Acute Coronary Syndromes: Making Best Use of Cardiac Drugs

October 1, 2002

ABSTRACT: For patients who present with ventricular fibrillation (VF) or pulseless ventricular tachycardia that is refractory to repeated countershocks, the drug of choice is amiodarone; the recommended dose for those who are receiving cardiopulmonary resuscitation is 300 mg given as an IV bolus. Vasopressin, 40 U IV, is an acceptable alternative to epinephrine in adults with VF that is resistant to electrical defibrillation. Standard heparin or low molecular weight heparin is indicated in patients who require reperfusion therapy and in those who have unstable angina or non-Q wave myocardial infarction (MI). The initial therapy for patients with acute myocardial ischemia usually includes morphine, oxygen, nitroglycerin, and aspirin, plus a ß-adrenergic blocking agent. Glycoprotein IIb/IIIa receptor inhibitors are currently recommended for patients who have non-Q wave MI or high-risk unstable angina.

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


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