Combined therapy with verapamil and propranolol in chronic stable angina

Combined Therapy With Verapamil and Propranolol in

Chronic Stable Angina

BALA SUBRAMANIAN, MD, FACC”

MICHAEL J. BOWLES, MRCP

ANTHONY B. DAVIES, MRCP

EDWARD 8. RAFTERY, BSc, MD,

FACC, FRCP

Harrow, Middlesex, England

The comparative efficacy of verapamil (360 mg daily) and propranolol (240 mg daily) was evaluated with computerized treadmill exercise in 22 patients with chronic stable angina in a placebo-controlled double-blind crossover study with 4 weeks on each active phase. Fourteen of these patients still had angina despite active drug therapy and they were further treated with a combination of verapamil(360 mg) and propranolol(l20 mg) for 4 weeks. The mean exercise time for these patients taking placebo was 4.6 f 0.22 minutes (mean f standard error of the mean) and this increased to 6.8 f 0.64 minutes with propranolol and 8.0 f 0.5 minutes with verapamil. A further increase to 10.1 f 0.88 minutes was observed with the combination of both drugs and seven patients became symptom-free. S-T segment crtteria improved with both drugs, and combination therapy produced a further reduction in peak S-T depression. Electro- cardiographic ambulatory monitoring showed no evidence of conduction defects and mean hourly heart rates were similar to those seen with propranolol alone. Left ventricular function indexes were not signiftcantly different from those obtained with propranolol. Combination therapy with verapamil and propranolol appears to be efficacious in the treatment of selected patients with severe chronic stable angina. The patients need to be carefully monitored for adverse effects.

The medical management of angina pectoris focuses on the relief of pain with nitrates and the reduction of frequency of attacks with beta adrenergic receptor blocking agents. 1-5 The nitrates act by producing peripheral vasodilation and the beta adrenergic blocking agents by pre- dominantly reducing heart rate and blood pressure at rest and during exercise. Failure to respond to these drugs usually leads to referral for coronary arterial surgery, but this is not always freely available, and there is still some doubt about the long-term prognosis.6

From The Deoartment of Cardioloav and the Di- vision of Cl&al Sciences, North&k Park Hos- pital and Clinical Research Center, Watford Road, Harrow, Middlesex, England. Manuscript received March 30, 1981; revised manuscript received June 2, 1981, accepted June 25, 1981.

The demonstration that coronary arterial spasm plays an important part in the genesis of angina7 has led to renewed interest in the slow calcium channel-blocking agents as acceptable alternatives to beta adrenergic receptor blocking drugs. However, these groups of drugs are postulated to produce their effects by different mechanisms. They have been shown to dilate significantly not only the normal but also the nar- rowed segments of coronary arteries, producing a reduction in flow resistance.8 Verapamil has been shown to increase coronary sinus flow by dilating both resistance and conductance coronary vessels.g It is known to reduce afterload by peripheral vasodilation and some workers have shown a reduction in mvocardial oxygen consumption in vitro.lcJ1 Gould _- et al.12 reported a powerful chronic antihypertensive action with verapamil in patients with essential hypertension. In our earlier studies, we had clearly defined the effect of verapamil on heart rate at rest and during exercise. The heart rate at rest was mildly reduced and the maximal heart rate was unchanged even though exercise tolerance improved.13J4 It was therefore considered logical to combine these two groups of drugs (that is, beta blocking agents with a dominant negative chronotropic action and slow channel inhibitors acting by entirely different modes of action).

l Supported by the British Heart Foundation. Address for reprints: Bala Subramanian, MD,

Department of Cardiology and the Division of Clinical Sciences, Northwick Park Hospital and Clinical Research Center, Watford Road, Harrow, Middlesex HAI 3UJ, England.

January 1982 The American Journal of CARDIOLOGY Volume 49 125

VERAPAMIL WITH PROPRANOLOL IN ANGINA-SUBRAMANIAN ET AL

It has been reported15 that a combination of propranolol and nifedipine produces a potent synergism, but there is considerable concern that combinations of this kind with verapamil will have untoward effects on the conducting and contractile systems of the heart.lG2” Reports of complications arising from these combinations are based on intravenous dosing studies with high serum levels of the active drugs. It is possible that oral administration would be safer and effective in patients with severe resistant angina. We have tested this proposition in a controlled study to define a group of resistant patients and then observe their response to combined oral therapy with verapamil and propran- 0101.

Methods

Study patients: Twenty-two patients (20 men and 2 women whose ages ranged from 42 to 69 years) with chronic stable angina on exertion entered the study. The patients were re- quired to have unequivocal evidence of coronary artery disease, symptomatic stable angina and S-T segment changes on maximal treadmill exercise testing. Coronary artery disease was confirmed either by selective coronary arteriography or by transmural myocardial infarction in the 12 months pre- ceding the trial. All patients had classic angina on physical exertion relieved by rest and sublingual glyceryl trinitrate with a minimal incidence of four attacks/week. All of them had classic anginal pain on treadmill exercise testing and at least 1 mm S-T segment depression with a slope of less than 0.1 mV/s in two bipolar leads (CMs and CCs) during exercise. Only patients physically capable and mentally motivated to repeat treadmill exercise were entered in the final trial.

Exclusion criteria: All patients more than 70 years old and women of child-bearing age were excluded as were patients with recent myocardial infarction in the last 4 months or un- stable angina and those with severe symptoms who were clinically judged unsuitable for placebo treatment. Cardiac failure, bronchial asthma, peripheral vascular disease, blood pressure levels over 160/100 mm Hg at rest and insulin-de- pendent diabetes mellitus were the other exclusion criteria. Any patients receiving diuretic agents, digitalis and other cardiovascular medications were excluded from the study. Any patient showing more than 0.5 mm S-T depression during standing, hyperventilation and Valsalva maneuvers, or not exhibiting classic angina during the initial diagnostic treadmill exercise test or not showing 1 mm S-T segment depression in both bipolar leads was excluded.

Trial design: The initial inclusion criteria were based on a diagnostic exercise test performed without any treatment (16 patients) or after 4 weeks of complete withdrawal of cur-

TABLE I

Treadmill Protocol

Time Speed Gradient

Stage (min) (miles/h) (%)

1 3 Cl

; 3 z 4

: 3 8

4

“6 3 : :5

3” 3 20

7 4.5 20

rent medical treatment. Two patients were taking long-acting nitrates, two were taking oxyfedrine and two propranolol, 40 mg three times daily, before inclusion in the trial. No patient was given any other cardiac drug except the trial drugs and sublingual nitrates during the trial period.

The drugs were administered using a double-dummy technique. During the 1st 2 weeks that comprised the placebo run-in phase, the patients took two tablets, one each of verapamil and placebo propranolol, three times daily. In the crossover phase the two tablets were either active verapamil and placebo propranolol or active propranolol and placebo verapamil. This phase was double-blind. The third phase medications consisted of active verapamil(120 mg) and active propranolol (40 mg). This phase was single-blind. All verapamil tablets including placebo were identical in appearance and all propranolol tablets including both doses and placebo were identical. The tablets were packed in plastic containers with compartments identifying the day of the week and the time of drug administration.

All 22 patients were started on a double-blind crossover study of 4 weeks each with an initial 2 week placebo run-in period. After this study was completed, they were randomly given either propranolol, 240 mg daily, for 4 weeks or verapamil, 360 mg daily, in three divided doses. The randomization was based on the table of random numbers. The active drugs were crossed over at the end of 4 weeks. Fourteen patients who still had classic angina during treadmill exercise during both of the active periods were later treated with a combination of verapamil, 360 mg daily, and propranolol, 120 mg daily. This phase was single-blind.

Formal exercise testing was repeated at the end of the placebo period and after 4, 8 and 12 weeks of active drug therapy. Twenty-four hour ambulatory monitoring and estimation of left ventricular function by systolic time intervals (analyzed with an on-line computer system) were performed during each period to establish changes in resting heart rate, left ventricular function and the appearance of conduction defects.

Exercise testing: All tests were performed using a motor-driven treadmill whose speed and gradient were regularly calibrated and the program (Table I) governed by a computer (Marquette Computer Assisted System for Exer- cise). Two bipolar leads (CM5 and CCS) were continuously recorded before, during and after exercise in a 25:l compressed format.25 Digital printouts of S-T depression at the J point, S-T slope, heart rate and ectopic beat count were generated for every minute of the test and for a final analog trend plot of each complete test. Systolic blood pressure was measured every 3 minutes and at termination of exercise with a mercury sphygmomanometer.

From the computer printouts we derived the exercise time (time taken to development of angina or fatigue), the work load performed (product of distance walked in kilometers and sine angle of treadmill in degrees),26 the heart rate at rest, maximal heart rate, double product (systolic blood pressure X heart rate/loo), peak S-T depression in lead CM5 and S-T segment recovery at 5 minutes after exercise.

All exercise tests were maximal or limited by angina, dyspnea, fatigue or pain in the legs. All tests were performed in the morning between 90 to 150 minutes after the last dose of the drugs was administered and after 30 minutes of rest in a temperature-controlled laboratory. The standard safety precautions recommended by the American Heart Association were followed.27

Ambulatory electrocardiographic monitoring: Con- tinuous ambulatory monitoring of two electrocardiographic channels was performed using a frequency-modulated tape

126 January 1992 The American Journal of CARDIOLOGY Volume 49


TABLE II

Exercise Time During Basal, Placebo and Drug Treatment Periods for All Patients

Exercise Time (min)

Age Randomi-

Case (yr) Basal P Prop V V+B zation’

1 67 4.1 3.9 9.4 a.2 7.3 Prop : 55 51 3.8 3.4 4.2 3.6 5.7 3.0 6.6 7.2 16.7 7.0 V V

4 42 5.0 5.4 6.6 9.1 8.6 V 5

s5: 6.0 5.4 a.4 8.8 13.3 Prop

6 3.8 3.7 4.4 3.9 5.1 Prop

rzl t: 6.0 5.0 6.3 5.1 12.1 8.1 10.1 9.5 11.2 13.1 V Prop 9 64 5.0 5.1 5.9 10.8 12.5 V

10 5”; 4.9 4.7 5.9 8.5 9.1 V

:: 60 4.0 5.0 4.5 5.3 5.9 7.6 6.5 7.6 9.0 8.2 Prop Prop 13 66 5.2 5.0 6.3 7.3 9.7 V

Mean 4.8 4.8 6.8 8.0 10.1 SEM 0.22 0.22 0.64 0.5 0.88

l Randomization = drug received during first leg of crossover. P = placebo; Prop = propranolol, 80 mg three times daily; SEM = standard error of the mean. V = verapamil, 120 mg three times daily; V +

B = verapamil, 120 mg three times daily + propranolol, 40 mg three times daily.

recorder with a quartz controlled time channel (Oxford Medilog Mark II) for a minimum of 24 hours. All tapes were visually analyzed for prolongation of the P-R interval or higher degrees of heart block. Mean hourly heart rates were obtained using a computer program.2sT2s The S-T segment change at the J point in relation to the P-R interval was written out as a continuous trend. The number of episodes of S-T depression over 1 mm in 24 hours and the maximal depth of S-T change were obtained from this trend chart.

Left ventricular function: This variable was estimated noninvasively by measuring systolic time intervals in the supine posture. The first derivative of the electrical impedance cardiogram30 (dZ/dt) was used as the central arterial pulse wave form. The impedance cardiogram and electrocardiogram were simultaneously fed into a purpose-built minicomputer that calculated the systolic time intervals, that is, the preejection period, left ventricular ejection time, the ratio between the left ventricular ejection time and preejection period (PEP/LVET ratio), the interval between the peak of the R wave of the electrocardiogram and impedance cardiogram (RZ interval) and the ratio between amplitude of impedance waveform and RZ interval ([dZ/dt]/RZ ratio). The last two variables bear a close correlation to the other systolic time intervals and have been used for serial estimation of left ventricular function in other studies.31-35 Stroke volume and cardiac output were also obtained.

In this study, we used 100 beat averaging during quiet supine rest with additional averaging of the first 20 beats recorded with the breath held in expiration. All studies were performed in the morning after 20 minutes of supine rest. The data obtained included heart rate, stroke volume, cardiac output, preejection 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 and (dZ/dt)/RZ ratio.

Clinical monitoring was regularly carried out to detect untoward effects, which were noted on a standard ques- tionnaire. The project was approved by the Hospital Ethical Committee and informed consent was obtained from all patients.

Statistical analysis was performed with a programmed calculator using Student’s paired t test (two-tailed). Unless

otherwise indicated, mean values are expressed as mean values f standard error of the mean.

Results

Fourteen patients (12 men and 2 women) were given combination treatment with verapamil and propranolol; one patient was withdrawn from the trial because of dyspnea on accustomed exertion and development of an abnormal impedance waveform. Thirteen patients completed the trial period with no adverse effects; all reported data concern these patients.

Exercise time: The exercise times for individual patients are shown in Table II. The mean exercise time with placebo was 4.8 f 0.22 minutes and increased to 6.8 f 0.64 with propranolol (p <O.Ol), and with vera- pamil8.0 f 0.50 minutes (p <O.OOl) and with the combination therapy to 10.1 f 0.88 (p CO.001) (Fig. 1). Be- cause the exercise load was not linear but incremental, we calculated the work load performed26 (Fig. 2). There was a significant improvement in exercise time and work load performed with combination therapy when compared with values with placebo, propranolol or verapamil alone. Seven of 13 patients became free of angina with combination therapy. Two patients had a lesser exercise time with combination therapy than with propranolol or verapamil, and one patient showed no additional increase.

Heart rate (Table III): The mean heart rate at rest was 76 f 4 beatslmin with placebo, 55 f 3 with propranolol, 74 f 4 with verapamil and 54 f 2 with combination therapy. The maximal heart rate was 133 f 4 beats/min with placebo, 100 f 4 with propranolol, 129 f 3 with verapamil and 102 f 2 with combination therapy (Fig. 3).

Double product: The double product of systolic blood pressure and heart rate at peak exercise during treatment with placebo was 207 f 9 units, and was not significantly different with verapamil (205 f 7). Pro-



12

10

8

B 3 .5 6 ZE

4,

2,

0, A B C D

FIGURE 1. Mean maximal exercise time in minutes on each of the treatment periods. A = placebo; B = propranolol 240 mg/day; C = verapamil 360 mg/day; D = combination therapy (verapamil 360 mg/day and propranolol 120 mg/day). Standard errors are indicated by lines above each histogram. l = p <O.OOl versus placebo.

pranolol treatment produced a significant reduction to 161 f 7 units (p <O.Ol), and the combination therapy reduced this value to 177 f 9 (p <0.05).

S-T segment criteria: The maximal S-T change in lead CM5 was corrected for the increased exercise time by dividing it by exercise time. The degree of S-T segment recovery at 5 minutes after exercise was also derived. The maximal S-T change was not altered with verapamil but was reduced with propranolol and combination therapy. The corrected S-T segment depression was reduced significantly with all drugs and the combination produced a further significant improvement (p <O.Ol). The S-T segment recovery was not re- tarded by any of the drugs or the combination (Fig. 4).

30.

25.

20.

VI .Z 5 15.

10.

5.

B C D

FIGURE 2. Cumulative work load for each treatment period. Work load units = distance walked in kilometers X sine angle of treadmill in degrees. l = p <O.OOi versus placebo: l + = p <O.Ol versus placebo; other abbreviations as in Figure 1.

TABLE III

Comparative Data on Verapamil, Propranolol and Their Combination

Ambulatory electrocardiographic monitoring: No patient showed prolongation of the P-R interval or higher degrees of heart block. The 24 hour plot of heart rate is shown in Figure 5. This confirmed our findings on exercise testing and proved that no additional negative chronotropic effect appeared with combination therapy. The number of episodes of S-T depression in excess of 1 mm and the maximal depression were significantly less with combination therapy (Fig. 6 and 7).

Left ventricular function: N6 significant changes in any of the measured variables were observed with combination therapy (Fig. 8 and 9) except in one patient who experienced shortness of breath on the 2nd day. This patient had severe triple vessel disease and did not have any evidence of cardiac failure during placebo

Variables Measured PL (240Pmg) (36img) v+p PI VSP Plvs v Plvs VP PVSV Pvs VP VVSVP

Exercise time (min) 4.6 f 0.22 6.8 f 0.64 8.0 f 0.5 10.1 f 0.88 <O.Ol <O.OOl <O.OOl <0.05 <O.Ol <0.05 Work load (units) “.;;fi.“” 10.;;: $61 14.;; f $08 26.:;; if.32 <O.Ol <O.OOl <O.OOl <O.Ol <0.05 Resting heart rate <O.OOl co.05 <O.OOl <::Ol NS <O.OOl

(beatslmin) Maximal heart rate 133 f 4 100 f 4 129f3 102 f 2 <O.OOl NS <O.OOl <O.OOl NS <O.OOl

(beatslmin) M S-T (ChQ (mm)

I 2.49 f 0.32 1.72f 0.12 2.45 f 0.30 2.08f 0.32 <0.05 <002 NS

M S-T /exercise time 0.54f 0.08 0.28f 0.08 0.33f 0.06 0.24f 0.04 <O.Ol <o”lo”l <::Ol f&i NS <Zl (CM5) (mm)

S-T recovery in 1.91 f 0.33 1.28 f 0.15 1.50 f 0.19 1.43 f 0.28 <0.05 NS NS NS NS NS 5 minutes (CMs) (mm)

All values are mean f standard error of the mean. M S-T 4 = maximal S-T depression; NS = not significant; P = propranolol (240 mg); PI = placebo: V = verapamil(360 mg); VP = verapamil

(360 mg) -I propranolol(l20 mg).


VERAPAMIL WITH PROPRANOLOL IN ANGINA-SUBRAMANIAN ET AL.

ABCD ABCD \ B C D

Resting HR Maximal HR HR unit gain

FIGURE 3. Mean heart rate (HR) response in beats/min for each treatment period A, 6, C and D as in Figure 1. Heart rate unit gain = heart rate gain/exercise time X 10. * = p <O.OOi versus placebo.

treatment. He completed the verapamil and propranolol phase without undue adverse effects. On the 2nd day of the combination therapy, he complained of shortness of breath on accustomed exertion. No clinical or ra- diologic evidence of heart failure was detected. How- ever, the impedance cardiogram showed an early diastolic waveform, which has been reported to be an in- dicator of decreased left ventricular compliance.36 The patient was withdrawn from the trial and became symptom-free.

Adverse effects: During the controlled trial all except the one patient who was withdrawn from the study tolerated the drug combination well. No life-threatening complications were encountered during the trial.

3.0 -

2.5 -

2.0- z

; 1.5-

F?

1.0 -

0.5 -

O-

_I

ABCD A B C D ABCD

Peak ST 1 CM5 ST recovery Peak ST1 i Ex. time

FIGURE 4. Mean S-T segment depression (1) in millimeters for each treatment period A, B, C and D as in Figure 1. Peak S-T depression (ST$) is equivalent to ST depression immediately at termination of exercise. S-T recovery is the amount of S-T recovery taking place in 5 minutes after the point of exercise termination.

g 80- .& E

r; - 70- 0) z L

50’1 , , , , , , , , I I I 1 10 12 14 16 18 20 22 0 2 4 6 8 10

Time (hours)

FIGURE 5. Mean ambulatory hourly heart rates plotted for each treatment period throughout 24 hours. The maximal reduction of heart rate was seen with propranolol (80 mg three times a day). Closed circles = placebo; open circles = verapamil360 mgfday; open squares = verapamil360 mg/day + propranolol 120 mglday; closed squares = propranolol 240 mg/day.

Discussion

This study was designed to demonstrate the relative potency of verapamil and propranolol and explore the efficacy and safety of combined therapy. The first phase was double-blind and the combination phase was open to the observers. This procedure was considered essential to minimize the risk of untoward effects when

T

A B C D

FIGURE 6. The number of episodes of S-T depression (1) in excess of 1 mm in 24 hours in lead Cfvls during placebo (A), verapamil (B), pro- pcanolol (C) at?d combination therapy ID). There is a significant reduction of the episodes from 18 with placebo to 4 with combination. Placebo versus propranolol, p = <O.Ol; placebo versus verapamil, p = <O.Ol; placebo versus combination, p = <O.OOl: combination versus verapamil or propranolol, p = <0.05.



1 . . . . .,. >>: .\:. ---- Placebo :.:.: .\.. :.:j: :.. ..:i .A. ..::: ::::i . . . ..i. .:.:, R~ .:;:: .:.:. ::::: ::::: .,. :.: : . . . ::,.: ::,.: :::.: . . . . ..:. . . . . . :.:? i.2 :.::: ::::: .>,. ;:i;; ..:.: .,...

. ::jjj .A.. .a.. . . .

,;j::

,:::, . . . . . . . I .: . . :j.

.:i::

.,.

\:I:

..:.

. ..L

::::

i::

ii

.a.

. . : :.:.

:.::

:.:

< 0.05

I

RZc dZldt/RZ lCOlndex

FIGURE 9. Indexes of left ventricular function determined by impedance cardiography expressed for each treatment period as a percent of the placebo value. Open blocks = verapamil, 360 mg; stippled blocks = propranolol240 mg; clued blocks = verapamil360 mg -I propranolol 120 mg. CO = cardiac output; dZ/dt/RZ = Heather index .of contractility where dZ/dt is the time differentiated impedance change corrected for the R-Z interval. ICO index = impedance cardiac output index. RZc = corrected R-Z interval (interval from peak of R wave to impedance cardiogram); SV = stroke volume.

C D

FIGURE 7. The maximal depth of S-T depression (1) on 24 hour electrocardiographic monitoring was significantly reduced with combination therapy (D) whereas verapamil (B) or propranolol (C) given alone did not produce significant changes.

antianginal agents5J5,3g-43; we confirmed these findings in this study. Verapamil improved exercise time by 67 percent and propranolol by 42 percent, but the drugs clearly acted by different mechanisms. Propranolol reduced the heart rate at rest and maximal exercise heart rate by a negative chronotropic action. It produced an improvement in S-T changes and the angina1 threshold, and S-T changes occurred at a much lower heart rate. Verapamil did not reduce the resting or the maximal exercise heart rates and the S-T segment changes were unaffected at peak exercise. However, all these changes occurred after longer periods of exercise. Logically, a combination of these two drugs should possess additive or synergistic action and if the combination is safe it would have a clear therapeutic role.

Effects of combined therapy: The data obtained for the combined therapy seem to prove this point. The mean exercise time increased significantly; 10 of 13

using a combination that might be considered unsafe. We used objective methods of evaluation free from observer bias and variation to ensure reliable re- ,,lts.25>37,3s

Comparative effects of verapamil and propran- 0101: Verapamil and propranolol are both powerful

% 150

100

50

0

Placebo

TABLE IV

Comparison: Basal Untreated Tests and After 2 Weeks of Placebo Therapy (n = 40)

Exercise time (min) Heart rate/min at rest Maximal heart rate/min

Basal Placebo p value

5.2 f 0.3 5.3 f 0.2 NS 78 f 2 78 f 2 NS

126f2 128f2 NS 2.3 f 0.2 2.3 f 0.2

0.44 f 0.02 0.43 f 0.02 I% 2.0 f 0.14 2.0 f 0.14 NS

HR LVET PEP PEPlLVET

FIGURE 8. Mean resting heart rate (HR) and systolic time intervals with verapamil, 360 mg (open blocks), propranolol 240 mg (stippled blocks) and a combination of propranolol, 120 mg and verapamil, 360 mg (closed blocks) plotted as a percent of the corresponding placebo values. LVET = left ventricular ejection time; PEP = preejection period; l * = p <O.Ol compared with placebo; l = p <O.OOl compared with placebo.

All values are mean f standard error of the mean. p = probability.


patients showed improvement with either drug used alone. The resting and maximal heart rates with the combination of drugs were similar to those with propranolol alone. The S-T segment criteria were not ad- versely affected despite an increase in exercise time. The S-T segment recovery was unaltered and the corrected S-T depression was better with combination therapy than when verapamil was given alone. These patients had severely limited exercise tolerance and did not respond completely to either drug when given alone. Seven patients became symptom-free and had increased exercise tolerance with the combined treatment. The improvement in exercise tolerance and S-T segment changes demonstrated in the exercise laboratory was confirmed with 24 hour ambulatory monitoring of the S-T segment changes. There was a significant lessening in the number of episodes and the maximal depth of S-T segment depression with combination therapy.

The double product at peak exercise was not significantly altered with verapamil but decreased both with propranolol and the drug combination. In our previous studies we had found that verapamil did not reduce maximal exercise heart rate and peak double product but reduced the heart rate and double product at similar exercise time as placebo. 25 The combination seemed to be better than verapamil in this aspect also.

Possible adverse effects of combined therapy: The main objections to the combined therapy are the possibility of higher degrees of heart block, undue bradycardia and heart failure.1s-24 We planned our study to examine all these possibilities carefully. The ambulatory heart rates did not show any bradycardia or heart block with the drug combination and the noninvasive left ventricular function indexes showed that the combination is no more cardiodepressant than either drug given alone, except for one patient who had dyspnea on accustomed exertion and had to be withdrawn from the study.

Effect on left ventricular function: We used the electrical impedance cardiogram as a transducer to obtain a stable central arterial wave form to calculate systolic time intervals that are well established as reliable noninvasive indicators of left ventricular function. The validity of this technique has previously been reported. The use of this method yielded other noninvasive variables such as cardiac output and peak of R wave to impedance cardiogram (RZ) interval, which behaved in a similar manner to the systolic time intervals. These variables have been used in other studies to estimate left


ventricular function and enabled us to use a larger number of noninvasive variables to obviate the usual shortcomings of such techniques.:s1m:35

The treadmill exercise protocol was carefully evolved to yield objective data free from subjective bias and observer variations. The possibility that there would be a progressive improvement in exercise tolerance with progressive tests cannot be totally excluded but seems unlikely on scanning the individual results (Table II). We utilized this method successfully in a number of trials.1”,25,41,42 Table IV shows the reproducibility of this protocol in 40 patients with an untreated basal test and a placebo test.

Adverse effects: Adverse effects could not be satis- factorily defined in such a small trial. However, since conclusion of the trial we have .treated 40 patients with a similar combination of verapamil and propranolol and the adverse effects observed were hypotension (four patients), cardiac failure (three patients), bradycardia (one patient) and junctional rhythm (two patients). Therapy was discontinued in six of these nine patients and the reduction of propranolol dose to 20 mg three times daily controlled adverse effects in the other three. We believe that the incidence of adverse effects is not unduly large in a patient group with severely restricted exercise tolerance and consequent poor ventricular function.

We used a fixed dose regimen of 360 mg of verapamil and 120 mg of propranolol on empirical grounds; in the clinical situation improvement has been noted with even smaller doses of beta receptor blocking agents (for ex- ample, 20 mg two times a day), but we have not at- tempted to reduce the dose of verapamil because earlier studies indicated poor efficacy at smaller doses.44s45 However, this does not rule out the possibility of smaller doses in combined therapy.

In conclusion, verapamil and beta receptor blocking agents can be used in combination to improve exercise tolerance significantly and improve myocardial ischemia in patients with severe angina pectoris. However, careful monitoring of these patients is strongly advised to identify adverse effects that may occur.

Acknowledgment

We acknowledge the technical assistance of Brenda Christacopoulos, Jayshree Sarma and the secretarial assistance of Jean Wright. Verapamil (Cordilox, Isoptin) was supplied by Abbott Laboratories Ltd., Queenborough, Kent, England.

References

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2. Keyrilainen 0, Uusltalo A. Effects of metoprolol in angina pecto- J 1979;97:137-40. ris-a subacute study with exercise tests and a long term tolera- 6. McIntosh HD, Garcia JA. The first decade of aortocoronary bypass bility study. Acta Med Stand 1976;199:491-97. grafting, 1967-1977: a review. Circulation 1978;57:405-31.

3. Ekelund LG, Anders 0, Olsson ORO, Rossner S. Effects of the 7. Maser1 A, Sever1 S, De Nes M, et al. “Variant” angina: one aspect cardioselective beta-adrenergic receptor blocking agent-me- of a continuous spectrum of vasospastic myocardial ischemia. toprolol-in angina pectoris. A subacute study with exercise tests. Pathogenic mechanisms, estimated incidence and clinical and Br Heart J 1976;38:155+1. coronary arteriographic findings in 138 patients. Am J Cardiol

4. Rekhek N. Long-acting nitrates in ths treatment of angina pectoris. 1978;42:1019-35.



8.

9

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18. 19.

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Combined therapy with verapamil and propranolol in chronic stable angina

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