.
3. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 6: advanced cardiovascular life support. Section 1: introduction to ACLS 2000: overview of recommended changes in ACLS from the Guidelines 2000 Conference. Circulation. 2000;102(suppl):I86-I89.
4. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 6: advanced cardiovascular life support. Section 6: pharmacology II: agents to optimize cardiac output and blood pressure. Circulation. 2000;102(suppl): I129-I135.
5. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 7: the era of reperfusion. Section 1: acute coronary syndromes (acute myocardial infarction). Circulation. 2000;102(suppl):I172-I203.
6. Weaver WD, Fahrenbruch CE, Johnson DD, et al. Effect of epinephrine and lidocaine therapy on outcome after cardiac arrest due to ventricular fibrillation. Circulation. 1990;82:2027-2034.
7. Luomanmaaki K, Heikkila J, Hartel G. Bretylium tosylate: adverse effects in acute myocardial infarction. Arch Intern Med. 1975;135:515-518.
8. Chow MS, Kluger J, Lawrence R, et al. The effect of lidocaine and bretylium on the defibrillation threshold during cardiac arrest and cardiopulmonary resuscitation. Proc Soc Exp Biol Med. 1986; 182:63-67.
9. Haynes RE, Chinn TL, Copass MK, Cobb LA. Comparison of bretylium tosylate and lidocaine in management of out of hospital ventricular fibrillation: a randomized clinical trial. Am J Cardiol. 1981; 48:353-356.
10. Olson DW, Thompson BM, Darin JC, et al. A randomized comparison study of bretylium tosylate and lidocaine in resuscitation of patients from out-of-hospital ventricular fibrillation in a paramedic system. Ann Emerg Med. 1984;13:807-810.
11. Miller B, Craddock L, Hoffenberg S, et al. Pilot study of intravenous magnesium sulfate in refractory cardiac arrest: safety data and recommendations for future studies. Resuscitation. 1995;30:3-14.
12. Thel MC, Armstrong AL, McNulty SE, et al, for the Duke Internal Medicine Housestaff. Randomized trial of magnesium in in-hospital cardiac arrest. Lancet. 1997;350:1272-1276.
13. Kudenchuk PJ, Cobb LA, Copass MK, et al. Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl J Med. 1999;341:871-878.
14. Mostow ND, Rakita L, Vrobel TR, et al. Amiodarone: intravenous loading for rapid suppression of complex ventricular arrhythmias. J Am Coll Cardiol. 1984;4:97-104.
15. Scheinman MM, Levine JH, Cannom DS, et al, for the Intravenous Amiodarone Multicenter Investigators Group. Dose-ranging study of intravenous amiodarone in patients with life-threatening ventricular tachyarrhythmias. Circulation. 1995;92:3264-3272.
16. Kowey PR, Levine JH, Herre JM, et al, for the Intravenous Amiodarone Multicenter Investigators Group. Randomized double-blind comparison of intravenous amiodarone and bretylium in the treatment of patients with recurrent, hemodynamically destabilizing ventricular tachycardia or fibrillation. Circulation. 1995;92:3255-3263.
17. Singh BN, Venkatesh N, Nademanee K, et al. The historical development, cellular electrophysiology and pharmacology of amiodarone. Prog Cardiovasc Dis. 1989;31:249-280.
18. Rivers E, Wortsman J, Rady MY, et al. The effect of total cumulative epinephrine dose administered during human CPR on hemodynamic, oxygen transport, and utilization variables in the postresuscitation period. Chest. 1994;106:1499-1507.
19. Behringer W, Kittler H, Sterz F, et al. Cumulative epinephrine dose during cardiopulmonary resuscitation and neurologic outcome. Ann Intern Med. 1998;129:452-456.
20. Stiell IG, Hebert PC, Weitzman BN, et al. Highdose epinephrine in adult cardiac arrest. N Engl J Med. 1992;327:1045-1050.
21. Brown CG, Martin DR, Pepe PE, et al, for the Multicenter High-Dose Epinephrine Study Group. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. N Engl J Med. 1992;327:1051-1055.
22. Callaham M, Madsen CD, Barton CW, et al. A randomized clinical trial of high-dose epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac arrest. JAMA. 1992;268: 2667-2672.
23. Lindner KH, Haak T, Keller A, et al. Release of endogenous vasopressors during and after cardiopulmonary resuscitation. Heart. 1996;75:145-150.
24. Wenzel V, Lindner KH, Prengel AW, et al. Endobronchial vasopressin improves survival during cardiopulmonary resuscitation in pigs. Anesthesiology. 1997;86:1375-1381.
25. Lindner KH, Dirks B, Strohmenger HU, et al. Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. Lancet. 1997;349:535-537.
26. Lund-Johansen P. The Norwegian Multicenter Study on timolol after myocardial infarction, II: effect in different risk groups, causes of death, heart arrest, reinfarctions, rehospitalizations and adverse experiences. Acta Med Scand Suppl. 1981;651: 243-252.
27. Pedersen T. The Norwegian Multicenter Study on timolol after myocardial infarction—design, management, and results on mortality. Acta Med Scand Suppl. 1981;651:235-241.
28. Beta-Blocker Heart Attack Study Group. The beta-blocker heart attack trial. JAMA. 1981;246: 2073-2074.
29. Hjalmarson A, Elmfeldt D, Herlitz J, et al. Effect on mortality of metoprolol in acute myocardial infarction. A double-blind randomised trial. Lancet. 1981;2:823-827.
30. Hjalmarson A, Herlitz J, Holmberg S, et al, for the Goteborg Metoprolol Trial. Effects on mortality and morbidity in acute myocardial infarction. Circulation. 1983;67(pt 2):I26-I32.
31. The MIAMI Trial Research Group. Metoprolol in acute myocardial infarction: development of myocardial infarction. Am J Cardiol. 1985;56:23G-26G.
32. The MIAMI Trial Research Group. Metoprolol in acute myocardial infarction (MIAMI): a randomised, placebo-controlled international trial. Eur Heart J. 1985;6:199-226.
33. First International Study of Infarct Survival Collaborative Group. Randomised trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction: ISIS-1. Lancet. 1986;2:57-66.
34. Granger CB, Hirsch J, Califf RM, et al. Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction: results from the GUSTO-I trial. Circulation. 1996;93:870-878.
35. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med. 1998;339:436-443.
36. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med. 1998;338:1488-1497.
37. Kong DF, Califf RM, Miller DP, et al. Clinical outcomes of therapeutic agents that block platelet glycoprotein IIb/IIIa integrin in ischemic heart disease. Circulation. 1998;98:2829-2835.
38. Thrombolysis in Myocardial Ischemia. 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. Circulation. 1994;89: 1545-1556.

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