Coronary Care Cardiology 1992;81:59-65

Juan C. García-Rubira Dolores Romero Juan T. García-Martínez Jesús Rodríguez-Baños Víctor López José M. Cruz

Prevention of Myocardial Infarction by Nitroglycerin plus Intravenous Beta-Blockers

Coronary Care Unit, Hospital Universitario Virgen Macarena, Sevilla, Spain

Abstract Seven patients with ongoing angina with ST-scgmcnt eleva­ tion, refractory to oral nifedipine and intravenous nitroglycer­ in, were treated by adding intravenous beta-blockers. Chest pain resolved in all of them in a few minutes, and myocardial infarction did not develop in 5 patients. We recommend this approach for patients to whom thrombolytics are contraindi­ cated or have been very recently administered, although fur­ ther investigation is needed to extend its application more widely. It does not preclude the use of other therapies, if con­ sidered necessary.

Introduction Thrombolytic therapy has become the choice treatment in the early hours of acute myocardial infarction [1-4], However, this therapy is not free of adverse side effects, and a considerable number of patients are ex­ cluded from this approach because of con­ traindications or excessive time lag, so that other pharmacologic agents are being investi­ gated in an attempt to limit the infarct size. Beta-blockers are the most successful agents

Received: March 3.1992 Accepted: March 23. 1992

in this concern. We present a series of 7 patients who developed an episode of anginal pain with ST-segmcnt elevation, refractory to nitroglycerin and nifedipine, and who were treated by adding intravenous beta-blockers.

Methods Seven patients (4 male and 3 female, 41-64 years of age) having been previously admitted to our coro­ nary care unit because of acute myocardial infarction or unstable angina, who developed during their stay an

Dr. García-Rubira Unidad Coronaria Hospital Universitario Virgen Macarena Avenida Dr. Fcdriani 3 E -4 1009 Sevilla (Spain)

© 1992 S. Karger AG. Basel 0008-6312/92/ 0811 —0059S2.75/0

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Keywords Angina Beta-blockers Nitroglycerin Prevention of myocardial infarction ST-scgmcnt elevation

Table 1. Clinical and angiographic data

Pa­ Sex tient

Age years

Previous throm­ bolytic

Previous AMI

STsegment elevation

Beta­ blocker

Previous New duration AMI of pain, min

1

M

41

rtPA

anterior

VI-V4

propranolol (5 mg)

40

2

F

60

APSAC

no

VI-V4

metoprolol (4 mg)

3

M

64

rtPA

inferior

II. III. F

4

M

62

no

no

5

F

57

no

6

F

60

7

M

48

FE

Coronary stenosis

no

0.33

99% LAD. 90% RCA

30

no

0.65

80% LAD. 60% RCA. 40% Cx

metoprolol ( 10 mg)

40

yes

0.35

100% RCA. 80% Dl

VI-V4

propranolol (5 mg)

20

no

0.31

90% LAD. 90% Dl

lateral

I. L

propranolol (5 mg)

20

no

0.36

100% D l. 75% OM. 75% RCA

rtPA

no

11. III. F

propranolol (3 mg)

80

yes

0.43

90% RCA. 60% LAD

APSAC

inferior

II. III. F

atenolol (5 mg)

45

no

0.46

90% RCA

AMI = Acute myocardial infarction; LAD = left anterior descending; RCA = right coronary : Dl = first diagonal: OM = obstuse marginal: Cx = circumflex; FE = ejection fraction.

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age until systolic pressure fell under 95 mm Hg. The nitroglycerin infusion was then tapered off to recover a stable blood pressure. Repeated doses of 2-3 mg of a beta-blocker were then administered until relief of pain or a maximum of 15 mg (not reached in any patient). Four patients received propranolol. 2 metoprolol, and l atenolol.

Results Table 2 summarizes the hemodynamic ef­ fects of beta-blockers in our patients. The rate-pressure product declined in all cases, changing from 10,770 ± 2,134 to 7,890 ± 1,174. In this series we did not observe any side effect.

Garcia-Rubira/Romero/ Garcia-Marrinez/Rodriguez-Baños/ López/Cruz

Nitroglycerin plus Intravenous Beta-Blockers in MI

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attack of angina with ST-segment elevation which did not resolve with nitroglycerin and nifedipine, were included in this report. No patient was receiving vera­ pamil nor presented contraindications to beta-blockers. None of them was receiving oral beta-blockers. The reason for using this therapy instead of a thrombo­ lytic agent in patients l and 2 were very recent throm­ bolytic therapy in the first case and intracranial hema­ toma in the second one. The remaining patients re­ ceived beta-blockers as an attempt to limit the size of an evolving myocardial infarction, and a fibrinolytic agent would have been administered in the case of no relief of pain. Table l summarizes the clinical and angiographic data of patients. Coronary arteriography was subse­ quently obtained in all patients except in patient 6. whose coronary anatomy was previously known. All anginal attacks were initially treated with oral nifedi­ pine and intravenous nitroglycerin at increasing dos­

Table 2. Hemodynamic effect of intravenous beta- blockers

Patient

Before beta-blocker RPP

MBP

1 2 3 4 5 6 7

9.240 12.740 7.670 11.440 13.300 12,000 9,000

103 93 110 97 100 93 87

Mean

10.770

98

After beta-blocker RPP

MBP

HR

77 91 59 88 95 100 75

6.389 8.400 6.840 7,810 9.600 9.000 7.200

90 80 93 90 87 93 87

58 70 57 71 80 75 60

84

7.890

89

67

HR

Chest pain was alleviated in all patients before we reached the maximum target dose. ST-segment elevation disappeared in patients 2, 3 and 6. and diminished to previous mor­ phology in patients 1, 3, 5 and 7 (fig. 1-3). In all patients these effects were noted 5-20 min after the administration of the first dose of beta-blocker. Patients 2 and 6 had previously received thrombolytic therapy 1 week earlier because of acute myocardial ischemia with ST-seg­ ment elevation without developing myocar­ dial infarction. Patient 2 developed an intra­ cranial hematoma, thus contraindicating a second thrombolytic therapy. Despite high doses of nitrates, nifedipine and diltiazem. angina with ST-segment elevation throughout leads V1-V4 recurred, without response to intravenous nitroglycerin. Four milligrams of metoprolol were then administered, and both chest pain and ST-segment elevation disap­ peared. Patient 6 received 3 mg of proprano­ lol after 80 min of angina with ST-segment elevation in inferior leads. A previous coro­ nary arteriography showed severe stenosis of the right coronary artery, which was thought inadequate for bypass grafting. Despite the

quick relief of pain and the return of ST-seg­ ment to baseline, creatine kinase serum levels raised significantly. Patients 1,3 and 7 had previously received thrombolytic therapy because of acute myocar­ dial infarction 24-28 h earlier. All of them suf­ fered anginal pain with ST-segment elevation in the leads involved by the myocardial infarc­ tion. They were receiving aspirin, but heparin had been discontinued. A ‘hump’ in the curve of serum creatine kinase, suggestive of rein­ farction, was only observed in patient 3. Patient 4 was admitted to our unit because of variant angina which involved leads V IV4. One anginal attack did not resolve with the maximum tolerated dose of intravenous nitroglycerin and oral nifedipine. After add­ ing 5 mg of intravenous propranolol, pain and ST shift dissapeared, without creatine kinase elevation. Patient 5 suffered from a lateral infarction 3 days earlier, the ST-segment remaining ele­ vated in DI and aVL. Typical chest pain was not accompanied by clear changes in the elec­ trocardiogram, but by an increase in blood pressure. After 5 mg of propranolol, chest pain disappeared.

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RPP = Rate-pressure product: MBP = mean blood pressure; HR = heart rate.

In 4 out of 6 patients whose coronary arte­ riography was obtained after the therapeutic intervention, the coronary artery related to electrocardiographic changes was found to be patent, although severely stenosed. Five pa­ tients did not develop a new myocardial in­ farction. Patients 5 and 6 could be discharged with medical therapy. The remaining patients needed surgical revascularization.

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Fig. 2, Patient 6 suffered from recurrent severe chest pain with ST-segment elevation in inferior leads (b). despite high dose of intravenous nitroglycerin. Ten minutes after administration of 3 mg of intravenous propranoiol. chest pain disappeared and electrocardio­ graphic changes diminished remarkably (c). however, myocardial infarction developed.

Discussion The findings of De Wood et al. [5] pro­ vided impressive evidence of the main role of thrombotic occlusion of coronary arteries in the pathophysiology of acute myocardial in­ farction. In fact, the widespread use of throm­ bolytic therapy has substantially reduced the mortality of myocardial infarction [1-4], Pre­ vention of myocardial infarction by the early

Garcia-Rubira/Romero/ Garcia-Martinez/Rodrigucz-Banos/ Löpez/Cruz

Nitroglycerin plus Intravenous Beta-Blockers in MI

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Fig. 1. Precordial leads of patient 4 in basal (a) and during angina, while receiving nitroglycerin (b). After adding 5 nig of intravenous propranolol. ST shift dis­ appeared (c). CPK serum levels did not rise.

administration of a therapeutic agent would provide a solid basis for such approach. Da­ vies et al. [6] reported a series of 9 instances in 8 patients with accurately defined onset of chest pain and ST-segment elevation. They started intracoronary infusion of streptoki­ nase within 45-120 min of the onset of isch­ emic attack. Patency of the coronary artery could be reestablished in 6 cases. Myocardial infarction occurred in 1 of them, even though

6.t

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Fig. 3. Patient 7 had received thrombolytic therapy for inferior myocardial infarction 24 h before, devel­ oping Q waves (a). During angina ST segment raised in inferior leads despite intravenous nitroglycerin (b). After administration of 5 mg of propranolol, both chest pain and ST-segment shift vanished (c).

recanalization was achieved within 60 min of the onset of pain. No detectable infarction occurred in 5 others, despite recanalization was not achieved until 120-200 min. They suggest that other factors, apart from throm­ bosis. may be responsible for coronary occlu­ sion in the very early hours of infarction, con­ cluding that thrombolytic therapy cannot be effective in all patients. All patients we present here were in our cor­ onary unit when ST-segment elevation and chest pain started, so that onset of angina could be accurately established, and persis­ tence of pain and of electrocardiographic changes was suggestive of myocardial infarc­ tion. Administration of thrombolytic agents in so early time is related to prevention of myo­ cardial infarction in 22-50% of cases [6-8]. On the other hand, mortality can decrease by 15% in patients treated with beta-blockers during acute myocardial infarction, and over 5% of patients who received them because of clinical and electrocardiographic changes sug­ gestive of acute myocardial infarction did not have evidence of necrosis [9. 10], Beta-block­ ers act mainly through lowering heart rate, blood pressure and contractility, the main de­ terminants of myocardial oxygen consump­ tion. and this can occur without increase of the pulmonary artery wedge pressure, even in presence of moderately depressed left ventri­ cle performance [11], Zalewski et al. [ 12] also found beta-blockers to have a direct protec­ tive effect on myocardium from ischemia, apart from their systemic effects. In experi­ mentation with animals, beneficial effects of beta-blockers against ischemia are only seen after the development of collateral circulation by repeated intermittent occlusions of the cor­ onary artery [13], An additional effect is a modest antiplatelet activity of these drugs [14]. Barth et al. [15] have already successfully used intravenous esmolol in 21 patients with

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variant angina and non-stenotic coronary ar­ teries. Nevertheless, ischemic ST-segment ele­ vation lasting more than 30 min. refractory to nitroglycerin, is usually followed by acute myocardial infarction, and a beneficial effect of adding intravenous beta-blockers is not un­ conceivable. We think that this therapy may be recom­ mended in patients with major contraindica­ tions to thrombolytic agents, and in patients who had been very recently treated by throm­ bolysis. Although re-administration of throm­ bolytic agents could seem adequate, it is not free of severe side effects [7], so it is worth trying with nitroglycerin plus beta-blockers before. Further investigation is needed to ex­ tend these indications more widely, but it might be appropriate for most patients with prolonged ST-segment elevation refractory to conventional therapy. It is an inexpensive ap­ proach that requires little time, and with a low risk, if contraindications to the use of betablockers are taken into account. It does not preclude the use of other measures, as urgent coronary arteriography, coronary angioplasty or bypass grafting, intraaortic balloon pump or thrombolytic therapy in case they are con­ sidered necessary.

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ongoing angina and either ischemic ST-segment depression or previously documented coronary artery disease, but patients with STsegment elevation were excluded. Beta-block­ ers are usually contraindicated in patients with acute myocardial ischemia and ST-segment elevation, because of risk of an alphaadrenergic-mediated vasoconstriction [16]. However, Labovitz et al. [17] demonstrated that intravenous esmolol reduces both STsegment elevation and the decrease of ejec­ tion fraction induced by acute coronary occlu­ sion in 16 patients undergoing coronary an­ gioplasty. In fact, hundreds of patients with ST-segment elevation have been enrolled in several trials dealing with beta-blockers and acute myocardial infarction, and some of them did not develop mvocardial necrosis [9,10], All our patients were also receiving nitro­ glycerin. which has been shown to limit myo­ cardial infarction size [18]. Its maintenance probably plays a key role in the good results we offer in this short series, as spasm can be one of the factors responsible for coronary occlusion in the very early phases of infarc­ tion [6].' When transient occlusion of a coro­ nary artery cannot be rapidly relieved by intravenous nitroglycerin nor calcium block­ ers, beta-blockers might well salvage the via­ bility of a threatened, collateral-dependent myocardial area, and increase the time avail­ able for preventing myocardial infarction or even allow prolonged viability of this area. Maintenance of nitroglycerin can reestablish patency of the involved coronary artery, at least in some cases. Coronary arteriography found all our pa­ tients to have severe stenosis or total occlu­ sion in the coronary artery related to the elec­ trocardiographic changes, and collateral cir­ culation could have developed during the precedent months or years. Therefore, we cannot extend our results to patients with

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13 Mohri M. Tomoike H. Inouc T. Na­ kamura M: Amelioration by beta adrenergic blockade of regional myocardial dysfunction induced by coronary artery occlusion after, but not before collateral development in conscious dogs. Am Heart J 1989: 117:43-52. 14 Campbell WB. Johnson AR. Calla­ han KS. Graham RN: Antiplatelet activity of beta-adrenergic antago­ nists: Inhibition of thromboxane synthesis and platelet aggregation in patients receiving long-term propanolol treatment. Lancet 1981 :ii: 1982-1984. 15 Barth C. Ojile M. Pearson AC, Labovitz A.I: Ultra short acting intra­ venous beta-adrenergic blockade as add-on therapy in acute unstable an­ gina. Am Heart J 1991:121:782788. 16 Robertson RM, Wood AJ. Vaughn VK. et al: Exacerbation of vasotonic angina pectoris by propranolol. Cir­ culation 1982;65:281-285. 17 Labovitz AJ. Barth C. Castello R. Ojile M, Kern MJ: Attenuation of myocardial ischemia during coro­ nary occlusion by ultra short-acting beta-adrenergic blockade. Am Heart J 1991:121:1347-1352. 18 Jugdutt BI. Warnica JW: Intrave­ nous nitroglycerin to limit myocar­ dial infarct size, expansion and com­ plications. Effect of timing, dosage, and infarct location. Circulation 1988:78:906-919.

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1 Gruppo Italiano per lo Studio della Strcptochinasi nell'lnfarlo Miocardico (GISSI): Effectiveness of intra­ venous thrombolytic treatment in acute myocardial infarction. Lancet 1986x397-402. 2 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group: Randomized trial of intrave­ nous streptokinase, oral aspirin, both, or none among 17.187 cases of suspected acute myocardial infarc­ tion: ISIS-2. Lancet I988;ii:349360. 3 Wilcox RG. Von der Lippe G. Olsson CG. el al: Trial of tissue plas­ minogen activator for mortality re­ duction in acute myocardial infarc­ tion. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lan­ cet 1988;ii:525—530. 4 AIMS Trial Study Group: Effect of intravenous APSAC on mortality af­ ter acute myocardial infarction: Pre­ liminary' report of a placebo-con­ trolled clinical study. Lancet 1989:i: 545-549. 5 De Wood MA. Spores J. Notske R. et al: Prevalence of total coronary' occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980:303:897-902. 6 Davies GJ, Chicrchia S. Maseri A: Prevention of myocardial infarction by very early treatment with intra­ coronary streptokinase. N Engl J Med 1984;311:1488-1492.

Prevention of myocardial infarction by nitroglycerin plus intravenous beta-blockers.

Seven patients with ongoing angina with ST-segment elevation, refractory to oral nifedipine and intravenous nitroglycerin, were treated by adding intr...
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