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JACC Vol. 9,:-10 3
March 19H7:615 21
Sustained Release Verapamil, A Once Daily Preparation: Objective
Evaluation Using Exercise Testing, Ambulatory Monitoring and Blood
Levels in Patients With Stable Angina
RAVINDER S, KOHLI, MS, MD, MNAMS, OM, ERWIN A, RODRIGUES, MS, MRCP,
LIAM O. HUGHES, MS, MRCP, AVIJIT LAHIRI, MS, SS, MSc,
EDWARD B, RAFTERY, SSc, MD, FACe, FRCP
Harrow. Middlesex. England
The efficacy of a once daily, sustained release formulation of verapamil (Verapamil SR, 360 mg) was evaluated in 19 patients with chronic angina pectoris using
a double-blind placebo-controlled crossover protocol.
Evaluation by exercise testing, 24 hour electrocardiographic ambulatory monitoring and blood drug level
assays was performed at the end of each 2 week phase,
21 to 23 hours after the last dose. After the crossover
protocol, all patients were given sustained release verapamil for 4 weeks and the evaluation was repeated.
Exercise time (mean ± SEM) increased from 7.4 ± 0.6
minutes with placebo to 9.6 ± 0.8 minutes with verapamil (p < 0.001) and to 9.5 ± 0.7 minutes (p < 0.001)
after 4 weeks of therapy. The mean time to I mm ST
depression also increased significantly, from 4.5 ± 0.4
and 4.8 ± 0.5 minutes in bipolar leads CMs and CCs,
respectively, with placebo, to 5.5 ± 0.6 (p < 0.05) and
Verapamil was first introduced in 1962 as a coronary vasodilator (I) and its anti anginal effects were described by
Neumann and Luisada (2) in 1966, The plasma half-life of
the standard formulation is 4 hours. which necessitates
administration three to four times a day, Because repeated
dose regimens may compromise patient compliance, a new
sustained release preparation of verapamil (Verapamil SR,
360 mg) was recently developed to maintain satisfactory
blood levels of the drug over 24 hours after once daily
administration. We have evaluated the efficacy of once daily
therapy with this new preparation in patients with chronic
stable angina pectoris.
From the Department of Cardiology, Northwick Park Hospital & Chnical Research Centre, Harrow, Middlesex, England.
Manuscript received November II, 1985: revised manuscript received
February 19, 1986, accepted October 22, 1986.
Addre" for reprint,: E.B. Raftery, MD, Department of Cardiology,
Northwick Park Hospital and Clinical Research Centre, Watford Road,
Harrow, Middlesex, HAl 3LJJ. England.
© 1987 by the American College ot Cardiology
6.2 ± 0.5 minutes (p < 0.01) with verapamil. Maximal
ST depression and rest and peak heart rates were not
altered significantly. The mean rate-pressure product
was 208 ± 9.9 with placebo and decreased to 189 ± 7.7
(p < 0.05) with verapamil but rose to 200.6 ± 10.4
(p = NS) after 4 weeks of therapy.
The mean hourly heart rates were lower with the drug
than with placebo throughout the 24 hour period but
there was no significantbradycardia, arrhythmia or heart
block. Episodes of ambulatory ST segment depression
were also decreased by sustained release verapamil. Blood
levels at 21 to 23 hours after the last dose were within
the therapeutic range. The data indicate that this formulation of verapamil is effective when administered
once daily.
(J Am Coli Cardiol 1987;9:615-21)
Methods
Selection of patients. To be suitable for the trial, patients were required to have unequivocal evidence of obstructive coronary artery disease (determined by coronary
arteriography), classic angina on exertion relieved by rest
and sublingual administration of glyceryl trinitrate and a
minimal incidence of four attacks a week. All were required
to develop anginal pain on treadmill exercise testing in association with at least I mm ST segment depression with a
slope less than 0.1 mV/s in bipolar lead CM s or CC s, or
both. Only patients physically capable and mentally motivated for repeated treadmill exercise and Holter monitoring
were entered into the trial.
Patients older than 72 years and women of childbearing
age were excluded. Myocardial infarction in the preceding
4 months, unstable angina and severe symptoms that were
judged clinically to contraindicate placebo treatment, overt
cardiac failure, rest blood pressure levels in excess of 1601\00
0735-1097/W$3.50
KOHLI ET AL.
SUSTAINED RELEASE VERAPAMIL IN ANGINA
616
mm Hg and insulin-dependent diabetes mellitus were other
exclusion criteria. All patients receiving diuretic drugs, digitalis and other cardiovascular drugs were excluded, as were
those showing more than 0.5 mm ST segment depression
on standing, hyperventilation or the Valsalva maneuver.
All cardioactive medication (except sublingual nitroglycerin) was withdrawn for at least 7 days before entry
into the trial. Patients then entered into a single-blind (patient blind) placebo washout period of 14 days and at the
end of this period a maximal symptom-limited graded exercise test and 24 hour ambulatory monitoring were performed. Only patients fulfilling the entry criteria entered the
next phase, which consisted of two double-blind crossover
periods of 2 weeks each in which patients received either
sustained release verapamil, 360 mg once daily, or placebo
at approximately midday, crossing over to the alternative
drug in the next period. After this phase all patients were
given sustained release verapamil, 360 mg once daily, for
4 weeks when the evaluations were repeated. Exercise testing and 24 hour ambulatory electrocardiographic monitoring
were carried out at the end of each double-blind phase and
at the end of the open 4 week therapy period, the exercise
test being timed for 21 to 23 hours after the last dose. Blood
samples for drug level estimations were withdrawn at the
end of each phase, just before exercise.
The patients kept records of the number of anginal attacks, nitroglycerin consumption and side effects on diary
cards throughout the trial. All patients gave written informed
consent before entering the trial, which was approved by
the Hospital Ethical Committee.
Study patients. Nineteen patients were entered into the
study. Eighteen were men and the mean age was 57.9 years
(range 41 to 72). Eighteen completed the initial doubleblind crossover phase and 17 completed the final 4 week
phase.
Figure I. Mean ± SEM exercise time and time to I mm ST
depression (in leads CM) and CC) with placebo (n), Verapamil
SR (IIII) and medium-term (4 weeks) (~) therapy with Verapamil
SR. * P < 0.05; *** P < 0.01; **** P < 0.001.
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JACC Vol. 9. No.3
March 1987:615-21
Table I. Measured Exercise Variables in 19 Patients
I. Exercise time in minutes (to the nearest 0.1 minute)
2. Time to I mm ST depression in leads CM, and CC,
3. Maximal ST depression in leads CM, and CC,
4. Rest HR
5. Maximal (peak) HR
6. HR gain (maximal HR - rest HR)
7. HR unit gain (HR gain/exercise time)
8. Rest systolic BP
9. Maximal (peak) systolic BP
10. Rate-pressure ([maximal (peak) BP x maximal (peak)1 HRIlOO)
BP
=
blood pressure; HR
=
heart rate.
Exercise testing. A symptom (angina)-limited graded
treadmill exercise test was performed at the end of each
phase by means of a computer-assisted exercise system
(CASE, Marquette Electronics) linked to a Quinton treadmill, using a standardized graded exercise protocol (3,4).
Bipolar leads CM s and CCs were monitored continuously.
Each exercise test was performed in the morning with patients in the fasting state, 21 to 23 hours after the last dose
of medication, and carried out in a room with a controlled
temperature of 20°C to 24°C (5), on the same equipment,
between 9:00 and II :00 AM. The patients were requested
to refrain from smoking on the morning of the test and had
not taken sublingual nitroglycerin for at least 2 hours. The
electrocardiogram was monitored continuously before, during and for 5 minutes after exercise and was analyzed by a
microprocessor system that provided a continuous display
of heart rate, ectopic beat count, J point level (to the nearest
0.1 mm) and ST slope (to the nearest 0.1 mV/s). The systolic
blood pressure was measured by calibrated cuff sphygmomanometry and the data were fed into the computer every
3 minutes and at peak exercise. The digitized exercise test
variables were stored on a cassette tape and later played
back into a PDP 11/23 microcomputer for further data
computing. The exercise variables measured are listed in
Table I.
Ambulatory monitoring. Ambulatory electrocardiographic monitoring was carried out for 24 hours using the
same two leads (CM s and CCs ) used for exercise testing.
A frequency-modulated tape recorder (Oxford Medilog II)
with a quartz controlled time channel was used for this
purpose. Visual analysis of the tapes was performed to identify any prolongation of the PR interval or other conduction
defects. Mean hourly heart rates were obtained using a computer program (4). The tapes were played through an Oxford
PB4 replay unit and displayed on a Path-Finder system
(Reynolds Medical). The ST segment was also analyzed and
episodes of ST segment depression of more than I mm at
the J point with a planar or downsloping ST segment lasting
at least I minute were identified. The lead analyzed for ST
changes was CMs. Daytime and nighttime changes were
KOHLI ET AL.
SUSTAINED RELEASIo VERAPAMIL IN ANGINA
lACC Vol 9. No. ,
March 19X7:615 21
studied separately. The computer program and methods of
tape analysis have been described in detail elsewhere (6-8).
Blood levels. Samples for drug blood levels were withdrawn by venipuncture 21 to 23 hours after the last dose of
medication, before the patients were exercised. The blood
samples were centrifuged, the plasma was frozen and analyses for verapamil and norverapamil levels using high performance liquid chromatography with ftuorometric detection
were performed (9). Blood samples for biochemistry profiles
were also obtained at the end of each phase as a safety
measure.
Statistics. Statistical analysis was carried out using Student's paired t test (two-tailed). A probability value of less
than 0.05 was considered significant. Unless otherwise stated,
mean values ± SEM are shown.
Results
Exercise data (Table 2). Double-blind crossover period. All 19 patients developed angina while receiving placebo. Two patients became free of angina and had to stop
exercise because of fatigue while taking Verapamil SR.
The mean exercise time (Fig. I) with placebo was 7.4 ±
0.6 minutes and this increased significantly (p < 0.001) to
9.6 ± 0.8 minutes with Verapamil SR. The mean time to
I mm ST depression (Fig. I) in lead CMs increased from
a placebo value of 4.5 ± 0.4 to 5.6 ± 0.6 minutes with
the active drug (p < 0.05). Similarly, the time to I mm ST
depression in lead ce , increased from 4.8 ± 0.5 minutes
with placebo to 6.2 ± 0.6 minutes with verapamil (p <
0.01). Maximal ST depression in leads CMs and CCs showed
no statistically significantalteration with placebo; the values
617
200 -
160
~
120 ~
I
:F
~
60
1
.]
o
Peak
systolic BP
Resting
systolic BP
Figure 2. Mean ± SEM rest and peak systolic blood pressure
(BP) on exercise with placebo ([J), Verapamil SR (!III) and medium-term (4 weeks) (~) therapy with Verapamil SR. * p < 0.05;
*** P < 0.01.
in leads CM, and CCs were 2.0 ± 0.2 and 1.7 ± 0.2 mm
with placebo and 2.1 ± 0.2 and 1.9 ± 0.2 mm with Verapamil SR (p = NS), respectively.
Rest heart rate and peak exercise heart rate were
82.9 ± 3.3 and 128.2 ± 3.8 beats/min with placebo and
79.0 ± 3.3and 124.1 ± 3.9beats/min, respectively,withVerapamil SR (p = NS). Heart rate gain (maximal heart rate
- rest heart rate) with placebo was 45.33 ± 2.66 beats/min
and remained unchanged after verapamil (45.11 ± 2.91).
Heart rate unit gain decreased significantly from 7.0 ± 0.9
beats/min with placebo to 5.3 ± 0.6 with verapamil (p <
0.0 I). The rest systolic blood pressure with placebo was
Table 2. Results of Verapamil SR in Exercise Variables
Placebo
Exercise time (minutes)
1 mm Time CM,
Verapanul SR
Mean
+SD
.±.SEM
7.4
4.5
2.6
1.8
0.6
0.4
4.8
1.'1
2.0
1.7
82.9
128.2
45.3
7.0
140.0
163
208.4
0.8
0.9
14.2
16.2
11.I
3.9
19.1
24.2
42.3
Mean
Therapy for 4 Week>
Placebo
Versus
4 Week
Period
(p Value)
.:t.SD
'-SEM
'1.6
5.5
3.3
2.5
0.8
0.6
'1.5
5.4
2.8
2.2
0.7
0.5
<0.001
<.0.05
<.0.001
<' 0 .05
0.5
6.2
2.5
0.6
6.0
3.2
0.8
<.
'(U)[
<'(LOS
0.2
0.2
3.3
3.8
2.6
0.9
4.5
5.7
9.9
2.1
1.9
7.9
124.1
45.1
5.3
130.2
1528
189.6
0.8
0.8
139
165
12.3
2.5
13.5
16.7
32.7
0.2
0.2
33
3.9
2.3
0.6
3.2
3.9
7.7
2.3
1.9
77.8
128.6
46.1
5.6
137.2
155.5
200.6
1.0
1.0
14.8
20.2
11.5
2.6
17.8
19.8
42.9
0.3
0.3
3.6
4.9
2.8
0.6
4.3
4.8
10.4
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
Mean
'±'SD
+
SEM
Placebo
Versus
Verapamil
(p Value)
(minutes)
I rnrn Time CC,
(minutes)
Peak ST CM, (rnrn)
Peak ST CC, (rnm)
Re,t HR (beats/min)
Peak HR (beats/min)
HR (beats/min) gain
HR unit gain
Re,t BP (mm Hg)
Peak BP (rnm Hg)
Rate-pressure
product/IOO
BP = blood pressure: HR - heart rate.
<.'(U) I
«o.n:
<.0.05
<'.0.05
KOHLI ET AL.
SUSTAINED RELEASE VERAPAMIL IN ANGINA
618
lACC Vol. 9. No.3
March 1987:615-21
Figure 5. The mean hourly heart rate plots represent themaximal
250
minimal (8) and mean (C) heart rates over 24 hours, recorded
by ambulatory electrocardiographic monitoring. The values for
placebo (0), Verapamil SR (2 weeks (6) and 4 week (D) data
are depicted.
(A);
:5
200
~
<Xl
.~
:s
120
150
VI
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A
VI
X
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"Iii
100
110
t::
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SO
~
~
100
'i:
~
x sys-
Ul
tolic blood pressure/ 100) on exercise with placebo (D), Verapamil
SR (lIII) and medium-term (4 weeks) (~) therapy with Verapamil
SR.
<D
Figure 3. Mean ± SEM rate-pressure product (heart rate
140 ± 4.5 mm Hg and this decreased to 130.2 ± 3.2 mm
Hg with verapamil (p < 0.01) (Fig. 2). The peak systolic
blood pressure decreased from a placebo value of 163.2 ±
5.7 mm Hg to 152.8 ± 3.9 with verapamil (p < 0.05).
The heart rate-systolic pressure (Fig. 3) was 208.4 ± 9.9
with placebo and 189.6 ± 7.7 with verapamil (p < 0.05).
Final 4 week phase. Seventeen of the 19 patients completed this phase, during which they received Verapamil
SR, 360 mg once daily, at midday. The exercise time at
the end of this period, 9.5 ± 0.7 minutes, was significantly
greater than with placebo (p < 0.001) (Fig. I and 4). The
time to 1 mm ST depression (Fig. I) in leads CM s and CC s ,
5.4 ± 0.5 and 6.0 ± 0.8 minutes, respectively, was also
significantly greater than with placebo (p < 0.05). There
was no significant change in maximal ST depression compared with placebo. Rest heart rate, peak heart rate, heart
rate gain, heart rate unit gain, and rest and peak systolic
~
90
80
TIME OF DAY IN HOURS
85
80
75
70
65
60
12.00
20
M = 7.4
M = 9.7
M = 9.5
(4
18. 00
21:00
00. 00
03. 00
06. 00
TIME OF OAY IN HOURS
Figure 4. Individual changes in exercise time are shown for each
patient (n = 14) for placebo, Verapamil SR and medium-term
weeks) Verapamil SR therapy.
15dlO
100
c
90
18
VI
16
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80
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14
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12
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70
8
60
4
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Placebo
Verapamil
SR
4 weeks
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09.00
12.00
15.00
18.00
21:00 00.00
03.00
06.00
TIME OF DAY IN HOURS
KOHLI ET AL
SL:STAINED RELEASE VERAPAMIL IN ANGINA
JACC Vol. 9. No.3
March 1987:615 21
blood pressures were not significantly different after 4 weeks
of therapy with verapamil compared with the placebo values. The rate-pressure product at the end of this phase was
200.0 ± 10.4, which was not significantly different from
the placebo value (Fig. 3). There were no significant changes
between exercise indexes after the double-blind phase with
verapamil and those after the final 4 week open treatment
period.
Ambulatory monitoring. Heart rate data. The mean
hourly heart rate trends are shown in Figure 5. The heart
rate with Verapamil SR remained lowe! than during placebo
therapy 23 hours after the last dose. The mean minimal
hourly heart rate with verapamil was consistently lower than
the placebo value and the effect was more profound after
the 4 week period than after the double-blind phase. However, the heart rate was never low enough to produce symptoms (the lowest mean heart rate was 56 beats/min). A
similar effect on the mean maximal hourly heart rate was
observed, with the rate being lower with verapamil therapy.
The maximal difference in heart rates between placebo and
the 4 week drug period was observed at about 10:00 AM
(22 hours after the last dose), the curves diverging rapidly.
The smallest difference was observed 24 hours after the last
dose.
ST segment data (Table 3). The number of episodes of
significant ST depression averaged 2.6 ± 0.8 and 1.6 ±
0.4 in lead CM s during the day and night, respectively, with
placebo. The corresponding values after the double-blind
Verapamil SR phase were 1.2 ± 0.5 and 1.2 ± 0.2; after
the open 4 week phase they were 1.8 ± 0.4 and 1.6 ±
0.4, respectively (p = NS). The mean duration of significant
ST segment depression in lead CM s with placebo was 30.0
± 12.6 and 31.5 ± 9.5 minutes during the day and night,
respectively. This decreased to 9.3 ± 3.6 and 24.3 ± 7.6
minutes, respectively, after 2 weeks of verapamil (doubleblind phase) (p = NS). The duration of ST segment depression remained less than the placebo value after 4 weeks
(open phase) of verapamil, being 12.9 ± 5.3 and 29.6 ±
9.1 minutes during the day and night, respectively; this
difference was not statistically significant.
Blood levels. The mean verapamil levels were 159.8 ±
68.6 ng/ml after the initial 2 week (double-blind) phase and
167.1 ± 63.4 ng/ml after the 4 week therapy period. The
Table 3. Ambulatory ST Segment Variables in
eM, on
619
corresponding mean norverapamillevels were 198.0 ± 63.3
and 207.2 ± 75.1 ng/rnl, respectively.
Anginal attacks and sublingual nitroglycerin consumption. There was a reduction in the number of anginal
episodes after Verapamil SR (81 in 2 weeks) as compared
with placebo (170 in 2 weeks). Similarly, the consumption
of sublingual nitroglycerin decreased from 122 tablets in 2
weeks with placebo to 53 tablets in 2 weeks after Verapamil
SR therapy.
Side effects and withdrawals. The drug was well tolerated. Two patients developed constipation during active
treatment but this was not severe enough to warrant cessation
of therapy. One patient developed palpitation during both
placebo and active therapy; no arrhythmia was documented.
One patient was taken out of the study because of a
"withdrawal effect," consisting of worsening of angina and
an increase in blood pressure after crossover to the placebo
phase. Another patient could not complete the last 4 week
phase because of other medical problems.
Discussion
Neumann and Luisada (2) first reported the antianginal
effects of verapamil and these were later confirmed by other
studies (3,10-16). All these studies used multiple daily doses
of verapamil. The aim of the present study was to evaluate
objectively the sustained antianginal effects of Verapamil
SR, a new long-acting formulation for once daily administration in a strength of 360 mg.
In this preliminary study we endeavored to minimize
observer bias by performing computerized exercise testing
with the end point being controlled by the patient himself
(that is, the onset of angina or fatigue). The 24 hour electrocardiographic tape recordings were carried out on the day
before the exercise test in order to avoid any carryover
effects. We compared the efficacy of Verapamil SR with
placebo and then evaluated the medium-term effects after
4 weeks of therapy. To assess the duration of effect, the
exercise tests were carried out 21 to 23 hours after the last
dose, which was taken between 10:00 and 12:00 AM. Samples for drug levels were similarly taken 21 to 23 hours
after the last dose, and immediately before the exercise test.
Verapamil SR (± SEM)
Verapamil SR
Placebo
ST Segment Depression
No. of episodes> I mm
Duration (minutes)
Day
2.6.± 0.8
30.0 ± 12.6
Double-Blind Phase
Night
1.6 :±- 0.4
31.5 + 9.5
Day
1.2 + 0.5
9.3 + 3.6
Note: None of the VerapamiJ SR values were statistically different from the placebo values.
NIght
1.2 ::+: 0.2
24.3 T 7.6
4 Week Phase
Day
1.8 + 0.4
12.9 + 5.3
Night
1.6 ± 0.4
29.6 + 9.1
620
KOHLI ET AL.
SUSTAINED RELEAS E VERAPAMIL IN ANGINA
Pharmacokinetics. The pharmacokinetics of verapamil
have been well described (17- 20). The oral dose (20 to 100
times higher than the intravenous dose) is almost completely
absorbed but undergoes extensive first pass degradation in
the liver. The peak plasma level with the standard formulation of verapamil is reached between 30 and 90 minutes
after administration, whereas that of the once daily longacting verapamil (Verapamil SR) is reached in approximately 7.5 hours (2 1). The therapeutic plasma concentration
lies between 15 and 100 nglml. In a comparative study
between a single dose of standard verapamil (Cordilox, 80
mg) and Verapamil SR (240 mg) (21) the maximal plasma
concentrations of verapamil and norverapamil were
78.84 ± 44.04 and 52.74 ± 14.3 ng/ml, respectively, with
the former and 83.82 ± 32.87 and 69.60 ± 14.6 ng/rnl,
respectively, with the latter (21) . The lowest mean levels
of verapamil and norverapamil after 7 days of Cordilox (80
mg three times daily) and verapamil SR (240 mg) once daily
were 42.73 and 8 1.58 and 34.84 ng/rnl. respectively. These
levels were 8 and 24 hours after the last dose of Cordilox
(80 rng) and Verapamil SR (240 mg), respectively. These
data and those obtained in our study indicate a bioavailability
profile that is adequate for a once daily regimen.
Effect in exercise tests. In this study, the mean exercise
time was significantly prolonged by Verapamil SR and this
increase occurred in all but three patients. In one it remained
unchanged and in the other two it decreased. However, two
of these three patients showed an increase in exercise time
at the end of the 4 week phase (Fig. 4). There was also a
significant increase in the mean time to I mm ST depression.
Maximal ST depression did not show a signifi cant change.
because of the increase in exercise time required to produce
the same ST change, but there was a lesser degree of ST
depression with verapamilthan with placebo therapy at comparable levels of exercise. The increase in exercise time
after 4 weeks of open therapy with Verapamil SR was 23lJt.
which contrasts with an increase of 40Ck previously reported
in patients receiving the standard formulation for 4 weeks
( 14) . In assessing this observation, it has to be borne in
mind that these were different groups of patients.
Effect on Holter recordings. The 24 hour ambulatory
heart rate data showed the sustained effects of Verapamil
SR on heart rate, particularly in the 6 hours before the next
dose. This sustained effect is consistent with the high blood
levels observed. The reduction in the mean heart rate with
the drug was moderate and none of the patients developed
significant bradycardia or prolongation of the PR interval.
The number and duration of episodes of ST segment depression were reduced by verapamil compared with placebo and
this change was seen both during the day and at night.
Effect on angina. Verapamil SR decreased the number
of anginal attacks and sublingual nitroglycerin consumption,
although only two patients became free of angina while on
therapy for 4 weeks. In an earlier study (14) from our de-
JACC Vol. 9. No. 3
March 1987:615- 21
partment in which 28 patients were given the standard formulation of verapamil, 120 mg three times daily for 4 weeks,
II patients became free of angina on treadmill exercise.
Side effects. Side effects with Verapamil SR were infrequent. Two patients developed mild constipation, which
is known to occur in about 30tK of patients taking verapamil
(22). One of our patients experienced a withdrawal syndrome after starting placebo therapy after 2 weeks of Verapamil SR. Withdrawal effects after sudden cessation of
calcium antagonists have been recognized and have been
reported with verapamil (23-26).
Conclusions. Our data indicate that Verapamil SR (360
mg) is an effective antianginal agent when administered
once daily and that its actions are sustained over a 24 hour
period. It is also well tolerated and side effects are infrequent, the main being constipation as is the case with the
standard formulation. Comparison with previous studies
suggests that efficacy might be improved by using a larger
dose, but this remains to be established in further trials.
We are grateful to Miss B. Patel for her clerical assistance and Mr. W.
Muniweera for technical help. We thank Revlon Health Care Ltd. for
support and for the supply of the drugs.
References
I. Singh BN. Treatment of arrhythmias with verapamil. Lancet 1970;I:
563-4 .
2. Neumann M. Luisada AA. Double blind evaluation of orally administered lproveratril in patients with angina pectoris. Am J Med Sci
1966;251:552- 6.
3. Bala Subramanian V. Bowles M. Lahiri A. Davies AB. Raftery EB.
Long term antianginal action of verapamil assessed with quantitated
serial treadmill stress testing. Am J Cardiol 1981 ;48:529-35.
4. Khurmi NS. O'Hara MJ. Bowles MJ, Bala Subramanian V. Raftery
EB. Randomized double-blind comparison of galloparnil and propranolol in stable angina pectoris. Am J Cardiol 1984;53:684- 8.
5. Ellestad MH, Blornqvist CG. Naughton JP. Standards for adult exercise testing laboratories. Circulation 1979;58:42 1A- 30A.
6. Bala Subramanian V. Lahiri A. Raftery EB, Green H. Stolt FD.
Ambulatory ST segment monitoring. Problems. pitfalls. solutions and
clinical application. Br Heart J 1980;44:419- 25.
7. Bala Subramanian V. Khurmi NS. Bowles MJ. O'H ara M_ Rafter)
EB. Objective evaluation of three dose levels of diltiazem in patients
with chronic stable angina. J Am Coli Cardiel 1983; I:11 44 -53.
8. Khurrni NS. Bowles MJ. Bala Subramanian V, Raftery EB. Short and
long term efficacy of nicardipine assessed by placebo-controlled single
and double-blind crossover trials in patients with chronic stable angina.
J Am Coil Cardiol 1984;4:908- 17.
9. Cole SJc. Flanagan RJ. Johnston A, Holt DW. Rapid high-performance liquid chromatographic method for the measurement of verapamil
and nor-verapamil in blood. plasma or serum. J Chrornatogr 1981:2 18;
62 1-6 .
10. Sandler G, Clayton GA. Thornicroft SG. Clinical evaluation of verapamil in angina pectoris. Br Med J 1968;3:224- 7.
II. Livesley B. Cauley PF. Campbell RC. Oram S. Double-blind evaluation of verapamil, propranolol and isosorbide dinitrale againvt a
placebo in the treatment of angina pectoris. Br Med J 1973;I:375- 8.
l ACC Vol. 9, No.3
March 1987:615-21
12, Andersson F, Boye E, Christofferson E, et al. Assessment of verapamil
in the treatment of angina pectoris, Eur J Cardiol 1975;234:443- 8.
13. Bala Subramanian V, Lahiri A, Paramasivan P, Raftery EB. Veraparml
in chronic stable angina: a controlled study with computerized treadmill exercise. Lancet 1980;1:841- 4.
14, Bala Subramanian V, Bowles MJ. Khurmi NS, Davies AD, Raftery
EB. A randomized double-blind comparison of verapamil and nifedipine in chronic stable angina. Am J Cardiol 1982;50:696-703.
15. Bala Subramanian V, Bowles MJ, Khurmi NS, Raftery EB. Comparative evaluation of four slow channel blockers with propranolol in
stable angina pectoris (abstr). Circulation 1982;66(suppl 11): 11-8 .
16. Subramanian VB, Bowles MJ. Davies AB, Raftery EB. Calciumchannel blockade as primary therapy for stable angina pectoris. A doubleblind placebo-controlled comparison of verapamil and propranolol.
Am J Cardiol 1982:50:1158-63.
17. Schomerus M, Spiegelhalder B, Stieren B, Eichelbaum M. Physiologic disposition of verapamil in man. Cardiovasc Res 1976;10:605-12 .
18. McAllister RG, Kirsten EB. The pharmacology of veraparnil. IV.
Kinetic and dynamic effects after single intravenous and oral doses.
Clin Pharmacol Ther 1982;31 :41 8-23.
19. Eichelbaum M, Ende M, Ranberg G. Schomerus M. Dengler HJ. The
metabolism of C-D-L-verapamil in man. Drug Metab Dispos 1978;7:
145-50.
KOHLI ET AL.
SUSTAINED RELEASE VERAPAMIL IN ANGINA
621
20. Woodcock BG, Schulz W, Kober G, Rietbrock N. Direct derermination of hepatic extraction of verapamil in cardiac patients. Clin
Pharmacol Ther 1981;30:52- 6.
21 . Norris RJ. Muirhead DC, Christie RB. Devane JG. Bottini PB. The
bio-availability of a slow-release verapamil formulation. Br J Clin
Pract 1985;39(suppl 42):9-15 .
22. Bala Subramanian V, Bowles MJ. Penalver H, Davies AB, Raftery
EB. Verapamil in ischaemic hean disease- an objective study in 100
patients. In: Zancheui A, Krikler DM, eds. Calcium Antagonists in
Cardiovascular Therapy. Amsterdam: Excerpta Medica, 1981:11 8.
23. Bala Subramanian V, Bowles MJ. Khurmi NS, Davies AB, O'Hara
MJ. Raftery EB. Calcium antagonist withdrawal syndrome: objective
demonstration with frequency modulated ambulatory ST-segment
monitoring. Br Med J 1983;286:520-1.
24. Richmond DR, Freedman B, Kelly DT. Coronary spasm effect on
withdrawal of vasodilation therapy (abstr). Aust NZ J Med 1980;10:
376.
25. Raftery EB. Cardiovascular drug withdrawal syndromes. A potential
problem with calcium antagonists'! Drugs 1984:28:371-4.
26. Lahiri A, Dasgupta P. Rodrigues ER, Carboni GP, Cashman PMM,
Raftery EB. Acute withdrawal of therapy in patients with chronic
stable angina treated with verapamil. Drugs (in press).