Long-term antianginal action of verapamil assessed with quantitated serial treadmill stress testing

Long-Term Antianginal Action of Verapamil Assessed With

Quantitated Serial Treadmill Stress Testing

BALA SUBRAMANIAN, MB. MD, FACC’ MICHAEL BOWLES. MB, MRCP AVAJIT LAHIRI, MB, BS ANTHONY B. DAVIES, MB. MRCP EDWARD B. RAFTERY, BSc, MB, MD,

FACC, FRCP

Harrow, Middlesex, England

From The Department of Cardiology and the Di- vision of Clinical Sciences, Northwick Park Hos- pital and Clinical Research Centre, Watford Road, Harrow, Middlesex, England. Manuscript received January 14, 1981; revised manuscript received April 8. 1981, accepted April 9. 1981.

* Supported by the British Heart Foundation, London, England.

Address for reprints: Bala Sabramanian. MB, MD, FACC, Consuftant, Card& wnt, The Department of Cardiology and the Division of Clinical Sciences, Northwick Park Hospital and Clinical Research Centre, Watford Road, Harrow, Middlesex, England.

The long-term efficacy of verapamil in a dose of 360 mg daily in patients with chronic stable angina pectoris was assessed by quantltated serial treadmill exercise tests. Twenty-eight patients were Investigated with a placebo-controlled, double-blind, crossover protocol of 2 weeks each and aflerward all patients were put on long-term therapy. Exercise tests were performed at the end of the placebo period and afler 2,4,8,16,24 and 52 weeks of verapamil therapy. All 28 experienced angina during treadmill tests on placebo and the mean (f standard error of the mean) exercise time was 6.6 f 0.5 minutes. This increased to 9.2 f 0.8 minutes at 2 weeks and to 11.2 f 0.8 minutes at 4 weeks. Fifteen and 20 of the 28 patients became angina-free during treadmill exercise at 2 and 4 weeks, respectively. The consumption of nitroglycerin showed a similar improvement. The improvement was maintained at 1 year of follow-up. The on-line computer-analyzed S-T segment changes showed a statisti- cally significant improvement at all follow-up periods. Withdrawal of verapamil produced a return to pretreatment levels. The adverse effects noted were constipation in seven patients and reversible P-R interval prolongation In two. No heart failure occurred in any patient. These findings suggest that verapamil possesses a powerful and sustained antianginal action and, in a dose of 360 mg dally, merits a place as a primary therapeutic agent In the management of chronic stable angina.

The medical treatment of chronic stable angina is based on administration of nitrates and beta adrenergic blocking agents,’ 6 but these drugs are not always effective and their prolonged administration may lead to tachyphylaxis and undesirable effects. Patients with angina of this type are commonly considered candidates for coronary arterial bypass grafting. Furthermore, beta adrenergic blocking agents are contraindi- cated in those patients with bronchial asthma, peripheral vascular disease or bradycardia.7-10 There is obviously a need for a new range of drugs acting by a different mechanism to augment the available range of antianginal drugs.

In recent years, there has been a change in the concept of the funda- mental mechanism of angina pectoris. It has been established”~” that coronary arterial vasospasm can play an important role in the genesis of angina and that S-T segment changes, even if unaccompanied by pain, can be associated with profound hemodynamic alterations. Slow calcium channel blocking drugs have been shown to be effective against vasospasm.‘” Verapamil is a typical example of this group of drugs, which has been in clinical use for more than 15 years. We have been using verapamil to treat chronic stable angina for 7 years and recently documented its beneficial effects over a 4 week period.i4 In this communi- cation we report our assessment of the long-term efficacy of the drug over 1 year of continuous administration.

September 1981 The American Journal of CARDIOLOGY Volume 48 529

VERAPAMIL IN ANGINA-SUBRAMANIAN ET AL.

Methods

Study patients: Twenty-eight patients aged 43 to 69 years took part in the study. There were 25 men and 3 women. All had classic effort-induced angina occurring at least four times/week and relieved by rest and sublingual administration of glyceryl trinitrate. The diagnosis was confirmed by an initial multistage treadmill exercise testing performed while the patient was receiving no treatment, and each experienced angina with at least 1.0 mm S-T segment depression in leads CMF, and CC5 with a slope of less than 0.1 mV/s during the exercise. No patient was taking any drug except verapamil and glyceryl trinitrate during the entire study period. None suf- fered from severe hypertension or had S-T segment changes on standing, hyperventilation or the Valsalva maneuver. None had unstable angina, evidence of recent myocardial infarction in the last 4 months or peripheral vascular disease.

Trial protocol: Verapamil was administered in a dose of 120 mg administered three times daily, at 8 a.m., 2 p.m. and 8 p.m. The drug and a matching placebo were given in a randomized double-blind crossover design, and the order of medication was determined by a table of random numbers. The periods were 2 weeks each, and after the end of the crossover period all patients were treated with verapamil in the same dose and the trial was continued on an open basis for a total of 52 weeks. At the end of 1 year, drug treatment of all consenting patients was withdrawn gradually over 1 week and replaced by a placebo period lasting 4 weeks.

Assessment

Subjective evaluation: The effect of the placebo and verapamil was assessed both subjectively and objectively.

The patients maintained a detailed diary of the frequency of their angina1 attacks and glyceryl trinitrate consumption. They were instructed regarding the necessity of accurate in- formation and to take glyceryl trinitrate for angina1 attacks only.

Exercise testing: Objective assessment was performed by serial treadmill exercise testing before entry into the trial, after 2 weeks administration of placebo and after 2,4,8,16,24 and 52 weeks of verapamil therapy and 4 weeks after withdrawal of verapamil at the end of the 1 year period. All tests were performed in the morning 2 hours after a light breakfast and at 90 to 150 minutes after administration of the last dose of verapamil. The temperature of the laboratory during exercise was 24 f 2” C (mean f range), and the speed and the gradient of the treadmill were calibrated at weekly intervals. The patients arrived at the area at least 30 minutes before the test and rested comfortably. They were instructed not to smoke or to take any glyceryl trinitrate tablets on the morning of the test.

TABLE I

Treadmill Exercise Protocol

Stage

1

3’ :

6 7

Time in Minutes Speed (progressive) (miles/h)

: 3’ 15 1: :

16 : 21 4.5

Gradient (percent)

0

: 12

:: 20

The exercise test was performed with use of a microcom- puter-based system (Marquette Computer assisted system for exercise) linked to a Quinton treadmill. The treadmill protocol is shown in Table I. The speed and gradient were automatically controlled by the computer, and the test was timed with a built-in digital clock to an accuracy of 0.1 minute. All tests were continued until the patient’s symptoms war- ranted stopping the exercise. The criteria for cessation were moderately severe angina (grade II), pain in the legs, severe dyspnea, or fatigue. Standard safety and legal procedures as recommended by the American Heart Association were reg- ularly followed. l6 Two bipolar electrocardiographic leads ( CMF, and CC&) were continuously monitored at rest, during exercise and for a minimum of 5 minutes after exercise. Sys- tolic blood pressure was monitored every 3 minutes with a mercury sphygmomanometer.

The leads monitored were CM5 (manubrium sternum negative and LVF, exploring electrode) and CC& (RVs negative and LVS exploring electrode). A lead showing large P waves was used to monitor arrhythmias. The resting electrocardiogram was fed into the computer to form the resting template. The computer calculated the S-T segment depression at the J point in relation to the most horizontal part of the P-R segment and expressed it in multiples of 0.1 mm. The S-T slope was calculated between the J point and a point l/8 of the R-R interval after the J point. The averaged S-T segment depression, S-T slope, heart rate and ectopic beat count were printed automatically for both leads every minute during and after exercise. The electrocardiogram during the entire test was recorded continuously as 25 beats averaged as 1 at a paper speed of 1 mm/s with ectopic complexes being recorded in real time. On termination of the test a printout was obtained of the exercise time, maximal heart rate, maximal S-T depression and ectopic complex count. A continuous trend graph of S-T depression and S-T slope in all three leads and heart rate was also obtained. The measurement circuits of the computer were calibrated every day.

Data collection: From the continuous printouts the following data were available:

1. Resting heart rate, S-T segment levels. 2. Exercise heart rate, S-T levels, ectopic count every

minute during and after exercise. 3. Maximal heart rate. 4. Maximal S-T depression. 5. Exercise time. The following variables could then be calculated: 1. Heart rate gain = maximal heart rate minus resting heart

rate. 2. Heart rate recovery in 5 minutes = maximal heart rate

minus heart rate at 5 minutes after exercise. 3. Heart rate at same work load = heart rate after treat-

ment at the same exercise time at which the patient experienced angina during placebo therapy.

4. 1 mm time = time taken for developing 1 mm S-T depression from resting levels.

5. 2 mm time = time taken for developing 2 mm S-T depression from resting levels.

6. Corrected maximal S-T depression = S-T depression, immediately at the point of termination of exercise, corrected for resting values.

7. Maximal S-T depression/exercise time. 8. S-T recovery in 5 minutes of post exercise period. 9. Double product = systolic blood pressure times heart

rate divided by 100. Follow-up: Adverse effects and complications were looked

for carefully. During each visit patients were questioned in

530 September 1981 The American Journal of CARDIOLOGY Volume 48


detail from a standard questionnaire. Clinical examination was conducted to look in particular for pedal edema, raised jugular venous pressure and basal crepitations.

Statistical analysis was performed using Student’s t test.

Results

Twenty-eight patients started the trial and all completed 4 weeks of the study (Table II). One patient in whom a prolonged P-R interval (0.20 second increasing to 0.28 second) developed was withdrawn from the trial at 8 weeks of treatment. A second patient was withdrawn at 8 weeks because his symptoms worsened and a beta adrenergic blocking agent was added to his treatment. A third required an increase of the dose of verapamil to 480 mg and hence was withdrawn from the trial. One patient had an acute inferior myocardial infarction after 4 weeks, but recovered uneventfully. This patient was continued on verapamil therapy but was withdrawn from the trial. Three patients were lost to follow-up after 6 months of treatment. The data consist of studies on 28 patients followed up to 4 weeks, 24 patients followed up to 6 months and 21 patients followed up to 1 year.

Exercise time and angina during exercise (Fig. 1): All 28 patients experienced angina during the placebo period. The mean (f standard error of the mean) exercise time was 6.6 f 0.5 minutes. This increased to 9.2 f 0.8 minutes at 2 weeks (probability [p] <O.OOl) and to 11.2 f 0.8 minutes at 4 weeks of treatment (p <O.OOl). The exercise time between 2 and 4 weeks of treatment was also significantly different (p <O.OOl). At 8,16,24 and 52 weeks the mean time was 11.6,11.8, 12.9 and 11.7 minutes, respectively.

The exercise was stopped by angina during the placebo period in all 28 patients. At 2 weeks of treatment with verapamil, exercise was stopped because of angina in 13, leg pain in 6 and fatigue in 9 patients. At 4 weeks exercise was stopped because of angina in 8, leg pain in 6 and fatigue in 14 patients. Essentially, 20 patients became free of angina after 4 weeks of treatment. No patient who became angina-free at 4 weeks experienced angina at 8,16,24 or.52 weeks. The mean exercise time ranged from 1.9 to 12.8 minutes during the placebo period. This range increased to 2.9 to 18.8 minutes after 2 weeks of verapamil therapy, 4.0 to 18.8 minutes after 4 weeks, 4.2 to 19.8 minutes after 8 weeks, 4.2 to 20.3 minutes after 16 weeks and 6.3 to 20.8 minutes after 24 and 52 weeks, respectively.

Heart rate responses (Table II, Fig. 2): The resting heart rate was 74 f 3 beatslmin during the placebo period, 66 f 2 at 2 weeks of verapamil therapy and 65 f 2 at 4 weeks (p <O.OOl). Similar values were seen throughout the follow-up period. The maximal heart rate achieved at termination of the exercise test was 120 f 3,121 f 3 and 126 f 3 beats/min at the three testing periods and remained the same subsequently. The increase in heart rate was 47 f 3 beatslmin during the placebo period and 55 f 3 beatslmin at 2 weeks of verapamil therapy and 58 f 2 beats/min at 4 weeks (p <O.OOl). The heart rate recovery at 5 minutes after ex-

ercise was 43 f 2 during the placebo period and 45 f 2 at 2 weeks and 46 f 2 at 4 weeks of verapamil therapy (p = not significant [NS]). No change was seen during further follow-up tests.

The heart rate response at the same exercise time at which angina occurred during the placebo period was compared with the heart rate during identical exercise times at 2,4,8,16,24 and 52 weeks of verapamil therapy in each patient. The mean value with placebo was 120 f 3 beats/min at 6.6 minutes of exercise. This was reduced significantly at 2 weeks and 4 weeks of verapamil therapy (109 f 3 and 107 f 3 beats/mm, respectively) (p <0.005 and <O.OOl). Similar levels were observed throughout the follow-up period. The double product also followed a similar trend; it was not altered at peak exercise but was reduced significantly at similar exercise times.

S-T segment changes (Table II, Fig. 3): The mean maximal S-T depression noted was 2.0 f 0.2 and 1.7 f 0.1 in leads CM5 and CCs, respectively. In all the data to follow the S-T indexes will be given only for lead CMs because the changes in lead CCs were similar. At 2 weeks the mean maximal S-T depression was 1.7 f 0.1 mm (p = NS). However, these S-T changes occurred at an exercise time of 9.2 minutes during verapamil therapy compared with 6.6 minutes during the placebo period. The maximal S-T depression was therefore corrected for increased exercise time, and the value showed significant improvement in all subsequent tests.

The time taken for 1 mm S-T displacement to occur improved significantly and was maintained up to 1 year. The S-T segment change at the same exercise time during placebo test showed significant improvement at 2 weeks and was maintained at this level up to 1 year. The S-T segment recovery in the postexercise period

28

Exercise time

2mm time CM5

1 mm time CM5

2

1 O-I( I I 1 I I I

P 2 4 8 16 24 52

Weeks of treatment

FIGURE 1. Effect of long-term verapamil therapy on exercise time to development of angina and 1 mm and 2 mm S-T segment depression. All values are mean values f standard error of the mean. Asterisks indicate a probability (p) value of CO.001. The numbers under the graphs at each period indicate the number of patients studied. P = placebo.


VERAPAMIL IN ANGINA-SJBRAMANIAN ET AL.

TABLE II

Long-Term Effects of Verapamil (mean values f standard error of the mean)

Variable Placebo Period

Verapamil Therapy

2 Weeks 4 Weeks 6 Weeks 16 Weeks 24 Weeks 52 Weeks

1. 2.

3.

4.

5.

6.

3:

9.

10. 11. 12.

13.

14.

15.

16.

17. 18.

Exercise time (min) Resting heart rate

(beatsimin) Maximal heart rate

(beatsjmin) Heart rate gain

(beats/min) Heart rate recovery

in 5 minutes (beatsjmin)

Max S-T , CMs (mm)

i Max S-T , CCs (mm) Max S-T /ex time,

CM5 P-4 Max S-Tl/ex time,

CC5 b-4 1 mm time, CM5 (min) 2 mm time, CCs (min) S-T recovery in 5

minutes, CM5 (mm) S-T recovery in 5

minutes, CC5 (mm) S-T1 (same ex time),

CM5 (mm) S-T1 (same ex time),

CC5 (mm) Heart rate, same work

load (beats/min) Double product (peak) Double product, . .

same worK loaa

6.6 f 0.5 9.2 f 0.8 11.2 f 0.8 11.6 f 0.8 11.8 f 0.8 12.8 f 0.8 11.7 l 0.7 74 f 3 66 f 2 65 f 2 66 f 2 66 f 2 65 f 2 63 f 2

12043 121 f 3 126zt3 128f5 127f4 130 f 4 128 f 4

47 f 3 55 f 3 58 f 2 61 f3 60 f 4 63 f 3 60 f 3

43 f 2 45 f 2 46 f 2 46 f 2.2 48 f 2.3 47 f 2.6 50 f 2.5

2.0 f 0.2 1.7 f 0.1 2.0 f 0.2 2.3 f 0.2 2.3 f 0.2 2.2 f 0.2 2.0 f 0.2 1.9 f 0.1 1.6 f 0.1 1.8 +I 0.1 2.0 f 0.2 1.9 f 0.2 1.8 f 0.1 1.8 f 0.1

0.341 f .033 0.199 f 0.017 0.195 f 0.0 17 0.205 f 0.020 0.201 f 0.020 0.190 f 0.020 0.198 f 0.019

0.311 f ,030 0.194 f 0.017 0.169 f 0.0 14 0.187 f 0.018 0.172 f 0.014 0.150 f 0.014 0.170 f 0.017

4.4 f 0.3 6.3 f 0.5 7.2 6 0.5 7 f 0.6 7.4 f 0.4 8 f 0.5 8 f 0.7 6.3 f 0.6 8.9 f 0.8 9.3 f 0.8 9f 1.2 10f 1 11 f2 9 f 0.7 1.5 f 0.1 1.3 f 0.1 1.6 f 0.1 1.7 f 0.2 1.7 f 0.2 1.6 f 0.1 1.7 f 0.1

1.4 f 0.1 1.2 f 0.1 1.3 f 0.1 1.5 f 0.1 1.5 * 0.1 1.3 f 0.1 1.4 f 0.1

2.0 f 0.2 1.1 f 0.1 0.9 f 0.1 1.0 f 0.1 0.8 f 0.1 0.8 f 0.1 1.0 f 0.1

1.9 f 0.2 0.9 f 0.1 0.8 f 0.1 0.9 f 0.1 0.7 f 0.1 0.7 f 0.1 0.8 f 0.1

120f 3 109f3 107 f 3 107 f 3 106 f 3 105 f 3 102 f 3

179f8 169 f 8 176 f 11 174 * 9 175 f IO 179% 11 170f7 179f8 156f7 149 f 7 150 f 9 147 f 6 151 f 6 146f 7

Double product = systolic pressure times heart rate divided by 100; ex = exercise; Max = maximal; p = probability.

remained unaltered during the entire follow-up period despite the marked increase in exercise tolerance.

Nitroglycerin consumption: The patients had a mean rate of angina1 episodes of 14.1 f 5.3 during the placebo period of 2 weeks and 6.7 f 2.8 during the first 2 weeks of verapamil therapy (p <0.05). This rate was reduced to 4.0 f 2.2 at 4 weeks of therapy (p <O.Ol). The

mean number of glyceryl trinitrate tablets consumed was 19.6 f 5 during the placebo period. Consumption was reduced to 9.7 f 3.4 and 4.3 f 2.1 tablets at 2 and 4 weeks of treatment, respectively (p <O.Ol and p <O.OOl) and was sustained at the end of 1 year.

20-J r I I I I I I

P 2 4 8 16 24 52

Weeks of treatment

FIGURE 2. Effect of long-term verapamil therapy on heart rate (HR) during exercise testing. Single asterlsk indicates a p value of <O.OOl. a double asterlsk a p value of <O-01. P = placebo.

1.6-

1.2-

Peak ST 4

ST recovery

ST 4 same workload

o’4 1

%__ ST 4 IEx.time i* 0 VF

P 2 4 8 16 24 52

Weeks of treatment

FIGURE 3. Effect of long-term verapamil therapy on S-T segment variables. Asterlsk indicates a p value of <O.OOl. Ex. = exercise; P = placebo: ST1 = S-T segment depression; S-T recovery = peak S-T depression minus S-T depression 5 minutes after exercise.

532 September 1981 The American Journal of CARDIOLOGY Volume 48


TABLE II (continued)

p Values (placebo versus verapamil therapy)

Variable

Placebo Placebo vs. vs.

2 Weeks 4 Weeks

Placebo vs.

8 Weeks

Placebo vs.

18 Weeks

Placebo vs.

24 Weeks

Placebo vs.

52 Weeks

1. Exercise time (min) 2. Resting heart rate

(beatslmin) 3. Maximal heart rate

(beatslmin) 4. Heart rate gain

(beatslmin) 5. Heart rate recovery

in 5 minutes (beatsimin)

6. Max S-T . CM5 (mm) 7. Max S-T , CC5 (mm)

I 8. Max S-T /ex time, CM5 (mm)

9. Max S-Tl/ex time, CC5 (mm)

10. 1 mm time, CM5 (min) 11. 2 mm time, CC5 (min) 12. S-T recovery In 5

minutes, CM5 (mm) 13. S-T recovery in 5

minutes, CC5 (mm) 14. S-Ti (same ex time),

CM5 (mm) 15. S-T1 (same ex time),

CC5 (mm) 16. Heart rate, same work

load (beatslmin) 17. Double product (peak) 18. Double product,

same work load

<o.oo 1 <0.005

NS

<0.02

NS

NS NS

<O.OOl

<O.OOl

<O.OOl <o.oo 1

NS

NS

<O.OOl

<O.OOl

<O.OOl

NS <O.OOl

<O.OOl <O.OOl <O.OOl <O.Ol <O.Ol <O.Ol

NS <0.05 <0.05

<o.oo 1 <O.Ol <O.Ol

NS NS NS

NS NS NS

<o”:o, <K?Ol NS

<O.OOl

<O.OOl <O.OOl <O.OOl

<o.oo 1 <O.OOl <O.Ol <O.OOl NS <O.OOl

NS NS NS

NS NS NS




NS NS <O.OOl <f& <O.Ol

<O.OOl <0.02

<O.Ol

<O.OOl

NS

NS

<::01

<O.OOl

<O.OOl <O.Ol

NS

NS

<O.OOl

<O.OOl

<O.OOl

<oFfZl

<O.OOl <0.05

<0.05

<O.OOl

<O.Ol

NS NS

<O.Ol

<O.Ol

<O.OOl <O.Ol

NS

NS

<O.OOl

<O.OOl

<O.OOl

<0”:1

Drug withdrawal studies (Table III): Only 17 patients agreed to participate in the drug withdrawal studies. The verapamil dosage was gradually reduced over 1 week and the patients were given placebo for another 4 weeks. Six patients had to be withdrawn from this phase in the first week: Three experienced angina at rest, one had a marked increase in frequency of an- ginal episodes and two could not tolerate the recurrence of angina after 1 year. The mean exercise time in the others who completed this phase was 6.9 f 0.8 minutes and this time was not significantly different from that obtained during the placebo period 1 year earlier. Values for all other variables were also similar to those previ- ously obtained with placebo.

Discussion

Previous studies on verapamil in treatment of angina: Verapamil, a derivative of papaverine, was introduced in 1962 as a dilator of the coronary arteries. The first planned clinical trial of the drug was reported by Hoffmann16 in 1964. Neumann and Luisada,i7 using a double-blind protocol in 30 subjects, concluded that there was a significant decrease in nitroglycerin consumption in patients with angina taking verapamil. Sandler and co-workersl*Jg reported that the drug was as effective as 300 mg of propranolol daily. Livesley et al.1 reported similar findings. Andreasen et al.*O reported the results of a Danish multicenter trial in which

the use of verapamil resulted in a reduction of nitroglycerin consumption and an increase in exercise tolerance.

Other workers have reported inconsistent results with verapamil. HerxheimeF stated in a review article that verapamil had no advantage over propranolol and de- scribed some doubts regarding its safety and efficacy. Phear** found no significant difference between the drug and placebo. Careful analysis suggests that these inconsistent results were obtained when the workers used doses of 240 mg daily or less; most of the good results were obtained in patients receiving 360 mg of verapamil daily. In a pilot study we found that a daily dose of 360 mg of verapamil was superior to a daily dose of 120 mg of propranolol.*“- 25

Design of the drug trial protocol: We planned the current trial protocol carefully to eliminate most of the drawbacks associated with antianginal drug trials. The trial design used a double-blind, randomized, crossover protocol with a placebo phase. The basic data were de- rived from serial treadmill exercise tests with use of a comprehensive and sophisticated computer system. This permitted continuous recording of three electrocardiographic leads simultaneously, on-line S-T segment analysis with the S-T depression and slope for two leads printed out with heart rate and ectopic beat counts every minute and generation of a trend plot of several variables during and after exercise. The speed and ele-

September 1991 The Amerlcsn Journal of CARDIOLOGY Volume 49 533

VERAPAMIL IN ANQINA-SUBRAMANIAN ET AL

TABLE III

Data on Wlthdrawal of Verapamll In 11 Patlents

Variable Placebo A Placebo0 p

1. Exercise time (min) 6.7 f 0.5 6.9 f 0.8 NS 2. Resting heart rate 71 f 2 75f 3 NS

(beatslmin) 3. Maximal heart rate 123 f 4 128f4 NS

(beatslmin) 4. Heart rate aain 42 f 3 43f 4 NS

(beatslmi-) 5. Heart rate recovery 41 f3 40f 2 NS

in 5 minutes (beats/ min)

6. Max.%T I , CMs(mm) 2.1 f 0.2 2.3 f 0.3 NS 7. MaxS-T .CCs(mm) 2.0 f 0.3 2.2 f 0.4 NS 8. Max S-T lex time, 0.310 f 0.03 0.331 f 0.04 NS

CM5 (mm) 9. Max S-Tl/ex time, 0.301 f 0.03 0.320 f 0.03 NS

025 W-0 10. 1 mm time. CM5 (min) 4.5 f 0.3 4.6 f 0.4 NS 11. 2 mm time, CC5 (min) 6.3 f 0.7 6.6 f 0.7 NS 12. S-T recovery in 1.6 f 0.1 1.5fO.l NS

5 minutes,CM5 (mm) 13. S-T recoverv in 1.5 f 0.1 1.5fO.l NS

5 minutes, CC5 (mm) 14. Double product 181 f 8 176f 11 NS

Placebo A and B = before start of trial and after 1 year of verapamil therapy, respectively: other abbreviations as in Table II.

vation of the treadmill were also automatically controlled. This design almost eliminated observer bias during the trial. Further efforts to ensure repeatability included careful and repeated calibration of the treadmill speed and gradient and the program for S-T segment measurements. The laboratory temperature was carefully controlled, all tests were conducted between 9 a.m. and 11 a.m. with the patient in the postabsorptive state and between 90 and 150 minutes after the last dose of verapamil or placebo. The patients were not given any additional drugs except glyceryl trinitrate. The repeatability and reproducibility of this protocol have been found to be reliable.2”-27

Antianginal effects of verapamil: Our results indicate that verapamil has a distinct profile of action as an antianginal drug. The improvement in exercise ca- pacity was very significant and reached a peak at 4 weeks of treatment. All 28 patients in this study had angina during treadmill testing in the placebo phase at times ranging from 1.9 to 12.8 minutes (mean 6.6) of exercise. After 2 weeks of treatment with verapamil, 15 of these 28 had become free of angina and their exercise tests were terminated by fatigue or pain in the legs. After 4 weeks 20 patients had become free of angina. The improvement was most marked in those patients who had angina during the placebo phase at stage 2 or higher of our protocol. The patients who had an initial exercise tolerance of less than 3 minutes showed improvement but did not become free of symptoms. These patients also had three vessel disease on selective coronary arteriography. The improvement seen at 4 weeks was maintained up to 1 year of follow up and none of the patients experienced further angina once they became- free of pain. All 11 patients who completed the drug withdrawal phase also had angina on treadmill testing after withdrawal of verapamil.

Heart rate and blood pressure responses: The heart rate response to verapamil differed from the response to beta adrenergic blocking drugs. The resting heart rate was reduced only when it was elevated ini- tially, and no patient experienced resting bradycardia. The mean resting heart rate in these patients was reduced by 6 to 11 beats at the end of 1 year of treatment with verapamil. However, the exercise-induced tachy- cardia was blunted at each level of the treadmill test with verapamil therapy as compared with placebo. Nevertheless, the patients reached almost similar (or even higher) maximal heart rates to those needed during the placebo period at the extended exercise times after treatment with verapamil. This phenomenon gave rise to a somewhat paradoxical behavior of the double product. The systolic blood pressure was reduced moderately and the heart rate was unaffected or mildly increased at peak exercise. The peak double product was therefore unchanged. However, when the double product at the same exercise time as that measured during the placebo period was compared at each follow-up period, a significant reduction was demon- strated. In contrast, beta adrenergic blocking agents act by producing resting bradycardia and by decreasing the maximal heart rate response, the heart rate gain during exercise and the reduction in peak double product. Another interesting effect on heart rate with verapamil was the unaltered heart rate recovery 5 minutes after termination of exercise.

S-T segment responses: S-T segment changes were carefully examined. All S-T segment values were corrected algebraically to take into account the baseline S-T levels before exercise. The maximal S-T segment change observed with verapamil was not significantly different from the value with placebo, but this value occurred at a much higher exercise load with verapamil. We devised several objective criteria (1) to express the S-T segment changes corrected to variable exercise time and (2) to determine whether the onset of S-T depression was delayed after treatment. The latter was calculated from the continuous S-T segment trend graph by determining the times at which 1 mm and 2 mm S-T depression occurred. These were termed 1 mm and 2 mm times. We took the placebo exercise time as the standard work load and calculated the S-T changes and heart rate at the same work load during treatment with verapamil. Using these quantitative S-T analysis methods, we could calculate several S-T segment indexes to uncover the precise pattern of S-T segment changes. Verapamil produced a significant improvement in all the corrected S-T segment indexes, and no deterioration in the uncorrected maximal S-T segment changes. The onset of 1 mm and 2 mm S-T segment change was significantly delayed and S-T changes at identical work load as placebo were improved.

It has been suggested that antianginal drugs retard S-T segment recovery after exercise. WB We calculated the S-T segment recovery in a standard time of 5 minutes after termination of exercise. This S-T segment recovery was not significantly altered by verapamil therapy despite the marked increase in exercise time.

534 9aptamber 1981 The Amerlcrn Journal of CARDIOLOGY Volume 48


Nitroglycerin consumption: The consumption of glyceryl trinitrate was reduced from 19.6 to 9.7 tablets after 2 weeks of verapamil therapy and to 4.3 tablets after 4 weeks. This index became unreliable as time progressed because of the marked reduction in the frequency of angina1 episodes.

Possible limitations of study: Any long-term trial design is likely to have problems of reliability. Sponta- neous remissions and exacerbations of the disease are not rare. The ideal trial would have been a double-blind placebo controlled crossover study over the entire year. This design is unlikely to succeed because it would take too long to complete, many patients would drop out and the natural course of the disease would be unpredict- able. We also believe that it would be highly unethical to leave patients with severe angina pectoris deliberately untreated for periods as long as 1 year.

A withdrawal phase was therefore incorporated into the study, but only 17 patients volunteered for this phase. Six of these 17 could not tolerate the withdrawal phase, and in 1 patient a marked deterioration was objectively documented by 24 hour Holter monitoring. In the other 11 patients, there was no significant change in the values of the variables analyzed compared with those on the initial placebo test. Because of the small

1. Llvesley 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 19732: 375-8.

2. Prlchard BNC. Propranolol in the treatment of angina: a review. Postgrad Med J 1976;52:31-41.

3. KeyrKakten 0, Vusilab A. Effects of metoprotol in angina pectoris. A subacute study with exercise tests and a long term tolerability study. Acta Med Stand 1976;199:491-7.

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10. Palmer KN. Respiratory side effects of beta blockers (letter). Br Med J 1977;1:841.

11. Maser1 A, Beverl S, De Me8 M, et al. “Variant” angina: one aspect of a continuous spectrum of vasospastic myocardial ischemia. Pathogenic mechanisms, estimated incidence and clinical and coronary arteriographic findings in 138 patients. Am J Cardiol 1978;42:1019-35.

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number of patients who completed this phase, we used the initial placebo test as the standard for comparison. Subsequent studies have confirmed that angina is not uncommon after withdrawal of calcium ion antagonist therapy. We are in the process of elucidating this phenomenon more clearly.

Adverse effects: The main adverse effect noted was constipation, which was easily controlled with laxatives. Verapamil was very well tolerated at the dose used and no other unpleasant effects were encountered.

Therapeutic implications: The changes in exercise tolerance and S-T segment depression seen after verapamil therapy suggest that the drug is a very powerful antianginal agent with many desirable pharmacologic properties. The lack of adverse effects and absence of any effect on the bronchioles and peripheral circulation are distinct advantages over conventional beta blocking agents. The total amelioration of angina in 20 of the 28 patients suggests that the drug should be used as a primary therapeutic agent in chronic stable angina.

Acknowledgment

The technical help of Brenda Christacopoulos and Ian Eddy, and the secretarial assistance of Jean Wright is grate- fully acknowledged.

References

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Long-term antianginal action of verapamil assessed with quantitated serial treadmill stress testing

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