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Antihypertensive effects of pindolol
Anthypertensive
effects
of pindoiol
Three hundred pindoloi-treated patients with mild to moderate hypertension were evaluated in double-blind clinical trials conducted in the United States designed to evaluate the efficacy of pindolol in reducing blood pressure (BP). Pindolol was compared to placebo (05 patie&), propranolol (52 patients), hydrochlorothiazide (38 patients), a-methyldopa (62 patients), and chlorthalidone (14 patients) in seven studies that formed the data base included in a New Drug Application submitted to the Food and Drug Administration. All patients entered a preliminary 3-week placebo washout period during which all antihypertensive medication was withdrawn. After qualifying, they were randomly assigned to either the pindoiol or control treatment groups. Except for one study, the trial design involved a 3- to 6-week titration period fotlowed by a 3- to 7-week plateau or fixed-dose period. The remaining study evaluated three fixed dosage levels of pindolol compared to placebo in a parallel group study design. In five of seven trials, a supine diastolic BP of LWO but <120 mm Hg was required for entry, while in two studies, a supine diastolic BP of >g5 mm Hg was required. The results of the double-blind comparative trials indicate that pindolol administered as monotherapy was significantly superior to placebo administration and just as effective as propranolol, hydrochtorothiazide, a-methyidopa, or chlorthaiidone treatments. In all active treatment groups, a significant reduction from baseline BP was observed within the first week of treatment. The mean dose of pindolol administered during the plateau period was 40 to 50 mg/day given on a twice or three times a day dosage schedule, although the largest BP decrement occurred at dosages of 15 to 20 mg/day. Slight, but further decrements were observed for the pindoloi-treated groups as the dose was increased to a peak dose of 40 to 60 mg/day as allowed by the individual study protocols. Compared to propranolol, pindolol was as effective in reducing BP in two separate studies, but propranolol resulted in significantly greater reductions in heart rate. Nearly 60% of all the pindolol-treated patients manifested at least a 10 mm Hg reduction in the supine diastolic BP. One open-label study with severe hypertensive patients (supine diastolic BP 2 115 mm Hg) was designed primarily to evaluate the tong-term safety of pindolol administration but provided efficacy data for pindolol in combination with hydraiazine + hydrochlorothiazide + guanethidine. Qualified patients were randomly assigned to pindolol or an a-methyldopa/hydrochlorothiazide control treatment group. Hydralazine and guanethidine could be added to the treatment regimen of the control group if required. In combination with hydralazine and hydrochlorothiazlde, pindolol was as effective as the combination of a-methyldopa/hydrochlorothiazlde/hydralarine in reducing the BP of severe hypertensive patients. In addition, pindolol administered alone or in combination resulted in only slight and clinically insignificant reductions in pulse rate. (AM HEART J 104:374, 1982.)
Leonard
M. Gonasun, Ph.D., East Hanover,
N.J.
The observations regarding the antihypertensive properties of the a-adrenoceptor-blocking agents pronethalol and propranolol were first reported by Prichard’O in 1964 and Prichard and GillanY in 1969. Since then, several drugs with cw-adrenoceptor-blocking activity have been investigated and found effective in lowering blood pressure (BP).” One of these agents, pindolol (Visken), has been extensively studied throughout the world for the past 15 years** 5,$,l3 and during the past 5 years intensively investigated in the United States. This article summarizes the results obtained in the U.S. studies. From the Clinical Research Division, Sandoz, Inc. Reprint requests: Leonard M. Gonasun, Ph.D., Associate Director, Research, Sandoz, Inc., East Hanover, NJ 07936. 374
Clinical
METHODS
Between 1975and 19’79,793hypertensive patients were evaluated in the United States by 23 investigators. A total of 350 patients received pindolol as monotherapy for the treatment of mild to moderate essential hypertension, whereas 107 patients received pindolol either alone (27 patients) or in combination (80 patients) with other antihypertensive agentsfor the treatment of severehypertension. Three study designswere usedin evaluating the antihypertensive effects of pindolol. The basic design for all investigative studies of patients with mild to moderate essential hypertension was a double-blind, randomized, parallel treatment protocol; however, one design (usedfor one protocol) incorporated a fixed-dose treatment schedule, whereas the other (used for six protocols) required titration of the dosageto either an optional responseor to a peak dose specified for individual studies. The third design (used for one protocol) employed an open-label, 0002-8703/82/080374
+ 14$01.40/O
0 1982 The
C. V. Mosby
Co.
Volume
104
Number
2, Part II
Antihypertensive
effects
of pindolol
375
1. Dosagesin titrated dosestudies
Table
Study
Daily
drug
Hydrochlorothiazide
-
lo-30 mg b.i.d. 50-150 mg t.i.d. 250-750 mg t.i.d. -
Chlorthalidone
-
-
Placebo
-
-
Pindolol
lo-30 mg b.i.d. 20-120 mg q.i.d. -
Propranolol a-Methyldopa
dosage
lo-30 mg b.i.d. -
5-20 mg b.i.d.
-
250-1000 mg b.i.d. -
-
-
-
-
Placebo
25-15 mg b.i.d. 50-150 mg q.d. -
5-20 mg t.i.d. -
-
II. Treatment schedulefor patients with severehypertension
Table
Pindolol ’ (lo-20 mg kid.)
I
+ Hydralazine (25-50 mg q.i.d.)
’
ol-Methyldopa (250 mg t.i.d.1
cu-Methyldopa (250 mg t.i.d.)
+
-+
Hydrochlorothiazide (50mg q.d.)
*+ Hydrochlorothiazide (50 mg b.i.d.)
randomized, parallel treatment method and was conducted in patients with severe hypertension. In the latter studies, hydrazaline (Apresoline), hydrochlorothiazide (Esidrix), and guanethidine (Ismelin) were added sequentially to pindolol therapy to obtain optimal control of the patients’ BP, and the results were compared to those obtained in a control group treated with cY-methyldopa (Aldomet), hydrochlorothiazide, hydrazaline, and guanethidine. The names and affiliations of the principal investigators who conducted these clinical trials are listed alphabetically in Appendix I. Mild to moderate essential hypertension: Fixed-dose study. Following completion of a S-week, single-blind
placebo washout period during which the average supine diastolic BP was >95 mm Hg on 3 of 4 evaluation days (including the last evaluation), patients were randomly assignedto one of four treatment groups: placebo and pindolol, 15, 30, or 60 mg. The placebo-treated patients received their assignedstudy drug under double-blind conditions for the next 15 weeks.All patients treated with the active drug received 5 mg of pindolol three times a day for the first week. Approximately one third of these patients were then maintained on this dose for the remaining 14 weeks of the trial. Another third received pindolol, 10 mg three times a day at week 2, and were maintained on this dose for the next 13 weeks,while the remaining third received pindolol, 10 mg three times a day during week 2,15 mg three times a day during week 3, and 20 mg three times a day during weeks 4 through 15. The patients
were either
PHydrochlorothiazide (50 mg q.d.-50 mg b.i.d.)
I
tapered
off their
study
medication
’
* Guanethidine (lo-30 mg q.d.)
a-Methyldopa (500 mg t.i.d.)
+
t Hydralazine ’ (25-50 mg q.i.d.) Hydrochlorothiazide (50 mg b.i.d.1
* Guanethidine (lo-30 mg q.d.)
during weeks 16 and 17 or entered an open-label, longterm phaseof pindolol treatment. Mild to moderate essential hypertension: Titrated dose study. All patients initially observed a 3-week,
single-blind, placebowashout period. Those patients with an average supine diastolic BP of ~100 mm Hg on completing the washout period qualified for the next phaseof the study in which pindolol was compared with either placebo, propranolol, cu-methyldopa,hydrochIorothiazide, or chlorthalidone under randomized, doubleblind conditions. During the dosetitration period, which lasted 2 to 6 weeks, the patients received their assigned study medication in gradually increasingdosesuntil either an optimal responseor the peak dose specified by the individual protocols wasreached.The titration period was followed by a 4- to &week plateau (fixed-dose) period during which the patients were maintained on the dosage established during titration, unless an adverse reaction necessitateda dosereduction. They were then gradually withdrawn from the study drug over a l- to f-week period or entered an open-label, long-term phase of pindolol treatment. The dosagesadministered in these studies are listed in Table I. The most commonly evaluated dosageof pindolol was 10 to 30 mg twice a day; however, in one study 5 to 20 mg twice a day was given, and in a placebo controlled study 5 to 20 mg of pindolol three times a day was given. The dosagesof the active control drugs were those recommended in their respective package inserts. The doseof each study drug was titrated to an optimal goal that was
376
Gonasun
American
ii ii! 5
SYSTOLIC BLOOD PRESSURE
+10153 Pcb
0
155 1Smg
153 30mg
DIASTOLIC BLOOD PRESSURE 147 60mg
103 Pcb
104 15mg
103 30mg
100 60mg
B 2m >I %E P P 2
-lO-
-20
-
NO. PATIENTS
m’ d ui
-
Pcb PINDOLOL 15 mg
= 28
-30
30 mg 60
= 29 29
-10
l
Fig.
August, 1982 Heart Journal
= 29
1. Mean changefrom baselinesupine BP in patients receiving pindolol vs. placeboduring fixed-dose
period. III. Summary of background information fixed-dose
Table
study Treatment
Total No. patients Meanage(yr) “- SD Sex: Male Race: Black Mean weight (lb) + SD Previously treated
Placebo
I5 mg
30 mg
60 mg
32
37
37
33
52 k 11 100% 75%
49 + 11 97% 78%
50 k 10 100 % 86%
53 + 10 100% 94%
191 k 41 45%
194 -c 36 66.7%
185 rt 28 71.4%
199 f 31 57.670
defined as an average supine diastolic BP <90 mm Hg in two studiesand 585 mm Hg in the remaining four studies. Since the studies were double-blind, each patient had an equal chanceof having the doseof his or her assigneddrug titrated to its specified peak level. Severe hypertension. A randomized, open-label investigation wasconducted to assess the safety and efficacy of pindolol in combination with other antihypertensive agentsfor the treatment of patients with severehypertension and to compare the results to those obtained for an a-methyldopa control group. To qualify for the study, patients had to have an averagesupine diastolic BP ~115 mm Hg on two consecutive evaluation days during a preliminary drug-free period as well as evidence of endorgan involvement excluding retinopathy greater than grade II. For the pindolol-treated patients, therapy was initiated with 10 mg pindolol three times a day and increasedto a peak dose of 20 mg three times a day to produce optimal control of the patients’ BP. Subsequently, hydrazaline, hydrochlorothiazide, and guanethidine were added in the dosageslisted in Table II to obtain an optimal response.E’milarly, for the a-methyldopa/hydrochlorothiazide control group, hydrazaline and guanethidine were sequentially added to obtain an optimal response. All studies. For all studies discussedin this article, patients were excluded if they had any condition or disease that could interfere with the evaluations for
efficacy and safety. These included Cushing’ssyndrome, hyperthyroidism, pheochromocytoma, malignant or accelerated hypertension, bronchial asthmaor chronic obstructive pulmonary disease(COPD) requiring treatment, alcoholism, cerebral insufficiency, epilepsy, diabetes mellitus requiring insulin, angina, heart failure, myocardial infarction within the previous 6 months, bradycardia, atrioventricular conduction impairment greater than one-degree heart block, malabsorption syndromes, liver or kidney dysfunction, adverse reactions to @-blockers,or the useof drugs potentially toxic to a major organ. In the studies of mild to moderate hypertension, patients with severe hypertension were excluded. Patients were evaluated at weekly intervals during the initial stagesof study and thereafter were seenevery 2 to 4 weeks depending on the evaluation schedule for the particular protocol. At each patient visit, supine and standing BPS and radial pulse rates were recorded. Duplicate supineand standing readingswere taken two to three times eachvisit at 30-minute and l-hour intervals and the average computed for statistical analysis. The diastolic pressurewasrecorded at the point at which the Korotkeff soundsdisappeared,that is, onset of phase V. Data analyses. Parametric analyseswere performed for the BP and pulse data when the criterion of drug effect wasthe meanof all the measurementsmadeon the day of the visit. Separate one-way analyses of variance and covariance were performed, with the baselinedata usedas the covariant. Additionally, a repeated measurements model for the averagesobserved over the plateau periods was performed as the main drug effect, with the baseline used as the covariant. If requisites were satisfied, the analysis of covariance was performed which allowed adjusting the criterion value of the one-way analysis of variance and of the main drug effect as though all treatment groupshad the samemeanat baseline.The two requirements that had to be satisfied werehomogeneity of linear regression (slopes:(Y= 0.05) and a common slope significantly different from zero (a = 0.10). A two-tailed Student t-test was also employed to determine whether the average change from baselinewas significant.
Volume Number
104 2, Part II
Antihypertensive
ii = 3 0 B Em
SYSTOLIC BLOOD PRESSURE
r
+10
152 Pcb
0
153 15mg
effects of pindolol
377
DIASTOLIC BLOOD PRESSURE
149 30mg
147 60mg
106 Pcb
107 15mg
107 30m9
104 60 mg
-12
5s 2E E
-lO-
8
-20
s
NO. PATIENTS Pcb PINDOLOL 15mg 30 mg 60 mg
t
d
-3oL
ti +I
a
= 28 = 29 = 29 = 29
Fig. 2. Mean change from baselinestanding BP in patients receiving pindolol vs. placebo in fixed-dose
period.
SUPINE PULSE
+ lof I 4i2
0
11 Pcb
81 15mg
STANDING PULSE 76 30mg
78 60mg
89 Pcb
l?mg
308’mg
-8
-5
85 60 mg pJ
1uy d ti
-lO-
;
-2o-
A
PATIENTS
Pcb PINDOLOL 15 mg 30 mg 60 mg
-3o-
Fig.
NO.
= 28 = 29 = 29 = 29
3. Mean change from baselinepulse rate in patients receiving pindolol vs. placebo in fixed-dose
period.
RESULTS Mild to moderate
hypertension:
Fixed-dose
study.
In
this study, patients assigned to the active treatment groups received pindolol as the sole antihypertensive agent. Table III summarizes the demographic data of all 139 patients evaluated, including those given placebo. As shoan, 32 to 37 patients were randomly assigned to each treatment group, and these groups were comparable with respect to the patients’ mean age, sex (all but one were male), race (275 % black), weight, and history of previous treatment. The mean changes in supine BP using the repeated measurements model for each of the groups are plotted in Fig. 1. Each of the pindolol-treated groups demonstrated statistically significant decreases (p < 0.05) in BP from baseline values, and these decreases were statistically significantly greater than those demonstrated by the placebo-treated group. However, the pindolol-treated groups did not
differ significantly from one another in their BP response. Similar findings were observed for the standing BP (Fig. 2). The mean changes from baseline values for the supine and standing pulse rates are shown for the same period in Fig. 3. The 15 mg dose group demonstrated the peak pulse rate lowering effect with no further reductions as the dose increased to 30 and 60 mg daily. Since a dose-response relationship was not apparent in these data, further analyses were performed in a homogeneous subgroup of patients whose baseline supine diastolic BP exceeded 100 mm Hg. Other reports4 have indicated that the magnitude of the reduction is correlated with the level of the pretreatment BP. The results of the analyses for the supine and standing BPS are shown in Figs. 4 and 5. Just over 40% of the patients included in the analyses presented in Figs. 1 to 3 were included in this subgroup. The data clearly indicate a dose ordering of the BP response for both the systolic and diastolic
378
Gonasun
SYSTOLIC BLOOD PRESSURE 161 Pcb
166 16mg
101 3Omg
DIASTOLIC BLOOD PRESSURE 164 6Omg
107 Pcb
106 16mg
NO. PATIENTS:
106 30mg
104 6Omg
Pcb
= 12
PINDOLOL 15mg 30 mg 60 mg
= 15 = 15 = 13
Fig. 4. Mean change from baseline supine BP in patients receiving pindolol vs. placebo in fixed-dose period whose values were >200 mm Hg.
DIASTOLIC BLOOD PRESSURE 113
P
16 mg 30mg
-3
108 6@mmg
-8
T-
Q
-20
L
1
ti a
NO.
PATIENTS:
Pcb PINDOLOL 15mg 30 mg 60 mg
= 12 = 15 = 15 = 13
Fig. 5. Mean change from baseline standing BP in patients receiving pindolol vs. placebo in fixed-dose period whose supine diastolic BP was >lOO mm Hg.
BP. Each of the pindolol-treated groups demonstrated statistically significant decreases as compared to baseline values and the decreases obtained with placebo. Moreover, the decrement seen in the 60 mg group was statistically significantly greater than that seen in the 15 mg group. In contrast to the BP results for this subgroup of patients, there was no dose-response decrement in either the supine or standing pulse rates (Fig. 6). These data suggest that the intrinsic sympathomimetic activity (ISA) of pindolol did not interfere with its antihypertensive effect in patients with higher baseline BPS. Mild studies.
to
moderate
Six multicenter
hypertension:
Titrated
studies employing
‘dose
a titrated
dose schedule were designed to evaluate the safety and efficacy of pindolol in the treatment of hypertension. All patients participating in these studies received pindolol as the sole antihypertensive agent. Table IV summarizes the demographic data for a multicenter, placebo controlled study. As shown, approximately 35 patients were entered in each of the two treatment groups, and the background variables for the two groups were comparable. Within the first week of treatment with pindolol, 5 mg three times a day (Fig. 7), a statistically significant reduction in supine BP from baseline levels was achieved. This reduction with pindolol was significantly greater than that achieved with placebo treatment. The
Volume
104
Number
2, Part II
Antihypertensive +lO-
SUPINE PULSE
I iiiii
d Ki 4
84 Pcb -1-
0.
-10
-
-20
L
81 15mg
effects
of pindolol
379
STANDING PULSE
78 30mg
79 60mg
93 Pcb
NO.
PATIENTS:
91 15mg
88 30mg
Pcb PINDOLOL 15mg 30 mg 60 mg
86 60mg
=
12
= = =
15 15 13
Fig. 6. Mean change from baseline pulse in patients receiving pindolol vs. placebo in fixed-dose period whose supine diastolic BP was >lOO mm Hg.
180
I 158
160 I” E B
140
2 z %
120
8 2
m
P
100
99
PIN = PINDOLOL PC6
I PLACEBO MEAN Fig.
7.
DAILY
DOSE:
FIRST PINDOLOL
WEEK
15 trig
= PLACEBO
PLATEAU PERIOD 6 WEEKS 38 mg
Mean supine BP in multicenter study of patients receiving pindolol vs. placebo in titrated dose
period.
initial BP response was maintained and improved slightly as the dose of pindolol was titrated to a mean of 38 mg over the plateau period. Although not shown here, similar results were obtained for the standing BP. Despite the marked fall in BP, only a slight decrement occurred in the supine and standing pulse rates (Fig. 8). The mean reductions were 2 to 4 bpm supine and 4 to 8 bpm standing. Table V presents the demographic information for a multicenter, propranolol controlled study and shows that for each of the treatment groups, consisting of over 35 patients each, the background variables were comparable. Fig. 9 indicates that both drugs significantly reduced the supine BP from baseline values within the first week of treatment at
the doses administered. As the dose of pindolol was titrated upward to a mean of 40 mg/day over the plateau period, a further decrement in BP was observed. In contrast, as the dose of propranolol was increased to a mean of 20’7 mg, no further decrease was noted. In fact, during the plateau period, the mean decrement observed for the pindolol group was greater than that observed for the propranolol group. Although not shown here, similar results were obtained for the standing BP. The effect of both &blockers on resting supine and standing pulse rates is shown in Fig. 10. The mean decrements observed for the propranolol-treated group were greater than those observed for the pindolol group and these differences were statistically significant.
380
Gonasun
American
PINDOLOLPLACEBO SUPINE
+10-
.
76
0
73
PULSE
76
z I z
+ , o _
74
_
-
STANDING
82
0
N =
29
N =
30
August, 1982 Heart Journal
PULSE
80
60
-Y -10
-
-20
-
ii
PCB PIN
PCB
-lO-
PIN
PIN -20
PLATEAU PERIOD 6 WEEKS
FIRST WEEK
-3o-
-3o-
pcB
FIRST WEEK
PIN PLATEAU PERIOD 6 WEEKS PIN = PINDOLOL PCB = PLACEBO
Fig. 8. Mean change from baseline
pulse in multicenter
study of patients receiving pindolol vs. placebo in
titrated doseperiod.
IV. Summary of background information on patients receiving pindolol vs. placebo (multicenter study) Table
Treatment Total No. patients Mean age (yr) + SD Sex: Male Race Caucasian Black Mean weight (lb) k SD Previously treated
Table V. Summary of background receiving pindolol vs. propranolol
Total
Pindolol
Placebo
36 54 f 10 64%
34 53 * 12 59%
61% 39% 173 + 38 89%
53% 47% 178 f 37 79%
information (multicenter
on patients study)
Treatment
Pindolol
No. patients
37 53 * 13 49%
36 54 * 10 72%
51% 49% 177 k 35 76%
53% 47% 184 ‘- 34 83%
Mean age (yr) rt SD Sex: Male Race Caucasian Non-Caucasian Mean weight (lb) Previously treated
f
SD
Propranolol
In a second study, pindolol was compared to propranolol and chlorthalidone. The demographic information for the 48 patients studied (16 per treatment group) is listed in Table VI and indicates that the treatment groups were comparable. All three treatments resulted in comparable and statistically significant reductions from baseline values in the supine BP within the first week of treatment at
daily doses of 20 mg pindolol, 150 mg propranolol, and 50 mg chlorthalidone. During the plateau period (Fig. ll), the initial reductions were enhanced, but no statistically significant differences were detected between the study groups. The mean dosages achieved during the plateau period were 50 mg pindolol, 360 mg propranolol, and 107 mg chlorthalidone. Similar results were obtained for the standing BP. The mean changes in resting supine and standing pulse rates are shown in Figs. 12 and 13, respectively. Again, mean decrements were statistically significantly greater with propranolol than with pindolol. The results obtained from both of the propranolol controlled studies clearly indicate that pindolol was as effective as propranolol in reducing blood pres-
sure at one fifth to one seventh the dose, without producing the accompanying marked pulse rate decrements typically observed with propranolol. Two multicenter studies compared the efficacy of pindolol and cw-methyldopa in reducing BP. One study used a three times a day regimen of a-methyldopa, whereas the other used a twice a day regimen. The background variables for both studies are listed in Tables VII and VIII, respectively, and indicate that for each study, the treatment groups were comparable. As shown in Figs. 14 and 15, both pindolol and cY-methyldopa resulted in a statistically significant decrease in the supine BP within the first week of therapy, which was maintained through the plateau period. No statistically significant differences were noted between the two treatment groups in either study. As might be expected, increasing the dose of cu-methyldopa to over 1500 mg/day resulted
Volume Number
104 2, Part II
Antihypertensive
PINDOLOL-
effects of pindolol
381
N = 27
180 PROPRANOLOL
_
154
N = 30
151
z h #I
-
0 i
102
102
80 PIN = PINDOLOL L
P = PROPRANOLOL PLACE80
MEAN
DAILY
FIRST
WEEK
PLATEAU PERIOD 6 WEEKS
DOSE: PINDOLOL Propranolol
Fig. 9. Mean supine BP in multicenter titrated dose period.
20 80
40 207
mg mg
study of patient8 receiving pindolol vs. propranolol
PINDOLOL-
.
r 0
SUPINE
PULSE
75
74
76
+10 74
r
during
N = 27
PROPRANOLOL +10
mg mg
- N = 30 STANDING
84
83
PULSE
82
81
r 5 -lO-
z h
ii
a -20
-30‘
0
FIRST WEEK
PLATEAU PERIOD 8 WEEKS
FIRST WEEK
PIN
PLATEAU PERIOD 6 WEEKS = PINDOLOL
P = PROPRANOLOL
Fig.
10. Mean pulse in multicenter
study of patients receiving pindolol vs. propranolol in titrated dose
period.
in a greater decrement in the standing BP (Fig. 16), which was often symptomatic. No relevant changes occurred in either the supine or standing pulse rates in either study. Another multicenter study was designed to compare the BP-lowering effects of pindolol vs. hydrochlorothiazide. The demographic data for the 75 patients entered in this trial are summarized in Table IX and indicate that the treatment groups were comparable. Fig. 17 shows the BP responses in
the supine position. Both drugs resulted in statistically significant reductions of blood pressure from baseline values within the first week of treatment, with pindolol achieving a slightly greater mean reduction at the doses administered. During the plateau period, pindolol reduced the pressure even further as the daily dose was titrated to a mean of 55 mg. Similarly, the response to hydrochlorothiazide increased when the dose was increased to a mean of 144 mg. Similar results were also obtained for the
Gonasun
382
PINDOLOL
American
“I PROPRANOLOL SUPINE BLOOD
“o CHLORTHALIDONE PRESSURE
VI. Summery of background information on patients receiving pindolol vs. propranolol vs. chlorthalidone
Table
PINDOLOL - N=15 PROPRANOLOL - N=15 CHLORTHANLIDONE - N=14
ChlorthalPindolol
T
137
5
August, 1962 Heart Journal
0
Total No. patients Mean age (yr) + SD Sex: Male Race Caucasian Non-Caucasian Mean weight (lb) k SD Previously treated
Propranolol
16 49 k 8
idone
16 52 f 11
16 51 +- 13
25 %
19%
25%
19% 81%
198 810;>
13%, a1 %
170 f 22 81%
179 * 39 81%
174 f 33 81%
92 .:I .L
60
Table
1
patients 1 PLACEBO MEAN
DAILY
DOSE: PINDOLOL PROPRANOLOL CHLORTHALIDONE
PLATEAU PERIOD 4 WEEKS 50 m g 360 m g 107 m g PIN = PINDOLOL P = PROPRANOLOL C = CHLORTHANLIDONE
11. Mean change from baseline supine BP in multicenter study of patients receiving pindolol vs. propranolol vs. chlorthalidone in titrated dose period.
Fig.
standing BP. Fig. 18 shows the mean ,changes observed for the supine and standing pulse rates. Only a 4 to 6 bpm reduction in the supine position and a 5 to 7 bpm reduction in the standing position were noted for the pindolol group. These changes achieved statistical significance; however, they were not considered clinically significant. A second method of analysis was employed in evaluating the efficacy data in order to obtain a more clinically oriented view of the effectiveness of pindolol in reducing BP. Table X summarizes a categorical analysis of the patients’ responses in all the studies in which pindolol was administered as monotherapy for the treatment of mild to moderate essential hypertension. The classification was based on the average supine diastolic BP observed over the plateau period of study according to the repeated measurements model. The patients’ responses were then categorized into one of the following: a reduction to ~90 mm Hg, a reduction of ~10 but >90 mm Hg, a reduction of 5 to 9 mm Hg, and a reduction of 15 mm Hg or even an increase. In those studies employing a titrated dose schedule to achieve an optimal response, nearly 60% of the patients demonstrated an excellent response (categories 1 and 2),
VII.
Summary of background information on pindolol vs. a-methyldopa (multicenter
receiving
study)
Treatment Total No. patients Mean age (yr) + SD Sex: Male Race Caucasian Black Mean weight (lb) * SD Previously treated
Pindolol
a-Methyldopa (t.i.d.)
31 50 * 11 26%
23 54 * 9 43%
29% 71% 174 * 54 8770
22 ro 78% 168 IL 39 78%
23% demonstrated a fair response (category 3), and only 18% of the patients demonstrated no or poor responses according to these criteria. In the fixeddose study, 53% of the patients had an excellent response to pindolol treatment. Severe hypertension. A multicenter study was undertaken in patients with severe hypertension. The study was designed primarily to evaluate the long-term safety of pindolol administered in combination with other antihypertensive agents. However, the efficacy results obtained from these patients are summarized here. The demographic data for the 209 patients entered in this study are summarized in Table XI. More than 100 patients were evaluated in each treatment group and the data indicate that the treatment groups were comparable. The mean BP decrements from baseline values achieved in the supine position at the end of each treatment phase are shown for the pindolol and control treated groups in Figs. 19 and 20, respectively. Adminiatration of pindolol alone to this group of patients produced a mean reduction of 12/12 mm Hg.
Volume
104
Number
2, Part II
Antihypertensive
effects of pindolol
VIII. Summary of background information on patients receiving pindolol vs. a-methyldopa (multicenter study)
PINDOLOL - N=15 PROPRANOLOL - N=15 CHLORTHANLIDONE - N=14
Table
Treatment
a-Methyldopa (b.i.d.)
Pindolol
Total No. patients Mean age (yr) + SD Sex: Male Race Caucasian Black Mean weight (lb) -t SD Previously treated
38 52 t 10 84%
39 55 * 9 92%
34% 66 % 189 k 41 76%
.
36 5% 64 ‘Z 182 k 31 67%
FIRST WEEK
Summary of background information on patients receiving pindolol vs. hydrochlorothiazide (multicenter study) Table
IX.
Total No. patients Mean age (yr) + SD Sex: Male Race Caucasian Black Mean weight (lb) ? SD Previously treated
PLATEAU PERIOD 4 WEEKS
PIN = PINDOLOL P = PROPRANOLOL C = CHLORTHANLIDONE
12. Mean change from baseline supine pulse in multicenter study of patients receiving pindolol vs. propranolol vs. chlorthalidone in titrated doseperiod. Fig.
Hydrochlorothiazide
Pindolol
Treatment
383
37 48 AZ 1‘2 43%
38 48 * IO 53%
54% 46% 178 f 37 89%
53% 47% 1’73 k 38 87%
X. Number and percentage of pindolol-treated patients in each responsecategory Table
(Average Study
No. patients
design
Titrated dose Fixed dose *Classification 1 = reduction 3 = reduction
164 87
I
2
41% 38%
18% 15%
based on average supine diastolic
-30 J
Category over plateau
period) 3
23% 20%
FIRST WEEK
* 4
18% 28 %
BP over plateau period:
to 5 90 mm Hg, 2 = reduction of z 10 but < 90 mm Hg, of 5-9 mm Hg, 4 = reduction of < 5 mm Hg or an increase.
Sequential addition of hydralazine followed by hydrochlorothiazide resulted in further decreases with the addition of each agent. Following treatment with the combination of pindolol + hydralazine + hydrochlorothiazide, the mean reduction from baseline was 32/24 mm Hg (Fig. 19). A similar mean reduction was achieved with the combination of cr-methyldopa + hydrochlorothiazide + hydralazine (Fig. 20). Similar results also were observed for the standing BP. As with the studies previously described, only minimal reductions of 2 to 6 bpm occurred in the supine and standing pulse rates with pindolol administration.
1 PLATEAU PERIOD 4 WEEKS
PIN = PINDOLOL P = PROPRANOLDL C = CHLORTHANLIDONE
Fig. 13. Mean change from baseline standing pulse in multicenter study of patients receiving pindolol vs. propranolol vs. chlorthalidone in titrated doseperiod.
DISCUSSION
Over 300 pindolol-treated patients with mild to moderate essential hypertension were evaluated in randomized, double-blind, parallel treatment group studies conducted in the United States. These studies were designed to evaluate the efficacy of pindolol in reducing BP. In the studies, pindolol was compared to placebo, propranolol, hydrochlorothiazide, cr-methyldopa, and chlorthalidone. Additionally, one multicenter, randomized, open-label study of severely hypertensive patients was designed primarily to evaluate the long-term safety of pindolol administration but provided efficacy data for the use of pindolol in combination with hydralazine + hydrochlorothiazide + guanethidine. In both studies that utilized a placebo control, the
384
Gonasun
American
PINDOLOL
- N = 27
a-METHYLDOPA
PIN
August.1982 Heart Journal
- N = 21
= PINDOLOL
M = a-METHYLDOPA , FIRST
PLACEBO Mt%N
DOSE:
DULY
f,,NDOL(,L
PLATEAU FERIDD 8 WEEKS
2omg
a-METNYLOOPA Fig. $4. Mean supine BP in multicenter times a day in titrated dose study.
WEEK
760
63 mg
trig
1679
study of patients receiving pindolol vs. a-methyldopa
PINDOLOL 180
mg
r
T
T
three
- N = 37
@METHYLDOPA-
N =34
1
PINDOLOL PIN
= PINDOLOL
M = a-METHYLDOPA FIRST
PLACEBO MEAN
DAILY
DOSE
10 mg
PINDOLOL a-MRHYLDOPA
Fig. 15. Mean supine BP in multicenter day in titrated dose period.
WEEK
600
mg
PLATEAU PERIOD 7 WEEKS 36mg 1544mq
study of patients receiving pindolol vs. Lu-methyldopa twice a
efficacy of pindolol in lowering BP was clearly demonstrated without producing the marked reductions in pulse rate usually seen with P-blockers without ISA. The data obtained in the fixed-dose study from a homogeneous subgroup of patients with essential hypertension who had diastolic BPS exceeding 100 mm Wg indicated that a doseresponse relationship existed between the dose of pindolol and the mean BP decrements. In contrast, no dose-response relationship was noted for changes
in pulse rates. These data indicate that the ISA property of pindolol does not interfere with its antihypertensive effect. In two studies, pindolol was shown to be at least as effective as propranolol in reducing BP at one fifth to one seventh the dose without producing the marked reductions in resting supine and standing pulse rates typically observed with propranolol. These findings have also been reported by others?? suggesting that the antihypertensive effects of pin-
Volume
104
Number
2, Part II
Antihypertensive
PINDOLOL 1 aor-
0
160-
: y
140-
I
5 t ; 0 8 2 m
effects of pindolol
385
- N = 27
a-METHYLDOPA
- N = 21
120-
loo-
80-
PIN = PINDOLOL M = a-METHYLDOPA
I: L
PLACEfKl MEAN
DAILY
DOSE:
FIRST
PINDOLOL
180
t”
r
160
750
53n-q
mg
1679
study of patients
pindolol
120
1
loo
y
140 :I1
E
SO
z h
I
106
92
A.
H = HYDROCHLOROTHlAZlDE PLACEBO
DAILY
913
PIN = PINDDLOL t
MEAN
I
E 100
11
DOSE:
FIRST WEEK
PINDOLOL
HYDRDCHLOROTHlA2lDE
PLATEAU PERIOD 7 WEEKS
20 WI
55 w
6OWl
1umg
Fig. 17. Mean change from baseline supine BP in multicenter hydrochlorothiazide in titrated dose period.
dolol are not related to reductions in the resting pulse rate. A previous report’l has indicated that th;! antihypertensive effects of various D-blockers are equivalent regardless of the differences in some of the pharmacologic properties such as ISA, cardioselectivity, and membrane-stabilizing activity. It is noteworthy that the findings in the U.S. studies confirm the results typically seen throughout the world. Pindolol has also been shown to be as effective as Lu-methyldopa, hydrochlorothiazide, and chlorthalidone at the doses tested when administered as
- N = 35
139
I
104 97
three
1
151 145
w E a 8
vs. a-methyldopa
- N = 30
140 5 z
m9
HYDROCHLOROTHlAZlDE
154
E
receiving
PINDOLOL
_ 163
PLATEAU PERIOD 8 WEEKS
20mg
u -METHYLDOPA
Fig. 16. Mean standing BP in multicenter times a day in titrated dose period.
WEEK
Table
study of patients receiving pindolol vs.
Xl.
hypertension
Summary of background (multicenter study)
Treatment Total No. patients Mean age (yr) A SD Sex: Male
Race Caucasian Non-Caucasian Mean weight (lb) 2 SD
Pindolol 108 46 XL 11 52% 22 5 78%
181 * 36
information
severe
a-Meth.yldopal hydr&hl& thiazide 101 50 + 11 43% 33% 67% 182 + 42
306
Gonasun
American
PINDOLOL
- N = 30
HYDROCHLOROTHlA2lDE
SUPINE
August. 1982 Heart Journal
PULSE
- N = 35
STANDING
PULSE
A + S.D. RATE/MM
WEEK
PERIOD 7 WEEKS
WEEK
PLATEAU PERIGD 7 WEEKS
PIN = PINDOLOL Ii = HYDROCHLOROTHlA2lDE
Fia.
18. Mean change from baseline pulse in multicenter study of patients recieving pindolol vs.
hydrochlorothiazide in titrated doseperiod. PINDOLOL
TREATED
ALDOMET/ESIDRIXTREATED +10
+10 1
I”
I
N=105
12
N=23
1
N=96
192/122
192/121
0 i-
N=60
N=78
N=l5
J’;
1 2
N=41
-1
-23
2
-3
T ‘;
.40
1 -60
-6OJ MEAN
DAILY
DOSE:
PINDOLOL: APRESOLINE: ESIDRIX: ISMELIN:
MEAN 40 mg -
S4mg 134 mg -
67 mg 179mg 78mg -
66 mg 17s9 98 m 26 mg
DAILY
DOSE:
ALDOMET: ESIDRIX: APRESOLINE: ISMELIN:
804 mg 76 mg -
1362 96 129 -
mg mg mg
1534 mg 94 mg 124 mg 18 me
Fig. 19. Mean change from baseline supine BP in patients treated with pindolol plus hydrasaline plus hydrochlorothiazide in severe hypertension study.
Fig.
to patients with mild or moderate essential hypertension. A previous report! indicated that pindolol was as effective as cu-methyldopa when added to diuretic therapy in a similar group of patients and therefore supports the conclusion that pindolol is as effective as a-methyldopa. An analysis of the data for a smaller group of patients,3 which subsequently were pooled with the data described in this article, indicated that pindolol was as effective as hydrochlorothiazide. In a group of severely hypertensive patients, pindolol, when combined with hydralazine and
hydrochlorothiazide, and, in some patients, guanethidine, was effective in producing marked reductions in BP. The stepwise reductions in BP achieved in these patients demonstrate the additive effects of each of these drugs in treating this type of patient. Previous reports6v7 have also indicated that pindolol is an effective antihypertensive agent when combined with diuretic therapy or peripheral vasodilators in the treatment of severely hypertensive patients. Conclusions. The data reported from the U.S. studies show that pindolol is an effective antihyper-
monotherapy
20. Mean change from baseline supine BP in patients receiving cx-methyldopaplus hydrochlorothiazide plus hydrasaline in severehypertension study.
Volume
104
Number
2, Part II
Antihypertensiue
tensive agent when administered alone or in combination with diuretics and/or peripheral vasodilators. When administered alone, pindolol was found to be as effective as propranolol, hydroclorothiazide, chlorthalidone, and cr-methyldopa; moreover the reductions in BP were achieved without producing the marked reductions in resting pulse or heart rates usually observed with P-blockers without ISA. Additionally, pindolol has been shown to be an effective antihypertensive agent within the first week of treatment when administered at low dosages and to be effective when given twice a day.
4. 5. 6. 7. 8. 9.
REFERENCES
1. Beanlands DS, Allard PP, Wilson M, Orbeck KW, Hehnan AB, Lefebure R: Comparison of efficacv and safetv of nindo101 and alphamethyldbpa in treatment of mild to moderate hypertension: Results of a double-blind evaluation study. Clin Invest Med 1:139, 1978. 2. Collins IS, King IW: Pindolol (Visken, LB-46). A new treatment of hypertension: Report of a multicenter open study. Curr Ther Res 14:185, 1972. 3. Davidov ME, Green AM: Effect of pindolol on arterial Appendix Principal
investigators
John Arnold, M.D., Quincy Research Center, Kansas City, MO. Stephen Ayers, M.D., St. Louis University, St. Louis, MO. Richard Blum, M.D., Long Island Jewish Hillside Medical Center, New Hyde Park, N.Y. Albert Carr, M.D., Medical College of Georgia, Augusta, Ga. Elliot Coleman, M.D., Rancocas Valley Hospital, Willingboro, N.J. Charles Curry, M.D., Howard University, Washington, D.C. Michael Davidov, M.D., George Washington University School of Medicine, Falls Church, Va. Frank Finnerty, M.D., Hypertension Center of Washington, Washington, D.C. Richard Glassock, M.D., Harbor General Hospital, Torrance, Calif.
Study
design(s)
Double-blind Open-label Double-blind
Double-blind bel (1)
(1) and open-la-
Double-blind Open-label Double-blind
Double-blind Double-blind bel (1)
(1) and open-la-
10. 11. 12. 13.
effects of pindolol
387
pressure in patients with essential hypertension. Curr Ther Res 27:507, 1980. Dixon GT: Efficacy of antihypertensive drugs. Lancet 1:515, 1976. Laver MD, et al: Double-blind comparison of two betablocking drugs with previous therapy in the treatment of hypertension. Med J Aust 1:174, 1974. McNeil JJ, Louis WJ, Doyle AE, Vajidla FJ: Comparison of metoprolol and pindolol in the treatment of mild to moderate hypertension. Med J Aust 1:431, 1979. Morgan TO, Anavekar SN, Sabto J, Louis WJ, Doyle AE: A comparison of beta adrenergic blocking drugs in the treatment of hypertension. Postgrad Med J 50:253, 1974. Persson I: Combination therapy of essential hypertension with pindolol (Visken) and hvdralazine. Eur J Clin Pharmaco1 9:91, 1975. Persson I, Ulrich J: Treatment of hypertension with a new beta-blocking agent pindolol (Visken). Eur J Clin Pharmacol 6:217, 1973. Prichard BNC: Hypotensive action of pronethalol. Br Med J 1:1227, 1964. Prichard BNC, Boakes AJ: The use of beta-adrenoceptor blocking drugs in hypertension: A review. Curr Med Res Opin 4(suppl 5):51, 1977. Prichard BNC, Gillam PMS: Treatment of hypertension with propranolol. Br Med J 1:7, 1969. Turner AS: The use of prindolol in hypertension. Aust NZ J Med 3:316, 1973.
I Bruce Hamilton, M.D., Baltimore VA Hospital, Baltimore, Md. Herbert Jernow, M.D., White Plains, N.Y. Walter Kirkendall, M.D., University of Texas, Houston, Tex. Morton Maxwell, M.D., Cedars Sinai Medical Center, Los Angeles, Calif. Jorge Oms Rivera, M.D., Regional Hospital, Bayamon, Puerto Rico Alexander Schirger, M.D., Mayo Clinic, Rochester, Minn. James Schoenberger, M.D., Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Ill. Eugene Spiotta, M.D., Memphis, Tenn. Gundarshan Thind, M.D., University of Louisville Louisville, Ky. Nathaniel Winer, M.D., Truman Medical College, Kansas City, MO.
Double-blind
(2)
Double-blind Double-blind Double-blind Double-blind bel (1)
(1) and open-la-
Double-blind Double-blind
Double-blind Double-blind Double-blind bel (1)
(1) and open-la-
effects
of pindoiol
Three hundred pindoloi-treated patients with mild to moderate hypertension were evaluated in double-blind clinical trials conducted in the United States designed to evaluate the efficacy of pindolol in reducing blood pressure (BP). Pindolol was compared to placebo (05 patie&), propranolol (52 patients), hydrochlorothiazide (38 patients), a-methyldopa (62 patients), and chlorthalidone (14 patients) in seven studies that formed the data base included in a New Drug Application submitted to the Food and Drug Administration. All patients entered a preliminary 3-week placebo washout period during which all antihypertensive medication was withdrawn. After qualifying, they were randomly assigned to either the pindoiol or control treatment groups. Except for one study, the trial design involved a 3- to 6-week titration period fotlowed by a 3- to 7-week plateau or fixed-dose period. The remaining study evaluated three fixed dosage levels of pindolol compared to placebo in a parallel group study design. In five of seven trials, a supine diastolic BP of LWO but <120 mm Hg was required for entry, while in two studies, a supine diastolic BP of >g5 mm Hg was required. The results of the double-blind comparative trials indicate that pindolol administered as monotherapy was significantly superior to placebo administration and just as effective as propranolol, hydrochtorothiazide, a-methyidopa, or chlorthaiidone treatments. In all active treatment groups, a significant reduction from baseline BP was observed within the first week of treatment. The mean dose of pindolol administered during the plateau period was 40 to 50 mg/day given on a twice or three times a day dosage schedule, although the largest BP decrement occurred at dosages of 15 to 20 mg/day. Slight, but further decrements were observed for the pindoloi-treated groups as the dose was increased to a peak dose of 40 to 60 mg/day as allowed by the individual study protocols. Compared to propranolol, pindolol was as effective in reducing BP in two separate studies, but propranolol resulted in significantly greater reductions in heart rate. Nearly 60% of all the pindolol-treated patients manifested at least a 10 mm Hg reduction in the supine diastolic BP. One open-label study with severe hypertensive patients (supine diastolic BP 2 115 mm Hg) was designed primarily to evaluate the tong-term safety of pindolol administration but provided efficacy data for pindolol in combination with hydraiazine + hydrochlorothiazide + guanethidine. Qualified patients were randomly assigned to pindolol or an a-methyldopa/hydrochlorothiazide control treatment group. Hydralazine and guanethidine could be added to the treatment regimen of the control group if required. In combination with hydralazine and hydrochlorothiazlde, pindolol was as effective as the combination of a-methyldopa/hydrochlorothiazlde/hydralarine in reducing the BP of severe hypertensive patients. In addition, pindolol administered alone or in combination resulted in only slight and clinically insignificant reductions in pulse rate. (AM HEART J 104:374, 1982.)
Leonard
M. Gonasun, Ph.D., East Hanover,
N.J.
The observations regarding the antihypertensive properties of the a-adrenoceptor-blocking agents pronethalol and propranolol were first reported by Prichard’O in 1964 and Prichard and GillanY in 1969. Since then, several drugs with cw-adrenoceptor-blocking activity have been investigated and found effective in lowering blood pressure (BP).” One of these agents, pindolol (Visken), has been extensively studied throughout the world for the past 15 years** 5,$,l3 and during the past 5 years intensively investigated in the United States. This article summarizes the results obtained in the U.S. studies. From the Clinical Research Division, Sandoz, Inc. Reprint requests: Leonard M. Gonasun, Ph.D., Associate Director, Research, Sandoz, Inc., East Hanover, NJ 07936. 374
Clinical
METHODS
Between 1975and 19’79,793hypertensive patients were evaluated in the United States by 23 investigators. A total of 350 patients received pindolol as monotherapy for the treatment of mild to moderate essential hypertension, whereas 107 patients received pindolol either alone (27 patients) or in combination (80 patients) with other antihypertensive agentsfor the treatment of severehypertension. Three study designswere usedin evaluating the antihypertensive effects of pindolol. The basic design for all investigative studies of patients with mild to moderate essential hypertension was a double-blind, randomized, parallel treatment protocol; however, one design (usedfor one protocol) incorporated a fixed-dose treatment schedule, whereas the other (used for six protocols) required titration of the dosageto either an optional responseor to a peak dose specified for individual studies. The third design (used for one protocol) employed an open-label, 0002-8703/82/080374
+ 14$01.40/O
0 1982 The
C. V. Mosby
Co.
Volume
104
Number
2, Part II
Antihypertensive
effects
of pindolol
375
1. Dosagesin titrated dosestudies
Table
Study
Daily
drug
Hydrochlorothiazide
-
lo-30 mg b.i.d. 50-150 mg t.i.d. 250-750 mg t.i.d. -
Chlorthalidone
-
-
Placebo
-
-
Pindolol
lo-30 mg b.i.d. 20-120 mg q.i.d. -
Propranolol a-Methyldopa
dosage
lo-30 mg b.i.d. -
5-20 mg b.i.d.
-
250-1000 mg b.i.d. -
-
-
-
-
Placebo
25-15 mg b.i.d. 50-150 mg q.d. -
5-20 mg t.i.d. -
-
II. Treatment schedulefor patients with severehypertension
Table
Pindolol ’ (lo-20 mg kid.)
I
+ Hydralazine (25-50 mg q.i.d.)
’
ol-Methyldopa (250 mg t.i.d.1
cu-Methyldopa (250 mg t.i.d.)
+
-+
Hydrochlorothiazide (50mg q.d.)
*+ Hydrochlorothiazide (50 mg b.i.d.)
randomized, parallel treatment method and was conducted in patients with severe hypertension. In the latter studies, hydrazaline (Apresoline), hydrochlorothiazide (Esidrix), and guanethidine (Ismelin) were added sequentially to pindolol therapy to obtain optimal control of the patients’ BP, and the results were compared to those obtained in a control group treated with cY-methyldopa (Aldomet), hydrochlorothiazide, hydrazaline, and guanethidine. The names and affiliations of the principal investigators who conducted these clinical trials are listed alphabetically in Appendix I. Mild to moderate essential hypertension: Fixed-dose study. Following completion of a S-week, single-blind
placebo washout period during which the average supine diastolic BP was >95 mm Hg on 3 of 4 evaluation days (including the last evaluation), patients were randomly assignedto one of four treatment groups: placebo and pindolol, 15, 30, or 60 mg. The placebo-treated patients received their assignedstudy drug under double-blind conditions for the next 15 weeks.All patients treated with the active drug received 5 mg of pindolol three times a day for the first week. Approximately one third of these patients were then maintained on this dose for the remaining 14 weeks of the trial. Another third received pindolol, 10 mg three times a day at week 2, and were maintained on this dose for the next 13 weeks,while the remaining third received pindolol, 10 mg three times a day during week 2,15 mg three times a day during week 3, and 20 mg three times a day during weeks 4 through 15. The patients
were either
PHydrochlorothiazide (50 mg q.d.-50 mg b.i.d.)
I
tapered
off their
study
medication
’
* Guanethidine (lo-30 mg q.d.)
a-Methyldopa (500 mg t.i.d.)
+
t Hydralazine ’ (25-50 mg q.i.d.) Hydrochlorothiazide (50 mg b.i.d.1
* Guanethidine (lo-30 mg q.d.)
during weeks 16 and 17 or entered an open-label, longterm phaseof pindolol treatment. Mild to moderate essential hypertension: Titrated dose study. All patients initially observed a 3-week,
single-blind, placebowashout period. Those patients with an average supine diastolic BP of ~100 mm Hg on completing the washout period qualified for the next phaseof the study in which pindolol was compared with either placebo, propranolol, cu-methyldopa,hydrochIorothiazide, or chlorthalidone under randomized, doubleblind conditions. During the dosetitration period, which lasted 2 to 6 weeks, the patients received their assigned study medication in gradually increasingdosesuntil either an optimal responseor the peak dose specified by the individual protocols wasreached.The titration period was followed by a 4- to &week plateau (fixed-dose) period during which the patients were maintained on the dosage established during titration, unless an adverse reaction necessitateda dosereduction. They were then gradually withdrawn from the study drug over a l- to f-week period or entered an open-label, long-term phase of pindolol treatment. The dosagesadministered in these studies are listed in Table I. The most commonly evaluated dosageof pindolol was 10 to 30 mg twice a day; however, in one study 5 to 20 mg twice a day was given, and in a placebo controlled study 5 to 20 mg of pindolol three times a day was given. The dosagesof the active control drugs were those recommended in their respective package inserts. The doseof each study drug was titrated to an optimal goal that was
376
Gonasun
American
ii ii! 5
SYSTOLIC BLOOD PRESSURE
+10153 Pcb
0
155 1Smg
153 30mg
DIASTOLIC BLOOD PRESSURE 147 60mg
103 Pcb
104 15mg
103 30mg
100 60mg
B 2m >I %E P P 2
-lO-
-20
-
NO. PATIENTS
m’ d ui
-
Pcb PINDOLOL 15 mg
= 28
-30
30 mg 60
= 29 29
-10
l
Fig.
August, 1982 Heart Journal
= 29
1. Mean changefrom baselinesupine BP in patients receiving pindolol vs. placeboduring fixed-dose
period. III. Summary of background information fixed-dose
Table
study Treatment
Total No. patients Meanage(yr) “- SD Sex: Male Race: Black Mean weight (lb) + SD Previously treated
Placebo
I5 mg
30 mg
60 mg
32
37
37
33
52 k 11 100% 75%
49 + 11 97% 78%
50 k 10 100 % 86%
53 + 10 100% 94%
191 k 41 45%
194 -c 36 66.7%
185 rt 28 71.4%
199 f 31 57.670
defined as an average supine diastolic BP <90 mm Hg in two studiesand 585 mm Hg in the remaining four studies. Since the studies were double-blind, each patient had an equal chanceof having the doseof his or her assigneddrug titrated to its specified peak level. Severe hypertension. A randomized, open-label investigation wasconducted to assess the safety and efficacy of pindolol in combination with other antihypertensive agentsfor the treatment of patients with severehypertension and to compare the results to those obtained for an a-methyldopa control group. To qualify for the study, patients had to have an averagesupine diastolic BP ~115 mm Hg on two consecutive evaluation days during a preliminary drug-free period as well as evidence of endorgan involvement excluding retinopathy greater than grade II. For the pindolol-treated patients, therapy was initiated with 10 mg pindolol three times a day and increasedto a peak dose of 20 mg three times a day to produce optimal control of the patients’ BP. Subsequently, hydrazaline, hydrochlorothiazide, and guanethidine were added in the dosageslisted in Table II to obtain an optimal response.E’milarly, for the a-methyldopa/hydrochlorothiazide control group, hydrazaline and guanethidine were sequentially added to obtain an optimal response. All studies. For all studies discussedin this article, patients were excluded if they had any condition or disease that could interfere with the evaluations for
efficacy and safety. These included Cushing’ssyndrome, hyperthyroidism, pheochromocytoma, malignant or accelerated hypertension, bronchial asthmaor chronic obstructive pulmonary disease(COPD) requiring treatment, alcoholism, cerebral insufficiency, epilepsy, diabetes mellitus requiring insulin, angina, heart failure, myocardial infarction within the previous 6 months, bradycardia, atrioventricular conduction impairment greater than one-degree heart block, malabsorption syndromes, liver or kidney dysfunction, adverse reactions to @-blockers,or the useof drugs potentially toxic to a major organ. In the studies of mild to moderate hypertension, patients with severe hypertension were excluded. Patients were evaluated at weekly intervals during the initial stagesof study and thereafter were seenevery 2 to 4 weeks depending on the evaluation schedule for the particular protocol. At each patient visit, supine and standing BPS and radial pulse rates were recorded. Duplicate supineand standing readingswere taken two to three times eachvisit at 30-minute and l-hour intervals and the average computed for statistical analysis. The diastolic pressurewasrecorded at the point at which the Korotkeff soundsdisappeared,that is, onset of phase V. Data analyses. Parametric analyseswere performed for the BP and pulse data when the criterion of drug effect wasthe meanof all the measurementsmadeon the day of the visit. Separate one-way analyses of variance and covariance were performed, with the baselinedata usedas the covariant. Additionally, a repeated measurements model for the averagesobserved over the plateau periods was performed as the main drug effect, with the baseline used as the covariant. If requisites were satisfied, the analysis of covariance was performed which allowed adjusting the criterion value of the one-way analysis of variance and of the main drug effect as though all treatment groupshad the samemeanat baseline.The two requirements that had to be satisfied werehomogeneity of linear regression (slopes:(Y= 0.05) and a common slope significantly different from zero (a = 0.10). A two-tailed Student t-test was also employed to determine whether the average change from baselinewas significant.
Volume Number
104 2, Part II
Antihypertensive
ii = 3 0 B Em
SYSTOLIC BLOOD PRESSURE
r
+10
152 Pcb
0
153 15mg
effects of pindolol
377
DIASTOLIC BLOOD PRESSURE
149 30mg
147 60mg
106 Pcb
107 15mg
107 30m9
104 60 mg
-12
5s 2E E
-lO-
8
-20
s
NO. PATIENTS Pcb PINDOLOL 15mg 30 mg 60 mg
t
d
-3oL
ti +I
a
= 28 = 29 = 29 = 29
Fig. 2. Mean change from baselinestanding BP in patients receiving pindolol vs. placebo in fixed-dose
period.
SUPINE PULSE
+ lof I 4i2
0
11 Pcb
81 15mg
STANDING PULSE 76 30mg
78 60mg
89 Pcb
l?mg
308’mg
-8
-5
85 60 mg pJ
1uy d ti
-lO-
;
-2o-
A
PATIENTS
Pcb PINDOLOL 15 mg 30 mg 60 mg
-3o-
Fig.
NO.
= 28 = 29 = 29 = 29
3. Mean change from baselinepulse rate in patients receiving pindolol vs. placebo in fixed-dose
period.
RESULTS Mild to moderate
hypertension:
Fixed-dose
study.
In
this study, patients assigned to the active treatment groups received pindolol as the sole antihypertensive agent. Table III summarizes the demographic data of all 139 patients evaluated, including those given placebo. As shoan, 32 to 37 patients were randomly assigned to each treatment group, and these groups were comparable with respect to the patients’ mean age, sex (all but one were male), race (275 % black), weight, and history of previous treatment. The mean changes in supine BP using the repeated measurements model for each of the groups are plotted in Fig. 1. Each of the pindolol-treated groups demonstrated statistically significant decreases (p < 0.05) in BP from baseline values, and these decreases were statistically significantly greater than those demonstrated by the placebo-treated group. However, the pindolol-treated groups did not
differ significantly from one another in their BP response. Similar findings were observed for the standing BP (Fig. 2). The mean changes from baseline values for the supine and standing pulse rates are shown for the same period in Fig. 3. The 15 mg dose group demonstrated the peak pulse rate lowering effect with no further reductions as the dose increased to 30 and 60 mg daily. Since a dose-response relationship was not apparent in these data, further analyses were performed in a homogeneous subgroup of patients whose baseline supine diastolic BP exceeded 100 mm Hg. Other reports4 have indicated that the magnitude of the reduction is correlated with the level of the pretreatment BP. The results of the analyses for the supine and standing BPS are shown in Figs. 4 and 5. Just over 40% of the patients included in the analyses presented in Figs. 1 to 3 were included in this subgroup. The data clearly indicate a dose ordering of the BP response for both the systolic and diastolic
378
Gonasun
SYSTOLIC BLOOD PRESSURE 161 Pcb
166 16mg
101 3Omg
DIASTOLIC BLOOD PRESSURE 164 6Omg
107 Pcb
106 16mg
NO. PATIENTS:
106 30mg
104 6Omg
Pcb
= 12
PINDOLOL 15mg 30 mg 60 mg
= 15 = 15 = 13
Fig. 4. Mean change from baseline supine BP in patients receiving pindolol vs. placebo in fixed-dose period whose values were >200 mm Hg.
DIASTOLIC BLOOD PRESSURE 113
P
16 mg 30mg
-3
108 6@mmg
-8
T-
Q
-20
L
1
ti a
NO.
PATIENTS:
Pcb PINDOLOL 15mg 30 mg 60 mg
= 12 = 15 = 15 = 13
Fig. 5. Mean change from baseline standing BP in patients receiving pindolol vs. placebo in fixed-dose period whose supine diastolic BP was >lOO mm Hg.
BP. Each of the pindolol-treated groups demonstrated statistically significant decreases as compared to baseline values and the decreases obtained with placebo. Moreover, the decrement seen in the 60 mg group was statistically significantly greater than that seen in the 15 mg group. In contrast to the BP results for this subgroup of patients, there was no dose-response decrement in either the supine or standing pulse rates (Fig. 6). These data suggest that the intrinsic sympathomimetic activity (ISA) of pindolol did not interfere with its antihypertensive effect in patients with higher baseline BPS. Mild studies.
to
moderate
Six multicenter
hypertension:
Titrated
studies employing
‘dose
a titrated
dose schedule were designed to evaluate the safety and efficacy of pindolol in the treatment of hypertension. All patients participating in these studies received pindolol as the sole antihypertensive agent. Table IV summarizes the demographic data for a multicenter, placebo controlled study. As shown, approximately 35 patients were entered in each of the two treatment groups, and the background variables for the two groups were comparable. Within the first week of treatment with pindolol, 5 mg three times a day (Fig. 7), a statistically significant reduction in supine BP from baseline levels was achieved. This reduction with pindolol was significantly greater than that achieved with placebo treatment. The
Volume
104
Number
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Antihypertensive +lO-
SUPINE PULSE
I iiiii
d Ki 4
84 Pcb -1-
0.
-10
-
-20
L
81 15mg
effects
of pindolol
379
STANDING PULSE
78 30mg
79 60mg
93 Pcb
NO.
PATIENTS:
91 15mg
88 30mg
Pcb PINDOLOL 15mg 30 mg 60 mg
86 60mg
=
12
= = =
15 15 13
Fig. 6. Mean change from baseline pulse in patients receiving pindolol vs. placebo in fixed-dose period whose supine diastolic BP was >lOO mm Hg.
180
I 158
160 I” E B
140
2 z %
120
8 2
m
P
100
99
PIN = PINDOLOL PC6
I PLACEBO MEAN Fig.
7.
DAILY
DOSE:
FIRST PINDOLOL
WEEK
15 trig
= PLACEBO
PLATEAU PERIOD 6 WEEKS 38 mg
Mean supine BP in multicenter study of patients receiving pindolol vs. placebo in titrated dose
period.
initial BP response was maintained and improved slightly as the dose of pindolol was titrated to a mean of 38 mg over the plateau period. Although not shown here, similar results were obtained for the standing BP. Despite the marked fall in BP, only a slight decrement occurred in the supine and standing pulse rates (Fig. 8). The mean reductions were 2 to 4 bpm supine and 4 to 8 bpm standing. Table V presents the demographic information for a multicenter, propranolol controlled study and shows that for each of the treatment groups, consisting of over 35 patients each, the background variables were comparable. Fig. 9 indicates that both drugs significantly reduced the supine BP from baseline values within the first week of treatment at
the doses administered. As the dose of pindolol was titrated upward to a mean of 40 mg/day over the plateau period, a further decrement in BP was observed. In contrast, as the dose of propranolol was increased to a mean of 20’7 mg, no further decrease was noted. In fact, during the plateau period, the mean decrement observed for the pindolol group was greater than that observed for the propranolol group. Although not shown here, similar results were obtained for the standing BP. The effect of both &blockers on resting supine and standing pulse rates is shown in Fig. 10. The mean decrements observed for the propranolol-treated group were greater than those observed for the pindolol group and these differences were statistically significant.
380
Gonasun
American
PINDOLOLPLACEBO SUPINE
+10-
.
76
0
73
PULSE
76
z I z
+ , o _
74
_
-
STANDING
82
0
N =
29
N =
30
August, 1982 Heart Journal
PULSE
80
60
-Y -10
-
-20
-
ii
PCB PIN
PCB
-lO-
PIN
PIN -20
PLATEAU PERIOD 6 WEEKS
FIRST WEEK
-3o-
-3o-
pcB
FIRST WEEK
PIN PLATEAU PERIOD 6 WEEKS PIN = PINDOLOL PCB = PLACEBO
Fig. 8. Mean change from baseline
pulse in multicenter
study of patients receiving pindolol vs. placebo in
titrated doseperiod.
IV. Summary of background information on patients receiving pindolol vs. placebo (multicenter study) Table
Treatment Total No. patients Mean age (yr) + SD Sex: Male Race Caucasian Black Mean weight (lb) k SD Previously treated
Table V. Summary of background receiving pindolol vs. propranolol
Total
Pindolol
Placebo
36 54 f 10 64%
34 53 * 12 59%
61% 39% 173 + 38 89%
53% 47% 178 f 37 79%
information (multicenter
on patients study)
Treatment
Pindolol
No. patients
37 53 * 13 49%
36 54 * 10 72%
51% 49% 177 k 35 76%
53% 47% 184 ‘- 34 83%
Mean age (yr) rt SD Sex: Male Race Caucasian Non-Caucasian Mean weight (lb) Previously treated
f
SD
Propranolol
In a second study, pindolol was compared to propranolol and chlorthalidone. The demographic information for the 48 patients studied (16 per treatment group) is listed in Table VI and indicates that the treatment groups were comparable. All three treatments resulted in comparable and statistically significant reductions from baseline values in the supine BP within the first week of treatment at
daily doses of 20 mg pindolol, 150 mg propranolol, and 50 mg chlorthalidone. During the plateau period (Fig. ll), the initial reductions were enhanced, but no statistically significant differences were detected between the study groups. The mean dosages achieved during the plateau period were 50 mg pindolol, 360 mg propranolol, and 107 mg chlorthalidone. Similar results were obtained for the standing BP. The mean changes in resting supine and standing pulse rates are shown in Figs. 12 and 13, respectively. Again, mean decrements were statistically significantly greater with propranolol than with pindolol. The results obtained from both of the propranolol controlled studies clearly indicate that pindolol was as effective as propranolol in reducing blood pres-
sure at one fifth to one seventh the dose, without producing the accompanying marked pulse rate decrements typically observed with propranolol. Two multicenter studies compared the efficacy of pindolol and cw-methyldopa in reducing BP. One study used a three times a day regimen of a-methyldopa, whereas the other used a twice a day regimen. The background variables for both studies are listed in Tables VII and VIII, respectively, and indicate that for each study, the treatment groups were comparable. As shown in Figs. 14 and 15, both pindolol and cY-methyldopa resulted in a statistically significant decrease in the supine BP within the first week of therapy, which was maintained through the plateau period. No statistically significant differences were noted between the two treatment groups in either study. As might be expected, increasing the dose of cu-methyldopa to over 1500 mg/day resulted
Volume Number
104 2, Part II
Antihypertensive
PINDOLOL-
effects of pindolol
381
N = 27
180 PROPRANOLOL
_
154
N = 30
151
z h #I
-
0 i
102
102
80 PIN = PINDOLOL L
P = PROPRANOLOL PLACE80
MEAN
DAILY
FIRST
WEEK
PLATEAU PERIOD 6 WEEKS
DOSE: PINDOLOL Propranolol
Fig. 9. Mean supine BP in multicenter titrated dose period.
20 80
40 207
mg mg
study of patient8 receiving pindolol vs. propranolol
PINDOLOL-
.
r 0
SUPINE
PULSE
75
74
76
+10 74
r
during
N = 27
PROPRANOLOL +10
mg mg
- N = 30 STANDING
84
83
PULSE
82
81
r 5 -lO-
z h
ii
a -20
-30‘
0
FIRST WEEK
PLATEAU PERIOD 8 WEEKS
FIRST WEEK
PIN
PLATEAU PERIOD 6 WEEKS = PINDOLOL
P = PROPRANOLOL
Fig.
10. Mean pulse in multicenter
study of patients receiving pindolol vs. propranolol in titrated dose
period.
in a greater decrement in the standing BP (Fig. 16), which was often symptomatic. No relevant changes occurred in either the supine or standing pulse rates in either study. Another multicenter study was designed to compare the BP-lowering effects of pindolol vs. hydrochlorothiazide. The demographic data for the 75 patients entered in this trial are summarized in Table IX and indicate that the treatment groups were comparable. Fig. 17 shows the BP responses in
the supine position. Both drugs resulted in statistically significant reductions of blood pressure from baseline values within the first week of treatment, with pindolol achieving a slightly greater mean reduction at the doses administered. During the plateau period, pindolol reduced the pressure even further as the daily dose was titrated to a mean of 55 mg. Similarly, the response to hydrochlorothiazide increased when the dose was increased to a mean of 144 mg. Similar results were also obtained for the
Gonasun
382
PINDOLOL
American
“I PROPRANOLOL SUPINE BLOOD
“o CHLORTHALIDONE PRESSURE
VI. Summery of background information on patients receiving pindolol vs. propranolol vs. chlorthalidone
Table
PINDOLOL - N=15 PROPRANOLOL - N=15 CHLORTHANLIDONE - N=14
ChlorthalPindolol
T
137
5
August, 1962 Heart Journal
0
Total No. patients Mean age (yr) + SD Sex: Male Race Caucasian Non-Caucasian Mean weight (lb) k SD Previously treated
Propranolol
16 49 k 8
idone
16 52 f 11
16 51 +- 13
25 %
19%
25%
19% 81%
198 810;>
13%, a1 %
170 f 22 81%
179 * 39 81%
174 f 33 81%
92 .:I .L
60
Table
1
patients 1 PLACEBO MEAN
DAILY
DOSE: PINDOLOL PROPRANOLOL CHLORTHALIDONE
PLATEAU PERIOD 4 WEEKS 50 m g 360 m g 107 m g PIN = PINDOLOL P = PROPRANOLOL C = CHLORTHANLIDONE
11. Mean change from baseline supine BP in multicenter study of patients receiving pindolol vs. propranolol vs. chlorthalidone in titrated dose period.
Fig.
standing BP. Fig. 18 shows the mean ,changes observed for the supine and standing pulse rates. Only a 4 to 6 bpm reduction in the supine position and a 5 to 7 bpm reduction in the standing position were noted for the pindolol group. These changes achieved statistical significance; however, they were not considered clinically significant. A second method of analysis was employed in evaluating the efficacy data in order to obtain a more clinically oriented view of the effectiveness of pindolol in reducing BP. Table X summarizes a categorical analysis of the patients’ responses in all the studies in which pindolol was administered as monotherapy for the treatment of mild to moderate essential hypertension. The classification was based on the average supine diastolic BP observed over the plateau period of study according to the repeated measurements model. The patients’ responses were then categorized into one of the following: a reduction to ~90 mm Hg, a reduction of ~10 but >90 mm Hg, a reduction of 5 to 9 mm Hg, and a reduction of 15 mm Hg or even an increase. In those studies employing a titrated dose schedule to achieve an optimal response, nearly 60% of the patients demonstrated an excellent response (categories 1 and 2),
VII.
Summary of background information on pindolol vs. a-methyldopa (multicenter
receiving
study)
Treatment Total No. patients Mean age (yr) + SD Sex: Male Race Caucasian Black Mean weight (lb) * SD Previously treated
Pindolol
a-Methyldopa (t.i.d.)
31 50 * 11 26%
23 54 * 9 43%
29% 71% 174 * 54 8770
22 ro 78% 168 IL 39 78%
23% demonstrated a fair response (category 3), and only 18% of the patients demonstrated no or poor responses according to these criteria. In the fixeddose study, 53% of the patients had an excellent response to pindolol treatment. Severe hypertension. A multicenter study was undertaken in patients with severe hypertension. The study was designed primarily to evaluate the long-term safety of pindolol administered in combination with other antihypertensive agents. However, the efficacy results obtained from these patients are summarized here. The demographic data for the 209 patients entered in this study are summarized in Table XI. More than 100 patients were evaluated in each treatment group and the data indicate that the treatment groups were comparable. The mean BP decrements from baseline values achieved in the supine position at the end of each treatment phase are shown for the pindolol and control treated groups in Figs. 19 and 20, respectively. Adminiatration of pindolol alone to this group of patients produced a mean reduction of 12/12 mm Hg.
Volume
104
Number
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Antihypertensive
effects of pindolol
VIII. Summary of background information on patients receiving pindolol vs. a-methyldopa (multicenter study)
PINDOLOL - N=15 PROPRANOLOL - N=15 CHLORTHANLIDONE - N=14
Table
Treatment
a-Methyldopa (b.i.d.)
Pindolol
Total No. patients Mean age (yr) + SD Sex: Male Race Caucasian Black Mean weight (lb) -t SD Previously treated
38 52 t 10 84%
39 55 * 9 92%
34% 66 % 189 k 41 76%
.
36 5% 64 ‘Z 182 k 31 67%
FIRST WEEK
Summary of background information on patients receiving pindolol vs. hydrochlorothiazide (multicenter study) Table
IX.
Total No. patients Mean age (yr) + SD Sex: Male Race Caucasian Black Mean weight (lb) ? SD Previously treated
PLATEAU PERIOD 4 WEEKS
PIN = PINDOLOL P = PROPRANOLOL C = CHLORTHANLIDONE
12. Mean change from baseline supine pulse in multicenter study of patients receiving pindolol vs. propranolol vs. chlorthalidone in titrated doseperiod. Fig.
Hydrochlorothiazide
Pindolol
Treatment
383
37 48 AZ 1‘2 43%
38 48 * IO 53%
54% 46% 178 f 37 89%
53% 47% 1’73 k 38 87%
X. Number and percentage of pindolol-treated patients in each responsecategory Table
(Average Study
No. patients
design
Titrated dose Fixed dose *Classification 1 = reduction 3 = reduction
164 87
I
2
41% 38%
18% 15%
based on average supine diastolic
-30 J
Category over plateau
period) 3
23% 20%
FIRST WEEK
* 4
18% 28 %
BP over plateau period:
to 5 90 mm Hg, 2 = reduction of z 10 but < 90 mm Hg, of 5-9 mm Hg, 4 = reduction of < 5 mm Hg or an increase.
Sequential addition of hydralazine followed by hydrochlorothiazide resulted in further decreases with the addition of each agent. Following treatment with the combination of pindolol + hydralazine + hydrochlorothiazide, the mean reduction from baseline was 32/24 mm Hg (Fig. 19). A similar mean reduction was achieved with the combination of cr-methyldopa + hydrochlorothiazide + hydralazine (Fig. 20). Similar results also were observed for the standing BP. As with the studies previously described, only minimal reductions of 2 to 6 bpm occurred in the supine and standing pulse rates with pindolol administration.
1 PLATEAU PERIOD 4 WEEKS
PIN = PINDOLOL P = PROPRANOLDL C = CHLORTHANLIDONE
Fig. 13. Mean change from baseline standing pulse in multicenter study of patients receiving pindolol vs. propranolol vs. chlorthalidone in titrated doseperiod.
DISCUSSION
Over 300 pindolol-treated patients with mild to moderate essential hypertension were evaluated in randomized, double-blind, parallel treatment group studies conducted in the United States. These studies were designed to evaluate the efficacy of pindolol in reducing BP. In the studies, pindolol was compared to placebo, propranolol, hydrochlorothiazide, cr-methyldopa, and chlorthalidone. Additionally, one multicenter, randomized, open-label study of severely hypertensive patients was designed primarily to evaluate the long-term safety of pindolol administration but provided efficacy data for the use of pindolol in combination with hydralazine + hydrochlorothiazide + guanethidine. In both studies that utilized a placebo control, the
384
Gonasun
American
PINDOLOL
- N = 27
a-METHYLDOPA
PIN
August.1982 Heart Journal
- N = 21
= PINDOLOL
M = a-METHYLDOPA , FIRST
PLACEBO Mt%N
DOSE:
DULY
f,,NDOL(,L
PLATEAU FERIDD 8 WEEKS
2omg
a-METNYLOOPA Fig. $4. Mean supine BP in multicenter times a day in titrated dose study.
WEEK
760
63 mg
trig
1679
study of patients receiving pindolol vs. a-methyldopa
PINDOLOL 180
mg
r
T
T
three
- N = 37
@METHYLDOPA-
N =34
1
PINDOLOL PIN
= PINDOLOL
M = a-METHYLDOPA FIRST
PLACEBO MEAN
DAILY
DOSE
10 mg
PINDOLOL a-MRHYLDOPA
Fig. 15. Mean supine BP in multicenter day in titrated dose period.
WEEK
600
mg
PLATEAU PERIOD 7 WEEKS 36mg 1544mq
study of patients receiving pindolol vs. Lu-methyldopa twice a
efficacy of pindolol in lowering BP was clearly demonstrated without producing the marked reductions in pulse rate usually seen with P-blockers without ISA. The data obtained in the fixed-dose study from a homogeneous subgroup of patients with essential hypertension who had diastolic BPS exceeding 100 mm Wg indicated that a doseresponse relationship existed between the dose of pindolol and the mean BP decrements. In contrast, no dose-response relationship was noted for changes
in pulse rates. These data indicate that the ISA property of pindolol does not interfere with its antihypertensive effect. In two studies, pindolol was shown to be at least as effective as propranolol in reducing BP at one fifth to one seventh the dose without producing the marked reductions in resting supine and standing pulse rates typically observed with propranolol. These findings have also been reported by others?? suggesting that the antihypertensive effects of pin-
Volume
104
Number
2, Part II
Antihypertensive
PINDOLOL 1 aor-
0
160-
: y
140-
I
5 t ; 0 8 2 m
effects of pindolol
385
- N = 27
a-METHYLDOPA
- N = 21
120-
loo-
80-
PIN = PINDOLOL M = a-METHYLDOPA
I: L
PLACEfKl MEAN
DAILY
DOSE:
FIRST
PINDOLOL
180
t”
r
160
750
53n-q
mg
1679
study of patients
pindolol
120
1
loo
y
140 :I1
E
SO
z h
I
106
92
A.
H = HYDROCHLOROTHlAZlDE PLACEBO
DAILY
913
PIN = PINDDLOL t
MEAN
I
E 100
11
DOSE:
FIRST WEEK
PINDOLOL
HYDRDCHLOROTHlA2lDE
PLATEAU PERIOD 7 WEEKS
20 WI
55 w
6OWl
1umg
Fig. 17. Mean change from baseline supine BP in multicenter hydrochlorothiazide in titrated dose period.
dolol are not related to reductions in the resting pulse rate. A previous report’l has indicated that th;! antihypertensive effects of various D-blockers are equivalent regardless of the differences in some of the pharmacologic properties such as ISA, cardioselectivity, and membrane-stabilizing activity. It is noteworthy that the findings in the U.S. studies confirm the results typically seen throughout the world. Pindolol has also been shown to be as effective as Lu-methyldopa, hydrochlorothiazide, and chlorthalidone at the doses tested when administered as
- N = 35
139
I
104 97
three
1
151 145
w E a 8
vs. a-methyldopa
- N = 30
140 5 z
m9
HYDROCHLOROTHlAZlDE
154
E
receiving
PINDOLOL
_ 163
PLATEAU PERIOD 8 WEEKS
20mg
u -METHYLDOPA
Fig. 16. Mean standing BP in multicenter times a day in titrated dose period.
WEEK
Table
study of patients receiving pindolol vs.
Xl.
hypertension
Summary of background (multicenter study)
Treatment Total No. patients Mean age (yr) A SD Sex: Male
Race Caucasian Non-Caucasian Mean weight (lb) 2 SD
Pindolol 108 46 XL 11 52% 22 5 78%
181 * 36
information
severe
a-Meth.yldopal hydr&hl& thiazide 101 50 + 11 43% 33% 67% 182 + 42
306
Gonasun
American
PINDOLOL
- N = 30
HYDROCHLOROTHlA2lDE
SUPINE
August. 1982 Heart Journal
PULSE
- N = 35
STANDING
PULSE
A + S.D. RATE/MM
WEEK
PERIOD 7 WEEKS
WEEK
PLATEAU PERIGD 7 WEEKS
PIN = PINDOLOL Ii = HYDROCHLOROTHlA2lDE
Fia.
18. Mean change from baseline pulse in multicenter study of patients recieving pindolol vs.
hydrochlorothiazide in titrated doseperiod. PINDOLOL
TREATED
ALDOMET/ESIDRIXTREATED +10
+10 1
I”
I
N=105
12
N=23
1
N=96
192/122
192/121
0 i-
N=60
N=78
N=l5
J’;
1 2
N=41
-1
-23
2
-3
T ‘;
.40
1 -60
-6OJ MEAN
DAILY
DOSE:
PINDOLOL: APRESOLINE: ESIDRIX: ISMELIN:
MEAN 40 mg -
S4mg 134 mg -
67 mg 179mg 78mg -
66 mg 17s9 98 m 26 mg
DAILY
DOSE:
ALDOMET: ESIDRIX: APRESOLINE: ISMELIN:
804 mg 76 mg -
1362 96 129 -
mg mg mg
1534 mg 94 mg 124 mg 18 me
Fig. 19. Mean change from baseline supine BP in patients treated with pindolol plus hydrasaline plus hydrochlorothiazide in severe hypertension study.
Fig.
to patients with mild or moderate essential hypertension. A previous report! indicated that pindolol was as effective as cu-methyldopa when added to diuretic therapy in a similar group of patients and therefore supports the conclusion that pindolol is as effective as a-methyldopa. An analysis of the data for a smaller group of patients,3 which subsequently were pooled with the data described in this article, indicated that pindolol was as effective as hydrochlorothiazide. In a group of severely hypertensive patients, pindolol, when combined with hydralazine and
hydrochlorothiazide, and, in some patients, guanethidine, was effective in producing marked reductions in BP. The stepwise reductions in BP achieved in these patients demonstrate the additive effects of each of these drugs in treating this type of patient. Previous reports6v7 have also indicated that pindolol is an effective antihypertensive agent when combined with diuretic therapy or peripheral vasodilators in the treatment of severely hypertensive patients. Conclusions. The data reported from the U.S. studies show that pindolol is an effective antihyper-
monotherapy
20. Mean change from baseline supine BP in patients receiving cx-methyldopaplus hydrochlorothiazide plus hydrasaline in severehypertension study.
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104
Number
2, Part II
Antihypertensiue
tensive agent when administered alone or in combination with diuretics and/or peripheral vasodilators. When administered alone, pindolol was found to be as effective as propranolol, hydroclorothiazide, chlorthalidone, and cr-methyldopa; moreover the reductions in BP were achieved without producing the marked reductions in resting pulse or heart rates usually observed with P-blockers without ISA. Additionally, pindolol has been shown to be an effective antihypertensive agent within the first week of treatment when administered at low dosages and to be effective when given twice a day.
4. 5. 6. 7. 8. 9.
REFERENCES
1. Beanlands DS, Allard PP, Wilson M, Orbeck KW, Hehnan AB, Lefebure R: Comparison of efficacv and safetv of nindo101 and alphamethyldbpa in treatment of mild to moderate hypertension: Results of a double-blind evaluation study. Clin Invest Med 1:139, 1978. 2. Collins IS, King IW: Pindolol (Visken, LB-46). A new treatment of hypertension: Report of a multicenter open study. Curr Ther Res 14:185, 1972. 3. Davidov ME, Green AM: Effect of pindolol on arterial Appendix Principal
investigators
John Arnold, M.D., Quincy Research Center, Kansas City, MO. Stephen Ayers, M.D., St. Louis University, St. Louis, MO. Richard Blum, M.D., Long Island Jewish Hillside Medical Center, New Hyde Park, N.Y. Albert Carr, M.D., Medical College of Georgia, Augusta, Ga. Elliot Coleman, M.D., Rancocas Valley Hospital, Willingboro, N.J. Charles Curry, M.D., Howard University, Washington, D.C. Michael Davidov, M.D., George Washington University School of Medicine, Falls Church, Va. Frank Finnerty, M.D., Hypertension Center of Washington, Washington, D.C. Richard Glassock, M.D., Harbor General Hospital, Torrance, Calif.
Study
design(s)
Double-blind Open-label Double-blind
Double-blind bel (1)
(1) and open-la-
Double-blind Open-label Double-blind
Double-blind Double-blind bel (1)
(1) and open-la-
10. 11. 12. 13.
effects of pindolol
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pressure in patients with essential hypertension. Curr Ther Res 27:507, 1980. Dixon GT: Efficacy of antihypertensive drugs. Lancet 1:515, 1976. Laver MD, et al: Double-blind comparison of two betablocking drugs with previous therapy in the treatment of hypertension. Med J Aust 1:174, 1974. McNeil JJ, Louis WJ, Doyle AE, Vajidla FJ: Comparison of metoprolol and pindolol in the treatment of mild to moderate hypertension. Med J Aust 1:431, 1979. Morgan TO, Anavekar SN, Sabto J, Louis WJ, Doyle AE: A comparison of beta adrenergic blocking drugs in the treatment of hypertension. Postgrad Med J 50:253, 1974. Persson I: Combination therapy of essential hypertension with pindolol (Visken) and hvdralazine. Eur J Clin Pharmaco1 9:91, 1975. Persson I, Ulrich J: Treatment of hypertension with a new beta-blocking agent pindolol (Visken). Eur J Clin Pharmacol 6:217, 1973. Prichard BNC: Hypotensive action of pronethalol. Br Med J 1:1227, 1964. Prichard BNC, Boakes AJ: The use of beta-adrenoceptor blocking drugs in hypertension: A review. Curr Med Res Opin 4(suppl 5):51, 1977. Prichard BNC, Gillam PMS: Treatment of hypertension with propranolol. Br Med J 1:7, 1969. Turner AS: The use of prindolol in hypertension. Aust NZ J Med 3:316, 1973.
I Bruce Hamilton, M.D., Baltimore VA Hospital, Baltimore, Md. Herbert Jernow, M.D., White Plains, N.Y. Walter Kirkendall, M.D., University of Texas, Houston, Tex. Morton Maxwell, M.D., Cedars Sinai Medical Center, Los Angeles, Calif. Jorge Oms Rivera, M.D., Regional Hospital, Bayamon, Puerto Rico Alexander Schirger, M.D., Mayo Clinic, Rochester, Minn. James Schoenberger, M.D., Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Ill. Eugene Spiotta, M.D., Memphis, Tenn. Gundarshan Thind, M.D., University of Louisville Louisville, Ky. Nathaniel Winer, M.D., Truman Medical College, Kansas City, MO.
Double-blind
(2)
Double-blind Double-blind Double-blind Double-blind bel (1)
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Double-blind Double-blind
Double-blind Double-blind Double-blind bel (1)
(1) and open-la-