Comparison of verapamil and nifedipine in the treatment of variant angina pectoris: Preliminary observations in 10 patients

Comparison of Verapamil and Nifedipine in The Treatment of Variant Angina Pectoris: Preliminary Observations in IO Patients M. JOHNSON,

MD

DAVID

STACEY

R. MAURITSON.

MD

JAMES

T. WILLERSON,

L. DAVID

HILLIS,

MD,

MD, FACC FACC

with the technical assistance of BEVERLY __._.._. SNOWY

.I. ERCK _. ______ B. BROWN

Dallas, Texas

From the Department of Internal Medicine, Cardiovascular Division, University of Texas Health Science Center, Dallas, Texas. This work was supported by Grant HL-17669 (Ischemia SCOFt) from the National Institutes of Health, Bethesda, Maryland. Manuscript received November 18. 1980; revised manuscript received January 12. 1981, accepted January 15. 1981. Address foe reprints: L. David Hillis. MD, Room L5 134, University of Texas Health Science Center. 5323 Harry Hines Boulevard, Dallas, Texas

75235.

To assess the relative efficacy of verapamii, nifedipine and placebo in the therapy of patients with variant angina pectoris, 10 such patients (6 men and 4 women, average age 52 years) were treated for 2 month pertods with verapamii (mean f standard devlation 400 f 80 mg/day in three to six equal doses; range 240 to 480 mg/day), nlfedipine (82 f 31 mg/day in four to six equal doses; range 40 to 160 mg/day) and placebo. Eight of the 10 patients were maintained throughout the study on a stable regimen of oral isosorblde dinltrate (137 f 56 mg/day in four to six equal doses; range 40 to 200 mg/day). Before the study, all underwent cardiac catheterization: ei@t had no fixed coronary artery dtsease, ona had single vessel and one had triple vessel disease. Two patients had been resuscitated from sudden cardiac death before the study. Each patient underwent calibrated two channel ambulatory electrocardiographic monitoring for 24 hours during each week of the study. During each 2 month period, the foilowlng data were quantitated: (1) chest pains per week, (2) nitroglycerin tablets used per week, (3) required hospitalizations for clinical instability, (4) adverse effects, and (5) episodes of transient S-T segment deviation on ambulatory monitoring. The number of chest pains per week, the number of nitroglycerin tablets used per week and the number of transient S-T segment deviations on caiibrated two channel ambulatory electrocardiographic monitoring were similar during treatment with verapamii and nlfedlpine and less than wtth placebo. Hospttaitzatton for clinical instabiilty was requtred in two pattents taking placebo and in two taking nlfedipine; no patient required hospitalization during treatment with verapamii. Verapamii caused mild constipation in two patients, stnus nodal pauses in one pattent and pafpltations in one; none of these effects forced a discontinuation or substantlai reduction in dosage. in contrast, the dosage of nlfedipine was reduced because of induced orthostatic hypotension in two patients, marked pedal dizziness edema in one patient and nausea, anorexia and nonorW&atk in three. Thus verapamii and nifediptne showed slmiiar efficacy in the treatment of variant angina, although nlfedfpina was associated wlth more substantial adverse effects than either placebo or verapamii in this small number of patients.

Over the past 10 to 15 years a group of pharmacologic agents known as calcium antagonists has been used extensively outside the United States for the treatment of several different forms of ischemic heart disease, including variant angina pectoris. These agents inhibit the movement of calcium from the extra- to the intracell space in both cardiac and arterial smooth muscle and. as a result. mav diminish both arterial tone and myocardial contractility. Of the available calcium antagonists, verapamil and nifedipine appear promising in the therapy of variant angina. Preliminary reportsl-s have shown that both agents are effica-

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cious in this syndrome. compare their efficacy gina.

This study in patients

ET AL.

was performed to with variant an-

Methods Study Patients Ten patients (six men and four women, average age 52 years) were diagnosed as having Prinzmetal’s variant angina pectoris after they had one or more episodes of angina at rest associated with reversible S-T segment elevation of at least 0.2 mV on electrocardiography. In 8 of the 10 patients, the S-T segment elevation occurred in one or more of the 11 standard electrocardiographic leads (excluding aVR); in the other two, multiple episodes of S-T segment elevation of at least 0.2 mV were recorded on a calibrated two channel Holter monitor. In association with these episodes, no patient demonstrated evidence of myocardial necrosis on electrocardiographic, enzymatic (as assessed by serum creatine kinase and creatine kinase MB isoenzyme measurements) or scintigraphic (as evaluated by technetium stannous pyrophosphate imaging) study. At cardiac catheterization, 8 of the 16 patients had no fixed coronary artery disease (defined as at least 70 percent narrowing of luminal diameter), one had single vessel and one had triple vessel coronary artery disease. During the months before enrollment in the study, one patient with angiographically normal coronary arteries had three myocardial infarctions and one episode of sudden cardiac death from which he was resuscit,ated, all presumably due to coronary arterial spasm; another patient with only a 20 percent fixed stenosis of the proximal right coronary artery had survived an episode of sudden death. The criteria that served as bases of exclusion from the study are shown in Table I.

Study Design After the diagnosis of variant angina pectoris was established, a therapeutic trial of 10 months’ duration was begun

TABLE I Bases of Exclusion From Study Underlying diseases Congestive heart failure (manifested by cardiomegaly, hepatomegaly. alveolar rales, Ss, venous hypertension, pulmonary capillary wedge pressure > 12 mm Hg, cardiac index <2 liters/min) Uncontrolled systemic arterial hypertension (diastolic blood pressure >115mmHg) Hypotension (systolic blood pressure <90 mm Hg) Associated valve or conaenital cardiac disease Azotemia (serum creatir%e >2 mg percent) Clinically important hepatic disease (serum bilirubin >2 mg percent, serum glutamic oxaloacetic transaminase or serum glutamid pynivic transaminase three times the upper limit of normal) Clinically important electrolyte imbalance Insulin-dependent diabetes mellitus Myocardial infarction within 3 months of study A terminal illness of any sort Sick sinus syndrome (without a functioning ventricular pacemaker) Electrocardiographic abnormalities Left bundle branch block Severe bradycardia (GO beats/min) Second or third degree atrioventricular block Atrial flutter or fibrillation Preexcitation syndrome Concomitantly administered medications Disopyramide Beta adrenergic blocking agents Another investigational drug Miscellaneous Reluctance to give informed consent

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in each patient. The first 8 months consisted of 4 two month periods during which placebo and verapamil* (mean f standard deviation 400 f 80 mg/day in three to six equal doses; range 240 to 480 mg/day) were administered as part of a double-blind, randomized, double crossover trial. During the final 2 months, nifedipinet (82 f 31 mg/day in four to six equal doses; range 40 to 160 mg/day) was administered as an “open label” medication (that is, neither blinded nor randomized).* In all patients verapamil and nifedipine were administered in dosages that afforded maximal relief of angina without limiting adverse effects. In addition to treatment with placebo, verapamil and nifedipine, 8 of the 10 patients were treated throughout the study with oral isosorbide dinitrate (137 f 56 mgfday in four to six divided doses; range 40 to 200 mgl day).

Variables Analyzed Clinical response to therapy: During the study, each of the 10 patients was seen at least monthly by one of the investigators, and the following were quantitated: (1) episodes of angina per week (recorded daily by the patient in a diary), (2) sublingual nitroglycerin tablets consumed per week (recorded daily by the patient in a diary), (3) adverse effects, and (4) hospitalizations required because of failure of treatment and clinical instability. Electrocardiographic response to therapy: For 24 hours during each week of the study, each patient underwent calibrated two channel ambulatory electrocardiographic monitoring. Two bipolar monitoring leads were used. Channel 1 recorded a QRS-T complex resembling lead Vs or standard lead II in a 12 lead electrocardiogram from an exploring electrode at the V5 or Vs position and a reference electrode to the right of the manubrium sterni. Channel 2 recorded a QRS-T complex that resembled lead Vi or Vz in a 12 lead electrocardiogram from an exploring electrode at the fourth or fifth intercostal space to the right of the sternum and a reference electrode to the left of the manubrium sterni. The fifth (ground) electrode was placed in the V5R position. Thus, channel 1 was an inferolateral channel, and channel 2 an anteroinferior channel. Before the initial Holter monitor was recorded in each patient, the signal from each channel was recorded on a standard electrocardiograph with the patient standing, sitting, supine and lying on the left and right sides, as well as during hyperventilation. The complexes were examined to ensure that changes in position and in breathing did not cause S-T segment deviations. Each patient returned weekly to have a Holter monitor attached by one of us or the technical assistants, after which normal activity was resumed. Twenty-four hours later, the patient returned to have the Holter monitor removed. Before each recording period, the recorder (DelMar Avionics Electrocardiocorder, model 445, DelMar Avionics Corp, Irvine, California) was loaded with a new magnetic tape reel, and a 1 mV calibration test signal was recorded for 3 minutes. Then, after the patient cable was attached to the Holter recorder, the clock contained within the recorder was set, and the patient was instructed to use the event signal button when chest pain occurred. In addition, he was instructed to maintain a written diary of symptoms and activities during the monitoring period. Kindly supplied by Knoll Pharmaceutical Company, Whippany, New Jersey. + Kindly supplied by Pfizer Pharmaceutical Company, New York, New York. t The reason for this course of therapy was the unavailability of properly packaged medications.

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At the end of each recording period, the Holter recorder and diary were removed from the patient, and the 1 mV calibration signal recorded at the beginning of each tape was used to calibrate the Electrocardioscanner (DelMar Avionics Millivolt Calibrator, model 356B; DelMar Avionics Electrocardioscanner, model 655). Specifically, the gain control on the scanner was adjusted so that a 1 mV calibration signal caused a 10 mm deflection of the recording needle on the chart recorder. All Holter equipment performed in accordance with American Heart Association specifications with respect to rate and frequency response necessary to record S-T segment alterations reliably.6 After the scanner was calibrated, each channel was scanned at 120 times real time using the Audio Visual Superimposed Electrocardiographic Presentation (AVSEP) method. During scanning, the superimposed PQRS-T complexes on the AVSEP screen were scrutinized continuously by one of us. Whenever an S-T alteration from baseline was suspected, scanning was interrupted, and the recording was transcribed onto Electrocardiochart? recording paper for an exact measurement of the S-T segment. In addition, the electrocardiographic recording was charted and the S-T segment position measured whenever the patientevent signal appeared on the tape. The S-T segment position was judged in relation to the P-R intervals immediately before and after the S-Tsegment. A straight edge was used to construct a line between the P-R intervals of the two adjacent P-QRS-T complexes, and the position of the S-T segment was measured in millimeters of vertical distance above or below the line 80 ms after the J point. S-T segment deviations were defined as transient vertical displacements in S-T segment position relative to baseline position. The S-T segment deviations from the baseline position were said to occur if S-T depression or elevation of at least 1 mm (0.1 mV) relative to the baseiine position was present for at least 1 minute. One minute of S-T segment deviation was required in an attempt to minimize misinterpretation due to transient motion artifact. For each tape, the following were quantitated: (1) hours of recording satisfactory for analysis, (2) episodes of S-T segment deviation, and (3) highest grade of ventricular ectopic activity (using the modified Lown grading system7).

ET AL.

Data Analysis In our study, each variable was quantitated during the latter 4 months of blinded therapy (2 months with placebo, 2 months with verapamil) as well as the 2 months with nifedipine therapy. A repeated measures analysis of variance was performed for each variable analyzed to determine if some groups were different from others, after which the Newman-Keuls multiple comparison procedure was performed.s The Friedman chi-square nonparametric tests was also used to evaluate each variable, after which nonparametric multiple comparisons were performed. When the effects of non-normality were sufficient to cause substantial disagreement between parametric and nonparametric procedures, results of the nonparametric analysis were reported. All values were expressed as mean f standard deviation; mean f standard error was used for the purposes of the figures only. A probability (p) value of 0.05 or less was considered significant, unless specifically stated otherwise. When comparing the frequency of clinical instability among placebo, verapamil and nifedipine, a standard chi-square analysis was performed and, when appropriate, Fisher’s exact test was used. Again, a p value of 0.05 or less was considered significant. Results

compliance: Drug compliance for the 10 patients during the three treatment periods was 87 f 12 percent for placebo (range 67 to loo), 89 f 8 percent for verapamil (range 74 to 100) and 84 f 13 percent for nifedipine (range 50 to 100) (difference not significant). Clinical response to therapy: During therapy with both verapamil and nifedipine, the frequency of angina was reduced (p = 0.066) in comparison with placebo (Table II, Fig. 1). Similarly, nitroglycerin consumption Drug

110

s

30 % TABLE II Clinical and Electrocardiographic

Responses to Therapy Vera-

Variable Angina1 episodes/week Mean f SD Range Nitroglycerin tablets/week Mean f SD Range S-T segment deviations/week Mean f SD Range Highest grade of ventricular arrhythmia (Lown grading system)6 Mean f SD Range

Placebo

pamil

Nifedipine

15.9 f 37.2 O-106.1

2.2 f 3.3’ o-5.1

1.2 f 1.5’ o-4.7

la.3 f 46.4 0.13-150

3.2 f 5.6+ o-17.8

2.4 f 4.3+ o-14.3

6959F O-333

“1% o-44.4

40.1 f 40.5 O-l 16.9

OPlacebo

3.3 f 1.6 o-5

p = 0.066 in comparison with placebo. + p <0.05. l

$ \ a B 20.r w” 6 .5 P a IO-

2.5 f 1.5 L o-5

3.4 f 1.5 l-5

Verapamil

Nifedipine

FtGURE 1. Number of angina1epispdes per week during placebo (left), verapamil (middle) and nifedipine (right). Each line represents one patient, and the mean’ f standard error of the mean is shown for each treatment procedure. No difference in the frequency of angina occurred between verapamil and nifedipine. + p = 0.066 when compared with placebo.

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15Or

\

ET AL.

2

s

Y-

\

:100-

3

\ % 80.‘5 ‘5 w 60n E E

40-

: cn I- 20cn

I*2

O-

I Placebo

Verapamil

FIGURE 2. Number of nitroglycerin tablets consumed per week during placebo (left), verapamil (middle) and nifedipine (right). Each Ilm represents one patient, and the mean f standard error of the mean is shown for each treatment procedure. In comparison with placebo, nitroglycerin utilization was less during treatment with verapamil and nifedipine, and there was no difference between these two agents. * p <0.05 when compared with placebo.

decreased significantly during therapy with both verapamil and nifedipine (Table II, Fig. 2). During therapy with placebo, there were no adverse effects. During the 2 months of verapamil therapy, one patient had palpitations (in conjunction with an accelerated atrioventricular nodal rhythm on Holter monitor), one had asymptomatic sinus nodal pauses of 2 seconds’ duration during sleep and two had mild constipation. None of these adverse effects forced a discontinuation or marked reduction in dosage of verapamil. During nifedipine therapy, six patients had adverse effects, all of which limited the dosage that could be administered: two had orthostatic hypotension, one had substantial pedal edema and three complained of nausea, anorexia and nonorthostatic dizziness. During placebo therapy, 2 of the 10 patients required hospitalization because of severe angina; 2 patients required hospitalization for chest pain during nifedipine therapy, and no patient was hospitalized during treatment with verapamil (difference not significant). No patient had a myocardial infarction or died. Electrocardiographic response to therapy: During the 6 months of study in all 10 patients, a total of 5,169 hours of two channel ambulatory electrocardiographic monitoring were analyzed (1,733 hours during placebo therapy, 1,681 hours during verapamil therapy and 1,755 hours during nifedipine therapy). The number of episodes of transient S-T segment deviation on calibrated two channel ambulatory electrocardiographic monitoring was less during therapy with verapamil and nifedipine than during placebo therapy (Table II, Fig. 3). There was no difference among the three pharmacologic agents in the complexity of ventricular ectopic activity.

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I Placebo

Nifedipine

I*

Vempamil

Nifedipine

FlGURE 3. Number of transient S-T segment deviations per week on ambulatory electrocardiographic monitoring during placebo (left), verapamil (middle) and nifedipine (rlght). Each llrw represents cne patient, and the mean f standard error of the mean is shown for each treatment pocedue. In comparison wtth placebo, the frequency of S-T segment deviations was reduced during verapamil and nifedipine and there was no difference between these two agents. p CO.05 when compared with placebo. l

Discussion Initial reports on the therapeutic use of calcium antagonist agents demonstrated that perhexiline maleate,‘O prenylamine lactate,i’ diltiazem,i2Js verapami11*2~14-*6 and nifedipine3-sJ7v18 are efficacious in several forms of ischemic heart disease, including variant angina pectoris. To date, however, the therapeutic efficacy of the different calcium antagonists has not been compared. Therefore, this study was performed to compare verapamil and nifedipine in patients with variant angina. Verapamil: Verapamil, a papaverine derivative available outside the United States since 1962, has been shown to be efficacious in several clinical circumstances. It is a very effective agent for the treatment of supraventricular tachyarrhythmia, especially paroxysmal supraventricular tachycardia.‘g*20 It exerts a powerful depressant effect on sinoatrial nodal automaticity and atrioventricular nodal conduction.1g,20 It has been used in a limited manner as an antihypertensive agent, and is beneficial in the patient with hypertrophic cardiomyopathy. 21~22Finally, it has been used in patients with a variety of ischemic heart disease syndromes, including exert.ional angina14315 and angina at rest.‘” Because of its potent influence on the cardiac conduction system, verapamil should not be administered to the patient with second or third degree atrioventricular block, sick sinus syndrome or suspected digitalis intoxication. In addition, it has a substantial negative inotropic effect and should therefore be administered cautiously to the patient with advanced cardiac failure. Because of this negative inotropic influence, it is recommended that verapamil not be administered simultaneously with beta adrenergic blocking agents or disopyramide.

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Nifedipine: Nifedipine is an especially powerful dilator of both systemic and coronary arteries. Like verapamil, it appears useful in several clinical circumstances. First, nifedipine is an effective antihypertensive agent.23 Second, it has been used as a myocardial “protectant” during cardiopulmonary bypass.24 Third, it is efficacious in patients with both angina of effort17,25 and angina at rest,18 and preliminary uncontrolled studies have shown it to be very effective in those with variant angina pectoris. 4,5 In contrast to verapamil, nifedipine exerts little if any influence on the cardiac conduction system. In addition, it exerts little negative inotropic effect and, as a result, can be administered concomitantly with propranolol.17 Ambulatory electrocardiographic monitoring for detection of S-T segment deviation: Since its de-

scription over 20 years ago26F27,ambulatory electrocardiographic monitoring has become established as an excellent technique for the detection of cardiac arrhythmia, but only over the past 5 years has it been utilized for the detection of transient ischemic S-T-T wave alterations.17,2s-34 The equipment available for monitoring during the 1960s offered poor fidelity for S-T segment reproduction.35 However, since 1969 all manufactured monitoring equipment has met or exceeded American Heart Association specifications for the reliable recording of S-T segment alterations.6fs--3s Provided that the limitations of a bipolar electrocardiographic system are accepted and careful attention is given to proper calibration and to maneuvers that exclude positional S-T segment alterations, ambulatory electrocardiographic recordings that accurately reflect transient S-T segment alterations can be obtained. In this study, weekly ambulatory electrocardiographic monitoring was performed in an effort to assess objectively the frequency of transient episodes of myocardial ischemia in an outpatient environment. The precise relation between myocardial ischemia and chest pain remains poorly defined.3g>40In patients with angina on effort and associated coronary artery disease, 60 to 80 percent of ischemic episodes (detected by transient S-T segment depression) occur without concomitant chest pain,173,41,42 and numerous reports43-47 have emphasized that episodes of painless S-T segment deviation occur frequently in patients with variant angina pectoris. Therefore, in our study calibrated two channel ambulatory electrocardiographic monitoring was used

to allow an objective assessment of disease activity independent of subjective influences. Verapamil

versus nifedipine in variant angina:

Our study demonstrates that verapamil and nifedipine are similarly efficacious in the therapy of variant angina. Subjectively, both agents reduced the frequency of angina and of nitroglycerin consumption. Objectively, both drugs diminished the frequency of transient ischemic S-T segment alterations by calibrated two channel ambulatory electrocardiographic monitoring. Adverse effects occurred more frequently during nifedipine therapy, and in 6 of the 10 patients these effects limited the dose of nifedipine that could be administered. In contrast, adverse effects with verapamil were minor and did not drastically alter the dosage. Although the results of this study are exciting and encouraging, further studies are needed to assess completely the relative effects of verapamil and nifedipine. Because our study encompasses only 10 patients, the results will require confirmation in a larger number of patients with variant angina. In this study, placebo and verapamil were administered as part of a double-blind and randomized protocol, but nifedipine was administered as an “open label” medication. Future studies will require the blinded administration of both calcium antagonists. Despite these limitations, this study clearly shows that verapamil and nifedipine are both highly efficacious in the therapy of variant angina pectoris. Clinical implications: In the patient with variant angina pectoris, both verapamil and nifedipine are effective therapeutic agents. The availability of both agents allows the patient with variant angina to receive the drug best suited for his specific needs, taking into account the presence or absence of conduction system disease, concomitant supraventricular tachyarrhythmias or depressed left ventricular function.48 If a patient does not tolerate one of these drugs, the other can be administered and a similar beneficial response anticipated. Acknowledgment We acknowledge the secretarial assistance of Juanita Alexander, the technical assistance of Joan R. Cary, and the support of the cardiology fellows and medical house officers at Parkland Memorial Hospital and the Veterans Administration Hospital, Dallas, Texas. We also acknowledge the expert assistance of Wayne Woodward, PhD, and Alan C. Elliott in the analysis of the data.

References Hansen JF, Sandoe E. Treatment of Prinzmetal’s angina due to coronary artery spasm using verapamil: a report of three cases. Eur J Cardiol 1978:7:327-35. Solberg LE, Nfsaen RG, Vlleafra RE, Callahan JA. Prinzmetal’s variant angina-response to verapamil. Mayo Clin Proc 1978; 53:256-g. Muller JE, Gunfher SJ. Nifedipine therapy for Prinzmetal’s angina. Circulation 1978;57:137-9. Gofdbq S, Rekhek N, WIfeon J, Hlrahfeld JW Jr, Yulfer J, Kastor JA. Nifedipine in the treatment of Prinzrnetal’s (variant) angina. Am J Cardiol 1979;44:804-10.

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5. Anlman E, Muller J, Goldberg S, el al. Nifedipine therapy for coronary artery spasm. N Engl J bled 1980;302:1269-73. 6. Plpberger HV, Arzbaecher RC, Berson AS, et al. Recommendations for standardization of leads and of specifications for instruments in electrocardiography and vectorcardiography. Circulation 1975;52:Suppl II:1 l-31. 7. Lown B, Woff M. Approaches to sudden death from coronary heart disease. Circulation 1971;44:130-42. 8. Noether GE. Introduction to Statistics. goston: Houghton Mifflin, 1971;147-50. 9. Zar JH. Biostatistical Analysis. New York: Prentice-Hall, 1974,

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173-7. 10. Raabe DS Jr. Treatment of variant angina pectoris with perhexiline maleate. Chest 1979;75:152-6. 11. Winsor T, Bleffer K, Cole S, et al. A double-blind, double crossover trial of prenylamine in angina pectoris. Am Heart J 1971;82:4354. 12. Feldman RL, Whittle JL, Pepine CJ, Curry C, Contl CR. Effects of the calcium antagonist diltiazem in patients with variant angina (abstr). Circulation 1980;62:Suppl lll:lll-296. 13. Schroeder JS, Rosenthal S, Ginsburg R, Lamb I. Medical therapy of Prinzmetal’s variant angina. Chest 1980;Suppl 78:231-3. 14. Sandler G, Clayton GA, Thornicrofl SG. Clinical evaluation of verapamil in angina pectoris. Br Med J 1968;3:224-7. 15. Lfvesley B, Catley PF, Campbell RC, Oram S. Double-blind evaluation of verapamil, propranolol, and isosorbide dinitrate against a placebo in the treatment of angina pectoris. Br Med J 1973; 1~375-8. 16. Parodi 0, Maser1 A, Simonetti I. Management of unstable angina at rest by verapamil: a double-blind cross-over study in coronary care unit. Br Heart J 1979;41:167-74. 17. Lynch P, Dargie H, Krikler S, Krlkier D. Objective assessment of antianginal treatment: a double-blind comparison of propranolol, nifedipine, and their combination. Br Med J 1980;3:184-7. 18. Previtali M, Salerno JA, Tavazzi L, et al. Treatment of angina at rest with nifedipine: a short-term controlled study. Am J Cardiol 1980;45:825-30. 19. Heng YK, Singh BN, Roche AHJ, Norris RM, Mercer CJ. Effects of intravenous verapamil on cardiac arrhythmias and on the electrocardiogram. Am Heart J 1975;90:487-98. 20. Schamroth L, Krikler DM, Garrett C. Immediate effects of intravenous verapamil in cardiac arrhythmias. Br Med J 1972;l: 660-4. 2 1. Rosing DR, Kent KM, Borer JS, Sektes SF, Maron BJ. Epstein SE. Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy. I. Hemodynamic effects. Circulation 1979;80:1201-7. 22. Rosing DR, Kent KM, Maron BJ, Epstein SE. Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy. II. Effects on exercise capacity and symptomatic status. Circulation 1979;60: 1208-13. 23. Kuwajima I, Ueda K, Kamuta C, et al. A study of the effects of nifedipine in hypertensive crisis and severe hypertension. Jpn Heart J 1978;19:455-67. 24. Clark RE, Christlieb IY, Henry PD, et al. Nifedipine: a myocardial protective agent. Am J Cardiol 1979;44:825-31. 25. Moskowitz RM, Picclni PA, Nacarelli GV, Zelis R. Nifedipine therapy for stable angina pectoris: preliminary results of effects on angina frequency and treadmill exercise response. Am J Cardiol 1979;44:811-6. 26. Halter NJ. Radioelectrocardiography: a new technique for cardiovascular studies. Ann NY Acad Sci 1957;65:913-23. 27. Halter NJ. A new method for heart studies. Science 1961;134: 1214-20. 28. Golding B, Wolf E, Tzivoni D, Stern S. Transient S-T elevation detected by 24-hour ECG monitoring during normal daily activity. Am Heart J 1973;86:501-7. 29. Clark PI, Glasser SP. Problem: angina with borderline coronary

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lesions. Cardiovasc Med 1979;4:555-8. 30. Wolf E, Tsivoni D, Stern S. Comparison of exercise tests and 24-hour ambulatory electrocardiographic monitoring in detection of S-T-T changes. Br Heart J 1974;38:90-5. 31. Stem S, Tzivonl D. Early detection of silent ischaemic heart disease by 24-hour electrocardiographic monitoring of active subjects. Br Heart J 1974;36:481-6. 32. Stern S, Tzlvoni D, Stern Z. Diagnostic accuracy of ambulatory ECG monitoring in ischemic heart disease. Circulation 1975;52: 1045-g. 33. Michelson EL, Josephson ME. Use and limitations of the ambulatory ECG. Cardiovasc Med 1979;4:533-41. 34. Crawford MH, Mendoza CA, D’Rourke RA, et al. Limitations of continuous ambulatory electrocardiogram monitoring for detecting coronary artery disease. Ann Intern Med 1978;89:1-5. 35. Hlnkle LE Jr, Meyer J, Stevens M, Carver ST. Tape recordings of the ECG of active men: limitations and advantages of the Holter-Avionics instruments. Circulation 1967;36:752-84. 36. Allen RD, Gettes LS, Phalan C, Avington MD. Painless S-T segment depression in patients with angina pectoris. Chest 1976; 691467-73. 37. Stern S, Tzvonl D. The reliability of the Holter-Avionics system in reproducing the S-T-T segment. Am Heart J 1972;84:427-8. 38. Hansmann DR, Yeshaya A, Pepine C, Schang S, Blelfer S. Halter electrocardiography vs treadmill stress test for ischemic S-T segment changes and arrhythmia detection. Amb Electrocardiol 1978;1:5-13. 39. Gorlin R. Pathophysiology of cardiac pain. Circulation 1965;32: 138-48. 40. Parker, JO, West RO, Case RB, Chierrg MA. Temporal relationships of myocardial lactate metabolism, left ventricular function, and S-T segment depression during angina precipitated by exercise. Circulation 1969;40:97-111. 41. Kennedy HL, Underhill SJ, Caralis DG, Kahn MA, Peblete PF. Detection of non-angina1 or “silent”.ischemic S-T segment depression in patients with ischemic heart disease (abstr). Am J Cardiol 1978;37:147. 42. Schang SJ, Pepine CJ. Transient asymptomatic S-T segment depression during daily activity. Am J Cardiol 1977;39:396402. 43. Haberern NA, Khaja FU, Barold SS. Significance of episodic painless S-T segment elevation at rest in ischemic heart disease. J Electrocardiol 1975;8:173-7. 44. Prchkov VK, Mookherjee S, Schlesa W, Dbeld Al. Variant angina1 syndrome, coronary artery spasm, and ventricular fibrillation in absence of chest pain. Ann Intern Med 1974;81:858-9. 45. Laks M, Dahlgren J, Mandel WJ. The dynamic ECG in the diagnosis of variant angina pectoris. J Electrocardiol 1974;7:93-6. 46. Guaui 1111, Dliverl MT, Potese A, Flerentini C, Magrfni F. Repetitive myocardial ischemia of Prinzmetal type without angina pectoris. Am J Cardiol 1976;37:923-7. 47. Chiche P, Haiat R. Transient S-T segment elevation occurring without angina1 pain. Correlations with Prinzmetal’s angina. J Electrocardiol 1975;8:275-80. 48. Ellrodt G, Chew YC, Singh BN. Therapeutic implications of slow-channel blockade in cardiocirculatory disorders. Circulation 1980;62:669-79.

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