- Email: [email protected]
Double-blind, randomized, placebo-controlled comparison of propranolol and verapamil in the treatment of patients with stable angina pectoris
Double-Blind, Randomized, Placebo-Controlled Comparison of Propranolol and Verapamil in the Treatment of Patients with Stable Angina Pectoris
JOHNSON,
M.D.’
DAVID
STACEY R.
M.
MAURITSON,
M.D.
JAMES
R.
CORBETT.
WAYNE
L.
T.
DAVID
Dallas.
M.D.
WOODWARD,
JAMES
Ph.D.
WILLERSON, HILLIS,
This study was performed to compare the relative efficacies of propranolol and verapamil in patients with stable angina pectoris. In 18 patients (16 men, two women, mean age 58 years) with coronary artery disease and angina of effort, the results of low (40 mg every 6 hours) and high-dose (80 mg every 6 hours) propranolol therapy were compared to those of low (80 mg every 6 hours) and high-dose (120 mg every 6 hours) verapamil therapy in a doubleblind, randomized, placebo-controlled evaluation which lasted eight weeks: two weeks of placebo therapy, two weeks of propranolol or verapamil (one week low-dose, one week high-dose) therapy, three days of down-titration followed by one week of placebo therapy, two weeks of propranolol or verapamil therapy (whichever was not given earlier in the trial) (one week low-dose, one week high-dose) and three days of down-titration. During each period the following were quantitated: (1) chest pains/week; (2) nitroglycerin used/week; (3) transient ischemic S-T segment deviations and highest grade of ventricular ectopic activity on two-channel Halter monitor; (4) S-T segment deviations during supine bicycle exercise; (5) left ventricular volumes and ejection fraction at rest and during exercise (assessed by equilibrium gated blood pool scintigraphy); and (6) pulmonary function studies. Propranolol and high-dose verapamil therapy significantly reduced the frequency of angina, and high-dose verapamil therapy diminished both the need for ni-
M.D.
M.D.
Texas
troglycerin and the frequency of transient ischemic S-T segment deviations on Halter monitor. Neither agent exerted a clinicallyimportant deleterious influence on left ventricular volumes or the ejection fraction. Forced vital capacity and forced expiratory volume were worsened by propranolol but not by verapamil. Thus, in the patient with angina of effort, verapamil is a satisfactory therapeutic alternative to propranolol. From the Departments diovascular
of Internal Medicine,
Division, and Radiology,
Car-
Division of
Nuclear Medicine, the University of Texas Health Science Center and Parkland Memorial Hospital, Dallas, Texas. This study was supported by NIH lschemic SCOR Grant HL 17669. Requests for reprints should be addressed to Dr. L. David Hillis. Room L5 134. University of Texas Health Science Center. 5323 Harry Hines Boulevard. Dallas, TX 75235.
Manuscript
accepted
* Present address:
March 5. 1981.
Teal Point Road, Route 6. Box 374. Mt Home. AR 72653.
Over the past 15 years, propranolol has been shown to be highly efficacious in the treatment of anaina of effort I l-91. However. it must be administered carefully to the ierson with brbnchbspastic pulmonary disease, since it may cause pulmonary function to deteriorate [ lo]. In addition, it should be administered with caution to the patient with diabetes mellitus. since it mav or-event recoanition of hvooalvcemia [ lo]. Finally. propranolol may’induce psy&ologic de$es
September
1981
The American
Journal of Medicine
Volume
71
443
PROPRANOLOL
TABLE I
VERSUS
VERAPAMIL
IN STABLE
Bases of Exclusion
ANGINA-JOHNSON
from the Present Study
Underlvina Diseases 1. Congestive heart failure (manifested rales, S3, pulmonary cardiac 2.
index <2
capillary
by cardiomegaly,
wedge pressure
>I2
alveolar mm Hg,
liters/minute)
Uncontrolled systemic arterial pressure > 115 mm Hg)
3.
Hypotension
4.
Sick sinus syndrome
hypertension
(systolic blood pressure
<90
(diastolic
blood
mm Hg)
(without a functioning ventricular
pace-
maker) 5. 6. 7.
Azotemia (serum creatinine >2.5 mg/lOO ml) Clinically-important liver disease (serum bilirubin >2 mg/lOO ml, serum glutamic oxaloacetic transaminase or serum glutamic pyruvic transaminase >3 times normal) 9. Insulin-dependent diabetes mellitus 10. A terminal illness (i.e., cancer) a.
Electrocardiographic Abnormalities
the present
in a double-blind, assessing
(by the Romhilt-Estes
444
study was performed
propranolol randomized,
the relative
Sepfember 1981
18 patients
34 to 69 years) of propranoioi terization disease
criteria
efficacies
were enrolled
(at least
consent
in an eight week comparison * In 15 of them cardiac
and demonstrated
70 percent
iuminai
coronary
artery
cathe-
coronary
diameter
had single vessel coronary
vessel
was obtained,
mean age 58 years, range
artery
narrowing).
artery disease, two
disease,
eight had triple
vessel coronary artery disease, and two had disease of ail three coronary arteries and the left main coronary artery. Of formed,
patients
in whom
one had survived
catheterization
a previous
was
myocardiai
not perinfarction,
and the other two had typical angina by history, an ischemic electrocardiographic response to exercise and a reduction in left ventricular wall
motion
ejection
coupled
during
with segmental
exercise
detected
by
gated blood pool scintigraphy.
Ail 18 patients averaged
fraction
abnormalities
equilibrium
had stable
5.4 years
(range,
angina,
the duration
0.2 to 20 years).
of which
Eight patients
had had at least one myocardiai infarction before study. Three patients were maintained throughout the study with a stable
to compare
dose
of oral
isosorbide
dinitrate
(10 to 40 mg four times
daily). The criteria
for exclusion
from the study are displayed
Table I. Study Design. The design of the study is shown 1. The initial two weeks comprised a single-blind period (placebo knew
A) (that is, the physicians,
it was a placebo
composed
period).
of a double-blind,
in
in Figure placebo
but not the patients,
The final
six weeks
randomized
were
comparison
of
propranoloi and verapamil therapy. Patient assignment by random drawing was performed at the beginning of this period. During weeks
3 and 4, either
propranoiol
or verapamil
was administered: during week 3, low-dose (propranoiol. 40 mg every 6 hours; verapamii, 80 mg every 6 hours) and during week
4 high-dose
pamii,
(propranoloi,
120 mg every
80 mg every
6 hours) therapy
6 hours;
was given.
vera-
Following
week 4, the dose was tapered over 3 days, after which the patient entered a one week placebo period (placebo B). This was followed by two weeks of therapy with the other intervention being evaluated: the first week low-dose therapy, the second week high-dose therapy. Finally, this dose was tapered over three days. Response to Therapy.
Clinical
seen weekly
Each of the patients
by one of us, and the following
was
were quantitated:
therapy
placebo-controlled
The American
informed
and verapamii.
was performed
the three
and verapamil of these
After
(16 men, two women,
had double
Verapamil, a slow channel calcium antagonist, has been used extensively outside the United States in the treatment of stable angina pectoris. In several trials, it has been proved to be superior to placebo therapy in the relief of angina [ 1 i-14]. In contrast to propranolol, verapamil does not cause bronchoconstriction [ 151 and does not influence the recognition of hypoglycemia. Although the efficacy of propranolol and verapamil therapy has been demonstrated previously, few attempts have been made to compare these agents. Both Sandler et al. [ 161 and Livesley et al. [ 171 demonstrated that propranolol, 300 mg/day, and verapamil, 360 mg/day, were equally effective in reducing the frequency of angina and the use of nitroglycerin. Balasubramanian et al. [ 181 showed that verapamil increased angina1 threshold and diminished electrocardiographic alterations during exercise when compared to the placebo and to small doses (120 mg/day) of propranolol. In these previous studies various doses of propranolol and verapamil have not been compared, nor has their effect on left ventricular performance been examined. low and high-dose
Patient Population.
Three patients
1191) 3. Severe bradycardia (<50 beats/min) 4. Second or third degree atrioventricular block 5. Atrial flutter or fibrillation 6. Pre-excitation syndrome Concomitantly-Administered Medications 1. Disopyramide 2. Digitalis 3. Another investigational drug Miscellaneous 1. Clinically-important electrolyte imbalance 2. Inability to undergo exercise testing
Therefore,
symptomatically (by quantitating episodes of angina and consumption of nitroglycerin) and objectively (by measuring exercise capacity and ischemic electrocardiographic alterations during exercise). In addition, the effects of propranolol and verapamil therapy on left ventricular volumes and ejection fraction were assessed with the patients at rest and during exercise with equilibrium gated blood pool scintigraphy. METHODS
Concomitant valvular or congenital cardiac disease Anemia (hemoglobin < 12 g/ 100 ml)
1. Left bundle branch block 2. Left ventricular hypertrophy
ET AL.
agents
trial, both
Journal of Medicine
* Kindly provided by Knoll Pharmaceutical Co., Whippany, Jersey, appropriately packaged for a double-blind study.
Volume
71
New
PROPRANOLOL
(1) episodes
of angina/week
(recorded
in a diary), (2) nitroglycerin
tablets
tablet counts) and (3) adverse tablets
(Nitrostat@,
Parke-Davis,
(assessed
Stabilized
Inc.) were
Holler
nitroglycerin
b
performed,
14 Days
from which a cardiothoracic
INTERVENTION
cebo A, intervention each
patient
A, placebo
underwent
to Therapy. Ambulatory Near the end of the plaB and intervention
two-channel
Holter
24 hours (Figure 1). Two bipolar Channel 1, an inferolateral channel, plex
ratio was calculated
1
1). Response monitoring:
resembling
electrocardiogram
from
V5 or V6 position the manubrium recorded
and a reference
sterni. Channel
sternum
to fifth
and a reference
brium stern].
space
electrode
channel,
lead V 1 or V2 electrode
to the right
of the
to the left of the manu-
electrode
was placed
Prior to the initial Holter
ventilation
to insure that changes
Before
S-T segment
each
each
and in breathing
Model
the recorder
(DelMar
(mV) calibration
445, DelMar
Avionics
recorder
signal was recorded. to the recorder,
event-signal
contained
was instructed
button when chest pain occurred
a diary of symptoms
a
and activities.
Exerase Goted
Test rlth
Pool Scmhgraphy
2-Channel
c
PA and Lateral
d
Pulmonary
Holler
Funchcm Testmq
I
I
-J
A schematic outline of the study design. In addi-’ tion to the variables listed, each patient was seen and examined weekly by one of us, at which time the frequency of angina/ episodes and the consumption of nitroglycerin tablets were noted.
Electrocardiographic Supine
exercise
response testing
to supine
was performed
gometer (Engineering Dynamics Corporation, [ 221. Resting and exercise electrocardiograms or a truncal
cable
to use the
segment
deviation
in mV was measured
necessary
to record
After calibration. time
Presentation
segment scribed
alteration
Visual (AVSEP)
alterations
signal appeared
S-T segment intervals
[ 201.
reliably
Electrocardio-
method.
Scintigraphic
Response
to Therapy.
A, intervention
the recording
was judged
in relation
displacement
80 msec after the
During
fraction
was tran-
systolic
volumes
the
to the P-R
and was measured
80 milliseconds
(msec)
S-T segment deviation pretation due to motion were
quantitated:
for 1 minute.
One minute
of
was required to minimize misinterartifact. For each tape, the following
(1) hours
of recording
satisfactory
for
analysis; (2) episodes of S-T segment deviation: and (3) highest grade of ventricular ectopic activity (using the modified Lown grading system) [ 2 11.
during
the final two
A and intervention
B period,
ventriculography
was per-
of red blood cells with 30 mCi according to the All studies were
60 to 120 minutes after a regularly-scheduled
of study medication. described
after the J point. For the purposes of this study. S-T segment deviation was said to occur if S-T depression or elevation of L 1 mm (0.1 mV) was present
performed
ejection
whenever
radionuclide
after in vivo labeling
viously
of the S-T segment.
was performed
formed
an S-T
Whenever
on the tape.
deviation
of vertical
specifications
Superimposed
before and after the S-T segment
in millimeters
All
at 120 times real
was suspected,
such transcription
655).
was scanned
onto paper for a measurement
In addition, event
S-T segment
each channel
using the Audio
graphic
Heart Association
12 lead system
by auscultation
of technetium-99m sodium pertechnetate, technique described previously [22,23].
met American
er-
Lowell, MA) were moni-
was used for all exercise
J point. Blood pressure was determined each minute of exercise. days of placebo
the recording,
the same system
DelMar equipment
exercise:
studies), and S-T segment deviation was assessed in the lead with the greatest rest-to-exercise S-T segment change. S-T
Ir-
within the
Model
bicycle
with a bicycle
rest and exercise
Electrocardioscanner,
I
Figure 7.
the recorder was removed, and the Electrocardioscanner was calibrated (DelMar Avionics Millivolt Calibrator, Model 3568; Avionics
nwmtor
Chest X-Roy
Corp.,
and to maintain
Following
Tolerance Blood
b 24 hr
(for each patient,
After the patient
the clock
was set, and the patient
-t
Avionics
vine, CA) was loaded with a new tape reel, and a 1 millivolt was attached
i
“A”
_
tored by the Frank lead system
deviation.
recording,
Electrocardiocorder.
in position
1
in the
recording,
channel was recorded on an electrocardiographic machine with the patient standing. sitting, supine and during hyperdid not cause
! High1c
LOW
to the right of
from an exploring
The fifth (ground)
lead V5R position.
resembled
intercostal
Test1n9
for
at the lead
2, an anterior-inferior
on a 12-lead electrocardiogram at the fourth
Funchon
B period,
monitoring
electrode electrode
which
._
lead II on a 12-lead
an exploring
a QRST complex
L.._
leads were employed. recorded a QRST com-
lead V5 or standard
Momtor
Pulmonary
used to insure Placebo “A”
Electrocardiographic electrocardiographic
ET AL.
o. 24 hr. 2-Channel
by
equal tablet effectiveness. Near the end of placebo A, intervention A and intervention B period, a chest film was (Figure
IN STABLE ANGINA---JOHNSON
daily by the patient
used/week
effects.
VERSUS VERAPAMIL
Extracardiac
Data collection [24-261.
was performed
From these data, left ventricular
[ 27.281 as well as end-diastolic were quantitated [ 27,29,30].
Response
cebo A, intervention
dose as pre-
to Therapy.
A, placebo
each patient underwent testing 60 to 120 minutes
and end-
Near the end of pla-
B and intervention
B period,
spirometric pulmonary function after receiving a regular dose of
study medication. Data Analysis. All patient diaries, nitroglycerin tablet counts, chest films. Holter monitors, rest and exercise electrocardiograms, scintigrams,
rest and exercise
equilibrium
and pulmonary
function
gated
test results
blood
pool
were ana-
lyzed without knowledge of the order in which propranolol and verapamil were administered. The data first were examined to determine if a “period effect” existed, that is, to ascertain if the order of administration influenced the response to either intervention [ 3 1.321. This analysis did not demonstrate
September 1981
a period
The American
effect.
Journal
Therefore,
of Medicine
data
from
Volume 71
each
445
FROPRANOLOL VERSUS VERAPAMIL
IN STABLE ANGINA-JOHNSON
ET AL
Clinical and Electrocardiographic Variables During Therapy with Placebo,
TABLE II
Propranolol
Propranolol Placebo A
Variable
7.9 12.0 43.4 2.1 3.0
Angina/week TNGlweek Cardiothoracic ratio (%) S-T segment deviations124 hours Highest grade of ectopy on Halter monitor FVC (% predicted) FEV, o (% predicted) FEV,, 5 (% predicted) FEF25-75 (% predicted) NOTE: All figures are mean = forced expired volume in ’ p <0.05 in comparison to t p <0.05 in combarison to
therapeutic
intervention
of treatment peated
measures
determine which
the Newman-Keuls
was performed
[ 33,341.
3.5 f 7.9’ 5.8 f 15.5
for analysis
variable
regardless
analyzed,
of variance
was performed
were different
from others.
multiple
comparison
Nonparametric
to after
procedure
procedures
were
16 14 5,,\ H s: 10 5 .5 5 BP * 6-
Hiah
Plocrbo
LOW
Figure 2. The number of angina1 episodes1 week during each of the treatment periods. In comparison to placebo A, the frequency of angina was reduced during low and highdose propranolol and high-dose verapamil therapy. ’ p < 0.05 in comparison to placebo A.
446
September
1961
High-Dose
PlaceboB
3.1 5.4 45.1 1.2 2.8
f 7.6’ f 13.7 f 5.5” f 1.9 f 1.8
5.7 f 9.2 8.0 f 14.8 2.3 : j.0 3.2 f 1.2
77 78 75 64
f 15-r f 19” f 20 f 33’
83f 17 82f 17 78f 17 67 f 26
Low-Dose 4.6 f 6.1 6.9 f 11.3
High-Dose 1.7 Jo 2.7’
2.4 43.4 0.6 2.8
f 3.9’ f 5.4 f 1.2’ f 1.6
82% 16 84f 18 80f 17 76 f 32
The American
RESULTS
a re-
also used to evaluate each variable, and thB results of this analysis were similar to those obtained with the NewmanKeuls procedure. When rest and exercise values during treatment with the same pharmacologic agent were compared, the paired t test was used. All values are expressed as mean f standard deviation. A p value of 0.05 or less is considered significant.
Placebo A
Verapamil
~f SD. TNG = nitroglycerin; FVC = forced vital capacity; FEV , o = forced expired volume in 1 second; FEVo 5 l/2 second and FEF 25 75 = forced expired midflow. placebo A. propranolol or verapamil.
For each
analysis
if some groups
f 10.9 f 17.3 f 5.1 f 3.2 f 1.5
82f 15 82f 19 78 f 20 70 f 30
were grouped
sequence.
Low-Dose
and Verapamil
Journal of Medicine
Drug Compliance. In all patients compliance was assessed by actual tablet counts. All 18 subjects were 90 to 100 percent compliant (mean, 96 percent) with the prescribed study medications. In each patient serum concentrations of propranolol and verapamil were measured during high-dose therapy to confirm that compliance with the prescribed regimen was adequate. All blood sampling was performed 2 hours after the ingestion of a regularly scheduled dose of study medication. For the 18 patients, the serum propranolol concentrations averaged 127 f 75 (range, 19 to 286) ng/ml, and the serum verapamil concentrations were 188 f 85 (range, 51 to 326) ng/ml. Clinical Response to Therapy. During treatment with low and high-dose propranolol as well as high-dose verapamil, the number of episodes of angina pectoris per week decreased in comparison to placebo A period (Table II, Figure 2). Nitroglycerin utilization was reduced during therapy with highdose verapamil (Table II, Figure 3). The cardiothoracic ratio on chest film was greater during propranolol therapy than during that with placebo or verapamil (Table II). The 18 patients complained of only an occasional untoward effect. With high-dose propranolol therapy, one had palpitations, one had excessive fatigue, and one had constipation. On high-dose verapamil therapy, one had orthostatic hypotension, one had mild nausea, and one complained of constipation. One patient was not advanced to high-dose verapamil therapy because of orthostatic symptoms; in the other 17, untoward effects did not force a discontinuation or a reduction in dosage of either medication. Electrocardiographic Response to Therapy. Ambulatory electrocardiographic monitoring: For the 18 patients, a total of 1,650 hours of Holter monitor re-
Volume 71
PROPRANOLOL VERSUS VERAPAMIL
IN STABLE ANGINA-JOHNSON
ET AL.
30
Placebo
/-
I
‘: 5 20 P J .5 r F E
10
z
A
Propranolol
B
Veropamll
The number of nitroglycerin tablets used1 wee1k Figure 3. during each of the treatment periods. In comparison to placebo A, high-dose verapamil therapy diminished the use of nitroglycerin. * p < 0.05 when compared to placebo A.
cordings was analyzed. During therapy with verapamil, the number of episodes of S-T segment deviation was reduced (Table II, Figure 4). Neither propranolol nor verapamil exerted a demonstrable effect on the severity of ventricular ectopic activity (Table II, Figure 4). Electrocardiographic response to supine bicycle exercise: Prior to exercise testing, heart rate was lower during propranolol therapy than during placebo therapy (Table ill). At the maximum workload common to the three studies, it increased during all three interventions and was highest during placebo therapy and lowest during propranolol therapy. Resting systolic blood pressure was lower during verapamil therapy than during placebo or propranolol therapy (Table ill). At the maximum workload common to the three studies, it increased with all agents. At this workload, the systolic blood pressure during propranolol therapy was lower than that during placebo therapy (Table Ill). The maximum S-T segment deviation at the workload common to all three studies was greatest during placebo therapy and significantly less (p <0.05) during propranolol and verapamil therapy (Table Ill, Figure 5). Scintigraphic Response to Therapy. During the three exercise studies (performed near the end of placebo A, high-dose propranolol and high-dose verapamil therapy), the highest workload achieved was similar, as was the maximal oxygen uptake (Table Ill). Resting left ventricular end-diastolic volume index was similar for the three agents. At the maximum workload common to the three studies, it increased during placebo therapy (Table III, Figure 6). At this workload, end-diastolic volume index for the three agents was similar. Resting left ventricular end-systolic volume index was larger during verapamil therapy than during placebo therapy, and
RI
q
Propranolol Verapamil
T
l-
Flgure 4.
I
I
The number of transient S-T segment deviations on 24-hour P-channel Halter monitor (top panel) and the highest grade of ventricular ectopy (bottom panei) during treatment with the three pharmacologic agents. Verapamil reduced the frequency of S-T segment deviations, but neither propranolol nor verapamil exerted a demonstrable effect on ventricular ectopy. p CO.05 when compared to placebo A. l
during exercise it increased further during verapamil therapy. At the maximum workload common to the three studies, there was no demonstrable difference in end-systolic volume index among the three agents (Table Ill, Figure 6). Resting left ventricular ejection fraction was higher during propranolol therapy than during verapamil therapy. With exercise, left ventricular ejection fraction was unchanged during placebo and propranolol therapy, whereas it was reduced slightly during verapamil therapy (Figure 6). At the maximum workload common to all three studies, left ventricular ejection fraction during propranolol therapy remained higher than during treatment with verapamil (Table III, Figure 6). Extracardiac Response to Therapy. Forced vital capacity and forced expired volume in 1 .O second were reduced during treatment with propranolol, in comparison to placebo and verapamil therapy (Table II,
September 1981
The American Journal of Medicine
Volume 71
447
PROPRANOLOL VERSUS VERAPAMIL IN STABLE ANGINA-JOHNSON
TABLE III
ET AL.
Hemodynamic and Scintigraphic Variables at Rest and During Exercise During Therapy with Placebo, Propranolol and Verapamil Variable
Placebo
Resting heart rate (beats/min) Peak heart rate at maximum workload common to all agents Resting systolic blood pressure (mm Hg) Peak systolic blood pressure at maximum workload common to all agents Maximum net S-T deviation with exercise (mV) MVOs (% predicted) LVEDVI (ml) Rest Exercise LVESVI (ml) Rest Exercise LVEF Rest Exercise
Propranolol
73f 11 124 * 19
55 f 6’ 90 f 12*+
Verapamil 69f 113 f
10 15’
143 * 19 162 f 24
137 f 21 167 f 20”
129 f 13’ 177 f 21
0.15 f 0.06
0.09 f 0.06”
0.08 * 0.04’
43f
15
45f
15
46f
15
59 f 20 65 f 23
68% 19 70 f 20
69 f 22 72 * 27
30% 14 33% 16
31 f 334
35 f 39f
0.57 f 0.16 0.53 f 0.18
16 16
0.60 zk 0.16+ 0.57 f 0.16*+
16’ 19
0.54 * 0.14 0.50 * 0.14
NOTE: All figures are mean f SD. LVEDVI = left ventricular end-diastolic volume index; LVESVI = left ventricular end-systolic volume index; LVEF = left ventricular ejection fraction. p <0.05 in comparison to placebo A. + p <0.05 in comparison to propranolol or verapamil. l
Figure 7). Forced expired flow (FEFss_rs) was lower during treatment with propranolol than during that with verapamil therapy (Table II). COMMENTS Over the past 15 to 20 years propranolol [l-9] and verapamil [ 1 l-141 have been shown to be efficacious
1
I
0.20
0
1
I Platebo
Propranolol
Verapamll
Figure 5. The maximum S-T segment deviation (in mV) at the maximum workload common to all three exercise studies. Compared to placebo therapy, propranolol and verapamil therapy reduced the magnitude of S-T segment deviation. p < 0.05 in comparison to placebo. l
446
September
1961
The American Journal of Medicine
in the therapy of stable angina pectoris, but few studies have compared them in a randomized, double-blind fashion. Both Sandier et al. [ 161 and Livesley et al. [ 171 found that propranolol (300 mg/day) and verapamil(360 mg/day) were comparable in reducing the frequency of angina and improving exercise performance. The present study demonstrates that low- (160 mg/day) and high-dose (320 mg/day) propranolol therapy and highdose verapamil (480 mg/day) therapy were similarly effective in reducing the frequency of angina (Table II, Figure 2). Furthermore, high-dose verapamil therapy reduced both the requirement for nitroglycerin (Figure 3) and the number of transient ischemic S-T segment alterations on Holter monitor (Figure 4). In short, the present study shows that the efficacy of high-dose verapamil therapy was equal or superior to that of propranolol. In contrast, the effects of low-dose verapamil therapy were indistinguishable from those of placebo therapy, thus confirming the previous observations of Phear [35]. It is conceivable that the therapeutic efficacy of low-dose verapamil therapy may improve if it is administered for longer than seven days. Previous studies have shown that the (usually intravenous) administration of propranolol or verapamil causes a negative inotropic effect [36-401, but neither agent has been shown to exert a deleterious influence on left ventricular volumes and ejection fraction [25,41-461. In the present study verapamil induced a slight increase in resting end-systolic volume index, and, as a result, ejection fraction was reduced (both at rest
Volume 71
pf3op~~~oLoL VEFSUS VERAPAMIL IN STABLE ANGINA-JOHNSON
n
I -r
s .i
T
T..
T
T
T,
Placebo
_ loor
q
ET
AL.
1 Propronolol
T
T
T
T
fgj
Vsropomil
T i
T
T
0.80
J Figure 7. Forced vital caDacitv, as a percent of predicted (top panel), and forced expired volume in 7 secbnd, as a percent of predicted (bottom panel), during treatment with placebo A and 8, propranolol and verapamil. p < 0.05 when compared to placebo A and verapamil.
0.60
5 ._ ‘: 0.40 iJ 3
0
l
-Rest
Exercise
Figure 6. Left ventricular end-diastolic volume index (top panel), end-systolic volume index (miWle panel) and ejection fraction (lower panel) at rest (left) and during the maximum workload common to all three exercise studies (right) for the three pharmacologic agents. y p < 0.05 when compared to placebo at rest; f p CO.05 when compared to propranolol at rest; p < 0.05 in comparison to the same pharmacologic agent at rest; fl p < 0.05 when compared to both placebo and verapamil during exercise. l
and with exercise)
during verapamil therapy (Table III, Figure 6). Although clinical evidence of left ventricular dysfunction did not develop during verapamil therapy in any of these 18 patients, these alterations in endsystolic volume and ejection fraction provide evidence that verapamil must be administered with caution to the patient with depressed left ventricular performance. Modern electrocardiographic monitoring equipment allows for the reliable recording and interpretation of both rhythm disturbances and S-T segment alterations. In a group of subjects with stable angina, Stern et al. [ 47,481 showed that ambulatory electrocardiographic monitoring identified most patients with coronary artery disease, and Schang and Pepine [49] showed that transient S-T segment deviation on a calibrated Holter monitor served as a reliable index of myocardial ischemia. The present study utilizes such S-T segmental-
terations to determine the relative efficacies of propranolol and verapamil. With this technique, verapamil diminished the frequency of S-T segment deviations, whereas propranolol exerted no demonstrable effect. Neither agent had a significant effect on ventricular ectopy (Table II, Figure 4). Aside from its beneficial influence in the treatment of angina pectoris, verapamil does not cause bronchoconstriction and, therefore, offers no problem in the patient with pulmonary disease. Although none of the patients in this study had severe pulmonary disease, most of them were smokers and had modest reductions in forced vital capacity and forced expiratory volume. During therapy with propranolol, these parameters of pulmonary function worsened, but during verapamil treatment, no change in forced vital capacity and forced expiratory volume could be demonstrated (Figure 7). The present study demonstrates that both propranolol and verapamil are efficacious in the therapy of stable, exertional angina pectoris, but each agent was administered for only two weeks (one week lowdose, one week high-dose). Previous studies [6,7,9] have shown that propranofol is of continued benefit during long-term use. In contrast, the therapeutic efficacy of verapamil has been shown only for as long as eight weeks [ 181. Although the long-term beneficial effect of verapamil in the patient with stable angina remains to be determined, the studies of Neumann and Luisada [ 1 l] as well
September 1981
The American Journal of Medicine
Volume 71
449
PROPRANOLOL VERSUS VERAPAMIL
IN STABLE ANGINA-JOHNSON
as Balasubramanian, et al. [ 181 do not suggest that tolerance to verapamil develops, at least over a period of six to eight weeks. Thus, it is hoped that long-term verapamil therapy will exert a salutary effect similar to that demonstrated in the present study. In conclusion, high-dose verapamil (480 mg/day) therapy is equal or superior to high-dose propranolol (320 mg/day) therapy in the alleviation of angina pectoris and the need for nitroglycerin. Although verapamil induces a slight increase in end-systolic volume and a slight decrease in resting and peak-exercise ejection fraction, neither agent exerts a clinically-important deleterious influence on left ventricular performance.
ET AL.
Finally, propranolol causes a worsening of pulmonary function. To obtain a full therapeutic effect from verapamil, it should be administered in large doses, since smaller doses appear similar to placebo in the relief of angina. For the patient with stable angina in whom propranolol is not suitable, high-dose verapamil is a legitimate and reasonable therapeutic alternative. ACKNOWLEDGMENT
We acknowledge the skilled technical assistance of Mr. Scott Lyons and Mr. Norman Vance, the assistance of Alan C. Elliott in the analysis of the data, and the assistance of Joan R. Cary, R.N.
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Romhilt DW. Estes EH: A point score system for the ECG diagnosis of left ventricular hypertrophy. Am Heart J 1968; 75: 752-759. Pipberger HV, Arzbaecher RC, Berson AS, et al.: Recommendations for standardization of leads and of specifications for instruments in electrocardiography and vectorcardiography. Circulation 1975; 52: 11-31. Lown B, Wolf M: Approaches to sudden death from coronary heart disease. Circulation 1971; 44: 130-142. Pulido J, Doss J. Twieg D, et al.: Submaximal exercise testing afler acute myocardial infarction. Myocardial scintigraphic and electrocardiographic observations. Am J Cardiol 1979; 42: 19-28. Stokely EM, Parkey RW, Bonte FJ, Graham KD, Stone MJ, Willerson JT: Gated blood pool imaging following technetium-99m pyrophosphate scintigraphy. Radiology 1976; 120: 433-434. Firth BG, Dehmer GJ, Corbett JR, Lewis SE, Parkey RW, Willerson JT: Effect of chronic oral digoxin therapy on ventricular function at rest and peak exercise in patients with ischemic heart disease. Am J Cardiol 1980; 46: 481-490. Dehmer GJ, Falkoff M, Lewis SE, Hillis LD, Parkey RW, Willerson JT: Effect of oral propranolol on rest and exercise left ventricular ejection fraction, volumes, and segmental wall motion in patients with angina pectoris. Assessment with equilibrium gated blood pool imaging. Br Heart J 1981; (in press). Dehmer GJ, Lewis SE, Hillis LD, Corbett J, Parkey RW, Willerson JT: Exercise-induced alterations in left ventricular volumes and the pressure/volume relationship. A sensitive indicator of left ventricular dysfunction in patients with coronary artery disease. Circulation, 1981; 63: 10081018. Dehmer GJ, Lewis SE, Hillis LD, et al.: Determination of left ventricular volumes from the time-activity data derived from equilibrium gated blood pool scans. Am J Cardiol 1980; 45: 293-300. Ashburn WL, Schelberl HR, Verba J: Left ventricular ejection fraction-a review of several radionuclide angiographic approaches using the scintillation camera. Prog Cardiovasc Dis 1978; 20: 267-277. Lewis SE, Dehmer GJ, Falkoff M, Hillis LD, Willerson JT: A nongeometric method for the scintigraphic determination of left ventricular volume: contrast correlation (abstract) J Nucl Med 1979; 20: 661. Slutsky R. Karliner J, Ricci D, et al.: Left ventricular volumes by gated equilibrium radionuclide angiography: a new method. Circulation 1979; 60: 556-564. Koch GG: The use of non-parametric methods in the statistical
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analysis of the two-period change-over design. Biometrics 1972; 28: 577-584. Grizzle JE: The two-period change-over design and its use in clinical trials. Biometrics 1965; 21: 467-480. Noether GE: Introduction to Statistics. Boston: Houghton Mifflin, 1971: 147-149. Zar JH: Biostatistical Analysis. Englewood Cliffs, NJ: Prentice-Hall, Inc., 1974; 152-154. Phear DN: Verapamil in angina: a double-blind trial. Br Med J 1968; 2: 740-741. Coltart DJ, Alderman EL, Robison SC, Harrison DC: Effect of propranolol on left ventricular function, segmental wall motion, and diastolic pressure-volume relation in man. Br Heart J 1975; 37: 357-364. Helfant RH, Herman MV, Gorlin R: Abnormalities of left ventricular contraction induced by beta adrenergic blockade. Circulation 1971; 43: 641-647. Nayler WG, Szeto J: Effect of verapamil on contractility, oxygen utilization, and calcium exchangeability in mam-
42.
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malian heart muscle. Cardiovas Res 1972; 6: 120-128. Newman RK, Bishop VS, Peterson DF, Leroux EJ, Horwitz LD:
Effect of verapamil on left ventricular performance in conscious dogs. J Pharmacol Exp Ther 1977; 201: 723730. Mangiardi LM, Hareman RJ, McAllister RG Jr., Bhargava V, Surawicz B, Shabetai R: Electrophysiologic and hemodynamic effects of verapamil: correlation with plasma drug concentrations. Circulation 1978; 57: 366-372. Marshall RC, Berger HJ, Reduto LA, Cohen LS, Gottschalk A, Zaret BL: Assessment of cardiac performance with quan-
September
47.
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49.
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titative radionuclide angiocardiography. Effects of propranolol on global and regional left ventricular function in coronary artery disease. Circulation 1978; 58: 808-814. Battler A, Ross J. Slutsky R, Pfisterer M, Ashburn W. Froelicher V: Improvement of exercise-induced left ventricular dysfunction with oral propranolol in patients with coronary heart disease. Am J Cardiol 1979; 44: 318-324. Parker JO, West RO, DiGiorgi S: Hemodynamic effects of propranolol in coronary heart disease. Am J Cardiol 1968; 21: 11-19. Atterhog JH, Ekelund LG: Haemodynamic effects of intravenous verapamil at rest and during exercise in subjectively healthy middle-aged men. Eur J Clin Pharmacol 1975; 8: 317-322. Ferlinz J, Easthope JL, Aronow WS: Effects of verapamil on myocardial performance in coronary disease. Circulation 1979; 59: 313-319. Johnson SM, Mauritson DR. Corbett J. Dehmer GJ, Willerson JT, Hillis LD: Effects of verapamil and nifedipine on left ventricular function in patients with Prinzmetal’s variant angina. Am J Cardiol 1981; 47: 1289-1294. Stern S, Tzivori D: Early detection of silent ischemic heart disease by 24-hour electrocardiographic monitoring in inactive subjects. Br Heart J 1974; 36: 481-486. Stern S, Tzivori D. Stern Z: Diagnostic accuracy of ambulatory ECG monitoring in ischemic heart disease. Circulation 1975; 52: 1045-1049. Schang SJ Jr, Pepine CJ: Transient asymptomatic S-T segment depression during daily activity. Am J Cardiol 1977; 39: 396-402.
The American
Journal
of Medicine
Volume 71
451
JOHNSON,
M.D.’
DAVID
STACEY R.
M.
MAURITSON,
M.D.
JAMES
R.
CORBETT.
WAYNE
L.
T.
DAVID
Dallas.
M.D.
WOODWARD,
JAMES
Ph.D.
WILLERSON, HILLIS,
This study was performed to compare the relative efficacies of propranolol and verapamil in patients with stable angina pectoris. In 18 patients (16 men, two women, mean age 58 years) with coronary artery disease and angina of effort, the results of low (40 mg every 6 hours) and high-dose (80 mg every 6 hours) propranolol therapy were compared to those of low (80 mg every 6 hours) and high-dose (120 mg every 6 hours) verapamil therapy in a doubleblind, randomized, placebo-controlled evaluation which lasted eight weeks: two weeks of placebo therapy, two weeks of propranolol or verapamil (one week low-dose, one week high-dose) therapy, three days of down-titration followed by one week of placebo therapy, two weeks of propranolol or verapamil therapy (whichever was not given earlier in the trial) (one week low-dose, one week high-dose) and three days of down-titration. During each period the following were quantitated: (1) chest pains/week; (2) nitroglycerin used/week; (3) transient ischemic S-T segment deviations and highest grade of ventricular ectopic activity on two-channel Halter monitor; (4) S-T segment deviations during supine bicycle exercise; (5) left ventricular volumes and ejection fraction at rest and during exercise (assessed by equilibrium gated blood pool scintigraphy); and (6) pulmonary function studies. Propranolol and high-dose verapamil therapy significantly reduced the frequency of angina, and high-dose verapamil therapy diminished both the need for ni-
M.D.
M.D.
Texas
troglycerin and the frequency of transient ischemic S-T segment deviations on Halter monitor. Neither agent exerted a clinicallyimportant deleterious influence on left ventricular volumes or the ejection fraction. Forced vital capacity and forced expiratory volume were worsened by propranolol but not by verapamil. Thus, in the patient with angina of effort, verapamil is a satisfactory therapeutic alternative to propranolol. From the Departments diovascular
of Internal Medicine,
Division, and Radiology,
Car-
Division of
Nuclear Medicine, the University of Texas Health Science Center and Parkland Memorial Hospital, Dallas, Texas. This study was supported by NIH lschemic SCOR Grant HL 17669. Requests for reprints should be addressed to Dr. L. David Hillis. Room L5 134. University of Texas Health Science Center. 5323 Harry Hines Boulevard. Dallas, TX 75235.
Manuscript
accepted
* Present address:
March 5. 1981.
Teal Point Road, Route 6. Box 374. Mt Home. AR 72653.
Over the past 15 years, propranolol has been shown to be highly efficacious in the treatment of anaina of effort I l-91. However. it must be administered carefully to the ierson with brbnchbspastic pulmonary disease, since it may cause pulmonary function to deteriorate [ lo]. In addition, it should be administered with caution to the patient with diabetes mellitus. since it mav or-event recoanition of hvooalvcemia [ lo]. Finally. propranolol may’induce psy&ologic de$es
September
1981
The American
Journal of Medicine
Volume
71
443
PROPRANOLOL
TABLE I
VERSUS
VERAPAMIL
IN STABLE
Bases of Exclusion
ANGINA-JOHNSON
from the Present Study
Underlvina Diseases 1. Congestive heart failure (manifested rales, S3, pulmonary cardiac 2.
index <2
capillary
by cardiomegaly,
wedge pressure
>I2
alveolar mm Hg,
liters/minute)
Uncontrolled systemic arterial pressure > 115 mm Hg)
3.
Hypotension
4.
Sick sinus syndrome
hypertension
(systolic blood pressure
<90
(diastolic
blood
mm Hg)
(without a functioning ventricular
pace-
maker) 5. 6. 7.
Azotemia (serum creatinine >2.5 mg/lOO ml) Clinically-important liver disease (serum bilirubin >2 mg/lOO ml, serum glutamic oxaloacetic transaminase or serum glutamic pyruvic transaminase >3 times normal) 9. Insulin-dependent diabetes mellitus 10. A terminal illness (i.e., cancer) a.
Electrocardiographic Abnormalities
the present
in a double-blind, assessing
(by the Romhilt-Estes
444
study was performed
propranolol randomized,
the relative
Sepfember 1981
18 patients
34 to 69 years) of propranoioi terization disease
criteria
efficacies
were enrolled
(at least
consent
in an eight week comparison * In 15 of them cardiac
and demonstrated
70 percent
iuminai
coronary
artery
cathe-
coronary
diameter
had single vessel coronary
vessel
was obtained,
mean age 58 years, range
artery
narrowing).
artery disease, two
disease,
eight had triple
vessel coronary artery disease, and two had disease of ail three coronary arteries and the left main coronary artery. Of formed,
patients
in whom
one had survived
catheterization
a previous
was
myocardiai
not perinfarction,
and the other two had typical angina by history, an ischemic electrocardiographic response to exercise and a reduction in left ventricular wall
motion
ejection
coupled
during
with segmental
exercise
detected
by
gated blood pool scintigraphy.
Ail 18 patients averaged
fraction
abnormalities
equilibrium
had stable
5.4 years
(range,
angina,
the duration
0.2 to 20 years).
of which
Eight patients
had had at least one myocardiai infarction before study. Three patients were maintained throughout the study with a stable
to compare
dose
of oral
isosorbide
dinitrate
(10 to 40 mg four times
daily). The criteria
for exclusion
from the study are displayed
Table I. Study Design. The design of the study is shown 1. The initial two weeks comprised a single-blind period (placebo knew
A) (that is, the physicians,
it was a placebo
composed
period).
of a double-blind,
in
in Figure placebo
but not the patients,
The final
six weeks
randomized
were
comparison
of
propranoloi and verapamil therapy. Patient assignment by random drawing was performed at the beginning of this period. During weeks
3 and 4, either
propranoiol
or verapamil
was administered: during week 3, low-dose (propranoiol. 40 mg every 6 hours; verapamii, 80 mg every 6 hours) and during week
4 high-dose
pamii,
(propranoloi,
120 mg every
80 mg every
6 hours) therapy
6 hours;
was given.
vera-
Following
week 4, the dose was tapered over 3 days, after which the patient entered a one week placebo period (placebo B). This was followed by two weeks of therapy with the other intervention being evaluated: the first week low-dose therapy, the second week high-dose therapy. Finally, this dose was tapered over three days. Response to Therapy.
Clinical
seen weekly
Each of the patients
by one of us, and the following
was
were quantitated:
therapy
placebo-controlled
The American
informed
and verapamii.
was performed
the three
and verapamil of these
After
(16 men, two women,
had double
Verapamil, a slow channel calcium antagonist, has been used extensively outside the United States in the treatment of stable angina pectoris. In several trials, it has been proved to be superior to placebo therapy in the relief of angina [ 1 i-14]. In contrast to propranolol, verapamil does not cause bronchoconstriction [ 151 and does not influence the recognition of hypoglycemia. Although the efficacy of propranolol and verapamil therapy has been demonstrated previously, few attempts have been made to compare these agents. Both Sandler et al. [ 161 and Livesley et al. [ 171 demonstrated that propranolol, 300 mg/day, and verapamil, 360 mg/day, were equally effective in reducing the frequency of angina and the use of nitroglycerin. Balasubramanian et al. [ 181 showed that verapamil increased angina1 threshold and diminished electrocardiographic alterations during exercise when compared to the placebo and to small doses (120 mg/day) of propranolol. In these previous studies various doses of propranolol and verapamil have not been compared, nor has their effect on left ventricular performance been examined. low and high-dose
Patient Population.
Three patients
1191) 3. Severe bradycardia (<50 beats/min) 4. Second or third degree atrioventricular block 5. Atrial flutter or fibrillation 6. Pre-excitation syndrome Concomitantly-Administered Medications 1. Disopyramide 2. Digitalis 3. Another investigational drug Miscellaneous 1. Clinically-important electrolyte imbalance 2. Inability to undergo exercise testing
Therefore,
symptomatically (by quantitating episodes of angina and consumption of nitroglycerin) and objectively (by measuring exercise capacity and ischemic electrocardiographic alterations during exercise). In addition, the effects of propranolol and verapamil therapy on left ventricular volumes and ejection fraction were assessed with the patients at rest and during exercise with equilibrium gated blood pool scintigraphy. METHODS
Concomitant valvular or congenital cardiac disease Anemia (hemoglobin < 12 g/ 100 ml)
1. Left bundle branch block 2. Left ventricular hypertrophy
ET AL.
agents
trial, both
Journal of Medicine
* Kindly provided by Knoll Pharmaceutical Co., Whippany, Jersey, appropriately packaged for a double-blind study.
Volume
71
New
PROPRANOLOL
(1) episodes
of angina/week
(recorded
in a diary), (2) nitroglycerin
tablets
tablet counts) and (3) adverse tablets
(Nitrostat@,
Parke-Davis,
(assessed
Stabilized
Inc.) were
Holler
nitroglycerin
b
performed,
14 Days
from which a cardiothoracic
INTERVENTION
cebo A, intervention each
patient
A, placebo
underwent
to Therapy. Ambulatory Near the end of the plaB and intervention
two-channel
Holter
24 hours (Figure 1). Two bipolar Channel 1, an inferolateral channel, plex
ratio was calculated
1
1). Response monitoring:
resembling
electrocardiogram
from
V5 or V6 position the manubrium recorded
and a reference
sterni. Channel
sternum
to fifth
and a reference
brium stern].
space
electrode
channel,
lead V 1 or V2 electrode
to the right
of the
to the left of the manu-
electrode
was placed
Prior to the initial Holter
ventilation
to insure that changes
Before
S-T segment
each
each
and in breathing
Model
the recorder
(DelMar
(mV) calibration
445, DelMar
Avionics
recorder
signal was recorded. to the recorder,
event-signal
contained
was instructed
button when chest pain occurred
a diary of symptoms
a
and activities.
Exerase Goted
Test rlth
Pool Scmhgraphy
2-Channel
c
PA and Lateral
d
Pulmonary
Holler
Funchcm Testmq
I
I
-J
A schematic outline of the study design. In addi-’ tion to the variables listed, each patient was seen and examined weekly by one of us, at which time the frequency of angina/ episodes and the consumption of nitroglycerin tablets were noted.
Electrocardiographic Supine
exercise
response testing
to supine
was performed
gometer (Engineering Dynamics Corporation, [ 221. Resting and exercise electrocardiograms or a truncal
cable
to use the
segment
deviation
in mV was measured
necessary
to record
After calibration. time
Presentation
segment scribed
alteration
Visual (AVSEP)
alterations
signal appeared
S-T segment intervals
[ 201.
reliably
Electrocardio-
method.
Scintigraphic
Response
to Therapy.
A, intervention
the recording
was judged
in relation
displacement
80 msec after the
During
fraction
was tran-
systolic
volumes
the
to the P-R
and was measured
80 milliseconds
(msec)
S-T segment deviation pretation due to motion were
quantitated:
for 1 minute.
One minute
of
was required to minimize misinterartifact. For each tape, the following
(1) hours
of recording
satisfactory
for
analysis; (2) episodes of S-T segment deviation: and (3) highest grade of ventricular ectopic activity (using the modified Lown grading system) [ 2 11.
during
the final two
A and intervention
B period,
ventriculography
was per-
of red blood cells with 30 mCi according to the All studies were
60 to 120 minutes after a regularly-scheduled
of study medication. described
after the J point. For the purposes of this study. S-T segment deviation was said to occur if S-T depression or elevation of L 1 mm (0.1 mV) was present
performed
ejection
whenever
radionuclide
after in vivo labeling
viously
of the S-T segment.
was performed
formed
an S-T
Whenever
on the tape.
deviation
of vertical
specifications
Superimposed
before and after the S-T segment
in millimeters
All
at 120 times real
was suspected,
such transcription
655).
was scanned
onto paper for a measurement
In addition, event
S-T segment
each channel
using the Audio
graphic
Heart Association
12 lead system
by auscultation
of technetium-99m sodium pertechnetate, technique described previously [22,23].
met American
er-
Lowell, MA) were moni-
was used for all exercise
J point. Blood pressure was determined each minute of exercise. days of placebo
the recording,
the same system
DelMar equipment
exercise:
studies), and S-T segment deviation was assessed in the lead with the greatest rest-to-exercise S-T segment change. S-T
Ir-
within the
Model
bicycle
with a bicycle
rest and exercise
Electrocardioscanner,
I
Figure 7.
the recorder was removed, and the Electrocardioscanner was calibrated (DelMar Avionics Millivolt Calibrator, Model 3568; Avionics
nwmtor
Chest X-Roy
Corp.,
and to maintain
Following
Tolerance Blood
b 24 hr
(for each patient,
After the patient
the clock
was set, and the patient
-t
Avionics
vine, CA) was loaded with a new tape reel, and a 1 millivolt was attached
i
“A”
_
tored by the Frank lead system
deviation.
recording,
Electrocardiocorder.
in position
1
in the
recording,
channel was recorded on an electrocardiographic machine with the patient standing. sitting, supine and during hyperdid not cause
! High1c
LOW
to the right of
from an exploring
The fifth (ground)
lead V5R position.
resembled
intercostal
Test1n9
for
at the lead
2, an anterior-inferior
on a 12-lead electrocardiogram at the fourth
Funchon
B period,
monitoring
electrode electrode
which
._
lead II on a 12-lead
an exploring
a QRST complex
L.._
leads were employed. recorded a QRST com-
lead V5 or standard
Momtor
Pulmonary
used to insure Placebo “A”
Electrocardiographic electrocardiographic
ET AL.
o. 24 hr. 2-Channel
by
equal tablet effectiveness. Near the end of placebo A, intervention A and intervention B period, a chest film was (Figure
IN STABLE ANGINA---JOHNSON
daily by the patient
used/week
effects.
VERSUS VERAPAMIL
Extracardiac
Data collection [24-261.
was performed
From these data, left ventricular
[ 27.281 as well as end-diastolic were quantitated [ 27,29,30].
Response
cebo A, intervention
dose as pre-
to Therapy.
A, placebo
each patient underwent testing 60 to 120 minutes
and end-
Near the end of pla-
B and intervention
B period,
spirometric pulmonary function after receiving a regular dose of
study medication. Data Analysis. All patient diaries, nitroglycerin tablet counts, chest films. Holter monitors, rest and exercise electrocardiograms, scintigrams,
rest and exercise
equilibrium
and pulmonary
function
gated
test results
blood
pool
were ana-
lyzed without knowledge of the order in which propranolol and verapamil were administered. The data first were examined to determine if a “period effect” existed, that is, to ascertain if the order of administration influenced the response to either intervention [ 3 1.321. This analysis did not demonstrate
September 1981
a period
The American
effect.
Journal
Therefore,
of Medicine
data
from
Volume 71
each
445
FROPRANOLOL VERSUS VERAPAMIL
IN STABLE ANGINA-JOHNSON
ET AL
Clinical and Electrocardiographic Variables During Therapy with Placebo,
TABLE II
Propranolol
Propranolol Placebo A
Variable
7.9 12.0 43.4 2.1 3.0
Angina/week TNGlweek Cardiothoracic ratio (%) S-T segment deviations124 hours Highest grade of ectopy on Halter monitor FVC (% predicted) FEV, o (% predicted) FEV,, 5 (% predicted) FEF25-75 (% predicted) NOTE: All figures are mean = forced expired volume in ’ p <0.05 in comparison to t p <0.05 in combarison to
therapeutic
intervention
of treatment peated
measures
determine which
the Newman-Keuls
was performed
[ 33,341.
3.5 f 7.9’ 5.8 f 15.5
for analysis
variable
regardless
analyzed,
of variance
was performed
were different
from others.
multiple
comparison
Nonparametric
to after
procedure
procedures
were
16 14 5,,\ H s: 10 5 .5 5 BP * 6-
Hiah
Plocrbo
LOW
Figure 2. The number of angina1 episodes1 week during each of the treatment periods. In comparison to placebo A, the frequency of angina was reduced during low and highdose propranolol and high-dose verapamil therapy. ’ p < 0.05 in comparison to placebo A.
446
September
1961
High-Dose
PlaceboB
3.1 5.4 45.1 1.2 2.8
f 7.6’ f 13.7 f 5.5” f 1.9 f 1.8
5.7 f 9.2 8.0 f 14.8 2.3 : j.0 3.2 f 1.2
77 78 75 64
f 15-r f 19” f 20 f 33’
83f 17 82f 17 78f 17 67 f 26
Low-Dose 4.6 f 6.1 6.9 f 11.3
High-Dose 1.7 Jo 2.7’
2.4 43.4 0.6 2.8
f 3.9’ f 5.4 f 1.2’ f 1.6
82% 16 84f 18 80f 17 76 f 32
The American
RESULTS
a re-
also used to evaluate each variable, and thB results of this analysis were similar to those obtained with the NewmanKeuls procedure. When rest and exercise values during treatment with the same pharmacologic agent were compared, the paired t test was used. All values are expressed as mean f standard deviation. A p value of 0.05 or less is considered significant.
Placebo A
Verapamil
~f SD. TNG = nitroglycerin; FVC = forced vital capacity; FEV , o = forced expired volume in 1 second; FEVo 5 l/2 second and FEF 25 75 = forced expired midflow. placebo A. propranolol or verapamil.
For each
analysis
if some groups
f 10.9 f 17.3 f 5.1 f 3.2 f 1.5
82f 15 82f 19 78 f 20 70 f 30
were grouped
sequence.
Low-Dose
and Verapamil
Journal of Medicine
Drug Compliance. In all patients compliance was assessed by actual tablet counts. All 18 subjects were 90 to 100 percent compliant (mean, 96 percent) with the prescribed study medications. In each patient serum concentrations of propranolol and verapamil were measured during high-dose therapy to confirm that compliance with the prescribed regimen was adequate. All blood sampling was performed 2 hours after the ingestion of a regularly scheduled dose of study medication. For the 18 patients, the serum propranolol concentrations averaged 127 f 75 (range, 19 to 286) ng/ml, and the serum verapamil concentrations were 188 f 85 (range, 51 to 326) ng/ml. Clinical Response to Therapy. During treatment with low and high-dose propranolol as well as high-dose verapamil, the number of episodes of angina pectoris per week decreased in comparison to placebo A period (Table II, Figure 2). Nitroglycerin utilization was reduced during therapy with highdose verapamil (Table II, Figure 3). The cardiothoracic ratio on chest film was greater during propranolol therapy than during that with placebo or verapamil (Table II). The 18 patients complained of only an occasional untoward effect. With high-dose propranolol therapy, one had palpitations, one had excessive fatigue, and one had constipation. On high-dose verapamil therapy, one had orthostatic hypotension, one had mild nausea, and one complained of constipation. One patient was not advanced to high-dose verapamil therapy because of orthostatic symptoms; in the other 17, untoward effects did not force a discontinuation or a reduction in dosage of either medication. Electrocardiographic Response to Therapy. Ambulatory electrocardiographic monitoring: For the 18 patients, a total of 1,650 hours of Holter monitor re-
Volume 71
PROPRANOLOL VERSUS VERAPAMIL
IN STABLE ANGINA-JOHNSON
ET AL.
30
Placebo
/-
I
‘: 5 20 P J .5 r F E
10
z
A
Propranolol
B
Veropamll
The number of nitroglycerin tablets used1 wee1k Figure 3. during each of the treatment periods. In comparison to placebo A, high-dose verapamil therapy diminished the use of nitroglycerin. * p < 0.05 when compared to placebo A.
cordings was analyzed. During therapy with verapamil, the number of episodes of S-T segment deviation was reduced (Table II, Figure 4). Neither propranolol nor verapamil exerted a demonstrable effect on the severity of ventricular ectopic activity (Table II, Figure 4). Electrocardiographic response to supine bicycle exercise: Prior to exercise testing, heart rate was lower during propranolol therapy than during placebo therapy (Table ill). At the maximum workload common to the three studies, it increased during all three interventions and was highest during placebo therapy and lowest during propranolol therapy. Resting systolic blood pressure was lower during verapamil therapy than during placebo or propranolol therapy (Table ill). At the maximum workload common to the three studies, it increased with all agents. At this workload, the systolic blood pressure during propranolol therapy was lower than that during placebo therapy (Table Ill). The maximum S-T segment deviation at the workload common to all three studies was greatest during placebo therapy and significantly less (p <0.05) during propranolol and verapamil therapy (Table Ill, Figure 5). Scintigraphic Response to Therapy. During the three exercise studies (performed near the end of placebo A, high-dose propranolol and high-dose verapamil therapy), the highest workload achieved was similar, as was the maximal oxygen uptake (Table Ill). Resting left ventricular end-diastolic volume index was similar for the three agents. At the maximum workload common to the three studies, it increased during placebo therapy (Table III, Figure 6). At this workload, end-diastolic volume index for the three agents was similar. Resting left ventricular end-systolic volume index was larger during verapamil therapy than during placebo therapy, and
RI
q
Propranolol Verapamil
T
l-
Flgure 4.
I
I
The number of transient S-T segment deviations on 24-hour P-channel Halter monitor (top panel) and the highest grade of ventricular ectopy (bottom panei) during treatment with the three pharmacologic agents. Verapamil reduced the frequency of S-T segment deviations, but neither propranolol nor verapamil exerted a demonstrable effect on ventricular ectopy. p CO.05 when compared to placebo A. l
during exercise it increased further during verapamil therapy. At the maximum workload common to the three studies, there was no demonstrable difference in end-systolic volume index among the three agents (Table Ill, Figure 6). Resting left ventricular ejection fraction was higher during propranolol therapy than during verapamil therapy. With exercise, left ventricular ejection fraction was unchanged during placebo and propranolol therapy, whereas it was reduced slightly during verapamil therapy (Figure 6). At the maximum workload common to all three studies, left ventricular ejection fraction during propranolol therapy remained higher than during treatment with verapamil (Table III, Figure 6). Extracardiac Response to Therapy. Forced vital capacity and forced expired volume in 1 .O second were reduced during treatment with propranolol, in comparison to placebo and verapamil therapy (Table II,
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PROPRANOLOL VERSUS VERAPAMIL IN STABLE ANGINA-JOHNSON
TABLE III
ET AL.
Hemodynamic and Scintigraphic Variables at Rest and During Exercise During Therapy with Placebo, Propranolol and Verapamil Variable
Placebo
Resting heart rate (beats/min) Peak heart rate at maximum workload common to all agents Resting systolic blood pressure (mm Hg) Peak systolic blood pressure at maximum workload common to all agents Maximum net S-T deviation with exercise (mV) MVOs (% predicted) LVEDVI (ml) Rest Exercise LVESVI (ml) Rest Exercise LVEF Rest Exercise
Propranolol
73f 11 124 * 19
55 f 6’ 90 f 12*+
Verapamil 69f 113 f
10 15’
143 * 19 162 f 24
137 f 21 167 f 20”
129 f 13’ 177 f 21
0.15 f 0.06
0.09 f 0.06”
0.08 * 0.04’
43f
15
45f
15
46f
15
59 f 20 65 f 23
68% 19 70 f 20
69 f 22 72 * 27
30% 14 33% 16
31 f 334
35 f 39f
0.57 f 0.16 0.53 f 0.18
16 16
0.60 zk 0.16+ 0.57 f 0.16*+
16’ 19
0.54 * 0.14 0.50 * 0.14
NOTE: All figures are mean f SD. LVEDVI = left ventricular end-diastolic volume index; LVESVI = left ventricular end-systolic volume index; LVEF = left ventricular ejection fraction. p <0.05 in comparison to placebo A. + p <0.05 in comparison to propranolol or verapamil. l
Figure 7). Forced expired flow (FEFss_rs) was lower during treatment with propranolol than during that with verapamil therapy (Table II). COMMENTS Over the past 15 to 20 years propranolol [l-9] and verapamil [ 1 l-141 have been shown to be efficacious
1
I
0.20
0
1
I Platebo
Propranolol
Verapamll
Figure 5. The maximum S-T segment deviation (in mV) at the maximum workload common to all three exercise studies. Compared to placebo therapy, propranolol and verapamil therapy reduced the magnitude of S-T segment deviation. p < 0.05 in comparison to placebo. l
446
September
1961
The American Journal of Medicine
in the therapy of stable angina pectoris, but few studies have compared them in a randomized, double-blind fashion. Both Sandier et al. [ 161 and Livesley et al. [ 171 found that propranolol (300 mg/day) and verapamil(360 mg/day) were comparable in reducing the frequency of angina and improving exercise performance. The present study demonstrates that low- (160 mg/day) and high-dose (320 mg/day) propranolol therapy and highdose verapamil (480 mg/day) therapy were similarly effective in reducing the frequency of angina (Table II, Figure 2). Furthermore, high-dose verapamil therapy reduced both the requirement for nitroglycerin (Figure 3) and the number of transient ischemic S-T segment alterations on Holter monitor (Figure 4). In short, the present study shows that the efficacy of high-dose verapamil therapy was equal or superior to that of propranolol. In contrast, the effects of low-dose verapamil therapy were indistinguishable from those of placebo therapy, thus confirming the previous observations of Phear [35]. It is conceivable that the therapeutic efficacy of low-dose verapamil therapy may improve if it is administered for longer than seven days. Previous studies have shown that the (usually intravenous) administration of propranolol or verapamil causes a negative inotropic effect [36-401, but neither agent has been shown to exert a deleterious influence on left ventricular volumes and ejection fraction [25,41-461. In the present study verapamil induced a slight increase in resting end-systolic volume index, and, as a result, ejection fraction was reduced (both at rest
Volume 71
pf3op~~~oLoL VEFSUS VERAPAMIL IN STABLE ANGINA-JOHNSON
n
I -r
s .i
T
T..
T
T
T,
Placebo
_ loor
q
ET
AL.
1 Propronolol
T
T
T
T
fgj
Vsropomil
T i
T
T
0.80
J Figure 7. Forced vital caDacitv, as a percent of predicted (top panel), and forced expired volume in 7 secbnd, as a percent of predicted (bottom panel), during treatment with placebo A and 8, propranolol and verapamil. p < 0.05 when compared to placebo A and verapamil.
0.60
5 ._ ‘: 0.40 iJ 3
0
l
-Rest
Exercise
Figure 6. Left ventricular end-diastolic volume index (top panel), end-systolic volume index (miWle panel) and ejection fraction (lower panel) at rest (left) and during the maximum workload common to all three exercise studies (right) for the three pharmacologic agents. y p < 0.05 when compared to placebo at rest; f p CO.05 when compared to propranolol at rest; p < 0.05 in comparison to the same pharmacologic agent at rest; fl p < 0.05 when compared to both placebo and verapamil during exercise. l
and with exercise)
during verapamil therapy (Table III, Figure 6). Although clinical evidence of left ventricular dysfunction did not develop during verapamil therapy in any of these 18 patients, these alterations in endsystolic volume and ejection fraction provide evidence that verapamil must be administered with caution to the patient with depressed left ventricular performance. Modern electrocardiographic monitoring equipment allows for the reliable recording and interpretation of both rhythm disturbances and S-T segment alterations. In a group of subjects with stable angina, Stern et al. [ 47,481 showed that ambulatory electrocardiographic monitoring identified most patients with coronary artery disease, and Schang and Pepine [49] showed that transient S-T segment deviation on a calibrated Holter monitor served as a reliable index of myocardial ischemia. The present study utilizes such S-T segmental-
terations to determine the relative efficacies of propranolol and verapamil. With this technique, verapamil diminished the frequency of S-T segment deviations, whereas propranolol exerted no demonstrable effect. Neither agent had a significant effect on ventricular ectopy (Table II, Figure 4). Aside from its beneficial influence in the treatment of angina pectoris, verapamil does not cause bronchoconstriction and, therefore, offers no problem in the patient with pulmonary disease. Although none of the patients in this study had severe pulmonary disease, most of them were smokers and had modest reductions in forced vital capacity and forced expiratory volume. During therapy with propranolol, these parameters of pulmonary function worsened, but during verapamil treatment, no change in forced vital capacity and forced expiratory volume could be demonstrated (Figure 7). The present study demonstrates that both propranolol and verapamil are efficacious in the therapy of stable, exertional angina pectoris, but each agent was administered for only two weeks (one week lowdose, one week high-dose). Previous studies [6,7,9] have shown that propranofol is of continued benefit during long-term use. In contrast, the therapeutic efficacy of verapamil has been shown only for as long as eight weeks [ 181. Although the long-term beneficial effect of verapamil in the patient with stable angina remains to be determined, the studies of Neumann and Luisada [ 1 l] as well
September 1981
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PROPRANOLOL VERSUS VERAPAMIL
IN STABLE ANGINA-JOHNSON
as Balasubramanian, et al. [ 181 do not suggest that tolerance to verapamil develops, at least over a period of six to eight weeks. Thus, it is hoped that long-term verapamil therapy will exert a salutary effect similar to that demonstrated in the present study. In conclusion, high-dose verapamil (480 mg/day) therapy is equal or superior to high-dose propranolol (320 mg/day) therapy in the alleviation of angina pectoris and the need for nitroglycerin. Although verapamil induces a slight increase in end-systolic volume and a slight decrease in resting and peak-exercise ejection fraction, neither agent exerts a clinically-important deleterious influence on left ventricular performance.
ET AL.
Finally, propranolol causes a worsening of pulmonary function. To obtain a full therapeutic effect from verapamil, it should be administered in large doses, since smaller doses appear similar to placebo in the relief of angina. For the patient with stable angina in whom propranolol is not suitable, high-dose verapamil is a legitimate and reasonable therapeutic alternative. ACKNOWLEDGMENT
We acknowledge the skilled technical assistance of Mr. Scott Lyons and Mr. Norman Vance, the assistance of Alan C. Elliott in the analysis of the data, and the assistance of Joan R. Cary, R.N.
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