The golden hours of the myocardial infarction: Nonthrombolytic interventions

SPECIAL CONTRIBUTION aspirin, myocardial infarction; beta-blockers, myocardial infarction; calcium channel blockers; lidocaine, myocardial infarction; myocardial infarction; nitrates, myocardial infarction

The Golden Hours of the Myocardial Infarction: Nonthrombolytic Interventions Emergency care of patients with acute myocardial infarction requires active decision making to use agents that may improve morbidity and mortality. Thrombolysis remains the primary tool to accomplish this goal. Other pharmacologic agents, including lidocaine, nitrates, calcium channel blockers, f~-blockers, and aspirin, have been used acutely in myocardial infarction in the hopes of preventing death and salvaging myocardium. The decision to select one or all of these agents requires a knowledge of the clinical evidence of their efficacy and risk-to-benefit ratios. The clinical studies of the use of these agents acutely in the management of myocardial infarction are reviewed. [Mitchell JM, Wheeler WS: The golden hours of the myocardial infarction: Nonthrombolytic interventions. Ann Emerg Med May 1991;20:540-548.] INTRODUCTION Because of the reassessment of lidocaine, the advent of thrombolytic and aggressive reperfusion therapy, and newer data on the usefulness of other agents, especially aspirin and p-blockers, the management of acute myocardial infarction has changed significantly in the past decade. Previous management was directed at reduction of infarct extension and the prevention and treatment of arrhythmic deaths. This consisted mainly of bedrest, oxygen, pain relief, prophylactic antiarrhythmics, and treatment of complications. Now, in addition to previous directives, the goal in myocardial infarction therapy is preservation of myocardium in an attempt to improve mortality as well as postinfarction lifestyle and morbidity. Although reperfusion holds the most promise in myocardial salvage, studies continue to search for adjunct agents that may decrease myocardial oxygen demand as well as infarct size. Other agents studied in myocardial infarction management include prophylactic lidocaine, nitrates, calcium channel blockers, f~-blocking agents, and aspirin. This article presents an overview of the clinical studies of the use of these agents acutely in myocardial infarction and determines guidelines for their use. Trials from a literature search of the past seven years as well as older landmark studies are included.

Joyce M Mitchell, MD, FACEP* William S Wheeler, MD, FACCt Greenville, North Carolina From the Departments of Emergency Medicine* and Medicine,t East Carolina University School of Medicine/Pitt County Memorial Hospital, Greenville, North Carolina.

Received for publication March 12, 1990. Revision received October 12, 1990. Accepted for publication December 18, 1990. Presented at the Winter Symposium of the American College of Emergency Physicians in Tucson, Arizona, March 1990. Address for reprints: Joyce M Mitchell, MD, FACER Department of Emergency Medicine, East Carolina University School of Medicine/Pitt County Memorial Hospital, Greenville, North Carolina 27858-4354.

LIDOCAINE Initially synthesized and used as a local anesthetic in 1943, lidocaine demonstrated suppressive effects on ventricular premature beats (VPBs) during studies of the hemodynamic effects of its IV administration in the 1950s. 1 With the development of coronary care units in the 1960s, the prevention of ventricular fibrillation was advocated by Lown et al, 2 who also promoted the concept of warning arrhythmias that heralded the onset of ventricular fibrillation. Lidocaine was therefore administered when warning arrhythmias occurred. The theory of warning arrhythmias, however, was not supported in further studies. Ventricular fibrillation did not occur in all patients with warning arrhythmias and did occur in their absence, g-6 It was at this time that truly prophylactic use of lidocaine began. Lidocaine was administered to patients with suspected myocardial infarction before the recognition of ventricular ectopy or arrhythmias. The concept of prophylactic lidocaine is controversial. It has been adamantly advocated by some and highly questioned by others. The rationale

20:5 May 1991

Annals of Emergency Medicine

540/97

M Y O C A R D I A L INFARCTION Mitchell & Wheeler

TABLE 1. Lidocaine in acute myocardial infarction

Reference

Year

Setting

Lie et al lo

1974

Hospital

Barnaby et alit Koster and Dunningr2

1983 1985

Hospital Prehospital

Dunn et a113

1985

Varied

No. of Patients Treated Placebo Total

Route

Dose (mg)

Infusion (mg/min)

Treatment or Study Period (br)

107

105

212

IV

100

3

48

111 2,987

... 3,037

111 6,024

IV IM

75 400

4.-~.2

48 1

207

195

402

IM IV

300 100

1

End Points VF, VPBs, mortality VE VT, VPBs VE mortality VE mortality

VF, venbieular fibrillation; VPBs, ventbcular premature beats; ~ ventrieular lachycardia.

for its use should be based on four basic assumptions, which are disCussed: 1) primary ventricular fibrillation is common in myocardial infarction, 2) the occurrence of ventricular fibrillation increases mortality, 3] lidocaine prevents p r i m a r y ventricular fibrillation and improves mortality, and 4) the benefits of lidocaine outweigh its adverse effects. Based on the clinical trials reported, the use of prophylactic lidocaine in all patients with suspected myocardial infarction is not supported. 7 First, studies have demonstrated a 3% to 10% in-hospital occurrence of primary ventricular fibrillation in association with m y o c a r d i a l infarction. s-lo Many sudden deaths occur outside of the hospital, and the incidence of ventricular fibrillation is inversely related to the time of onset of chest pain. lo Second, this has been suggested by several studies of in-hospital mortality of patients with primary ventricular fibrillation. An average of 19% of those with primary ventricular fibrillation died compared with an average of 8% in patients without primary ventricular fibrillation. 1 These n u m b e r s do not i n c l u d e p a t i e n t s with secondary ventricular fibrillation associated with congestive heart failure. This suggests that prevention of ventricular fibrillation would have a favorable effect on outcome in patients with myocardial infarction. Third, animal studies have shown mixed results on the effects of lidocaine in the suppression of ventricular a r r h y t h m i a s . Several clinical studies have assessed the efficacy of prophylactic lidocaine in preventing ventricular fibrillation in acute myocardial infarction. The characteristics of these trials are outlined (Table 1). Lie et al studied 212 patients with documented myocardial infarction. H 98/541

P a t i e n t s were excluded from the study if they were more than 70 years old or had congestive heart failure, shock, complete atrioventricular block, bradycardia, or persistent ventricular tachycardia or ventricular fibrillation on admission. None of the treated patients developed ventricular fibrillation. Of the placebo group, nine developed ventricular fibrillation; this was a statistically significant difference and supported the ass u m p t i o n that lidocaine prevents ventricular fibrillation. All but one of the nine were successfully defibrillated. In four of nine patients who developed ventricular fibrillation warning arrhythmias did not occur, suggesting that warning arrhythmias were not helpful in the decision to administer lidocaine. The mortality rates in both groups were the same. Barnaby et al treated all patients in their study with lidocaine within 24 hours of the onset of acute myocardial infarction. 1~ Exclusion criteria were similar to those in Lie et al's study. No patients developed ventricular fibrillation. Thirty-two percent had warning arrhythmias, and 4% had n o n s u s t a i n e d ventricular tachycardia. Four developed hypotension, and one developed bradycardia. Thirty percent of patients suffered symptoms of lidocaine toxicity, none of which was major. Despite the fact that this was an uncontrolled study, the investigators made the conclusion that prophylactic lidocaine was efficacious in suppression of ventricular fibrillation and that its use was particularly important outside the coronary care unit where close monitoring and rapid defibrillation were less available. In 1985, Koster and Dunning studied the use of prophylactic IM lidocaine in prehospital-care patients with suspected myocardial infarcAnnals of Emergency Medicine

tion.13 All patients were admitted to the study based on symptoms regardless of age, with exclusions for severe congestive heart failure, pretreatment with lidocaine, and resuscitation from ventricular fibrillation or by a physician's judgment. Of the patients included in the study, myocardial infarction was documented in 1,935. The IM route was selected because of its ease of use in the prehospital phase; it had been demonstrated previously to produce therapeutic serum levels 15 minutes after injection. Ventricular fibrillation was treated by defibrillation. The study period was one hour. During this time, eight of the treated and 17 of the untreated patients developed ventricular fibrillation (P = NS). However, in the last 45 minutes of the study, two of the lidocaine-treated and 12 of the untreated patients developed ventricular fibrillation, which was statistically significant. Ventricular fib r i l l a t i o n was d e f i b r i l l a t e d succ e s s f u l l y in all b u t one of t h e patients, in whom it was unrecognized and untreated for 11 minutes. The m o r t a l i t y rates in patients who developed ventricular fibrillation were virtually the same in both groups. More patients treated with ]idocaine developed asystole, but asystolic deaths in both groups were the same. The total mortality for both groups was also essentially the same. The authors concluded that if ventricular fibrillation had not been treated, by defibrillation, the administ r a t i o n of l i d o c a i n e w o u l d have caused a 31% reduction in mortality. Therefore, prophylactic IM ]idocaine would be useful in the setting in which potential sudden death is possible and immediate defibrillation is not available. Finally, Dunn et al studied the effects of lidocaine in patients with 20:5 May 1991

MYOCARDIAL INFARCTION Mitchell & Wheeler

TABLE 2. IV nitroglycerin in acute myocardial infarction

Reference Bussman et al2o

No. of Patients Year Treated Placebo Total Time*

Duration of Study (hr)

1981

31

29

60

Varied

48

Jaffe et a117 Flaherty et al2~

1983 1983

43 56

42 48

85 104

Within 10 hr Within 12 hr

? 24 Varied

Korewicki et a122

1984

39

38

77

Within 8 hr

48

End Points Infarct size (OK, CK-M8) infarct size (CK) Infarct extension, new heart failure, arrhythmias, infarct size, mortality Infarct size (OK), hemodynamics

*Onsel of symptoms to initiation of therapy

suspected myocardial infarction. 14 These patients were treated in the prehospital phase (78%), in the emergency department (18%), or after admission (4%) with similar exclusion criteria as previous studies. Of the patients studied, 364 had either myocardial infarction or acute coronary insufficiency. During the study period, three untreated patients developed v e n t r i c u l a r fibrillation (P = NS), and three lidocaine-treated patients developed sustained ventricular tachycardia (P = NS). More patients treated with lidocaine developed 2:1 atrioventricular block or asystole with death, but this.was not statistically significant. The mortality outside the study period was the same in both groups. Although the authors stated that their study may have been too small to create statistically significant differences in the two groups, they concluded that prophylactic lidocaine should not be advocated as the routine practice in acute myocardial infarction. Fourth, Rademaker et al studied adverse side effects in patients who received prophylactic lidocaine (100 mg IV followed by a 3 mg/min infusion) compared with those who did not. is T h e y f o u n d t h a t lidocaine caused significantly more side effects, albeit minor in m a n y cases, and that they were more common in patients without myocardial infarction. Five of 145 patients suffered life-threatening side effects, including seizures, coma with respiratory arrest, and persistent severe sinus bradycardia. They concluded that the adverse effects of lidocaine may negate its routine prophylactic use. Yusuf et al pooled the results of 11 randomized trials of 8,527 patients, which showed that lidocaine reduced 20:5 May 1991

the risk of ventricular fibrillation by 36% with a c o n c o m i t a n t but only borderline statistically significant doubling of fatal asystole. 16 They concluded that the routine use of antiarrhythmics in asymptomatic patients was not supported by pooled data. These studies suggest that lidocaine is effective in preventing primary ventricular fibrillation, but the mortality in treated versus untreated patients was the same. 11d4 Recently, Hines et al performed a meta-analysis of the studies on prophylactic lidocaine, supporting this finding. 7 They also showed that monitored patients with uncomplicated myocardial infarction were more likely to die during the treatment period if they received the drug. Despite potential psychological and physical consequences of resuscitation from ventricular fibrillation, the adverse effects of lidocaine probably outweigh its routine use due to the negative mortality effect and the potential of life-threatening side effects in patients who are suspected but later disproved of suffering acute myocardial infarction. The conclusion of Koster and Dunning is probably a good guideline for the use of prophylactic lidocaine: When defibrillation is unavailable and potential ventricular fibrillation is possible, prophylactic lidocaine may improve mortality. 13 With the development of emergency medical technician-defibrillation status, the need for this in the prehospital phase of management of patients with suspected myocardial infarction might be eliminated.

NITRATES Nitrates have been used since the Annals of Emergency Medicine

latter part of the 1800s for chest pain syndromes but were previously considered inappropriate for use in acute myocardial infarction because of potential side effects. These adverse effects include hypotension and reflex tachycardia, which in turn would increase myocardial oxygen consumption as well as the i d i o s y n c r a t i c b r a d y c a r d i c / h y p o t e n s i v e response seen in some patients. 17 Theoretically, however, nitrates should have beneficial effects because of two main actions. First, preload and afterload reductions result in decreased left ventricular filling pressures, thus decreasing myocardial oxygen demands. In experimental studies, nitrates have been shown during acute coronary occlusion to increase collateral blood flow to ischemic areas with a secondary potential benefit on infarct size. is There have been several trials addressing the effects of nitrates on myocardial infarction. Current recommendations advocate the use of nitrates in selected patients. In 1976, Awan et al administered 0.4 mg nitroglycerin sublingually to 11 patients with documented acute m y o c a r d i a l infarction.I9 Patients were not included in this small study if they were hypotensive or demonstrated conduction disturbances, persistent arrhythmias, heart failure, or pericarditis. Infarct size was determined by precordial mapping of ST segments and was found to be decreased by sublingual nitroglycerin. This led to further studies using IV nitroglycerin because it was more titratable and side effects could be avoided. The characteristics of these studies are outlined (Table 2). Bussman et al studied patients with acute myocardial infarction documented by clinical, ECG, and enzyme criteria. ~° All patients received SwanGanz catheterization and were included in the study only if pulmonary arterial diastolic or capillary pressures were more than 15 m m Hg. Infarct size was determined by creatine kinase (CK), CK-MB, and peaks of each. The groups were also subgrouped into early (within eight hours; mean, 4.5 hours) and late (after eight hours; mean, 12.8 hours) treatment. The results demonstrated significant reduction in infarct size with nitroglycerin in both early and late treatment groups, although early treatment was associated with better 542/99

M Y O C A R D I A L INFARCTION Mitchell & Wheeler

TABLE 3. Nifedipme in acute myocardial infarction No. of Patients Initial Dose Treated Placebo Total mg Route Time (hr)*

Reference

Year

Muller et a127

1984

82

89

171

20

0ral

Sirnes et a128

1984

112

115

227

10

0ral

Wilcox et a129 (Trent trial)

1986

2240

' 2,251

4,491

10

Sublingual

Branagan et al3o

1986

46

52

98

10

Sublingual

Gottlieb et a131

1988

64

68

132

10

Walker et a132

1988

217

217

434

10

?

Sublingual

Subsequent Doses

Duration

End Points

(Within 6) 4.6+1 (Within 12) 5.5 +_ 2.9 (Within 4): 32% (8): 68% (12): 81% (Within 6) 3.3 z 0.2

Every 4 hr

14 days

Threatened MIAMI, infarct size (CK-MB), mortality Infarct size (CK-MB), mortality Mortality

(Within 12) 8.0% = 02

Repeat every hr for 2, 6 weeks then 10-30 mg every 6 hr Every 4 hr for 24 hr orally, 48 hours every 4 hr for 24 hr

(Within 6) 2.3

Repeat 10 m, 5 times daily 6 weeks for 2 days, 4 times daily Repeat 4 hr every 6 hr Approximately 28 days Repeat 4 hr, orally every 6 hr

3 days

Infarct size (CK-MB), threatened MIAMI, mortality Infarct size (CK, echocardiogram, nuclear scans) Infarct size (CK, CK-MB, others)

*Onset of symptoms to first dose MI, myocardial infarction. (), inclusion criteria

results. The study group, however, was small. Jaffe et al studied the effect and safety of IV nitroglycerin in patients with documented myocardial infarction. 17 Patients were excluded for cardiogenic shock, severe heart failure with tachycardia, and severe hypertension. Before r a n d o m i z a t i o n , the patients were classified according to site of infarct. Infarct size was measured by CK gram equivalents per meter squared. There was a borderline significant reduction in infarct size for all patients. Nitroglycerin showed a significant reduction in infarct size among patients with inferior myocardial infarctions, a positive but not statistically significant trend in subendocardia] myocardial infarctions, and no change in anterior wall myocardial infarctions. M o r p h i n e r e q u i r e m e n t s were the same in patients regardless of treatment or infarct location. Six patients developed transient laypotension w i t h o u t deleterious effects. T h e y concluded that IV nitroglycerin was safe and effective in the reduction of infarct size in patients with inferior myocardial infarctions. Flaherty et al studied the effects of IV nitroglycerin on the clinical parameters of infarct extension, new heart failure, ventricular arrhythmias, and early death as well as laboratory parameters of infarct size (thallium perfusion scans, gated cardiac blood pool scans, two-dimensional echocardiography, precordial 100/543

E C G m a p p i n g , and serial CK). 21 N i n e t y - s e v e n p a t i e n t s had docum e n t e d myocardial infarction. Patients were excluded for age of more than 75 years, hypotension, bradycardia, and severe hypertension. At the end of their study, no difference in clinical or laboratory parameters could be determined. By retrospective subgrouping of patients into groups treated less or more than ten hours after onset of symptoms, they were able to determine some difference. Individually considered, nitroglycerin did not affect the clinical complications of myocardial infarction, but early treatment with nitroglycerin significantly reduced the combination of death, infarct extension, heart failure, and ventricular arrhythmias. The three-month mortality was improved in the early nitrog l y c e r i n g r o u p (P = NS). CK p a r a m e t e r s were not affected, but there appeared to be improvement in ejection fraction measurements with early nitroglycerin treatment. Flaherty et al also recommended that the data be interpreted with caution because of the size and retrospective subgroup analysis and proposed that recommended routine nitroglycerin in acute myocardial infarction await larger trials. 21 Korewicki et al demonstrated reduction in CK parameters if the drug was administered within eight hours. 22 Other studies have refuted the preferential reduction of infarct size in inferior myocardial.infarcAnnals of Emergency Medicine

tions demonstrated by Jaffe, 23 but two studies demonstrated improvement in patients with anterior myocardial infarctions.24, 25 It is difficult to m a k e definitive conclusions about the routine use of nitrates acutely in myocardial infarction based on the data of individual studies. Pooling of results suggests that IV nitrates improve m o r t a l i t y and m a y reduce infarct size.t6,18, 26 This positive trend and the fact that IV nitroglycerin is relatively safe, with adverse effects that are usually easily managed, suggest that nitrates should be used acutely in myocardial infarction in selected patients, especially those w i t h p e r s i s t e n t chest pain. After screening patients who may be susceptible to its hypotensive effects, those who are hypovolemic or may require high filling pressures to maintain cardiac output such as right ventricular infarction, IV nitrog l y c e r i n can r e a s o n a b l y be used safely. The advocation of routine use, however, should probably await larger studies. CALCIUM CHANNEL BLOCKERS

Since their introduction, calcium channel blockers have been used for a variety of cardiovascular diseases. Theoretically, the benefits of calcium channel blockers used a c u t e l y in myocardial infarction include relief of coronary artery spasm; in animals, improved collateral flow to ischemic areas; reduction of oxygen demand 20:5 May 1991

MYOCARDIAL INFARCTION Mitchell & Wheeler

by decreasing afterload, heart rate, and myocardial contractility; and reduction of calcium entry into cells, which may be related to ischemic cell injury and is of particular interest in patients who undergo reperfusion. The agents nifedipine, verapamil, and dihiazem each have different cardiovascular effects and should be considered separately. Although animal studies have been promising, clinical studies have not substantiated t h e m , and c a l c i u m c h a n n e l blockers are not advocated for routine use in the acute management of myocardial infarction.

Nifedipine There have been several clinical studies on the effect of nifedipine administration acutely in myocardial infarction; study characteristics are given (Table 3). In an early trial, Muller et a] found that nifedipine did not affect the progression of threatened to actual myocardial infarction, had no impact on infarct size, did not improve six-month mortality, and was associated with a significantly higher two-week mortality. 27 This increased mortality, however, may be attributed to no deaths in the placebo group at two weeks. In the Norwegian NifedipJne Multicenter Trial, Sirnes et a] found no effect on CK or six-week mortality. 28 The Trial of Early N i f e d i p i n e in A c u t e M y o c a r d i a l I n f a r c t i o n (the Trent trial) showed no improvement in one-month mortality. 29 Sixty-four percent of these patients had documented myocardial infarctions, and the drug was administered early, within four hours, to only 32% of the patients. In 1986, Branagan et al performed a much smaller study, but treatment was a d m i n i s t e r e d earlier. 3o In this trial, nifedipine had no impact on one-month mortality, CK, or the progression of threatened to actual myocardial infarction. The CK data, however, were complete in less than half the study population. Gottlieb et al studied the effects of larger nifedipine doses. 31 They demonstrated no statistically significant improvement in peak CK, mortality, or recurrent myocardial infarction but commented that a m u c h larger patient population might be necessary for statistical significance. Finally, Walker et al found no change 20:5 May 1991

in in-hospital mortality or infarct size by enzyme determination when nifedipine was given even earlier. 32

Verapamil Fewer studies have involved the use of verapami] acutely in myocardial infarction. In 1984, the Danish Muhicenter Group on Verapamil and Myocardial Infarction administered placebo or IV verapamil shortly after admission to 1,436 patients. 33 The time interval from onset of symptoms to initiation of treatment varied from within six hours in 422 patients to more than 24 hours in 107 patients. Verapamil was given in an initial dose of 0.1 mg/kg IV and 100 mg orally followed by 100 mg orally three times a day for six months. Treatment was stopped if myocardial infarction was excluded. The end points of the study were six- and 12m o n t h m o r t a l i t y and reinfarction rates. Verapamil was found to have no effect on any parameter, even in patients treated early. A small study by Bussman et al looked at infarct size reduction by v e r a p a m i l i n s t e a d of m o r t a l i t y data. 34 Fifty-four patients were randomized to receive placebo or verapamil 5 mg IV and then 5 to 10 mg/ hr by infusion for two days. They demonstrated a 30% reduction in infarct size by e n z y m e s in the verapamil group. This is the only clinical trial demonstrating benefit from the use of verapamil in the management of acute myocardial infarction.

Diltiazern Gibson et al demonstrated that diltiazem significantly reduced the reinfarction rate in the first 14 days in pat i e n t s w i t h n o n - Q wave infarctions. 3s In a larger trial, d i h i a z e m showed a slight but not significant benefit on mortality and reinfarction in patients followed 12 to 52 months after myocardial infarction. 36 Subgroup analysis demonstrated significant benefits in those patients with non-Q wave myocardial infarctions. Additional subgroup analysis suggested improvement in adverse cardiac events in patients without pulmonary congestion and worsening of mortality and reinfarction rates in patients with pulmonary congestion. In both studies, dihiazem was started late, at least 24 hours after infarction. Despite the large studies of secondary prevention by dihiazem, only one Annals of Emergency Medicine

small, preliminary clinical study of its acute use in myocardial infarction has been done to determine its effects on infarct size and mortality. 37 Thirty-two patients with acute myocardial i n f a r c t i o n c o m p l e t e d the study and received either placebo or dihiazem 10 mg IV over two minutes within six hours of symptoms, followed by 15 mg/hr for 72 hours and then 60 mg orally every six hours for three weeks. Infarct size was determined by radionuclide studies done on admission, at 48 hours, and at three weeks. CK data were available in most patients and showed no benefit from diltiazem. However, there was i m p r o v e m e n t in the ejection fraction and a decrease in the infarct defect in those treated with dihiazero. The study must be interpreted with caution because of the sample size. The c a l c i u m c h a n n e l blockers have been studied with great enthusiasm for their potential effects on myocardial salvage and mortality in acute myocardial infarction. It seems apparent from the trials that they are not useful in the acute management of myocardial ischemia or infarction. However, in secondary prevention and prophylaxis against recurrent ischemia, d i h i a z e m appears to have beneficial effects after non-Q wave infarction. Even more exciting is their potential use in the reduction of calciummediated ischemic injury after reperfusion. This, however, was not substantiated in a trial by Erbel et al, who aggressively managed 149 patients with acute myocardial infarction. 38 All patients received aspirin, IV streptokinase and heparin, intracoronary streptokinase, and coronary angioplasty if the lesion was more than 75% occluded. The c o n t r o l group r e c e i v e d placebo, and the treated group received nifedipine 20 mg sublingually and 0.2 mg infused into the occluded coronary artery, followed by 20 mg three times a day. Nifedipine was not shown to have a protective effect on reperfused myoeardium based on enzyme data, left ventricular function demonstrated by cineventriculography, or mortality.

13-BLOCKING AGENTS Of all the agents, f3-blockers have been studied the most extensively. The c l i n i c a l effects of early IV f3-blockade on acute myocardial in544/101

M Y O C A R D I A L INFARCTION Mitchell & Wheeler

TABLE 4. /V ~3-blockers in acute myocardial infarction No. of Patients Treated Placebo Total

Reference

Year Agent

Hjalmarson et a143 (Goteburg)

1981 Metoprolol

698

697

1,395

Yusuf et a142

1983 Atenolol

244

233

ICSG44

1984 Timolo[

73

Roberts et a[45

1984 Propranolol

134

mg

Initial Dose Time (hr)*

15t

(Within 48) 11.3 _+ 0.3

477

5~,

(Within 12) 5.0

71

144

1

(Within 4)

135

269

0.I kg

(Within 18) (Within 4): <2% (Within 8): 50% (Within 18): 100%

Subsequent Doses

Duration

End Points

50 mg orally at 15 rain 50 mg orally every 6 hr x 48 hr 100 mg orally every 12 hr 50 mg orally immediately every 12 hr x 1, 100 rng orally every day

90 days

Mortality (VT, VF), infarct size

10 days

IV infusion 0.6 mg/hr 24 hr, 10 mg orally four times daily Orally to maintain heart rate 45-60

Hospital stay

Infarct size (OK, ECG), threatened MI-,MI, arrhythmias, chest pain, morbidity and mortality Infarct size (vector, CK), pain

7 days

Infarct size (CK-MB)

16+ days

Mortafity,arrhythmias, chest pain

6 days or discharge

1 month

MIAMI4~

1985 Metoprolol

2,877

2,901

5,778

15t

(Wdhin 24)

ISIS-147

1986 Atenolol

8,037

7,990

16,027

5¢

(Within 12) 5.0

50 mg orally at 15 min every 6 hr for 2 days, 100 mg every 12 hr for more than 16 days 50 mg orally at 10 min, at 12 hr, 100 mg dally

(Within 6)

10 mg four times daily

Roque et a148 (TIARA)

1987 Timolol

102

98

200

5.5§

Mortality

Infarct size (CK, CK-MB), arrhythmias

*Mean time from onset ol symptoms to first dose tin three individual doses every two minutes !Over five minutes ~Bolus divided in four doses over ~'o hours ( ) inclusion criteria. V], ventrinular tachycardia; VE ventricular fibrillation: MI, myocardial infarction

farction have been examined in 30 trials including a total of 28,000 patients. Very good data have demonstrated that secondary p r e v e n t i o n with f~-blockers has decreased mortality and reinfarction by 25% in selected patients. 39 The theoretical benefits of early f3-blockade in acute myocardial infarction include decreased oxygen consumption by reduction in heart rate and myocardial contractility and blunted effect of high circulating catecholamines during the stress of infarction resulting in decreased oxygen c o n s u m p t i o n and reduction in the incidence of ventricular fibrillation. Based on recent clinical trials, there is significant enthusiasm for the use of IV ~-blockers in the acute management of selected patients with myocardial infarction. Experimental studies have suggested that 13-blockade decreased infarct size w h e n g i v e n before or shortly after coronary artery ligation.4O,41 Early clinical trials with 102/545

oral B-blocking agents demonstrated no benefit from their use early in myocardial infarction, but f3-blockade was often delayed because of the time factor required for oral agents to have an effect. 4~ Studies of early IV I3-blockade have yielded mixed results. Interpreting the data is difficult because many trials were too small and the drug was often administered late in the course of infarction; characteristics of these studies are given (Table 4). Exclusion criteria were similar for each. The Goteburg trial reported the effects of early IV metoprolol on acute myocardial infarction. 43 Nine hundred seventy-one of 1,395 patients were subsequently documented to have myocardial infarction. Exclusion criteria included contraindications to B-blockade (bradycardia, hypotension, a t r i o v e n t r i c u l a r block, congestive heart failure, or bronchospastic airway disease) or the need for i m m e d i a t e B-blockade. Metoprolol doses were reduced in paAnnals of Emergency Medicine

tients with adverse effects. The drug was begun within six hours in 44% and within 24 hours in 91% of patients. They demonstrated a significant reduction (8.9% for placebo vs 5.7% for treated) in m o r t a l i t y at three months. There was also a 15% decease in enzyme-estimated infarct size and fewer episodes of ventricular tachycardia and ventricular fibrillation in the treated group. Yusuf et al studied atenolol in patients with suspected myocardial infarction. 4~ The trial was not blinded because the effects of atenolol on heart rate could not allow true blindedness. They found that atenolol significantly reduced the progression of threatened myocardial infarction to myocardial infarction. In patients with myocardial infarction at the outset of the study, atenolol significantly decreased infarct size by enzyme and R wave score measurements. There were nonsignificant reductions in ventricular arrhythmias and cardiac arrest w i t h atenolol. 20:5 May 1991

MYOCARDIAL INFARCTION Mitchell & Wheeler

Early mortality appeared to be reduced, but two-year m o r t a l i t y for both treated and untreated groups was the same. The I n t e r n a t i o n a l Collaborative Study Group performed a small study on the effects of IV timolol given early. 44 They found no significant difference in in-hospital mortality, but the need for analgesics and infarct size by enzyme and vector analyses was significantly reduced by timolol. Roberts et al of the Multicenter Investigation for the Limitation of Infarct Size (MILIS) group studied the effects of IV propranolol. 4s T h e y found no significant difference in enzyme-estimated infarct size, technetium scan uptake areas, or 36-month mortality. It is important to note, however, that in 50% of the patients, treatment was initiated more than eight hours after the onset of symptoms. The Metoprolol In Acute Myocardial Infarction (MIAMI) group reported a large s t u d y of early IV metoprolol administration in acute myocardial infarction. 46 They looked primarily at its effects on 15-day mortality but also determined differences in the incidence of ventricular fibrillation, infarct size, and tolerance of the drug. They found no significant difference in the 15-day mortality or incidence of ventricular fibrillation. Retrospective analysis revealed t h a t m e t o p r o l o l had a greater effect on mortality in a selected high-risk population and that, w h e n g i v e n early ( w i t h i n s e v e n hours), had positive effects on the incidence of acute myocardial infarction size by enzyme activity. The use of metoprolol was also associated with a significantly reduced incidence of supraventricular tachycardia, use of cardiac glycosides, and pain medication requirements. The largest and probably the best study of the acute use of p-blockade in myocardial infarction was First International Study of Infarct Survival (ISIS-I).47 Their primary goal was to evahiate the effects of atenolol on vascular mortality at one week and an average of 20 months. They ~ound a significant reduction in mortality with atenolol during the treatment period, all of which was apparent in days 0 and 1. After the treatment period, there was no apparent effect of early atenolol on survival. 20:5 May 1991

Roque et al of the Timolol en Infarcto, Republica, Argentina group (TIARA) reported a smaller trial of early timolol and its effects on infarct size and late ventricular arrhythmias. 48 The timolol group had a significant reduction in ventricular arrhythmias and in infarct size by enzyme analysis as well as a decrease in 30-day and two-year mortality, albeit not statistically significant. Finally, the Thrombolysis in Myocardial I n f a r c t i o n trial (TIMI-2), which studied the effects of thrombolytic agents with or without early angiography and percutaneous transluminal coronary angioplasty, also included a prospective subgroup of patients comparing early IV or late oral metoprolol. 49 This is the only trial that studied the combination of B-blockade and t h r o m b o l y s i s and also c o m p a r e d e a r l y v e r s u s late ~-blockade. For t h e e a r l y t r e a t m e n t , IV metoprolol was given to a total dose of 15 mg plus an oral dose of 50 mg on day 1, followed by 100 mg twice daily. The late treatment group was begun on 50 mg orally twice daily on day 6. This subgroup comprised 1,390 patients. End points included ejection fraction at rest and with exercise at days 6 and 42, mortality, and recurrent ischemia or infarction. While not appearing to affect ejection fraction or mortality, recurrent ischemia and reinfarction were significantly reduced at six days in the early treatment group. In a prespecified subgroup treated within two hours of symptoms with IV metoprolol, death and recurrent myocardial infarction were significantly reduced compared with late treatment. An i n t e r e s t i n g p o s s i b i l i t y was raised by the ISIS-1 data. so Investigators studied the death records of the early mortality group (days 0 through 1). In the atenolol-treated patients, five died of cardiac rupture and 15 died of electromechanical dissociation (EMD) (total, 20). In a control group, 17 died of cardiac rupture and 37 died of EMD (total, 54). In all but one of 22 patients who died of EMD who underwent autopsy, cardiac rupture was the pathologic cause of death, so the authors consider it likely that EMD is frequently due to cardiac rupture. This suggests that the early prevention of death by atenolol may be due to prevention of cardiac rupture by decreasing the rate Annals of Emergency Medicine

and force of ventricular contraction, thus decreasing stress on the acutely necrotic myocardium. In the control group, there was a slight increase in the incidence of ventricular fibrillation, whereas there was a slight increase in fatal bradycardia/asystole in the atenolol group. The insignificant excess of one fatal arrhythmia was offset by the reduction in the other. Obviously, p-blocking agents have been studied extensively in the treatment of coronary artery disease and m y o c a r d i a l infarction. There are some conclusions about their use that can be reached from the data. It appears that it is the p-blockade and not the specific agent used that has positive effects on acute myocardial infarction because the studies performed have encompassed several agents with similar results. Early administration of f~-blocking agents appears to have beneficial effects on mortality, infarct size, nonfatal cardiac arrest, and reinfarction. The exact mechanism of improved mortality remains unclear, but it may be due to prevention of ventricular fibrillation and cardiac rupture. The character of p-blockers makes their routine use difficult because of the potential side effects of bradycardia, hypotension, and congestive heart failure. However, in the studies done, few severe adverse side effects were reported, probably because of careful exclusion criteria. Therefore, patients s h o u l d be s e l e c t e d c a r e f u l l y for f3-blockade therapy, and routine use is not yet advocated.

ASPIRIN An overview of ten trials using aspirin or other antiplatelet drugs in secondary prevention after first myocardial infarction demonstrated significant reduction in serious vascular events: reinfarction, stroke, and vascular death. Similar results were seen in two trials of patients with unsta~ ble angina. 16 In 1988, the ISIS-2 study of 17,187 patients studied the effects on mortality of streptokinase, aspirin, and the combination of the two against standard treatment, sl Streptokinase and aspirin significantly reduced five-week m o r t a l i t y w h e n given alone within 24 hours of symptoms. A combination of the two was significantly better in mortality reduction than either agent alone and appeared to be additive. Aspirin significantly reduced the incidence of 546/103

MYOCARDIAL INFARCTION Mitchell & Wheeler

nonfatal reinfarction and stroke and reduced the excess of .nonfatal reinfarction reported among the streptokinase-only patients. The reduction in mortality seen with aspirin and streptokinase remains significant at late follow-up, a median of 15 months. The very character of aspirin, its cost and safety, makes it an optimal drug to use in the management of acute myocardial infarction. A few simple questions about nasal polyps, asthma, or true allergic reactions to aspirin in the past screen the patient who may have deleterious side effects from its administration. Thei ISIS-2 study yields very optimistic' data about aspirin alone and in combination with thrombolysis. In patients without contraindications to its use, aspirin administration should be part of the routine management of acute myocardial infarction.

SUMMARY Because of the changes in the management of acute myocardial infarction, physicians face a more challenging, active, and dynamic decis i o n - m a k i n g p r o c e s s w h e n confronted with a patient with an acute myocardial event. Because most interventions are required within a certain window of time before irreversible m y o c a r d i a l damage is completed, emergency physicians often bear the responsibility for early decision making. Except for aspirin, the data do not support the routine use of these agents in the acute management of myocardial infarction. Selection of each agent must be made on an individual basis. Thrombolysis remains the best option for reduction of infarct size and mortality. Guidelines can be suggested for other agents. Truly prophylactic lidocaine, advocated previously for all patients with myocardial i n f a r c t i o n or i s c h e m i a , is probably not indicated unless one is faced with a long delay until a defibrillator is available. The use of prophylactic lidocaine appears to prevent ventricular fibrillation, but it does not improve overall mortality when ventricular fibrillation can be rapidly defibrillated and may be associated with an increase in bradycardia and asystole. IV nitroglycerin probably has beneficial effects and should therefore be used in patients with c o n t i n u i n g 104/547

chest pain and without contraindications to its use. The side effects of nitroglycerin are usually easily managed. However, larger studies of nitrates will be required before they are a d v o c a t e d as r o u t i n e t h e r a p e u t i c agents. The American Heart Association also recognizes that there are insufficient data to recommend routine use of nitrates. 52 The data strongly suggest that calcium channel blockers have no beneficial effects in the acute management of myocardial infarction and should not be used in this setting. Multiple studies have demonstrated that f3-blocking agents can be administered safely to the 50% of patients with acute myocardial infarction who are hemodynamically stable. 53 Metoprolol and atenolol are currently approved in this setting. The initial r e c o m m e n d e d dose of metoprolol is 15 mg given in divided doses over 15 minutes. Five milligrams of atenolol is administered over five minutes. Because of the potential risk of f~-blockade, however, these agents are recommended only in carefully selected patients, not as a routine therapy. Exclusion criteria include h y p o t e n s i o n , bradycardia, a t r i o v e n t r i c u l a r block, congestive heart failure, or a history of bronchospastic airway disease. The ease of use and positive effects of aspirin should make it a first-line t h e r a p y in m y o c a r d i a l i n f a r c t i o n management. Except in patients with true aspirin allergy or a history of nasal polyps with asthma, aspirin in the dosage of either one baby aspirin tablet (80 mg) or one adult tablet (325 mg) should be routinely given to patients presenting with acute myocardial infarction or unstable angina. Acute myocardial infarction is no longer merely a diagnostic challenge. Active therapeutic decision making, often in the ED, m a y have longstanding implications for outcome. This review has attempted to define the roles of prophylactic lidocaine, nitrates, calcium channel blockers, B-blockers, and aspirin in myocardial infarction management.

REFERENCES 1. Berte LE, Harrison DC: Should prophylactic antiarrhythmic drug therapy be employed in acute myocardial infarction? Cardiovasc Clin 1983;13:173:181. 2. Lown B, Fakhro AM, Hood WB, et ah The coronary care unit: New" perspectives and directions. JAMA 1967;199:188q98. 3. Dhurandhar RW, MacMillan RL, Brown.KWG: Pri-

Annals of Emergency Medicine

mary ventricular fibrillation complicating acute myocardial infarction. Am J Cardio] 1971;27:347-g51. 4. Bennett MA, Pentecost BL: Warning of cardiac arrest due to ventricular fibrillation and tachycardia. Lancet 1972~h1351d357. 5. EI-Sherif N, Myerburg RJ, Scherlag BJ: Electrocardiographic antecedents of primary ventricular fibrillation: Value of the R-on-T pltenmnenon in myocardial infarction. Br Heart J 1976;38:415-422. 6. Lie KI, Wellens HJJ, Durrer D: Characteristics and predictability of primary ventricular fibrillation. Eur J Cardioi 1974;h379-384. 7. Hine LK, Laird N, Hewitt, et al: Meta-analytic evidence against prophylactic use of lidocaine in acute myocardial infarction. Arch Intern Med 1989;149: 2694-2698. 8. Conley MJ, McNeer JR, Lee LK, et ah Cardiac arrest complicating acute myocardial infarction: Predictability and prognosis. A m J Cardiol 1977;39:7-12. 9. Lawrie DM, Goddard M, Greenwood TW, et al: A coronary care unit in the routine management of acute myocardial infarction. Lmlcet 1967;1:109-114. 10. Lawrie DM, Higgins MR, Godman MJ, et al: Ventricular fibrillation complicating acute myocardial infarction. Lancet 1968;2:523-528. 1I. Lie KI, Wellens HJ, van Capelle FJ, et al: Lidocaine in the prevention of primary ventricular fibrillation: A double-blind, randomized study of 212 consecutive patients. N EngI J Med 1974;29I;1324-1326. 12. Barnaby PF, Barrett PA, Lvoff R: Routine prophylactic lidoeaine in acute myocardial infarction. Heart Lung 1983; 12:362-366. 13. Koster RW, Dunning AJ: IM lidocaine for prevention of lethal arrhythmias in the prehospitalization phase of acute myocardial infarction. N Engi ] Med 1985;313:1i05-1110. 14. Dunn HM, McComb JM, Kinney CD, et al: Prophylactic lidocaine in the early phase of suspected myocardial infarction. Am Heart J 1985;110:353-362. 15. Rademaker AW, Kellen J, Tam YK, et ah Character of adverse effects of prophylactic lidocaine in the coronary care unit. C]in Pharmacol Ther 1986;40:71-80. 16. Yusuf S, Wittes J, Friedman L: Overview of results of randomized clinical trials in heart disease: 1. Treatm e n t s f o l l o w i n g m y o c a r d i a l i n f a r c t i o n . JAMA 1988;260:2088-2263. 17. Jaffe AS, Geltman EM, Tiefenbrunn AJ, et ah Reduction of infarct size in patients with inferior infarction with intravenous glyceryl trinitrate: A randomized study. Bz Heart J 1983;49:452-460. 18. Kjekshus J: Nitrates in acute myocardial infarction. Drugs 1987;33/suppl 4):140-146. 19. Awan NA, Amsterdam EA, Vera Z, et ah Reduction of isehemie injury by sublingual nitroglycerin in patients with acute myocardial infarction. Circulation 1976;54:761-765. 20. Bussman W-D, Passek D, Seidel W; et ah Reduction of CK and CK-MB indexes of infarct size by intravenous nitroglycerin. Circulation 1981;63:615-622. 21. Flaherty JT, Becket LC, Bulkley BH, et ah A ran t domized prospective triai of intravenous nitroglycerin in patients with acute myocardial infarction. Circulation 1983;68:576-588. 22. Korewicki l, Kraska T~ Opolski G, et ah Beneficial effects of intravenous nitroglycerin on haemodynamics and enzymaticalIy estimated infarct size. Eur Heart J 1984;5:697~704. 23. Osuna PP, Moreno LMG, Jimenez AA, et al: Isosor ~ bide dinitrate sublingual therapy for inferior myocardial infarction: Randomized trial to assess infarct size limitation. A m J CardioI 1985;55:330-334. 24. Jugdutt BI, Sussex BA, Wamica JW, et ah Persistent reduction in left ventricular asynergy in patients with acute myocardial infarction by intravenous infusion of nitroglycerin. Circulation 1983;68:1264-i273. 25. Derrida JP, SaI R, Chiche P: Favorable effects of prolonged nitroglycerin infusion in patients with acute myocardial infarction. A m Heart J 1978;96:833-834.

20:5 May 1991

MYOCARDIAL INFARCTION Mitchell & Wheeler

26. Yusuf S, Collins R, MacMahon S, et ah Effect of intravenous nitrates on mortality in acute myocardial infarction: An overview of the randomised trials. Lancet 1988~h1088-1092. 27. Muller JE, Morrison J, Stone PH, et ah Nifedipine therapy for patients with threatened and acute myocardial infarction: A randomized, double-blind, placebocontrolled comparison. Circulation 1984;69:740-747. 28. Sirnes PA, Overskeid K, Pedersen TR, et ah Evolution of infarct size during the early use of nifedipine in patients with acute myocardial infarction: The Norwegian Nifedipine Multicenter Trial. Circulation 1984; 70:638-644. 29. Wilcox RG, Hampton JR, Banks DC, et ah Trial of early nifedipine in acute myocardial infarction: The Trent study. Br Med J 1986;293:1204-1208. 30. Branagan JP, Walsh K, Kelly P, et ah Effect of early treatment with nifedipine in suspected acute myocardial infarction. Eur Heart J 1986;7:859 865. 31. Gottlieb SO, Becker LC, Weiss JL, et ah Nifedipine in acute myocardial infarction: An assessment of left ventricular function, infarct size, and infarct expansion. Br Heart J 1988;59:411-418. 32. Walker LJE, MacKenzie G, Adgey AAJ: Effect of nifedipine on enzymatically estimated infarct size in the early phase of acute myocardial infarction. Br Heart J 1988;59:403-410. 33. Danish Multicenter Study Group on Verapamil in Myocardial Infarction: Verapamil in acute myocardial infarction. A m [ Cardioi 1984;54:24E-28E. 34. Bussmann W-D, Seher W, Gruengras M: Reduction of creatine kinase and creatine kinase-MB indexes of infarct size by intravenous verapamil. A m J Cardioi 1984;54:1224-1230. 35. Gibson RS, Boden WE, Theroux P, et ah Dittiazem and reinfarction in patients with non-Q-wave myocar-

20:5 May 1991

dial infarction: Results of a double blind, randomized, multicenter trial. N Engi J Med 1986;315:423-429. 36. Multicenter Diltiazem Post-infarction Research Group: The effect of diltiazem on mortality and reinfarction after acute myocardial infarction. N EngI J Med 1988;319:385-392. 37. Zannad F, Amor M, Karcher G, et ali Effect of diltiazero on myocardial infarct size estimated by enzyme release, serial thallium-201 single-photon emission coin puted tomography and radionuclide angiography. A m J Cardio] 1988;6h1172-1177. 38. Erbei R, Pop T, Meinertz T, et al: Combination of calcium channel blocker and thrombolytic therapy in acute myocardial infarction. A m Heart J 1988;115: 529-538. 39. Held P, Yusuf S: Early intravenous beta-blockade in acute myocardial infarction. Cardiology 1989;76: 132 143. 40. Miura M, Thomas R, Ganz W, et al: The effect of delay in propranolol administration on reduction of myocardial infarct size after experimental coronary artery occlusion in dogs. Circulation 1979;59:1148 1157.

45. Roberts R, Croft C, Gold HK, et al: Effect of propranolol on myocardial-infarct size in a randomized blinded m n l t i c e n t e r trial. N EngI J Med i984;311: 218-224. 46. The MIAMI Trial Research Group: Metoprolol in Acute Myocardial Infarction (MIAMI]: A randomized placebo-controlled international trial. Eur Heart J 1985~6:199-226. 47. ISIS-1 (First International Study of Infarct Survival) Collaborative Group: Randomised trial of intravenous ateno[ol among 16,027 cases of suspected acute myocardial infarction: ISIS-1. Lancet 1986;2:57-65. 48. Roque F, Amuehastegui LM, Morillos MAL, et ah Beneficial effects of timolol on infarct size and late ventricular tachycardia in patients with acute myocardial infarction. Circniatiorl 1987;76:610-617. 49. The TIMI Study Group [results of the Thrombolysis In Myocardial Infarction (TIMI) Phase II Trial]: Compar~ ison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction. N Engf J Med 1989;320: 618-627.

41. Jennings RB, Reimer KA: Salvage of ischemic myocardium. Mod Concepts Cardiovasc Dis 1974;43: 125-130.

50. ISIS-1 Collaborative Group: Mechanisms for the early mortality reduction produced by beta blockade started early in acute myocardial infarction. Lancet 1988;h921-923.

42. Yusuf S, Sleight P, Rossi P, et af: Reduction in infarct size, arrhythmias and chest pain by early intravenous beta blockade in suspected acute myocardial infarction. Circulation 1983;67(suppl I):I-3~I 41.

51. ISIS-2 Collaborative Group: Randomized trial of IV streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction. Lancet 1988;2:349 360.

43. Hjalmarson A, Herlitz [, Malek I, et ah Effect on mortality of metoprolol in acute myocardial infarction: A double-blind randomised trial. Lancet 1981;2:823-827.

52. American Heart Association: Advanced Cardiac Life Support. Dallas, American Heart Association, 1987, p 13.

44. The IntemationaI Collaborative Study Group: Reduction of infarct size with the early use of timolol in acute myocardial infarction. N Engl J Med 1984;310: 9-15.

53. Frishman WH, Skolnick AE, Lazar EJ, et al: B-Ad~ renergic blockade and calcium channel blockade in myocardial infarction. Med Cfin North A m 1989; 73:409-436.

Annals of Emergency Medicine

548/105