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Double-blind randomized crossover trial of verapamil and propranolol in chronic stable angina
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ECG changes
ergonovine provocation in variant angina patients with coronary artery spasm. AM HEART J 103:161, 1982. 13. Braunwald E, editor: Heart disease: A textbook of cardiovascular medicine. Philadelphia, 1980, W.B. Saunders Co, pp 231-234. 14. Ellestad ME: Stress testing: Principles and practice. Philadelphia, 1975, F.A. Davis Co, p 125.
with
coronary
artery
spasm
15. Stein I, Weinstein J: Further studies of the effect of ergonovine on the coronary circulation. J Lab Clin Med 36:66, 1950. 16. Epstein S: Value and limitations of the electrocardiographic response to exercise in the assessment of patients with coronary artery disease: Controversies in cardiology. II. Am J Cardiol 42:667, 1978.
Double-blind randomized crossover trial of verapamil and propranolol in chronic stable angina Propranolol (240 mg daily) and verapamil (360 mg daily) were objectively compared for their respective efficacy in the treatment of chronic stable angina pectoris. Twenty-two patients were studied in a randomized placebo controlled, double-blind crossover trial with 4 weeks on each active drug treatment. Multistage treadmill exercise with computer-asslsted ECG analysis was performed after 2 weeks on placebo and at the end of each I-week active drug treatment. The mean exercise time to produce angina was 5.5 minutes (SEM + 0.4 minutes) on placebo and this increased to 7.8 (kO.5) minutes on propranolol and 9.1 (~~0.5) minutes on verapamil. The improvement in exercise time of verapamil over propranolol was statistically significant (p < 0.01). Ten patients became free of angina with verapamil and four with propranolol. Resting and maximal exercise heart rates were significantly reduced by propranolol; verapamil did not reduce the maximal heart rate but reduced the resting heart rate slightly. However, the heart rate increase per minute of exercise was significantly diminished (p < 0.001). ST segment changes showed improvement with both drugs despite marked differences in hea@ rate profile. The overall efficacy of the slow calcium channel blocker, verapamil, compares favorably with that of a standard beta-adrenoreceptor blocking drug (propranolol), thus providing a new perspective in the management of angina pectorfs. These two classes of drugs seem to act by different mechanisms and it is suggested that if patients are resistant or intolerant to one of these drugs, the other can be used to yield a beneficial response. (AM HEART J 106:1297, 1983.)
Michael J. Bowles, M.B., B.Ch., V. Bala Subrarnanian, M.D.,* Anthony B. Davies, M.B., B.S., and Edward B. Baftery, B.Sc., M.D. Harrow, Middlesex, England
Beta-adrenoreceptor blocking agents have been established as the drugs of choice in chronic stable angina and have been in extensive clinical use for has become the the last 20 years. I-5 Propranolol standard against which all other agents are com-
From the Department of Cardiology and Division of Clinical Sciences, Northwick Park Hospital and Clinical Research Centre. Received for publication Sept. 24, 1981; revision received Apr. 26, 1982; accepted
June
Reprint Hospital,
requests: Watford
*Supported
19, 1982. Dr. E. B. Raftery, Dept. Rd., Harrow HA1 3UJ,
by the British
Heart
Foundation.
of Cardiology, Northwick Middlesex, England.
Park
pared.‘s5v6 Interest in the use of slow calcium channel blockers in angina pectoris has recently been revived, particularly in Prinzmetal’s and unstable angina, in which coronary artery vasospasm has been shown to play a critical etiologic role.7-g In these cases beta-adrenoreceptor blockade is usually ineffective and verapamil has proved useful in doses of 120 to 840 mg daily.‘O Verapamil’s use in chronic stable angina is also under intense investigation. We have investigated the antianginal action of the slow calcium channel blocker, verapamil, with objective methods11-15 designed to eliminate observer bias, and have conducted a double-blind, cross-over trial 1297
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I. Treadmill protocol
Stage 1
2 3 4 5 6 I
Time (min)
Speed (mph)
Percent gradient
3 3 3 3 3 3 3
2 3 3 3 3 3 4.5
0 4 8 12 16 20 20
comparing verapamil in a dose of 360 mg daily with placebo in 28 patients.16 We found that the drug produced a significant improvement of exercise tolerance and ST segment changes. These beneficial actions were obtained with minimal effects on the resting and exercise heart rate. The next logical step
was to compare the potency and mode of action of verapamil with a standard beta-adrenoreceptor blocking drug. The evaluation of this comparison was considered to be of practical importance to the clinician and the pharmacologist. The trial was conducted using a method identical to the previous
studies. METHODS
Twenty-five patients with confirmed chronic stable angina (age range 41 to 69 years, 22 malesand 3 females) participated in the trial. Inclusion criteria. The patients were requirtd to have unequivocal evidence of coronary artery disease,symptomatic stable angina, and ST segmentchangeson maximal treadmill exercise testing. Coronary artery disease was confirmed by selective coronary arteriography, at which time all patients were judged to have evidence of good left. ventricular function which wasalsomeasuredby noninvasive methods on each treatment phase. Seventy percent luminal narrowing of one or more major coronary arteries was taken as significant disease.All patients had classicalangina on physical exertion relieved by rest and sublingual nitroglycerin, with a minimum frequency of four attacks per week. All developed classicalangina1pain on treadmill exercise testing with at least 1 mm ST segment depression (slope lessthan 0.1 mV/sec) in two bipolar leads (CM, and CC,) during exercise. Only patients physically capable and mentally motivated for repeated treadmill exercise were entered in the final trial. Exclusion criteria. Patients over 70 years of age and females in the childbearing years were excluded. Those having myocardial infarction in the preceding 4 months, patients with unstable angina, and patients having severe symptoms who were clinically judged as unsuitable for placebo treatment were also excluded. Cardiac failure, bronchial asthma, peripheral vascular disease, resting blood pressurelevels above 160/100 mm Hg, and insulin-
1983
Heat-i Journal
dependent diabetes mellitus were other exclusion criteria. Any patients receiving diuretics, digitalis, and other cardiovascular medications were excluded from the study. Any patient showing more than -0.5 mm ST depression on standing, hyperventilation, and the Valsalva maneuver, or who did not develop classical angina on the initial diagnostic treadmill exercisetest and did not show 1 mm ST segment depression in both bipolar leads was also excluded. Trial design. The initial inclusion criteria were basedon a diagnostic exercise test performed without any treatment (19 patients) or after 4 weeksof complete withdrawal of current medical treatment. Two patients were taking long-acting nitrates, two were on oxyfedrine, and two were on propranolol, 40 mg thrice daily, before inclusion in the trial. None of the patients was given any other cardiac drugsexcept the trial drugs and sublingual nitrates during the trial period. The drugs were administered using a double-dummy technique. During the first, 2 weeks which comprised the placebo run-in phase, the patients took two tablets, one eachof verapamil and propranolol placebo, thrice daily. In the crossover phase the two tablets were either active verapamil and placebo propranolol or active propranolol and placebo verapamil. This phasewas double-blind. All verapamil tablets including placebo were identical in appearance and all propranolol tablets including both dosesand placebowere identical. The tablets were packed in plastic containers with compartments identifying the day of the week and the time of drug administration. All 25 patients were started on a double-blind crossover study of 4 weeks each with an initial 2-week placebo run-in period. Following this they were randomized on to propranolol, 240 mg daily, or verapamil, 360 mg daily, in three divided dosesfor 4 weeks,at the end of which time each patient crossedover to the alternate regime. Since 4 weeks elapsed between each exercise test, no washout period was incorporated. Formal exercisetesting and left ventricular function estimateswere repeated at the end of placebo and at 4 and 8 weeksof active drug therapy. Subjective evaluation. The patients were instructed in the use of a diary card to document the frequency of angina1 episodes and nitroglycerin consumption. The importance of not using prophylactic nitroglycerin during the trial period was emphasizedto each patient. Exercise testing. All tests were performed .using a motor-driven treadmill, the speedand gradient of which were regularly calibrated and the program (Table I) governed by a computer (Marquette Computer Assisted System for Exercise). Two bipolar leads (CM, and CC,) were continuously recorded before, during, and after exercise in a 25: 1 compressedformaLl Digital printouts of ST depressionat the J point, ST slope, heart rate, and ectopic count were generated for every minute of the test and for a final analog trend plot of each complete test. Systolic blood pressurewasmeasuredevery 3 minutes and at termination of exercise with a mercury sphygmomanometer. All exercise tests were maximal or limited by angina, dyspnea, fatigue, or pain in the legs. All were
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Table
Randomized verapamil-propranolol
Exercise time Work load Resting heart rate Maximum heart rate Heart rate gain Heart rate recovery 5’ Double product 1 mm time (CM,) 1 mm time (CC,) 2 mm time (CM,) 2 mm time (CCs) MST (CM,) MST (CC,) MST/ex.time (CM,) MST/ex.time (CC,) ST same workload (CM,) ST same workload (CC,) Heart rate same workload ST Recovery 5’ (CM,) ST Recovery 5’ (CC,) values
1299
II. Comparisonsof the antianginal effects of verapamil and propranolol Placebo
All
trial in stable angina
are mean
5.5 6.1 76 135 58 51 216 3.3 2.9 4.3 4.3 2.4 2.1 0.48 0.42 2.3 2.2 131 1.9 1.7
zk + ? k -I* iz + + f + f + + f + f * f f
0.4 1.4 3 3 3 2 8 0.4 0.4 0.5 0.6 0.2 0.2 0.06 0.05 0.20 0.18 3 0.2 0.2
Propranolol (240 md 7.8 14.8 56 104 47 39 164 5.7 5.5 7.3 8.0 1.7 1.7 0.24 0.24 0.95 1.05 94 1.3 1.1
k + f + + + f 2 k +ck r + + f + zk * -t Yr
Verapamil (360 mg)
0.5 2.2 2 3 2 2 7 0.5 0.6 0.7 0.7 0.1 0.1 0.03 0.02 0.14 0.16 3 0.1 0.1
9.1
20.4 71 130 57 50 204 5.5 5.5 7.1 7.9 2.2 2.0 0.28 0.24 1.3 1.4 116 1.4 1.2
A
* 0.5
k rt +++-+ k k +k + -c f f
2.4 3 3 2 2 6 0.6 0.7 0.9 1.0 0.2 0.2 0.04 0.03 f 0.20 * 0.18 I? 3 It 0.2 -t 0.1
B
NS NS NS NS
C
NS NS NS NS NS NS NS NS NS NS
NS NS
0.001
-co.01
NS NS
+ S.E.M.
ex. time = exercise time; MST = peak ST depression. All heart rate values are in bpm. All ST segment values are in millimeters. Workload = (kilometres walked X sine angle of treadmill in degrees) U. p values for: placebo vs propranolol = A, placebo vs verapamil = B, propranolol
performed in the morning between 90 and 150 minutes after the last doseof the drug, and after 30 minutes rest in a temperature-controlled laboratory. The standard safety precautions recommendedby the American Heart Association were followed.17 The following variables were calculated from the exercise data: (1) exercise time (accuracy + 0.1 minute); (2) workload (combined product of speed of treadmill in kilometers, sine of angle of treadmill in degrees,gravitational constant, and body weight; the gravitational constant and body weight are constant factors over the trial period and were therefore taken as unity); (3) resting heart rate (RHR); (4) maximum heart rate (MHR); (5) heart rate gain (MI-IR minus RHR); (6) heart rate unit gain = heart rate gain/exercise time; (7) heart rate recovery over 5 minutes (MHR minus HR at 5 minutes after exercise termination); (8) heart rate sameworkload (HR developed at same exercise time and workload as on placebo); (9) 1 mm time (time taken for 1 mm ST displacement to occur during exercise); (10) 2 mm time (time taken for 2 mm ST displacement to occur during exercise); (11) maximum or peak ST depression(MST) accurate to + 0.1 mm; (12) MST/exercise time; (13) ST depressionsameexercisetime (ST depressionat the same exercise time as on placebo); (14) ST segment recovery over 5 minutes (MST minus ST depressionat 5 minutes after exercise); and (15) double product (maximum HR X maximum systolic blood pressure/lOO).All ST seg-
vs verapamil
= C.
Ill. Individual exercise times on verapamil and propranolol Table
Patient number
Placebo
1
3.9
9.4*
4.2 3.6 4.7 5.4 ILO.8 5.4 3.7 6.1 5.1 8.9 6.3 6.0 5.1 4.7 5.0 5.3 4.5 3.0 6.2 8.5 5.6
5.7 3.0 9.0 6.6 12.3* 8.4 4.4 4.9 8.1 9.9 12.1* 9.3 5.9 5.9 6.3 7.0 5.9 5.1 10.3 10.7 8.4+
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
All values in minutes. *Patient rendered angina-free.
Propranolol (240 md
Verapamil (360 mg) 8.2 6.6 7.2* 11.0: 9.1*
12.5* 8.8 3.9 10.7 9.5 11.3* 10.1 9.2
10.8 8.5* 7.3 7.6 6.5 5.1* 11.3* 12.5* 12.0*
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Rest H.R.
Ex. time
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Work load
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December, 1993 Heart Journal
-0 v
1. The mean exercise time in minutes for each treatment period is shown on the left. From a placebo value of 5.5 minutes, an improvement to 7.8 minutes of propranolol was obtained (p < O.OOl), and a further improvement to 9.1 minutes was achieved on verapamil (p < 0.001). There is a significant increasein exercisetime of verapamil over propranolol (p < 0.01). The workload performed (shown to the right) is calculated from the number of kilometers walked multiplied by the sine of the angle of the treadmill in degrees (U), and mirrors the improvement seen in exercise time with equivalent p values. Ex. time = exercisetime in minutes; PL = placebo; P = propranolol (240 mg daily); V = verapamil (360 mg daily); *p < 0.001comparedwith placebo. The lines aboue the bars indicate SEM. Fig.
ment values were calculated for both bipolar leads, CM, and CC,. Left ventricular function. This was estimated noninvasively by measuring systolic time intervals in the supine posture. The first derivative of the electrical impedance cardiogram (dZ/dt) was used as the central arterial pulse wave form. The impedance cardiogram and ECG were simultaneously fed into a purpose-built minicomputer which calculated the systolic time intervals, i.e., preejection period, left ventricular ejection time, ratio betweenthe left ventricular ejection time and pre-ejection period (PEP/LVET ratio), interval between the peak of the R wave of the ECG and impedance cardiogram (RZ interval), ratio between amplitude of impedance wave form and RZ interval (dZ/dt/RZ ratio), and ratio between amplitude of impedance waveform and heart rate (dZ/ dt/HR = ICO index). The last two parameters bear a close correlation to the other systolic time intervals and have been usedfor serial estimation of left ventricular function in other studies.‘s-22 Stroke volume and cardiac output were also obtained.21 In this study we used 100-beat averaging during quiet supine rest with additional averaging of the first 20 beats recorded with breath held in expiration. All studies were performed in the morning after supinerest for 20 minutes.
v
PL = Placebo P = Propranolol (240 mg) V = Verapamil (360 mg)
PL P
v
PL P
PVV Rest H.R. p< 0.001 Max. H.R. p< 0.001 H.R. same p
v :': p
2. The mean heart rates both at rest and during exercise are shown for the placebo phaseand each treatment period. At rest the heart rate wasreduced by 20 bpm on propranolol (p < 0.001)and by only 5 bpm on verapamil (p < 0.01). The maximum heart rate achieved during exercise was not significantly altered by verapamil, but was reduced by propranolol (p < 0.001). The heart rate developed during each treatment period for the same exercise time, and therefore by definition for the same workload ason placebo, showedsignificantly lower values for both verapamil (p < 0.001) and propranolol (p < 0.001). **p < 0.01. Other abbreviations as in Fig. 1.
Fig.
The data obtained included heart rate, stroke volume, cardiac output, pre-ejection period corrected for heart rate (PEP), left ventricular ejection time corrected for heart rate (LVET), PEP/LVET ratio (uncorrected), RZ interval corrected for heart rate (RZ interval index), and dZ/dt/RZ index. Patients were clinically examined during each visit for signsof cardiac failure and side effects were noted in a standard questionnaire. Statistics. Statistical analysis was performed using Student’s paired t test (two-tailed). Informed consent was obtained from all patients and the project was approved by the Hospital Ethical Committee. RESULTS
Twenty-two patients (20 males and 2 females) with an age range of 41 to 69 years completed the trial (Tables II and III). Placebo phase. All 22 patients developed classical
angina on treadmill exercise during the placebo phase. The mean weekly anginal frequency and nitroglycerin consumption was 15 -+ 7 and 17 +- 5, respectively. The exercise time to develop angina ranged from 3.0 minutes to 10.8 minutes (mean + SEM, 5.5 + 0.4 minutes), the corresponding mean
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22
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B
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-i-z
d 120 -1.4
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verapamil-propranolol
+1 104 -1.4
+2 68 -1.3
+3 79 -1.2
trial in stable angina
l4 74 -1.1
+5 74 -1.0
1301
1111 ST 129 -2.2
Fatii
i._l_,i_l;.ci-i;_!;_,‘P-Lb
Fig. 3. A patient’s computer-averaged ECGs with ST segment depression and heart rate. Top line shows
exercise time, second line shows heart rate, and third line indicates ST depression. During the placebo period pain developed at 4.7 minutes. On propranolol, pain developed at 5.9 minutes, and on verapamil fatigue was the only symptom at 8.5 minutes.
workload achieved being 6.1 + 1.4 U (Fig. 1). The mean resting heart rate was 76 +- 3 bpm and this increased at peak exercise to 135 + 3 bpm (Fig. 2). The gain in heart rate during exercise was 59 + 3 bpm and the heart rate increase per minute was 10.7 k 0.6 bpm. The heart rate recovered by 51 -C 2 bpm at 5 minutes postexercise and the ratio between heart rate gained and heart rate recovered was 0.86. The peak ST depression (MST) in lead CM, varied from 1.0 to 5.7 mm, with a mean value of 2.4 + 0.2 mm. The ST recovery at 5 minutes postexercise was 1.9 it 0.2 mm, the ratio of ST change to ST recovery being 0.80. The mean exercise time to produce 1 mm ST segment shift was 3.3 + 0.4 minutes and for 2 mm ST changes it was 4.3 r+ 0.5 minutes in lead CM,. Similar values were observed for the ST segment variables in lead CC, (Table I). The mean double product at termination of exercise was 216 + 8 U. Propranolol. All 22 patients reported an overall improvement in subjective well-being, although 12 mentioned tiredness as a new symptom. Angina frequency and nitroglycerin consumption were reduced to 10 + 6 and 12 + 5, respectively 0, < 0.01). The exercise time to produce angina
improved significantly on the beta-adrenoreceptor blocker. Four out of 22 stopped exercise due to fatigue rather than to angina, with a marked improvement in exercise performance in each case (Table III). The mean exercise time increased to 7.8 +- 0.5 minutes and the corresponding workload increased to 14.8 + 2.2 U (Fig. 1). Both these values were significantly better than with placebo (p < 0.001). The change in exercise tolerance ranged from -0.6 minutes to +5.8 minutes. The mean resting heart rate was reduced to 56 _+ 2 bpm and the maximal heart rate was reduced to 104 _+ 3 bpm (Fig. 2). The exercise heart rate gain was also reduced to 47 bpm in 7.8 minutes, resulting in a decrease of unit heart rate gain to 6.0 bpm. The peak double product was reduced to 164 f 7 U (p < 0.001). There was an apparent reduction of heart rate recovery to 39 + 2 bpm; however, the ratio between heart rate gain and recovery was unchanged at 0.83. The peak ST depression was improved to 1.7 mm; the range being 0.8 to 2.6 mm. Similarly, 1 mm and 2 mm times and the corrected ST variables showed a significant improvement when compared with placebo (p < 0.091). The ratio of ST recovery to ST change was unaltered at 0.77.
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(first
Fig. 4. Continuous trend plot for the samepatient as in Fig. 3, of ST segmentdepressions panel vertically) and heart rates (second panel) during each treatment period. Time is on the horizontal axis, with each marker representing 2 minutes, and ST depressionis on the vertical axis, with each marker showing 1 mm. The isoelectric line is shown by interrupted horizontal lines and end of exercise is shown by a vertical line in the middle of each panel. Heart rate is shown on the vertical axis in beatsper minute.
End point exercise symptoms are recorded.
The ST segment was markedly improved at the same exercise time as the placebo test (p < 0.001). Lead CC, showed similar changes to lead CM5, and the values are shown in Table II. Yerapamil. Ten patients became angina-free during this phase and stopped exercise because of fatigue. They had a significantly longer exercise time, suggesting a true improvement rather than a depressed left ventricular performance (Table III). There was a corresponding decrease in mean weekly anginal frequency to 5 + 3 and in nitroglycerin consumption to 3 +- 2 Cp < 0.001). There was a dramatic subjective improvement for all patients. Eight patients became constipated but were relieved by simple laxatives. There was a marked increase in exercise tolerance: the range of exercise time was from 3.9 to 12.5 minutes, with a mean value of 9.1 + 0.5 minutes. This increase was significantly higher than the placebo (p < 0.001) and the propranolol 07 < 0.01) values. The increase in exercise
time ranged from +0.2 minutes
to +6.6 minutes. The exercise time was longer than propranolol in 17, shorter in four, and identical in one patient. The mean workload increased to 20.4 + 2.4 U, which was significantly greater than both placebo and propran0101 (Fig. 1). The resting heart rate was mildly reduced to 71 f 3 bpm snd the maximum heart rate was 130 + 3 bpm (Fig. 2). The heart rate gain was unchanged at 59 _+ 2 bpm. The heart rate increase per minute of exercise time was, however, signibcantly reduced to 6.5 bpm as compared to 10.7 bpm on placebo and 6.0 bpm on propranolol. The peak double product was unaltered, but both heart rate and double product were reduced significantly at the same exercise time as placebo. The heart rate recovery was 50 +- 2 bpm, showing no change from placebo. The maximum ST depression in lead CM, did not show any change from placebo values (2.2 + 0.2 mm). However, this maximum ST depression was now seen at 9.1 minutes of exercise as compared
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% 150
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1
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1303
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HR
SV
CO
LVET
PEP
Fig. 5. Heart rate (HR), stroke volume (SV), cardiac output (CO), left ventricular ejection time index (LVET), and preejection period (PEP) on verapamil and propran0101.The valueshave beenexpressedas changescompared to the control placebo values. None of the drugs alter any of the variables significantly, and a mild increasein PEP is seenon propranolol therapy. Closed block = verapamil; stippled block = propranolol.
to 5.5 minutes on placebo. All the corrected ST values, 1 mm time, 2 mm time, and ST depression at the same exercise time as placebo showed significant reduction. The ST segment recovery was 1.4 + 0.2 mm, the ratio to ST change being 0.64 as compared to 0.80 on placebo. The ST changes in lead CC, were identical to those seen in lead CM, (Table II). Fig. 3 shows the computer-averaged ECG complexes and Fig. 4 shows the final analog trend plot of ST depression and heart rate for a single patient on all phases of the trial. Left ventricular function (Figs. 5 and 6). Most of the variables were not affected by either drug. The PEP/LVET ratio was significantly increased by propranolol and was unaffected by verapamil, suggesting no alteration in the myocardial contractility with verapamil and a mild reduction with proprano101. Side effects. Both drugs were well tolerated with few adverse effects. Constipation was a constant feature with verapamil and tiredness or lethargy appeared with propranolol. Two patients were withdrawn during the propranolol phase because of dyspnea at rest and severe hypotension. One patient
PEP/ LVET
RZc
dZIdt/ RZ
icol,dex
Fig. 6. PEP/LVET
ratio, RZ interval index (RZc), (dZ/ dt)/RZ index, and amplitude of dZ/dtiheart rate (ICOi”d,J on verapamil and propranolol therapy. Note the significant increase in PEP/LVET ratio on propranolol. **p = < 0.01.
developed a myocardial infarction and died during the verapamil phase, although there was a good initial response to treatment with a reduction in frequency and severity of angina. Autopsy revealed severe triple-vessel disease with total obstruction of the left anterior descending artery. No PR interval prolongation on the ECG in any of the patients was observed during either active drug phase. DISCUSSION Methods verapamil.
of drug evaluation-Early
experience
with
The accurate evaluation of antianginal drugs is fraught with numerous difficulties,23 not the least of which is the marked variation in the natural history of the condition.2* Hemodynamic variables include a mixture of fixed coronary obstruction and coronary artery spasm,2s the mechanisms of which lend themselves to differential pharmacologic approaches. There are problems associated with the pharmacologic properties of the drug tested,% and lastly all the difficulties inherent in the design of the system for testing.27 It is important, therefore, that
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as many of the variables as possible be eliminated by appropriate standardization which will also allow more meaningful comparisons to be made of the results from different centers. This trial has been designed to enable objective measurements of exercise data, the importance of which we have emphasized in earlier publications.“-l4 The trial investigates the comparative effects of verapamil and propranolol using the same methods as in a previous trial comparing veraparnil with placebo.16 The necessity of an adequate placebo duration with double-blind crossover techniques is now well accepted, both to eliminate observer bias and to produce results to which meaningful statistical analysis can be applied.28 Exercise periods have been sufficiently separated in time to minimize the effects of “warm-up” and training,2s and patient selection is carefully scrutinized to comply with standards recommended by the American Heart Association.17 Graded treadmill tests with predetermined workload increments were performed by all the patients and computer-assisted ECG analysis was utilized to provide exact quantitation of exercise times, ST segment levels, and heart rates during and after exercise, from which a number of indices of cardiac performance could then be calculated to provide insight into the effect and mode of action of the drugs. Verapamil has been in use for almost 20 years as an antiarrhythmic agent. It is known to have an antianginal action30 and Hoffmann31 performed the first planned clinical trial in 1964. Herxheimer32 stated that verapamil had no advantage over propranolol, and Phear33 found no significant difference between the drug and placebo. However, these early results were obtained with daily doses of 240 mg or less of verapami1,31-35 which did not allow for the extensive first-pass metabolism of the drug. Neumann and Luisada36 established the efficacy of verapamil(360 mg daily) in a double-blind crossover study in 1966. The necessity for comparison of verapamil with beta-adrenoreceptor blocking agents was soon realized, and Sandler et al.34 showed verapamil(360 mg daily) to be as effective as propranolol (300 mg daily). Livesley et al2 demonstrated that the effects of verapamil were at least equal to those of propranolol and that both drugs produced a similar reduction in heart rate, and de Oliveira6 found verapamil to be superior to propranolol. Efficacy of propranolol. In this trial we have used fixed doses of both verapamil and propranolol and therefore comparisons made between their effects must be viewed in the light of differing dose-
American
December, 1983 Heart Journal
response curves, which are known to be fairly steep for propranolol but appear flatter for verapamil. The propranolol dose was fixed at 80 mg thrice daily, at which it is commonly stated as providing adequate bradycardia.5s37 Propranolol improved the exercise time by 40 % . Its primary effect appeared to be a reduction of heart rate (resting heart rate was reduced by 26% and the maximum heart rate was reduced by 23%), which is in concordance with the findings of Livesley et a1.2 There was a marked reduction in the double product at the peak of exercise. The heart rate recovery was not altered. Maximum ST segment depression corrected for exercise time was significantly reduced. Efficacy and mode of action of verapamil. Verapamil had a different effect. It reduced the resting heart rate by only 6.5% and the maximum heart rate by 3 % , probably because the sinoatrial node depression is offset to some extent by the reflex tachycardia resultant from peripheral vasodilation. The heart rate recovery was not altered. The double product responses, which are known to correlate with changes in myocardial oxygen consumption,38*3g were blunted by verapamil at the peak of exercise but the decreases are considerably less than those observed after administration of propranolol, and do not offer a complete explanation of the mode of action of verapamil. Other determinants of myocardial oxygen consumption are geometric factors modifying ventricular wall stress40 and the contractile state of the myocardium.41 Although we did not demonstrate any significant effects on left ventricular function by the measurement of systolic time intervals, verapamil usually leads to mild depression in left ventricular function in patients with coronary artery disease,42 which could further decrease myocardial oxygen consumption and thereby improve the overall myocardial oxygen supply-demand relation. The maximum ST segment change was unaltered during the verapamil phase. The exercise time, however, increased by 66 % and the maximum heart rate and ST depression seen during placebo at 5.5 minutes now occurred at 9.1 minutes. These figures suggest an improved exercise tolerance with a delay in the appearance of myocardial ischemia. The corrected ST segment levels showed comparable changes with both drugs. Conclusions. Direct comparison of the two drugs is possible with these data. Verapamil has little negative chronotropic effect but improves exercise tolerance more than propranolol, probably because of a reduction of resistance in the systemic and coronary
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Randomized
arterioles as well as an intracellular oxygen-sparing effect, resulting in a net decrease in myocardial oxygen requirements with a concomitant increase in coronary perfusion. On the other hand, propranolol seems to act predominantly through its negative chronotropic effect. We would suggest that propranolol is the preferred treatment for patients with a resting tachycardia and marked chronotropic exercise response and that verapamil must be considered especially for those with a poor chronotropic response to exercise or with coexisting diabetes mellitus, peripheral vascular disease, or bronchoconstriction. These observations are of importance in that they provide for the practicing clinician a rational guide to the choice of treatment. We thank Ian Eddy and Mrs. Brenda Christocopoulos for their technical assistance and Mrs. Jean Wright for secretarial assistance.
15.
16.
17.
18.
19.
20.
21.
22. REFERENCES
1. Prichard BNC: Propranolol in the treatment of angina: A review. Postgrad Med J 52:31, 1976. 2. Livesley 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 2:375, 1973. 3. Keyrilainen 0, Uusitalo A: Effects of metoprolol in angina pectoris-a subacute study with exercise tests and a long term tolerability study. Acta Med &and 199:491, 1976. 4. Ekelund LG, Anders G, Olsson ORO, Rossner S: Effects of the cardioselective beta adrenergic receptor blocking agentmetoprolol-in angina pectoris. A subacute study with exercise tests. Br Heart J 38:155, 1976. 5. Thadani U, Parker JO: Propranolol in angina pectoris: Duration of improved exercise tolerance and circulatory effects after acute oral administration. Am J Cardiol 44:118, 1979. 6. Martins de Oliveira J: Comparative effects of verapamil and propranolol in patients with angina pectoris. Arch Bras Cardiol 31:45, 1978. 7. Braunwald E: Introduction: Calcium channel blockers. Am J Cardiol 46:1045, 1980. 8. Opie LH: Calcium antagonists. Lancet 1:806, 1980. 9. Leading article: Calcium antagonists and the heart. Br Med J 282:89:1981. 10. Kelly DT, Freedman B, Richmond DR: Verapamil in the treatment of coronary artery spasm at rest and on exercise. In Zanchetti A. Krikler DM. editors: Calcium antagonism in cardiovascular therapy: Experience with verapamil. Amsterdam, 1981, Excerpta Medica, p 185. 11. Bala Subramanian V, Khanna PK, Narayanan GR, Hoon RS: Verapamil in ischaemic heart disease-quantitative assessment by serial multistage treadmill exercise. Postgrad Med J 52:143, 2976. 12. Bala Subramanian V, Khanna PK, Hoon RS: On-line digital computer quantitated ST segment response to submaximal treadmill exercise. J Assoc Physicians India 23:1, 1975. V, Khanna PK, Narayanan GR, Hoon RS: 13. Bala Subramanian Quantified multistage treadmill exercise-a reliable method for testing antianginal drugs. J Assoc Physicians India 23:597, 1975. V: Assessment of antianginal drugs by 14. Bala Subramanian serial treadmill exercise In MacFarlane PW, editor: Progress
23.
verapamil-propranolol
trial
in stable angina
1305
in electrocardiography. Kent, 1979, Pitman Medical, p 329. Sheffield LT: Quantitative approach to exercise testing for ischaemic heart disease. In Snell HA, editor: Quantitation in cardiology. Amsterdam, 1972, University Press, p 223. Bala Subramanian V, Paramasivan R, Lahiri A, Raftery EB: Verapamil in chronic stable angina: A controlled study with computerised multistage treadmill exercise. Lancet 1:841, 1980. Ellestad MH, Chairman MD, Blomqvist CG, Naughton JP: Standards for adult exercise testing laboratories. Circulation 58:421A, 1979. Siegal JH, Fabian M, Lanken C, Levine M, Cole A, Nakwad M: Clinical and experimental use of thoracic impedance plethysmography in quantifying myocardial contractility. Surgery 67:907, 1970. Rasmussen JP, Sorensen B, Kann T: Evaluation of impedance cardiography as a non-invasive means of measuring systolic time intervals and cardiac output. Acta Anaesthesiol Stand 18:210,1975. Bala Subramanian V, Mathew OP, Behl A, Tewari SG, Hoon RS: Electrical impedance cardiogram in derivation of systolic time intervals. Br Heart J 40~268, 1978. Bala Subramanian V, Mathew OP, Tewari SC, Behl A, Sharma SC, Hoon RS: Alterations in left ventricular function in normal man on exposure to high altitude (3658 m). Br Heart J 40:276, 1978. Bala Subramanian V, Behl A, Das GR, Wadhwa AK, Mathew OP, Hoon RS: Effect of digoxin and diuretics on high altitude left ventricular dysfunction. Circulation 57:1180, 1978. Aronow WS: The medical treatment of angina pectoris. II. Design of an antianginal drug study. AM HEART J 84:132, 1972.
24.
25.
26. 27.
28. 29.
30.
31. 32. 33. 34. 35. 36.
37.
Duncan B, Fulton M, Morrison SL, Lutz W, Donald KW, Kerr F, Kirby BJ, Julian DG, Oliver MF: Prognosis of new and worsening angina pectoris. Br Med J 1:981, 1976. Maseri A, Severi S, De Nes M, L’Abbate A, Chierchia S, Marzilli M, Ballestra AM, Parodi 0, Biacini A, Distante A: “Variant” angina: One aspect of a continuous spectrum of vasospastic myocardial ischaemia. Pathogenic mechanisms, estimated incidence and clinical and coronary arteriographic findings in 138 patients. Am J Cardiol 42:1019, 1978. Aronow WS, Kaplan MA: Dilemma of angina pectoris. N Engl J Med 281:491, 1969. Redwood DR, Rosing DR, Goldstein RE, Beiner GD, Epstein SE: Importance of the design of an exercise protocol in the evaluation of patients with angina pectoris. Circulation 43:618, 1971. Feinstein AR: Should placebo-controlled trials be abolished? (Editorial) Eur J Clin Pharmacol 17:1, 1980. MacAlpine RN, Kattus AA: Adaptation to exercise in angina pectoris; the electrocardiogram during treadmill walking and coronary angiographic findings. Circulation 33:183, 1966. Parodi 0, Maseri A, Simonette I: Management of unstable angina at rest by verapamil: A double-blind cross-over study in coronary care unit. Br Heart J 41:167, 1979. Hoffmann P: Behandlung koronaren Durchblutungsstoningen mit Isoptin inder Praxis. Med Klin 59:1387, 1964. Herxheimer A: Claims for cordilox. Drug Ther Bull 5:85, 1967. Phear DN: Verapamil in angina. Br Med J 2:740, 1968. Sandler G, Clayton GA, Thornicroft SG: Clinical evaluation of verapamil in angina pectoris. Br Med J 3:224, 1968. Sandler G: Investigation of verapamil in the treatment of angina pectoris. Brux Med 50:669, 1970. Neumann M, Luisada AA: Double blind evaluation of orally administered iproveratril in patients with angina pectoris. Am J Med Sci 251:552, 1966. Lynch P, Dargie H, Krikler S, Krikler D: Objective assessment of antianginal treatment: A double-blind comparison of propranolol, nifedipine, and their combinations. Br Med J 281:184, 1980.
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Amsrlcan
38. Kitamura K, Jorgensen CR, Gold FL, Taylor HL, Wang Y: Hemodynamic correlates of myocardial oxygen consumption during upright exercise. J Appl Physiol 32:516, 1972. 39. Holmberg S, Serzysko W, Varnauskas E: Coronary circulation during heavy exercise in control subjects and patients with coronary artery disease. Acta Med Stand 190:465, 1971.
40. Rodbard S, Williams F, Williams C: The spherical dynamics of the heart (myocardial tension, oxygen consumption, coronary blood flow, and efficiency). AM HEART J 57:348, 1959.
Clinical characteristics electrophyeiologic te ventricular tachycardba
Heart
1683 Journal
41. Sonnenblick EH, Ross J, Core11 JN, Kaiser GA, Braunwald E: Velocity of contraction as a determinant of myocardial oxygen consumption. Am J Physiol 209:919, 1965. 42. Leon MB, Bonow RO, Rosing DR, Bacharach SL, Green MV, Epstein SE: Effects of verapamil alone and combined with propranolol on left ventricular systolic function in patients with coronary artery disease (abstr).Circulation 62(suppl 3):111, 1980.
and res&ts of in young adub with #W#on or verWicular
Thirty-one patients 16 to 40 years of age (mean + SD = 30.7 + 7 years) had one or more episodes of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Underlying cardiac abnormalities consisted most commonly of cardiomyopathy (ntne), long QT syndrome (LOTS) (flve), and mitral valve prolapse (five); no Identifiable heart dlsease was found in four patients. Programmed ventricular stimulation induced VT in only one of four patients with the LQTS but induced VT in 64% of 22 patients with other abnormalities. Chronic drug treatment was based either on serial electropharmacologic testing or was empiric when electrophysiologic testing failed to provoke an arrhythmia. Using this approach, we found a 13% incidence of recurrent VT and a 10% mortality over a follow-up period of 18.1 +_ 13.9 months. In young adults with VT or VF, an underlying cardiac abnormality can usually be found. Extensive evaluatton should be performed to uncover the underlying cardiac abnormality as this may Influence chronic management. (AM HEART J 106:1306, 1983.)
Fred Morady, M.D., Melvin M. Scheinman, M.D., David S. Hess, M.D., Rhona Chen, and Paul Banger, M.D. San Francisco, Calif.
Most people who experience a life-threatening episode of ventricular tachycardia (VT) or ventricular fibrillation (VF) are more than 50 years of age and have underlying coronary artery disease.“* Although malignant ventricular arrhythmias may occur in young people, this is relatively unusual. VT and VF in people under 40 years of age have been reported in association with underlying heart disease3-lo and also in the absence of identifiable organic heart disease.“-” However, because numbers of patients in
From the Department of Medicine, University of California-San Francisco. Received for publication Feb. 19, 1982; revision received May 5, 1982; accepted June 19, 1982. Reprint requests: Fred Morady, M.D., Room 573, Moffitt Hospital, University of California-San Francisco, San Francisco, CA 94143.
1306
the reports of VTNF in the young have been small, the relative frequency of various types of underlying heart disease versus absence of organic heart disease remains unclear. Programmed ventricular stimulation has been demonstrated to be extremely useful in determining an effective therapeutic regimen in patients with recurrent VT’s~20 and in survivors of out-of-hospital cardiac arrest.*l The vast majority of patients in these studies have been adults with coronary artery disease. Reports of electrophysiologic testing in young persons with malignant ventricular arrhythmias have involved only a small number of patients.5s l8 Thus the frequency of VT induction by programmed ventricular stimulation in young patients without coronary artery disease who have had VT or VF remains unclear. The goals of our study were (1) to assess the types and prevalence of
106 6
ECG changes
ergonovine provocation in variant angina patients with coronary artery spasm. AM HEART J 103:161, 1982. 13. Braunwald E, editor: Heart disease: A textbook of cardiovascular medicine. Philadelphia, 1980, W.B. Saunders Co, pp 231-234. 14. Ellestad ME: Stress testing: Principles and practice. Philadelphia, 1975, F.A. Davis Co, p 125.
with
coronary
artery
spasm
15. Stein I, Weinstein J: Further studies of the effect of ergonovine on the coronary circulation. J Lab Clin Med 36:66, 1950. 16. Epstein S: Value and limitations of the electrocardiographic response to exercise in the assessment of patients with coronary artery disease: Controversies in cardiology. II. Am J Cardiol 42:667, 1978.
Double-blind randomized crossover trial of verapamil and propranolol in chronic stable angina Propranolol (240 mg daily) and verapamil (360 mg daily) were objectively compared for their respective efficacy in the treatment of chronic stable angina pectoris. Twenty-two patients were studied in a randomized placebo controlled, double-blind crossover trial with 4 weeks on each active drug treatment. Multistage treadmill exercise with computer-asslsted ECG analysis was performed after 2 weeks on placebo and at the end of each I-week active drug treatment. The mean exercise time to produce angina was 5.5 minutes (SEM + 0.4 minutes) on placebo and this increased to 7.8 (kO.5) minutes on propranolol and 9.1 (~~0.5) minutes on verapamil. The improvement in exercise time of verapamil over propranolol was statistically significant (p < 0.01). Ten patients became free of angina with verapamil and four with propranolol. Resting and maximal exercise heart rates were significantly reduced by propranolol; verapamil did not reduce the maximal heart rate but reduced the resting heart rate slightly. However, the heart rate increase per minute of exercise was significantly diminished (p < 0.001). ST segment changes showed improvement with both drugs despite marked differences in hea@ rate profile. The overall efficacy of the slow calcium channel blocker, verapamil, compares favorably with that of a standard beta-adrenoreceptor blocking drug (propranolol), thus providing a new perspective in the management of angina pectorfs. These two classes of drugs seem to act by different mechanisms and it is suggested that if patients are resistant or intolerant to one of these drugs, the other can be used to yield a beneficial response. (AM HEART J 106:1297, 1983.)
Michael J. Bowles, M.B., B.Ch., V. Bala Subrarnanian, M.D.,* Anthony B. Davies, M.B., B.S., and Edward B. Baftery, B.Sc., M.D. Harrow, Middlesex, England
Beta-adrenoreceptor blocking agents have been established as the drugs of choice in chronic stable angina and have been in extensive clinical use for has become the the last 20 years. I-5 Propranolol standard against which all other agents are com-
From the Department of Cardiology and Division of Clinical Sciences, Northwick Park Hospital and Clinical Research Centre. Received for publication Sept. 24, 1981; revision received Apr. 26, 1982; accepted
June
Reprint Hospital,
requests: Watford
*Supported
19, 1982. Dr. E. B. Raftery, Dept. Rd., Harrow HA1 3UJ,
by the British
Heart
Foundation.
of Cardiology, Northwick Middlesex, England.
Park
pared.‘s5v6 Interest in the use of slow calcium channel blockers in angina pectoris has recently been revived, particularly in Prinzmetal’s and unstable angina, in which coronary artery vasospasm has been shown to play a critical etiologic role.7-g In these cases beta-adrenoreceptor blockade is usually ineffective and verapamil has proved useful in doses of 120 to 840 mg daily.‘O Verapamil’s use in chronic stable angina is also under intense investigation. We have investigated the antianginal action of the slow calcium channel blocker, verapamil, with objective methods11-15 designed to eliminate observer bias, and have conducted a double-blind, cross-over trial 1297
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1298 Table
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American
I. Treadmill protocol
Stage 1
2 3 4 5 6 I
Time (min)
Speed (mph)
Percent gradient
3 3 3 3 3 3 3
2 3 3 3 3 3 4.5
0 4 8 12 16 20 20
comparing verapamil in a dose of 360 mg daily with placebo in 28 patients.16 We found that the drug produced a significant improvement of exercise tolerance and ST segment changes. These beneficial actions were obtained with minimal effects on the resting and exercise heart rate. The next logical step
was to compare the potency and mode of action of verapamil with a standard beta-adrenoreceptor blocking drug. The evaluation of this comparison was considered to be of practical importance to the clinician and the pharmacologist. The trial was conducted using a method identical to the previous
studies. METHODS
Twenty-five patients with confirmed chronic stable angina (age range 41 to 69 years, 22 malesand 3 females) participated in the trial. Inclusion criteria. The patients were requirtd to have unequivocal evidence of coronary artery disease,symptomatic stable angina, and ST segmentchangeson maximal treadmill exercise testing. Coronary artery disease was confirmed by selective coronary arteriography, at which time all patients were judged to have evidence of good left. ventricular function which wasalsomeasuredby noninvasive methods on each treatment phase. Seventy percent luminal narrowing of one or more major coronary arteries was taken as significant disease.All patients had classicalangina on physical exertion relieved by rest and sublingual nitroglycerin, with a minimum frequency of four attacks per week. All developed classicalangina1pain on treadmill exercise testing with at least 1 mm ST segment depression (slope lessthan 0.1 mV/sec) in two bipolar leads (CM, and CC,) during exercise. Only patients physically capable and mentally motivated for repeated treadmill exercise were entered in the final trial. Exclusion criteria. Patients over 70 years of age and females in the childbearing years were excluded. Those having myocardial infarction in the preceding 4 months, patients with unstable angina, and patients having severe symptoms who were clinically judged as unsuitable for placebo treatment were also excluded. Cardiac failure, bronchial asthma, peripheral vascular disease, resting blood pressurelevels above 160/100 mm Hg, and insulin-
1983
Heat-i Journal
dependent diabetes mellitus were other exclusion criteria. Any patients receiving diuretics, digitalis, and other cardiovascular medications were excluded from the study. Any patient showing more than -0.5 mm ST depression on standing, hyperventilation, and the Valsalva maneuver, or who did not develop classical angina on the initial diagnostic treadmill exercisetest and did not show 1 mm ST segment depression in both bipolar leads was also excluded. Trial design. The initial inclusion criteria were basedon a diagnostic exercise test performed without any treatment (19 patients) or after 4 weeksof complete withdrawal of current medical treatment. Two patients were taking long-acting nitrates, two were on oxyfedrine, and two were on propranolol, 40 mg thrice daily, before inclusion in the trial. None of the patients was given any other cardiac drugsexcept the trial drugs and sublingual nitrates during the trial period. The drugs were administered using a double-dummy technique. During the first, 2 weeks which comprised the placebo run-in phase, the patients took two tablets, one eachof verapamil and propranolol placebo, thrice daily. In the crossover phase the two tablets were either active verapamil and placebo propranolol or active propranolol and placebo verapamil. This phasewas double-blind. All verapamil tablets including placebo were identical in appearance and all propranolol tablets including both dosesand placebowere identical. The tablets were packed in plastic containers with compartments identifying the day of the week and the time of drug administration. All 25 patients were started on a double-blind crossover study of 4 weeks each with an initial 2-week placebo run-in period. Following this they were randomized on to propranolol, 240 mg daily, or verapamil, 360 mg daily, in three divided dosesfor 4 weeks,at the end of which time each patient crossedover to the alternate regime. Since 4 weeks elapsed between each exercise test, no washout period was incorporated. Formal exercisetesting and left ventricular function estimateswere repeated at the end of placebo and at 4 and 8 weeksof active drug therapy. Subjective evaluation. The patients were instructed in the use of a diary card to document the frequency of angina1 episodes and nitroglycerin consumption. The importance of not using prophylactic nitroglycerin during the trial period was emphasizedto each patient. Exercise testing. All tests were performed .using a motor-driven treadmill, the speedand gradient of which were regularly calibrated and the program (Table I) governed by a computer (Marquette Computer Assisted System for Exercise). Two bipolar leads (CM, and CC,) were continuously recorded before, during, and after exercise in a 25: 1 compressedformaLl Digital printouts of ST depressionat the J point, ST slope, heart rate, and ectopic count were generated for every minute of the test and for a final analog trend plot of each complete test. Systolic blood pressurewasmeasuredevery 3 minutes and at termination of exercise with a mercury sphygmomanometer. All exercise tests were maximal or limited by angina, dyspnea, fatigue, or pain in the legs. All were
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Table
Randomized verapamil-propranolol
Exercise time Work load Resting heart rate Maximum heart rate Heart rate gain Heart rate recovery 5’ Double product 1 mm time (CM,) 1 mm time (CC,) 2 mm time (CM,) 2 mm time (CCs) MST (CM,) MST (CC,) MST/ex.time (CM,) MST/ex.time (CC,) ST same workload (CM,) ST same workload (CC,) Heart rate same workload ST Recovery 5’ (CM,) ST Recovery 5’ (CC,) values
1299
II. Comparisonsof the antianginal effects of verapamil and propranolol Placebo
All
trial in stable angina
are mean
5.5 6.1 76 135 58 51 216 3.3 2.9 4.3 4.3 2.4 2.1 0.48 0.42 2.3 2.2 131 1.9 1.7
zk + ? k -I* iz + + f + f + + f + f * f f
0.4 1.4 3 3 3 2 8 0.4 0.4 0.5 0.6 0.2 0.2 0.06 0.05 0.20 0.18 3 0.2 0.2
Propranolol (240 md 7.8 14.8 56 104 47 39 164 5.7 5.5 7.3 8.0 1.7 1.7 0.24 0.24 0.95 1.05 94 1.3 1.1
k + f + + + f 2 k +ck r + + f + zk * -t Yr
Verapamil (360 mg)
0.5 2.2 2 3 2 2 7 0.5 0.6 0.7 0.7 0.1 0.1 0.03 0.02 0.14 0.16 3 0.1 0.1
9.1
20.4 71 130 57 50 204 5.5 5.5 7.1 7.9 2.2 2.0 0.28 0.24 1.3 1.4 116 1.4 1.2
A
* 0.5
k rt +++-+ k k +k + -c f f
2.4 3 3 2 2 6 0.6 0.7 0.9 1.0 0.2 0.2 0.04 0.03 f 0.20 * 0.18 I? 3 It 0.2 -t 0.1
B
NS NS NS NS
C
NS NS NS NS NS NS NS NS NS NS
NS NS
0.001
-co.01
NS NS
+ S.E.M.
ex. time = exercise time; MST = peak ST depression. All heart rate values are in bpm. All ST segment values are in millimeters. Workload = (kilometres walked X sine angle of treadmill in degrees) U. p values for: placebo vs propranolol = A, placebo vs verapamil = B, propranolol
performed in the morning between 90 and 150 minutes after the last doseof the drug, and after 30 minutes rest in a temperature-controlled laboratory. The standard safety precautions recommendedby the American Heart Association were followed.17 The following variables were calculated from the exercise data: (1) exercise time (accuracy + 0.1 minute); (2) workload (combined product of speed of treadmill in kilometers, sine of angle of treadmill in degrees,gravitational constant, and body weight; the gravitational constant and body weight are constant factors over the trial period and were therefore taken as unity); (3) resting heart rate (RHR); (4) maximum heart rate (MHR); (5) heart rate gain (MI-IR minus RHR); (6) heart rate unit gain = heart rate gain/exercise time; (7) heart rate recovery over 5 minutes (MHR minus HR at 5 minutes after exercise termination); (8) heart rate sameworkload (HR developed at same exercise time and workload as on placebo); (9) 1 mm time (time taken for 1 mm ST displacement to occur during exercise); (10) 2 mm time (time taken for 2 mm ST displacement to occur during exercise); (11) maximum or peak ST depression(MST) accurate to + 0.1 mm; (12) MST/exercise time; (13) ST depressionsameexercisetime (ST depressionat the same exercise time as on placebo); (14) ST segment recovery over 5 minutes (MST minus ST depressionat 5 minutes after exercise); and (15) double product (maximum HR X maximum systolic blood pressure/lOO).All ST seg-
vs verapamil
= C.
Ill. Individual exercise times on verapamil and propranolol Table
Patient number
Placebo
1
3.9
9.4*
4.2 3.6 4.7 5.4 ILO.8 5.4 3.7 6.1 5.1 8.9 6.3 6.0 5.1 4.7 5.0 5.3 4.5 3.0 6.2 8.5 5.6
5.7 3.0 9.0 6.6 12.3* 8.4 4.4 4.9 8.1 9.9 12.1* 9.3 5.9 5.9 6.3 7.0 5.9 5.1 10.3 10.7 8.4+
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
All values in minutes. *Patient rendered angina-free.
Propranolol (240 md
Verapamil (360 mg) 8.2 6.6 7.2* 11.0: 9.1*
12.5* 8.8 3.9 10.7 9.5 11.3* 10.1 9.2
10.8 8.5* 7.3 7.6 6.5 5.1* 11.3* 12.5* 12.0*
1300
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et al.
American
Rest H.R.
Ex. time
llloz 5
.-c 5 .-2 ; .zi E w
Work load
120 a, 5 loo.F g 80-
9.15 87 6 54-
a
.... .:.,.: . ...:.,., ::,:: ‘:‘: ..A.:.... ..). :.:.:.:.; .,..... ..:.... ,:.:;y: .:.: ‘::::’:: .: ::I... . ::. 7)
PL P
v
-10
-a s ii
5
60-
5 f
40-
;:‘>: ...: .::i ?:‘i: ..i ..-..: ..+:.:: . ,.>:.> j:-::g :” .;.:,..i:. ;:I:: :;:y;;; i::: ..:.. 5>;.,y :.;: ..:. ..::::::: ,:::. j ::.: ~1
20 -
-5 OPL P
a PL P
H.R. same workload
140 -
’ 20
.:i
Max. H.R.
December, 1993 Heart Journal
-0 v
1. The mean exercise time in minutes for each treatment period is shown on the left. From a placebo value of 5.5 minutes, an improvement to 7.8 minutes of propranolol was obtained (p < O.OOl), and a further improvement to 9.1 minutes was achieved on verapamil (p < 0.001). There is a significant increasein exercisetime of verapamil over propranolol (p < 0.01). The workload performed (shown to the right) is calculated from the number of kilometers walked multiplied by the sine of the angle of the treadmill in degrees (U), and mirrors the improvement seen in exercise time with equivalent p values. Ex. time = exercisetime in minutes; PL = placebo; P = propranolol (240 mg daily); V = verapamil (360 mg daily); *p < 0.001comparedwith placebo. The lines aboue the bars indicate SEM. Fig.
ment values were calculated for both bipolar leads, CM, and CC,. Left ventricular function. This was estimated noninvasively by measuring systolic time intervals in the supine posture. The first derivative of the electrical impedance cardiogram (dZ/dt) was used as the central arterial pulse wave form. The impedance cardiogram and ECG were simultaneously fed into a purpose-built minicomputer which calculated the systolic time intervals, i.e., preejection period, left ventricular ejection time, ratio betweenthe left ventricular ejection time and pre-ejection period (PEP/LVET ratio), interval between the peak of the R wave of the ECG and impedance cardiogram (RZ interval), ratio between amplitude of impedance wave form and RZ interval (dZ/dt/RZ ratio), and ratio between amplitude of impedance waveform and heart rate (dZ/ dt/HR = ICO index). The last two parameters bear a close correlation to the other systolic time intervals and have been usedfor serial estimation of left ventricular function in other studies.‘s-22 Stroke volume and cardiac output were also obtained.21 In this study we used 100-beat averaging during quiet supine rest with additional averaging of the first 20 beats recorded with breath held in expiration. All studies were performed in the morning after supinerest for 20 minutes.
v
PL = Placebo P = Propranolol (240 mg) V = Verapamil (360 mg)
PL P
v
PL P
PVV Rest H.R. p< 0.001 Max. H.R. p< 0.001 H.R. same p
v :': p
2. The mean heart rates both at rest and during exercise are shown for the placebo phaseand each treatment period. At rest the heart rate wasreduced by 20 bpm on propranolol (p < 0.001)and by only 5 bpm on verapamil (p < 0.01). The maximum heart rate achieved during exercise was not significantly altered by verapamil, but was reduced by propranolol (p < 0.001). The heart rate developed during each treatment period for the same exercise time, and therefore by definition for the same workload ason placebo, showedsignificantly lower values for both verapamil (p < 0.001) and propranolol (p < 0.001). **p < 0.01. Other abbreviations as in Fig. 1.
Fig.
The data obtained included heart rate, stroke volume, cardiac output, pre-ejection period corrected for heart rate (PEP), left ventricular ejection time corrected for heart rate (LVET), PEP/LVET ratio (uncorrected), RZ interval corrected for heart rate (RZ interval index), and dZ/dt/RZ index. Patients were clinically examined during each visit for signsof cardiac failure and side effects were noted in a standard questionnaire. Statistics. Statistical analysis was performed using Student’s paired t test (two-tailed). Informed consent was obtained from all patients and the project was approved by the Hospital Ethical Committee. RESULTS
Twenty-two patients (20 males and 2 females) with an age range of 41 to 69 years completed the trial (Tables II and III). Placebo phase. All 22 patients developed classical
angina on treadmill exercise during the placebo phase. The mean weekly anginal frequency and nitroglycerin consumption was 15 -+ 7 and 17 +- 5, respectively. The exercise time to develop angina ranged from 3.0 minutes to 10.8 minutes (mean + SEM, 5.5 + 0.4 minutes), the corresponding mean
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lizsr -1
lzomgtcb
22
x4w
B
t3
0:
-i-z
d 120 -1.4
nmv l.?J -2.1
8.5
verapamil-propranolol
+1 104 -1.4
+2 68 -1.3
+3 79 -1.2
trial in stable angina
l4 74 -1.1
+5 74 -1.0
1301
1111 ST 129 -2.2
Fatii
i._l_,i_l;.ci-i;_!;_,‘P-Lb
Fig. 3. A patient’s computer-averaged ECGs with ST segment depression and heart rate. Top line shows
exercise time, second line shows heart rate, and third line indicates ST depression. During the placebo period pain developed at 4.7 minutes. On propranolol, pain developed at 5.9 minutes, and on verapamil fatigue was the only symptom at 8.5 minutes.
workload achieved being 6.1 + 1.4 U (Fig. 1). The mean resting heart rate was 76 +- 3 bpm and this increased at peak exercise to 135 + 3 bpm (Fig. 2). The gain in heart rate during exercise was 59 + 3 bpm and the heart rate increase per minute was 10.7 k 0.6 bpm. The heart rate recovered by 51 -C 2 bpm at 5 minutes postexercise and the ratio between heart rate gained and heart rate recovered was 0.86. The peak ST depression (MST) in lead CM, varied from 1.0 to 5.7 mm, with a mean value of 2.4 + 0.2 mm. The ST recovery at 5 minutes postexercise was 1.9 it 0.2 mm, the ratio of ST change to ST recovery being 0.80. The mean exercise time to produce 1 mm ST segment shift was 3.3 + 0.4 minutes and for 2 mm ST changes it was 4.3 r+ 0.5 minutes in lead CM,. Similar values were observed for the ST segment variables in lead CC, (Table I). The mean double product at termination of exercise was 216 + 8 U. Propranolol. All 22 patients reported an overall improvement in subjective well-being, although 12 mentioned tiredness as a new symptom. Angina frequency and nitroglycerin consumption were reduced to 10 + 6 and 12 + 5, respectively 0, < 0.01). The exercise time to produce angina
improved significantly on the beta-adrenoreceptor blocker. Four out of 22 stopped exercise due to fatigue rather than to angina, with a marked improvement in exercise performance in each case (Table III). The mean exercise time increased to 7.8 +- 0.5 minutes and the corresponding workload increased to 14.8 + 2.2 U (Fig. 1). Both these values were significantly better than with placebo (p < 0.001). The change in exercise tolerance ranged from -0.6 minutes to +5.8 minutes. The mean resting heart rate was reduced to 56 _+ 2 bpm and the maximal heart rate was reduced to 104 _+ 3 bpm (Fig. 2). The exercise heart rate gain was also reduced to 47 bpm in 7.8 minutes, resulting in a decrease of unit heart rate gain to 6.0 bpm. The peak double product was reduced to 164 f 7 U (p < 0.001). There was an apparent reduction of heart rate recovery to 39 + 2 bpm; however, the ratio between heart rate gain and recovery was unchanged at 0.83. The peak ST depression was improved to 1.7 mm; the range being 0.8 to 2.6 mm. Similarly, 1 mm and 2 mm times and the corrected ST variables showed a significant improvement when compared with placebo (p < 0.091). The ratio of ST recovery to ST change was unaltered at 0.77.
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(first
Fig. 4. Continuous trend plot for the samepatient as in Fig. 3, of ST segmentdepressions panel vertically) and heart rates (second panel) during each treatment period. Time is on the horizontal axis, with each marker representing 2 minutes, and ST depressionis on the vertical axis, with each marker showing 1 mm. The isoelectric line is shown by interrupted horizontal lines and end of exercise is shown by a vertical line in the middle of each panel. Heart rate is shown on the vertical axis in beatsper minute.
End point exercise symptoms are recorded.
The ST segment was markedly improved at the same exercise time as the placebo test (p < 0.001). Lead CC, showed similar changes to lead CM5, and the values are shown in Table II. Yerapamil. Ten patients became angina-free during this phase and stopped exercise because of fatigue. They had a significantly longer exercise time, suggesting a true improvement rather than a depressed left ventricular performance (Table III). There was a corresponding decrease in mean weekly anginal frequency to 5 + 3 and in nitroglycerin consumption to 3 +- 2 Cp < 0.001). There was a dramatic subjective improvement for all patients. Eight patients became constipated but were relieved by simple laxatives. There was a marked increase in exercise tolerance: the range of exercise time was from 3.9 to 12.5 minutes, with a mean value of 9.1 + 0.5 minutes. This increase was significantly higher than the placebo (p < 0.001) and the propranolol 07 < 0.01) values. The increase in exercise
time ranged from +0.2 minutes
to +6.6 minutes. The exercise time was longer than propranolol in 17, shorter in four, and identical in one patient. The mean workload increased to 20.4 + 2.4 U, which was significantly greater than both placebo and propran0101 (Fig. 1). The resting heart rate was mildly reduced to 71 f 3 bpm snd the maximum heart rate was 130 + 3 bpm (Fig. 2). The heart rate gain was unchanged at 59 _+ 2 bpm. The heart rate increase per minute of exercise time was, however, signibcantly reduced to 6.5 bpm as compared to 10.7 bpm on placebo and 6.0 bpm on propranolol. The peak double product was unaltered, but both heart rate and double product were reduced significantly at the same exercise time as placebo. The heart rate recovery was 50 +- 2 bpm, showing no change from placebo. The maximum ST depression in lead CM, did not show any change from placebo values (2.2 + 0.2 mm). However, this maximum ST depression was now seen at 9.1 minutes of exercise as compared
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_--.:j:. .i:> :$: +:. ::;:2 :g q.: *::::: z$: ;:> :::: 5::: .:::: .:.> *.: :.::: ::::: 8:; i... . :::; :.:.: :::: :::> ::::: ;g,;; g $$ ..i. 3.: ::::: .;:‘:: :y:: j::: ..._ u h >>; Randomized
verapamil-propranolol
% 150
1
1 I
trial
in stable angina
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:::9
.-----
HR
SV
CO
LVET
PEP
Fig. 5. Heart rate (HR), stroke volume (SV), cardiac output (CO), left ventricular ejection time index (LVET), and preejection period (PEP) on verapamil and propran0101.The valueshave beenexpressedas changescompared to the control placebo values. None of the drugs alter any of the variables significantly, and a mild increasein PEP is seenon propranolol therapy. Closed block = verapamil; stippled block = propranolol.
to 5.5 minutes on placebo. All the corrected ST values, 1 mm time, 2 mm time, and ST depression at the same exercise time as placebo showed significant reduction. The ST segment recovery was 1.4 + 0.2 mm, the ratio to ST change being 0.64 as compared to 0.80 on placebo. The ST changes in lead CC, were identical to those seen in lead CM, (Table II). Fig. 3 shows the computer-averaged ECG complexes and Fig. 4 shows the final analog trend plot of ST depression and heart rate for a single patient on all phases of the trial. Left ventricular function (Figs. 5 and 6). Most of the variables were not affected by either drug. The PEP/LVET ratio was significantly increased by propranolol and was unaffected by verapamil, suggesting no alteration in the myocardial contractility with verapamil and a mild reduction with proprano101. Side effects. Both drugs were well tolerated with few adverse effects. Constipation was a constant feature with verapamil and tiredness or lethargy appeared with propranolol. Two patients were withdrawn during the propranolol phase because of dyspnea at rest and severe hypotension. One patient
PEP/ LVET
RZc
dZIdt/ RZ
icol,dex
Fig. 6. PEP/LVET
ratio, RZ interval index (RZc), (dZ/ dt)/RZ index, and amplitude of dZ/dtiheart rate (ICOi”d,J on verapamil and propranolol therapy. Note the significant increase in PEP/LVET ratio on propranolol. **p = < 0.01.
developed a myocardial infarction and died during the verapamil phase, although there was a good initial response to treatment with a reduction in frequency and severity of angina. Autopsy revealed severe triple-vessel disease with total obstruction of the left anterior descending artery. No PR interval prolongation on the ECG in any of the patients was observed during either active drug phase. DISCUSSION Methods verapamil.
of drug evaluation-Early
experience
with
The accurate evaluation of antianginal drugs is fraught with numerous difficulties,23 not the least of which is the marked variation in the natural history of the condition.2* Hemodynamic variables include a mixture of fixed coronary obstruction and coronary artery spasm,2s the mechanisms of which lend themselves to differential pharmacologic approaches. There are problems associated with the pharmacologic properties of the drug tested,% and lastly all the difficulties inherent in the design of the system for testing.27 It is important, therefore, that
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as many of the variables as possible be eliminated by appropriate standardization which will also allow more meaningful comparisons to be made of the results from different centers. This trial has been designed to enable objective measurements of exercise data, the importance of which we have emphasized in earlier publications.“-l4 The trial investigates the comparative effects of verapamil and propranolol using the same methods as in a previous trial comparing veraparnil with placebo.16 The necessity of an adequate placebo duration with double-blind crossover techniques is now well accepted, both to eliminate observer bias and to produce results to which meaningful statistical analysis can be applied.28 Exercise periods have been sufficiently separated in time to minimize the effects of “warm-up” and training,2s and patient selection is carefully scrutinized to comply with standards recommended by the American Heart Association.17 Graded treadmill tests with predetermined workload increments were performed by all the patients and computer-assisted ECG analysis was utilized to provide exact quantitation of exercise times, ST segment levels, and heart rates during and after exercise, from which a number of indices of cardiac performance could then be calculated to provide insight into the effect and mode of action of the drugs. Verapamil has been in use for almost 20 years as an antiarrhythmic agent. It is known to have an antianginal action30 and Hoffmann31 performed the first planned clinical trial in 1964. Herxheimer32 stated that verapamil had no advantage over propranolol, and Phear33 found no significant difference between the drug and placebo. However, these early results were obtained with daily doses of 240 mg or less of verapami1,31-35 which did not allow for the extensive first-pass metabolism of the drug. Neumann and Luisada36 established the efficacy of verapamil(360 mg daily) in a double-blind crossover study in 1966. The necessity for comparison of verapamil with beta-adrenoreceptor blocking agents was soon realized, and Sandler et al.34 showed verapamil(360 mg daily) to be as effective as propranolol (300 mg daily). Livesley et al2 demonstrated that the effects of verapamil were at least equal to those of propranolol and that both drugs produced a similar reduction in heart rate, and de Oliveira6 found verapamil to be superior to propranolol. Efficacy of propranolol. In this trial we have used fixed doses of both verapamil and propranolol and therefore comparisons made between their effects must be viewed in the light of differing dose-
American
December, 1983 Heart Journal
response curves, which are known to be fairly steep for propranolol but appear flatter for verapamil. The propranolol dose was fixed at 80 mg thrice daily, at which it is commonly stated as providing adequate bradycardia.5s37 Propranolol improved the exercise time by 40 % . Its primary effect appeared to be a reduction of heart rate (resting heart rate was reduced by 26% and the maximum heart rate was reduced by 23%), which is in concordance with the findings of Livesley et a1.2 There was a marked reduction in the double product at the peak of exercise. The heart rate recovery was not altered. Maximum ST segment depression corrected for exercise time was significantly reduced. Efficacy and mode of action of verapamil. Verapamil had a different effect. It reduced the resting heart rate by only 6.5% and the maximum heart rate by 3 % , probably because the sinoatrial node depression is offset to some extent by the reflex tachycardia resultant from peripheral vasodilation. The heart rate recovery was not altered. The double product responses, which are known to correlate with changes in myocardial oxygen consumption,38*3g were blunted by verapamil at the peak of exercise but the decreases are considerably less than those observed after administration of propranolol, and do not offer a complete explanation of the mode of action of verapamil. Other determinants of myocardial oxygen consumption are geometric factors modifying ventricular wall stress40 and the contractile state of the myocardium.41 Although we did not demonstrate any significant effects on left ventricular function by the measurement of systolic time intervals, verapamil usually leads to mild depression in left ventricular function in patients with coronary artery disease,42 which could further decrease myocardial oxygen consumption and thereby improve the overall myocardial oxygen supply-demand relation. The maximum ST segment change was unaltered during the verapamil phase. The exercise time, however, increased by 66 % and the maximum heart rate and ST depression seen during placebo at 5.5 minutes now occurred at 9.1 minutes. These figures suggest an improved exercise tolerance with a delay in the appearance of myocardial ischemia. The corrected ST segment levels showed comparable changes with both drugs. Conclusions. Direct comparison of the two drugs is possible with these data. Verapamil has little negative chronotropic effect but improves exercise tolerance more than propranolol, probably because of a reduction of resistance in the systemic and coronary
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arterioles as well as an intracellular oxygen-sparing effect, resulting in a net decrease in myocardial oxygen requirements with a concomitant increase in coronary perfusion. On the other hand, propranolol seems to act predominantly through its negative chronotropic effect. We would suggest that propranolol is the preferred treatment for patients with a resting tachycardia and marked chronotropic exercise response and that verapamil must be considered especially for those with a poor chronotropic response to exercise or with coexisting diabetes mellitus, peripheral vascular disease, or bronchoconstriction. These observations are of importance in that they provide for the practicing clinician a rational guide to the choice of treatment. We thank Ian Eddy and Mrs. Brenda Christocopoulos for their technical assistance and Mrs. Jean Wright for secretarial assistance.
15.
16.
17.
18.
19.
20.
21.
22. REFERENCES
1. Prichard BNC: Propranolol in the treatment of angina: A review. Postgrad Med J 52:31, 1976. 2. Livesley 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 2:375, 1973. 3. Keyrilainen 0, Uusitalo A: Effects of metoprolol in angina pectoris-a subacute study with exercise tests and a long term tolerability study. Acta Med &and 199:491, 1976. 4. Ekelund LG, Anders G, Olsson ORO, Rossner S: Effects of the cardioselective beta adrenergic receptor blocking agentmetoprolol-in angina pectoris. A subacute study with exercise tests. Br Heart J 38:155, 1976. 5. Thadani U, Parker JO: Propranolol in angina pectoris: Duration of improved exercise tolerance and circulatory effects after acute oral administration. Am J Cardiol 44:118, 1979. 6. Martins de Oliveira J: Comparative effects of verapamil and propranolol in patients with angina pectoris. Arch Bras Cardiol 31:45, 1978. 7. Braunwald E: Introduction: Calcium channel blockers. Am J Cardiol 46:1045, 1980. 8. Opie LH: Calcium antagonists. Lancet 1:806, 1980. 9. Leading article: Calcium antagonists and the heart. Br Med J 282:89:1981. 10. Kelly DT, Freedman B, Richmond DR: Verapamil in the treatment of coronary artery spasm at rest and on exercise. In Zanchetti A. Krikler DM. editors: Calcium antagonism in cardiovascular therapy: Experience with verapamil. Amsterdam, 1981, Excerpta Medica, p 185. 11. Bala Subramanian V, Khanna PK, Narayanan GR, Hoon RS: Verapamil in ischaemic heart disease-quantitative assessment by serial multistage treadmill exercise. Postgrad Med J 52:143, 2976. 12. Bala Subramanian V, Khanna PK, Hoon RS: On-line digital computer quantitated ST segment response to submaximal treadmill exercise. J Assoc Physicians India 23:1, 1975. V, Khanna PK, Narayanan GR, Hoon RS: 13. Bala Subramanian Quantified multistage treadmill exercise-a reliable method for testing antianginal drugs. J Assoc Physicians India 23:597, 1975. V: Assessment of antianginal drugs by 14. Bala Subramanian serial treadmill exercise In MacFarlane PW, editor: Progress
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in electrocardiography. Kent, 1979, Pitman Medical, p 329. Sheffield LT: Quantitative approach to exercise testing for ischaemic heart disease. In Snell HA, editor: Quantitation in cardiology. Amsterdam, 1972, University Press, p 223. Bala Subramanian V, Paramasivan R, Lahiri A, Raftery EB: Verapamil in chronic stable angina: A controlled study with computerised multistage treadmill exercise. Lancet 1:841, 1980. Ellestad MH, Chairman MD, Blomqvist CG, Naughton JP: Standards for adult exercise testing laboratories. Circulation 58:421A, 1979. Siegal JH, Fabian M, Lanken C, Levine M, Cole A, Nakwad M: Clinical and experimental use of thoracic impedance plethysmography in quantifying myocardial contractility. Surgery 67:907, 1970. Rasmussen JP, Sorensen B, Kann T: Evaluation of impedance cardiography as a non-invasive means of measuring systolic time intervals and cardiac output. Acta Anaesthesiol Stand 18:210,1975. Bala Subramanian V, Mathew OP, Behl A, Tewari SG, Hoon RS: Electrical impedance cardiogram in derivation of systolic time intervals. Br Heart J 40~268, 1978. Bala Subramanian V, Mathew OP, Tewari SC, Behl A, Sharma SC, Hoon RS: Alterations in left ventricular function in normal man on exposure to high altitude (3658 m). Br Heart J 40:276, 1978. Bala Subramanian V, Behl A, Das GR, Wadhwa AK, Mathew OP, Hoon RS: Effect of digoxin and diuretics on high altitude left ventricular dysfunction. Circulation 57:1180, 1978. Aronow WS: The medical treatment of angina pectoris. II. Design of an antianginal drug study. AM HEART J 84:132, 1972.
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Duncan B, Fulton M, Morrison SL, Lutz W, Donald KW, Kerr F, Kirby BJ, Julian DG, Oliver MF: Prognosis of new and worsening angina pectoris. Br Med J 1:981, 1976. Maseri A, Severi S, De Nes M, L’Abbate A, Chierchia S, Marzilli M, Ballestra AM, Parodi 0, Biacini A, Distante A: “Variant” angina: One aspect of a continuous spectrum of vasospastic myocardial ischaemia. Pathogenic mechanisms, estimated incidence and clinical and coronary arteriographic findings in 138 patients. Am J Cardiol 42:1019, 1978. Aronow WS, Kaplan MA: Dilemma of angina pectoris. N Engl J Med 281:491, 1969. Redwood DR, Rosing DR, Goldstein RE, Beiner GD, Epstein SE: Importance of the design of an exercise protocol in the evaluation of patients with angina pectoris. Circulation 43:618, 1971. Feinstein AR: Should placebo-controlled trials be abolished? (Editorial) Eur J Clin Pharmacol 17:1, 1980. MacAlpine RN, Kattus AA: Adaptation to exercise in angina pectoris; the electrocardiogram during treadmill walking and coronary angiographic findings. Circulation 33:183, 1966. Parodi 0, Maseri A, Simonette I: Management of unstable angina at rest by verapamil: A double-blind cross-over study in coronary care unit. Br Heart J 41:167, 1979. Hoffmann P: Behandlung koronaren Durchblutungsstoningen mit Isoptin inder Praxis. Med Klin 59:1387, 1964. Herxheimer A: Claims for cordilox. Drug Ther Bull 5:85, 1967. Phear DN: Verapamil in angina. Br Med J 2:740, 1968. Sandler G, Clayton GA, Thornicroft SG: Clinical evaluation of verapamil in angina pectoris. Br Med J 3:224, 1968. Sandler G: Investigation of verapamil in the treatment of angina pectoris. Brux Med 50:669, 1970. Neumann M, Luisada AA: Double blind evaluation of orally administered iproveratril in patients with angina pectoris. Am J Med Sci 251:552, 1966. Lynch P, Dargie H, Krikler S, Krikler D: Objective assessment of antianginal treatment: A double-blind comparison of propranolol, nifedipine, and their combinations. Br Med J 281:184, 1980.
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38. Kitamura K, Jorgensen CR, Gold FL, Taylor HL, Wang Y: Hemodynamic correlates of myocardial oxygen consumption during upright exercise. J Appl Physiol 32:516, 1972. 39. Holmberg S, Serzysko W, Varnauskas E: Coronary circulation during heavy exercise in control subjects and patients with coronary artery disease. Acta Med Stand 190:465, 1971.
40. Rodbard S, Williams F, Williams C: The spherical dynamics of the heart (myocardial tension, oxygen consumption, coronary blood flow, and efficiency). AM HEART J 57:348, 1959.
Clinical characteristics electrophyeiologic te ventricular tachycardba
Heart
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41. Sonnenblick EH, Ross J, Core11 JN, Kaiser GA, Braunwald E: Velocity of contraction as a determinant of myocardial oxygen consumption. Am J Physiol 209:919, 1965. 42. Leon MB, Bonow RO, Rosing DR, Bacharach SL, Green MV, Epstein SE: Effects of verapamil alone and combined with propranolol on left ventricular systolic function in patients with coronary artery disease (abstr).Circulation 62(suppl 3):111, 1980.
and res&ts of in young adub with #W#on or verWicular
Thirty-one patients 16 to 40 years of age (mean + SD = 30.7 + 7 years) had one or more episodes of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Underlying cardiac abnormalities consisted most commonly of cardiomyopathy (ntne), long QT syndrome (LOTS) (flve), and mitral valve prolapse (five); no Identifiable heart dlsease was found in four patients. Programmed ventricular stimulation induced VT in only one of four patients with the LQTS but induced VT in 64% of 22 patients with other abnormalities. Chronic drug treatment was based either on serial electropharmacologic testing or was empiric when electrophysiologic testing failed to provoke an arrhythmia. Using this approach, we found a 13% incidence of recurrent VT and a 10% mortality over a follow-up period of 18.1 +_ 13.9 months. In young adults with VT or VF, an underlying cardiac abnormality can usually be found. Extensive evaluatton should be performed to uncover the underlying cardiac abnormality as this may Influence chronic management. (AM HEART J 106:1306, 1983.)
Fred Morady, M.D., Melvin M. Scheinman, M.D., David S. Hess, M.D., Rhona Chen, and Paul Banger, M.D. San Francisco, Calif.
Most people who experience a life-threatening episode of ventricular tachycardia (VT) or ventricular fibrillation (VF) are more than 50 years of age and have underlying coronary artery disease.“* Although malignant ventricular arrhythmias may occur in young people, this is relatively unusual. VT and VF in people under 40 years of age have been reported in association with underlying heart disease3-lo and also in the absence of identifiable organic heart disease.“-” However, because numbers of patients in
From the Department of Medicine, University of California-San Francisco. Received for publication Feb. 19, 1982; revision received May 5, 1982; accepted June 19, 1982. Reprint requests: Fred Morady, M.D., Room 573, Moffitt Hospital, University of California-San Francisco, San Francisco, CA 94143.
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the reports of VTNF in the young have been small, the relative frequency of various types of underlying heart disease versus absence of organic heart disease remains unclear. Programmed ventricular stimulation has been demonstrated to be extremely useful in determining an effective therapeutic regimen in patients with recurrent VT’s~20 and in survivors of out-of-hospital cardiac arrest.*l The vast majority of patients in these studies have been adults with coronary artery disease. Reports of electrophysiologic testing in young persons with malignant ventricular arrhythmias have involved only a small number of patients.5s l8 Thus the frequency of VT induction by programmed ventricular stimulation in young patients without coronary artery disease who have had VT or VF remains unclear. The goals of our study were (1) to assess the types and prevalence of