BRIEF REPORTS
Incidence of Adverse Events During Treatment with Verapamil for Suspected Acute Myocardial Infarction Margaret A. Arstall, Adrian J. Esterman,
MBBS, Msc,
John F. Beltrame, BMBS, Puneet Mohan, and John D. Horowitz, PhD
he potential clinical role of non-dihydropyridine calT cium antagonists, such as verapamil and diltiazem, in the managementof patients during and subsequentto acute myocardial infarction (AMI) is an area of considerable and changing controversy.’ Recent investigations suggest that both verapami11,2and diltiazem1*3,4exert beneficial effectsafter AMI, largely, if not entirely mediated by reduction in the incidence of reinfarction. However, there is considerableconcern about the useof these negatively inotropic calcium antagonistsin patients with significantly impaired left ventricular systolic function.1,2,4Although diltiazem may be beneficial in the periinfarct period3and verapamil may exert beneficial effects on both ischemia5 and infarct size6in this setting, the results of the only large randomized study conducted to date concerning the early use of verapamil- Danish Verapamil Infarction Trial-I (DAVIT-I)’ - discouraged initiation of verapamil therapy in the first week, representing the period of maximal risk for reinfarction. Specifically, in DAVIT-I the incidence of death due to cardiogenic shock or pulmonary edema,or both, complicating infarction was 5.3%,somewhathigher than in the placebo-treated patients (3.2%). These results of DAVIT-I may have been influenced by the use of large intravenous doses of the drug and by the absenceof thrombolytic therapy, which would be expectedto both reducethe potential risk of the developmentof cardiogenic shock and increasethe risk of reinfarction. Therefore, there is a needto reevaluatethis area of therapeutics.We prospectively examined the incidence of potential drugassociatedadverseeventsin consecutivepatients t.reated with intravenous or oral verapamil, or both, in the early managementof suspectedAMI. We also sought toIdetermine potential clinical parameters predisposing to the occurrenceof such adverseoutcomes.End points i.ncluded death, significant bradyarrhythmia requiring treatment due to hemodynamiccompromiseand symptomatic left ventricular failure. Frequency of theseoutcomeswas expressedas a percentagewith 95% confidenceintervals (CI). Correlates between 12 prospectivelychosenclinical variables and individual end points were determined using multiple logistic regression. Of 594 consecutive patients with suspected AMI admitted to the coronary care unit of a major teaching hospital between January 1, 1991 and December 31, 1991,335 (56.4%) received verapamil within the$rst 24 hours of admission and in the majority ofpatients, withFrom the Cardiology Unit, The Queen Eliibeth Hospital, The University of Adelaide, 28 Woodville Road, Woodville South, South Australia, Australia 5011; and the Epidemiology Branch, South Australian Health Commission, South Australia, Australia. Dr. A&all is suppxted by a National Heart Foundation Postgraduate Medical Research Grant. Manuscript received April 7,1992; revised manuscript received and accepted June 23,1992.
MD,
Ronald D. Wuttke,
BAPPSC,
in the jirst 2 hours. Among the remaining 259 patients (43.6%), the immediate use of verapamil was contraindicated in 74 (28.6%) due to hypotension, right ventricular infarction, symptomatic pulmonary congestion or known clinically significant left ventricular systolic dysfunction. Severe bradycardia or atrioventricular conduction disturbance precluded its use in 12 patients (4.6%). Therapy with other calcium antagonists was continued or begun in 63 (24.3%) and &adrenoceptor antagonists, either in combination with other calcium antagonists or alone, were continued or instituted in 90 patients (34.7%). Neither a calcium antagonist nor a ,0-adrenoceptor antagonist was prescribed in 21 patients (8.1%) by physician choice. No patient received verapamil and any P-adrenoceptor antagonists concurrently. The 335 patients receiving verapamil within the first 24 hours of admission had a mean age of 62 f 11 (SD) years (range 26 to 82 y) and 67% were men. Previous Qwave infarction was noted on admission electrocardiogram in 15.5%. Threatened infarct site was anterior in 45% of cases, inferoposterior in 39.5% and uncertain (because of nonspecific electrocardiographic changes or bundle branch block) in 15.5%. Evolution of AMI was confirmed in 52% of the group; the mean peak creatine kinase level was 1,678 f 1,357 IU,liter in this group and 35% of patients had Q-wave infarcts. Intravenous or oral (240 to 360 mg/day) verapamil, or both, was administered as previously described.8 The initial intravenous administration of verapamil (29.3% of patients studied) at 1 mg/min up to a maximum of 5 mg, or a decrease in systolic bloodpressure to 100 mg Hg was restricted to patients with transmural ischemia, without contraindications to verapamil and no p-adrenoceptor antagonist therapy in the preceding 24 hours, and usually associated with thrombolytic therapy. Other concomitant cardiac pharmacotherapy included intravenous streptokinase in 29.370, and intravenous or oral long-acting nitrates, or both, in 95.8% of patients; 16.1% of patients had received &adrenoceptor antagonists within the previous 24 hours. Among patients treated with verapamil, the clinical findings on arrival to the coronary care unit included a mean systolic blood pressure of 139 f 26 mm Hg (range 55 to 240) and mean heart rate of 76 f 15 beatslmin (range 25 to 130). No patient received verapamil until resolution of initial hypotension or bradycardia, or both. Asymptomatic pulmonary congestion diagnosed on chest x-ray or the Jinding of basal lung crackles on auscultation was noted in 7.5%. Over the subsequent 3 days, one or more significant adverse events including death, symptomatic bradycardia requiring treatment or symptomatic left ventricular failure occurred in 37 patients (11 .O%, 95% CI: 8.1 to 14.8%). Eight patients (2.4%, 95% CL 1.2 to 4.6%) died BRIEF REPORTS
1611
TABLE I Significant
Correlates of Adverse Outcome First Three Days After Onset of Infarction in Patients with Verapamil*
During the Treated
End Point
Clinical Variable Mean peak serum Creatine kinase Q-wave infarct Past Q-wave infarct Initial heart rate (> 100 beats/min) Initial pulmonary congestion
Bradyarrhythmia 9.2 (1.4-61.6) 31.3 (3.4-291.9)
Left Ventricular Failure
7.1
(1.4-37.2) 3.6 (1.0-12.7) 12.8 (2.8-59.6) 29.7 (4.3-40.5)
*Odds ratio and 95% confidence intervals are given for all parameters correlating (p CO.05) with the prospectively designated end points. Parameters used in multiple lo istic regression were: (1) age, (2) sex, (3) past Q-wave infarction, (4) Q-wave m .f archon, (5) peak serum creatine kinase, (6) use of intravenous verapamil, (7) use of thrombolytic therapy, (8) use of p-adrenergic receptor antagonists within the previous 24 hours, (9) initial systolic blood pressure ~100 mm Hg, (10) initial heart rate > 100 beatsimin, (11) Initial heart rate ~60 beats/min, (12) and initial pulmonary congestion. No significant correlates were found for death.
becauseof development of cardiogenic shock in 3 and sudden onset of electromechanical dissociation due to confirmed or presumed cardiac rupture in 5. Symptomatic bradyarrhythmias (sinus bradycardia or atrioventricular block) occurred in 15 patients (4.5%, 95% CI: 2.7 to 7.3%).In 4, the bradycardia immediately preceded the onset of electromechanical dissociation. Twenty-one patients (6.3%, 95% CI: 4.3 to 8.7%) developedsymptomatic left ventricular failure requiring treatment: 2 of these died within 3 days. Correlations betweenpatient characteristics and incidenceof adverseeventsare summarized in Table I. No variables weresignificantly predictive of death,probably reflecting type II error. However, the most common causeof death was not cardiogenic shock as was the case in the DAVIT I study,7 but cardiac rupture. Bradyarrhythmias were significantly associatedwith larger infarcts as was subsequent left ventricular failure. The strongestpredictor of the developmentof left ventricular failure was initial pulmonary congestion; tachycardia (possibly representing hemodynamic responseto incipient left ventricular failure) was also predictive of this adverseevent.Both previous and current transmural infarction were also significant correlates of the development of left ventricular failure.
1612
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
In summary, early mortality in this group of verapamil-treated patients tendedto be lower than in previously reported similar studies.7*g Furthermore, the incidenceof cardiogenic shock in this group of verapamil-treated patients also was low (0.9%). Nonfatal deterioration of hemodynamic function occurred more often, and was predicted by initial clinical parameters,suggestingpotential for hemodynamic compromise. This is consistent with previousexperiencewith both verapami12and diltiazem,4 but does not necessarilyrepresent a contraindication to the useof this classof drugs. The useof thrombolysis (in 29%of the study group) doesnot explain the low mortality. This disparity betweenour observationsand the early results of DAVIT-I7 and International Study of Infarct Survival-2g- while it may partially reflect differencesin patient selection- may be explained by the more cautious use of intravenous verapamil, the extensiveuse of thrombolysis for patients at risk of large infarcts, and perhaps synergistic cardioprotective effects betweenverapamil and nitroglycerin.8J0 Our data therefore suggestthat the potential disadvantages of verapamil treatment early in the course of AM1 can be minimized. The potential benefits of such treatment therefore require reexamination in a large placebo-controlled trial. 1. -Messerli FH. “Cardioprotection” - not all calcium antagonistsare created cqual. Am J Cardiol 1990;66:855-856.
2. The Danish Study Group on VerapamiI in Myocardial Infarction. Effect of verapamil on mortality and major eventsafter acute myocardial infarction (The Danish Verapamil Infarction Trial II - DAVIT II). Am J Cardiol 1990;66: 779-785. 3. GibsonRS, BodenWE, Therow. P, StraussHD, Pratt CM, GheorghiadeM, et al. Dikiazem and reinfarction in patientswith non-Q-wavemyocardial infarction. Results of a double-blind, randomized, multicenter trial. N Engl J Med 1986;315:423-429. 4. The Multicenter Diltiazem P&infarction Trial ResearchGroup. The effect of diltiazem on mortality andreinfarction after myocardial infarction. NEngl JA4ed 1988;319:385-392. 5. Heikkila J, Nieminen MS. Effects of verapamil in patientswith acute myocardiil infarction: hemodynamicsand function of normal and ischemicleft ventricular mywardium. Am Heart J 1984;107:241-247. 6. BussmanWD, Seher W, Gruengras M. Reduction of creatine kinase and creatine kinase-MB indexesof infarct size by intravenousverapamil. Am J Cardial 1984;54:1224-1230. 7. The Danish Study Group on Verapamil in Acute Myocardial Infarction. Verapamil in acute myocardial infarction. Eur Heart J 1984;5:516-528. 6. Lee KJ, Horowitz JD, McKay WJ, Gable AJ. MyocardiaI salvagewith streptokinase combinedwith nitroglycerine and verapamil in acute mywardial infarction. Int J Cardiol 1988;21:279-291. 9. ISIS-2 (.+ond International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187casesof suspectedacute myocardial infarction: ISIS-2. Lance? 1988;332:349-359. 10. Schwartz JS, Bathe RJ. Combinedeffects of calcium antagonistsand nitroglycerin on large coronary artery diameter. Am Heart J 1988;115:964-969.
DECEMBER 15, 1992
Incidence of Adverse Events During Treatment with Verapamil for Suspected Acute Myocardial Infarction Margaret A. Arstall, Adrian J. Esterman,
MBBS, Msc,
John F. Beltrame, BMBS, Puneet Mohan, and John D. Horowitz, PhD
he potential clinical role of non-dihydropyridine calT cium antagonists, such as verapamil and diltiazem, in the managementof patients during and subsequentto acute myocardial infarction (AMI) is an area of considerable and changing controversy.’ Recent investigations suggest that both verapami11,2and diltiazem1*3,4exert beneficial effectsafter AMI, largely, if not entirely mediated by reduction in the incidence of reinfarction. However, there is considerableconcern about the useof these negatively inotropic calcium antagonistsin patients with significantly impaired left ventricular systolic function.1,2,4Although diltiazem may be beneficial in the periinfarct period3and verapamil may exert beneficial effects on both ischemia5 and infarct size6in this setting, the results of the only large randomized study conducted to date concerning the early use of verapamil- Danish Verapamil Infarction Trial-I (DAVIT-I)’ - discouraged initiation of verapamil therapy in the first week, representing the period of maximal risk for reinfarction. Specifically, in DAVIT-I the incidence of death due to cardiogenic shock or pulmonary edema,or both, complicating infarction was 5.3%,somewhathigher than in the placebo-treated patients (3.2%). These results of DAVIT-I may have been influenced by the use of large intravenous doses of the drug and by the absenceof thrombolytic therapy, which would be expectedto both reducethe potential risk of the developmentof cardiogenic shock and increasethe risk of reinfarction. Therefore, there is a needto reevaluatethis area of therapeutics.We prospectively examined the incidence of potential drugassociatedadverseeventsin consecutivepatients t.reated with intravenous or oral verapamil, or both, in the early managementof suspectedAMI. We also sought toIdetermine potential clinical parameters predisposing to the occurrenceof such adverseoutcomes.End points i.ncluded death, significant bradyarrhythmia requiring treatment due to hemodynamiccompromiseand symptomatic left ventricular failure. Frequency of theseoutcomeswas expressedas a percentagewith 95% confidenceintervals (CI). Correlates between 12 prospectivelychosenclinical variables and individual end points were determined using multiple logistic regression. Of 594 consecutive patients with suspected AMI admitted to the coronary care unit of a major teaching hospital between January 1, 1991 and December 31, 1991,335 (56.4%) received verapamil within the$rst 24 hours of admission and in the majority ofpatients, withFrom the Cardiology Unit, The Queen Eliibeth Hospital, The University of Adelaide, 28 Woodville Road, Woodville South, South Australia, Australia 5011; and the Epidemiology Branch, South Australian Health Commission, South Australia, Australia. Dr. A&all is suppxted by a National Heart Foundation Postgraduate Medical Research Grant. Manuscript received April 7,1992; revised manuscript received and accepted June 23,1992.
MD,
Ronald D. Wuttke,
BAPPSC,
in the jirst 2 hours. Among the remaining 259 patients (43.6%), the immediate use of verapamil was contraindicated in 74 (28.6%) due to hypotension, right ventricular infarction, symptomatic pulmonary congestion or known clinically significant left ventricular systolic dysfunction. Severe bradycardia or atrioventricular conduction disturbance precluded its use in 12 patients (4.6%). Therapy with other calcium antagonists was continued or begun in 63 (24.3%) and &adrenoceptor antagonists, either in combination with other calcium antagonists or alone, were continued or instituted in 90 patients (34.7%). Neither a calcium antagonist nor a ,0-adrenoceptor antagonist was prescribed in 21 patients (8.1%) by physician choice. No patient received verapamil and any P-adrenoceptor antagonists concurrently. The 335 patients receiving verapamil within the first 24 hours of admission had a mean age of 62 f 11 (SD) years (range 26 to 82 y) and 67% were men. Previous Qwave infarction was noted on admission electrocardiogram in 15.5%. Threatened infarct site was anterior in 45% of cases, inferoposterior in 39.5% and uncertain (because of nonspecific electrocardiographic changes or bundle branch block) in 15.5%. Evolution of AMI was confirmed in 52% of the group; the mean peak creatine kinase level was 1,678 f 1,357 IU,liter in this group and 35% of patients had Q-wave infarcts. Intravenous or oral (240 to 360 mg/day) verapamil, or both, was administered as previously described.8 The initial intravenous administration of verapamil (29.3% of patients studied) at 1 mg/min up to a maximum of 5 mg, or a decrease in systolic bloodpressure to 100 mg Hg was restricted to patients with transmural ischemia, without contraindications to verapamil and no p-adrenoceptor antagonist therapy in the preceding 24 hours, and usually associated with thrombolytic therapy. Other concomitant cardiac pharmacotherapy included intravenous streptokinase in 29.370, and intravenous or oral long-acting nitrates, or both, in 95.8% of patients; 16.1% of patients had received &adrenoceptor antagonists within the previous 24 hours. Among patients treated with verapamil, the clinical findings on arrival to the coronary care unit included a mean systolic blood pressure of 139 f 26 mm Hg (range 55 to 240) and mean heart rate of 76 f 15 beatslmin (range 25 to 130). No patient received verapamil until resolution of initial hypotension or bradycardia, or both. Asymptomatic pulmonary congestion diagnosed on chest x-ray or the Jinding of basal lung crackles on auscultation was noted in 7.5%. Over the subsequent 3 days, one or more significant adverse events including death, symptomatic bradycardia requiring treatment or symptomatic left ventricular failure occurred in 37 patients (11 .O%, 95% CI: 8.1 to 14.8%). Eight patients (2.4%, 95% CL 1.2 to 4.6%) died BRIEF REPORTS
1611
TABLE I Significant
Correlates of Adverse Outcome First Three Days After Onset of Infarction in Patients with Verapamil*
During the Treated
End Point
Clinical Variable Mean peak serum Creatine kinase Q-wave infarct Past Q-wave infarct Initial heart rate (> 100 beats/min) Initial pulmonary congestion
Bradyarrhythmia 9.2 (1.4-61.6) 31.3 (3.4-291.9)
Left Ventricular Failure
7.1
(1.4-37.2) 3.6 (1.0-12.7) 12.8 (2.8-59.6) 29.7 (4.3-40.5)
*Odds ratio and 95% confidence intervals are given for all parameters correlating (p CO.05) with the prospectively designated end points. Parameters used in multiple lo istic regression were: (1) age, (2) sex, (3) past Q-wave infarction, (4) Q-wave m .f archon, (5) peak serum creatine kinase, (6) use of intravenous verapamil, (7) use of thrombolytic therapy, (8) use of p-adrenergic receptor antagonists within the previous 24 hours, (9) initial systolic blood pressure ~100 mm Hg, (10) initial heart rate > 100 beatsimin, (11) Initial heart rate ~60 beats/min, (12) and initial pulmonary congestion. No significant correlates were found for death.
becauseof development of cardiogenic shock in 3 and sudden onset of electromechanical dissociation due to confirmed or presumed cardiac rupture in 5. Symptomatic bradyarrhythmias (sinus bradycardia or atrioventricular block) occurred in 15 patients (4.5%, 95% CI: 2.7 to 7.3%).In 4, the bradycardia immediately preceded the onset of electromechanical dissociation. Twenty-one patients (6.3%, 95% CI: 4.3 to 8.7%) developedsymptomatic left ventricular failure requiring treatment: 2 of these died within 3 days. Correlations betweenpatient characteristics and incidenceof adverseeventsare summarized in Table I. No variables weresignificantly predictive of death,probably reflecting type II error. However, the most common causeof death was not cardiogenic shock as was the case in the DAVIT I study,7 but cardiac rupture. Bradyarrhythmias were significantly associatedwith larger infarcts as was subsequent left ventricular failure. The strongestpredictor of the developmentof left ventricular failure was initial pulmonary congestion; tachycardia (possibly representing hemodynamic responseto incipient left ventricular failure) was also predictive of this adverseevent.Both previous and current transmural infarction were also significant correlates of the development of left ventricular failure.
1612
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
In summary, early mortality in this group of verapamil-treated patients tendedto be lower than in previously reported similar studies.7*g Furthermore, the incidenceof cardiogenic shock in this group of verapamil-treated patients also was low (0.9%). Nonfatal deterioration of hemodynamic function occurred more often, and was predicted by initial clinical parameters,suggestingpotential for hemodynamic compromise. This is consistent with previousexperiencewith both verapami12and diltiazem,4 but does not necessarilyrepresent a contraindication to the useof this classof drugs. The useof thrombolysis (in 29%of the study group) doesnot explain the low mortality. This disparity betweenour observationsand the early results of DAVIT-I7 and International Study of Infarct Survival-2g- while it may partially reflect differencesin patient selection- may be explained by the more cautious use of intravenous verapamil, the extensiveuse of thrombolysis for patients at risk of large infarcts, and perhaps synergistic cardioprotective effects betweenverapamil and nitroglycerin.8J0 Our data therefore suggestthat the potential disadvantages of verapamil treatment early in the course of AM1 can be minimized. The potential benefits of such treatment therefore require reexamination in a large placebo-controlled trial. 1. -Messerli FH. “Cardioprotection” - not all calcium antagonistsare created cqual. Am J Cardiol 1990;66:855-856.
2. The Danish Study Group on VerapamiI in Myocardial Infarction. Effect of verapamil on mortality and major eventsafter acute myocardial infarction (The Danish Verapamil Infarction Trial II - DAVIT II). Am J Cardiol 1990;66: 779-785. 3. GibsonRS, BodenWE, Therow. P, StraussHD, Pratt CM, GheorghiadeM, et al. Dikiazem and reinfarction in patientswith non-Q-wavemyocardial infarction. Results of a double-blind, randomized, multicenter trial. N Engl J Med 1986;315:423-429. 4. The Multicenter Diltiazem P&infarction Trial ResearchGroup. The effect of diltiazem on mortality andreinfarction after myocardial infarction. NEngl JA4ed 1988;319:385-392. 5. Heikkila J, Nieminen MS. Effects of verapamil in patientswith acute myocardiil infarction: hemodynamicsand function of normal and ischemicleft ventricular mywardium. Am Heart J 1984;107:241-247. 6. BussmanWD, Seher W, Gruengras M. Reduction of creatine kinase and creatine kinase-MB indexesof infarct size by intravenousverapamil. Am J Cardial 1984;54:1224-1230. 7. The Danish Study Group on Verapamil in Acute Myocardial Infarction. Verapamil in acute myocardial infarction. Eur Heart J 1984;5:516-528. 6. Lee KJ, Horowitz JD, McKay WJ, Gable AJ. MyocardiaI salvagewith streptokinase combinedwith nitroglycerine and verapamil in acute mywardial infarction. Int J Cardiol 1988;21:279-291. 9. ISIS-2 (.+ond International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187casesof suspectedacute myocardial infarction: ISIS-2. Lance? 1988;332:349-359. 10. Schwartz JS, Bathe RJ. Combinedeffects of calcium antagonistsand nitroglycerin on large coronary artery diameter. Am Heart J 1988;115:964-969.
DECEMBER 15, 1992
