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Antihypertensive effect of a new dihydropyridine calcium antagonist, PN 200-110 (isradipine), combined with pindolol
AntihypertensiveEffect of a New Dihydropyridine CalciumAntagonist, PN 200-l 10 (Isradipine), CombinedWith Pindolol LENNART
HANSSON,
MD,
and
Preliminary results of a randomized, double-blind, placebo-controlled trial of PN 200-l 10 (isradipine) are reported. The study involves 5 centers and 61 patients with essential hypertension. Either PN 200110 or placebo was added to an ongoing daily regimen of 10 mg of pindolol to determine if this agent would enhance the effect of the P-adrenoreceptor blocking agent. PN 200-l 10 was given twice daily, starting with a dose of 2.5 mg or 5 mg, which could be doubled after 4 weeks. The average final dose
DAHLOF,
MD
was 6.3 mg given twice daily. Supine blood pressure was significantly reduced from a mean of 162/103 mm Hg to 144168 mm Hg (p
M
anv renorts have documented repeatedlv that lowering elevated arterial pressure significantly reduces hypertension-induced mortality and morbidity in cerebrovascular and cardiovascular diseases. However, several recent studies have shown a remarkably high incidence of morbidity’,” and mortality” in treated hypertensive patients compared with normotensive persons of the same sex and age from the same populations. One reason for this less than optimal response to therapy could be that blood pressure was not sufficiently lowered in any of these studies, In other words, if one wants to “normalize” a hypertensive patient’s risks, a reasonable first step should be to “normalize” the blood pressure.4 One obvious factor in attempting to achieve normotension in hypertensive patients is the need to agree on the aim of therapy. An equally important factor is whether blood pressure can be brought into the normal range with antihypertensive compounds while their side effects are limited. With these factors in mind, we chose to evaluate the new dihydropyridine derivative PN ZOO-110(isradipine) combined with pinFrom the Department of Medicine, University of Gtitcborg, Giitclmg,
BJORN
Sweden.
Address for reprints: Lcnnart Hmxson, MD, Department of hlcdicinc, University of Giitcborg, &&a Hospital, S-416 85 Gi% tcborg, Swetlen.
dolol in the treatment of hypertensive patients and to determine if this combination would effectively lower blood pressure into the normotensive range without causing unacceptable adverse effects.
Materials and Methods PN 200-110, a new calcium antagonist of the dihydropyridine group, is characterized by its distinct negative inotropic effect without causing a concomitant chronotropic effect.” It is a potent vasodilator with a long duration of action and virtually no myocardial depressant effect.” Because it is highly selective for vascular smooth muscle cells, PN ZOO-110produces coronary vasodilation at doses 12 to 14 times lower than those required for significant decreases in atrioventricular conduction time or the force of contraction.7 In anesthetized cats, PN ZOO-110has been shown to increase blood flow to heart, brain and skeletal muscle while significantly decreasing arterial pressure.” Sixty-one patients were recruited at 5 different centers Three patients were withdrawn from the study before they received PN 200-110; thus, data on the remaining 58 patients will be discussed here. There were 38 men and 20 women with an average age of 54 years (range 33 to 71) and an average weight of 82 kg [range 58 to 123). Upon routine diagnostic work-up, all were regarded as having essential hypertension and were treated with 10 mg of pindolol once daily. All
1378
1388
A SYMPOSIUM:
CALCIUM
ANTAGONISTS-EMERGING
CLINICAL
PN 200 -110
’ 130. -
MAP mm Hg n=20
A=18 (15%) p
120.
0 /
110 1 .
100 j
’
.
. .
/
0
0
.
0 0
.
0
l .
a
‘“G/. . . ; ;. , . , 90
100
110
120
130 Placebo
FIGURE 1. Difference in mean arterial pressure (MAP) in patients treated first with placebo (x axis) and then with PN 200-110 (y axis). (Data from Center A only.)
mrr Hg
150
PN ZOO-110 Y -+tr.
i 157
krl-
-*-
100
T -**rc-
70 Week
dosage
the participants gave their informed consent, and the study protocol was approved by the local ethics committees. The study began with a 3-week period during which patients were maintained on pindolol 10 mg once daily and also received placebo in a single-blind fashion. Patients whose diastolic blood pressure was >95 mm Hg were randomized to the double-blind phase to either a continuation of placebo for 8 weeks or PN ZOO-110at a starting dose of 2.5 or 5 mg twice daily, which could be doubled after 4 weeks if diastolic blood pressure was not <90 mm Hg. After 8 weeks, patients were crossed over to either PN 200-110 or placebo and again the dosage could be increased after 4 weeks. After randomization, patients were seen at 4week intervals. Blood pressure was measured after 5 minutes of supine rest and after 1 minute in the upright position using a mercury sphymomanometer [cuff balloon size 12 X 35 cm). Disappearance of the Korotkoff sounds (phase V) was used to determine diastolic blood pressure. Several clinical chemistry variables for blood and urine were also measured repeatedly during the trial and at each following visit, patients were questioned about side effects. Data from 1 center [Center A), at which 20 patients were studied, will be described in somewhat greater detail. Statistical analysis: Matched data were analyzed using &tailed test of paired data. If numbers were <30, this test was used; if numbers were 230, the normal distribution was used. Unmatched data were analyzed using the technique for analysis of differences between mean values, again using the t test for observations <3O and the normal distribution for observations of 230.
Results -I
100
OPPORTUNITIES
89
T -i#*y-
8
0 3.8mg
5.7mg
FIGURE 2. Average supine blood pressure in 20 patients while receiving placebo, then while receiving 2 sequential dosage levels of PN 200-110. (Data from Center A only.)
After the initial 3-week period with pindolol and placebo, the average blood pressure in the 58 patients was 162.4 f 14.4/104.0 f 5.0 mm Hg (mean f standard deviation). In the analysis of parallel groups, in which each patient constitutes his or her own control, administration of placebo for the next 8 weeks reduced blood pressure to an average of 161.5 f 15.3/103.1 f 7.3 mm Hg. This value did not differ significantly from blood pressure levels measured earlier, after the 3-week placebo run-in period. However, after 4 weeks of PN 200110 administration at an average dose of 3.8 mg twice daily, the average supine blood pressure was reduced to 148.8 f 13.8/94.1 f 9.5 mm Hg (p
January
30.
1987
THE
AMERICAN
200
PN 200-110 80
JOURNAL
OF
CARDIOLOGY
Volume
59
1398
SBP mmHg
190 180
70
170 160
60
150
ns
50 50 FIGURE therapy
3. Difference (x axis)
from Center
60 in supine
and later during
70 heart
rate
PN 200-110
80 Placebo (HR) therapy
during
placebo
(y axis).
(Data
A only.)
mmHg
D6P /
administration of PN ZOO-110at the first dose level, this value increased to 70 f 7.2 beats/min (difference not significant]; at the second dose level, heart rate remained about the same at 70 f 8.3 beats/min (difference not significant). In the 27 patients randomized to an initial dose of 2.5 mg twice daily, dosage was increased in 20 patients to 5 mg twice daily during the last 4 weeks of active treatment. In these 29 patients, MAP, which had been 123 f 10 mm Hg on placebo, decreased to 116 f 6 mm Hg with the smaller dose of PN 200-110 (p
I
.
70 FIGURE
80
4. Individual
diastolic
blood
(highest
individual
surements
90
changes
pressure
(DBP)
dose).
while
100
in systolic during
X = control
receiving
110
120
blood
pressure
(SBP)
therapy
with
PN 200-I
measurements;
treatment.
(Data
from
and 10
0 = mea-
Center
A only.)
PN200-110 '30
0
I
LO
50
60
years
70
----L---
1
x
-10.
x x al II
x
-2o-
r=OSO n=20 p
-3o-
x
x
x x %I
x x
x
I x x
h MAP% FIGURE
5. Relation
mean
arterial
(Data
from
between
pressure Center
(MAP)
patient during
age and the percent treatment
with
change
in
PN 200-110.
A only.)
ized to PN 200-110 during the first 8-week period completed this part of the study without problems but was then withdrawn during the subsequent placebo period because of an excessive increase in blood pressure. Two patients were withdrawn after 4 weeks of active treatment, one because of a number of diffuse complaints and the other because ulcerations developed on his lips. These ulcerations appeared to be unrelated
1408
A SYMPOSIUM:
CALCIUM
ANTAGONISTS-EMERGING
CLINICAL
to treatment with either pindolol or PN 200-110, because they persisted after withdrawal of both drugs. Side effects noted among the patients studied at Center A included these lip ulcerations, ankle swelling in 4 patients, which could be objectively demonstrated in 2, increased diuresis in 3, one of whom experienced nocturia, mild headaches in 2, and flushing in 1.
Discussion Antihypertensive therapy is known to reduce significantly the rates of mortality and morbidity due to hypertension-induced cerebrovascular and cardiovascular disease. Several recent studies, however, clearly show that routine therapy for hypertension is not completely effective, in that treated hypertensive patients are still at considerable risk compared with normotensive individuals.1-3 One major reason for this appears to be that strictly normotensive levels are rarely attained with conventional antihypertensive therapy.4 Against this background, an investigation was undertaken to determine if the quality of antihypertensive treatment could be improved by the use of a combination of agents without causing an undue increase in the incidence of severity of side effects. In this trial, patients whose essential hypertension was not ideally controlled on pindolol treatment alone (i.e., if diastolic blood pressures were >95 mm Hg) were given the new dihydropyridine derivative calcium antagonist PN 200-110. This agent in combination with pindolol proved to have a remarkable antihypertensive effect. In a double-blind comparison with placebo, the addition of the calcium antagonist resulted in an average decrease in blood pressure of 18/15 mm Hg. This means that blood pressure was reduced to strictly normotensive levels in the majority of patients in 1 center (Fig. 4). In fact, the average blood pressure obtained in Center A at the highest dose level was 135/82 mm Hg (Fig. 2). Still, it should be kept in mind that the dose of
OPPORTUNITIES
PN 200-110 was not increased if supine diastolic blood pressure had dropped to <90 mm Hg on the lower initial dose. Thus, even more pronounced decreases in blood pressure might have been attained if the higher dose had been given to all the patients. Obviously, a pronounced decrease in blood pressure is not desirable if it is associated with numerous or severe side effects. It is encouraging that only 2 patients had to be withdrawn from the trial while on active therapy with PN 200-110, and in at least 1 of these cases the medication did not appear to be the underlying cause of the patient’s complaints. Other adverse effects were comparatively few and mild and would be tolerable during long-term treatment. Treatment with the new calcium antagonist PN 200-110 in combination with the /3-adrenoceptor blocking compound pindolol constitutes a remarkably effective and well-tolerated antihypertensive regimen. Such a combination appears to be not only useful but perhaps also necessary if strictly normotensive blood pressure levels are to be attained in most patients with mild to moderate hypertension.
References 1. Lindholm L. Hypertension and its risks. Epidemiological studies in Swedish primary he&h care. Thesis, University of Lund, 1984. 2. Isles CG, Walker LM. Beevers GD, Brown I, Cameron HL. Clarke J, Hawthorne V. Hole D. Lever AF. Robertson IWK. Waoshaw IA. Mortolitv in patients of the Glasgow blood pressure clinic. J Hypertens’1986;4:141-i56. 3. Samuelsson 0. Hypertension in middle-aged men. Acto Med Stand 1986;suppl 702:1-79. 4. Hansson L, Robertson JIS. Is hypertension treated adequately? A report from the 1986 North Cope Meeting. r Hypertens 1986. in press. 5. Hof HP, Scholtysik G, Loutzenhiser R. Vuorela HJ, Neumann P. PN 200. 110.o new calcium antagonist: electrophysiologicol. inotropic. and chronotropit effects on guinea pig myocardial tissue and effects on contraction and calcium uptake of rabbit aorta. J Cardiovasc Phormacol 1984;6:399-406. 6. Hof RP, Hof A, Scholtysik G, Menninger K. Effects of the new calcium ontugonist PN 200-110on the myocordium and the regional peripheral circulation in anesthetized cats and dogs. r Cordiovosc Pharmacol1984;6:407-416. 7. Wada Y, Satoh K. Taira N. Separation of the coronary vasodilator from the cord& effects of PN 200-110, o new dihydropyridine calcium antagonist, in the dog heart. J Cardiovasc Phormacol 1985;7:190-196.
HANSSON,
MD,
and
Preliminary results of a randomized, double-blind, placebo-controlled trial of PN 200-l 10 (isradipine) are reported. The study involves 5 centers and 61 patients with essential hypertension. Either PN 200110 or placebo was added to an ongoing daily regimen of 10 mg of pindolol to determine if this agent would enhance the effect of the P-adrenoreceptor blocking agent. PN 200-l 10 was given twice daily, starting with a dose of 2.5 mg or 5 mg, which could be doubled after 4 weeks. The average final dose
DAHLOF,
MD
was 6.3 mg given twice daily. Supine blood pressure was significantly reduced from a mean of 162/103 mm Hg to 144168 mm Hg (p
M
anv renorts have documented repeatedlv that lowering elevated arterial pressure significantly reduces hypertension-induced mortality and morbidity in cerebrovascular and cardiovascular diseases. However, several recent studies have shown a remarkably high incidence of morbidity’,” and mortality” in treated hypertensive patients compared with normotensive persons of the same sex and age from the same populations. One reason for this less than optimal response to therapy could be that blood pressure was not sufficiently lowered in any of these studies, In other words, if one wants to “normalize” a hypertensive patient’s risks, a reasonable first step should be to “normalize” the blood pressure.4 One obvious factor in attempting to achieve normotension in hypertensive patients is the need to agree on the aim of therapy. An equally important factor is whether blood pressure can be brought into the normal range with antihypertensive compounds while their side effects are limited. With these factors in mind, we chose to evaluate the new dihydropyridine derivative PN ZOO-110(isradipine) combined with pinFrom the Department of Medicine, University of Gtitcborg, Giitclmg,
BJORN
Sweden.
Address for reprints: Lcnnart Hmxson, MD, Department of hlcdicinc, University of Giitcborg, &&a Hospital, S-416 85 Gi% tcborg, Swetlen.
dolol in the treatment of hypertensive patients and to determine if this combination would effectively lower blood pressure into the normotensive range without causing unacceptable adverse effects.
Materials and Methods PN 200-110, a new calcium antagonist of the dihydropyridine group, is characterized by its distinct negative inotropic effect without causing a concomitant chronotropic effect.” It is a potent vasodilator with a long duration of action and virtually no myocardial depressant effect.” Because it is highly selective for vascular smooth muscle cells, PN ZOO-110produces coronary vasodilation at doses 12 to 14 times lower than those required for significant decreases in atrioventricular conduction time or the force of contraction.7 In anesthetized cats, PN ZOO-110has been shown to increase blood flow to heart, brain and skeletal muscle while significantly decreasing arterial pressure.” Sixty-one patients were recruited at 5 different centers Three patients were withdrawn from the study before they received PN 200-110; thus, data on the remaining 58 patients will be discussed here. There were 38 men and 20 women with an average age of 54 years (range 33 to 71) and an average weight of 82 kg [range 58 to 123). Upon routine diagnostic work-up, all were regarded as having essential hypertension and were treated with 10 mg of pindolol once daily. All
1378
1388
A SYMPOSIUM:
CALCIUM
ANTAGONISTS-EMERGING
CLINICAL
PN 200 -110
’ 130. -
MAP mm Hg n=20
A=18 (15%) p
120.
0 /
110 1 .
100 j
’
.
. .
/
0
0
.
0 0
.
0
l .
a
‘“G/. . . ; ;. , . , 90
100
110
120
130 Placebo
FIGURE 1. Difference in mean arterial pressure (MAP) in patients treated first with placebo (x axis) and then with PN 200-110 (y axis). (Data from Center A only.)
mrr Hg
150
PN ZOO-110 Y -+tr.
i 157
krl-
-*-
100
T -**rc-
70 Week
dosage
the participants gave their informed consent, and the study protocol was approved by the local ethics committees. The study began with a 3-week period during which patients were maintained on pindolol 10 mg once daily and also received placebo in a single-blind fashion. Patients whose diastolic blood pressure was >95 mm Hg were randomized to the double-blind phase to either a continuation of placebo for 8 weeks or PN ZOO-110at a starting dose of 2.5 or 5 mg twice daily, which could be doubled after 4 weeks if diastolic blood pressure was not <90 mm Hg. After 8 weeks, patients were crossed over to either PN 200-110 or placebo and again the dosage could be increased after 4 weeks. After randomization, patients were seen at 4week intervals. Blood pressure was measured after 5 minutes of supine rest and after 1 minute in the upright position using a mercury sphymomanometer [cuff balloon size 12 X 35 cm). Disappearance of the Korotkoff sounds (phase V) was used to determine diastolic blood pressure. Several clinical chemistry variables for blood and urine were also measured repeatedly during the trial and at each following visit, patients were questioned about side effects. Data from 1 center [Center A), at which 20 patients were studied, will be described in somewhat greater detail. Statistical analysis: Matched data were analyzed using &tailed test of paired data. If numbers were <30, this test was used; if numbers were 230, the normal distribution was used. Unmatched data were analyzed using the technique for analysis of differences between mean values, again using the t test for observations <3O and the normal distribution for observations of 230.
Results -I
100
OPPORTUNITIES
89
T -i#*y-
8
0 3.8mg
5.7mg
FIGURE 2. Average supine blood pressure in 20 patients while receiving placebo, then while receiving 2 sequential dosage levels of PN 200-110. (Data from Center A only.)
After the initial 3-week period with pindolol and placebo, the average blood pressure in the 58 patients was 162.4 f 14.4/104.0 f 5.0 mm Hg (mean f standard deviation). In the analysis of parallel groups, in which each patient constitutes his or her own control, administration of placebo for the next 8 weeks reduced blood pressure to an average of 161.5 f 15.3/103.1 f 7.3 mm Hg. This value did not differ significantly from blood pressure levels measured earlier, after the 3-week placebo run-in period. However, after 4 weeks of PN 200110 administration at an average dose of 3.8 mg twice daily, the average supine blood pressure was reduced to 148.8 f 13.8/94.1 f 9.5 mm Hg (p
January
30.
1987
THE
AMERICAN
200
PN 200-110 80
JOURNAL
OF
CARDIOLOGY
Volume
59
1398
SBP mmHg
190 180
70
170 160
60
150
ns
50 50 FIGURE therapy
3. Difference (x axis)
from Center
60 in supine
and later during
70 heart
rate
PN 200-110
80 Placebo (HR) therapy
during
placebo
(y axis).
(Data
A only.)
mmHg
D6P /
administration of PN ZOO-110at the first dose level, this value increased to 70 f 7.2 beats/min (difference not significant]; at the second dose level, heart rate remained about the same at 70 f 8.3 beats/min (difference not significant). In the 27 patients randomized to an initial dose of 2.5 mg twice daily, dosage was increased in 20 patients to 5 mg twice daily during the last 4 weeks of active treatment. In these 29 patients, MAP, which had been 123 f 10 mm Hg on placebo, decreased to 116 f 6 mm Hg with the smaller dose of PN 200-110 (p
I
.
70 FIGURE
80
4. Individual
diastolic
blood
(highest
individual
surements
90
changes
pressure
(DBP)
dose).
while
100
in systolic during
X = control
receiving
110
120
blood
pressure
(SBP)
therapy
with
PN 200-I
measurements;
treatment.
(Data
from
and 10
0 = mea-
Center
A only.)
PN200-110 '30
0
I
LO
50
60
years
70
----L---
1
x
-10.
x x al II
x
-2o-
r=OSO n=20 p
-3o-
x
x
x x %I
x x
x
I x x
h MAP% FIGURE
5. Relation
mean
arterial
(Data
from
between
pressure Center
(MAP)
patient during
age and the percent treatment
with
change
in
PN 200-110.
A only.)
ized to PN 200-110 during the first 8-week period completed this part of the study without problems but was then withdrawn during the subsequent placebo period because of an excessive increase in blood pressure. Two patients were withdrawn after 4 weeks of active treatment, one because of a number of diffuse complaints and the other because ulcerations developed on his lips. These ulcerations appeared to be unrelated
1408
A SYMPOSIUM:
CALCIUM
ANTAGONISTS-EMERGING
CLINICAL
to treatment with either pindolol or PN 200-110, because they persisted after withdrawal of both drugs. Side effects noted among the patients studied at Center A included these lip ulcerations, ankle swelling in 4 patients, which could be objectively demonstrated in 2, increased diuresis in 3, one of whom experienced nocturia, mild headaches in 2, and flushing in 1.
Discussion Antihypertensive therapy is known to reduce significantly the rates of mortality and morbidity due to hypertension-induced cerebrovascular and cardiovascular disease. Several recent studies, however, clearly show that routine therapy for hypertension is not completely effective, in that treated hypertensive patients are still at considerable risk compared with normotensive individuals.1-3 One major reason for this appears to be that strictly normotensive levels are rarely attained with conventional antihypertensive therapy.4 Against this background, an investigation was undertaken to determine if the quality of antihypertensive treatment could be improved by the use of a combination of agents without causing an undue increase in the incidence of severity of side effects. In this trial, patients whose essential hypertension was not ideally controlled on pindolol treatment alone (i.e., if diastolic blood pressures were >95 mm Hg) were given the new dihydropyridine derivative calcium antagonist PN 200-110. This agent in combination with pindolol proved to have a remarkable antihypertensive effect. In a double-blind comparison with placebo, the addition of the calcium antagonist resulted in an average decrease in blood pressure of 18/15 mm Hg. This means that blood pressure was reduced to strictly normotensive levels in the majority of patients in 1 center (Fig. 4). In fact, the average blood pressure obtained in Center A at the highest dose level was 135/82 mm Hg (Fig. 2). Still, it should be kept in mind that the dose of
OPPORTUNITIES
PN 200-110 was not increased if supine diastolic blood pressure had dropped to <90 mm Hg on the lower initial dose. Thus, even more pronounced decreases in blood pressure might have been attained if the higher dose had been given to all the patients. Obviously, a pronounced decrease in blood pressure is not desirable if it is associated with numerous or severe side effects. It is encouraging that only 2 patients had to be withdrawn from the trial while on active therapy with PN 200-110, and in at least 1 of these cases the medication did not appear to be the underlying cause of the patient’s complaints. Other adverse effects were comparatively few and mild and would be tolerable during long-term treatment. Treatment with the new calcium antagonist PN 200-110 in combination with the /3-adrenoceptor blocking compound pindolol constitutes a remarkably effective and well-tolerated antihypertensive regimen. Such a combination appears to be not only useful but perhaps also necessary if strictly normotensive blood pressure levels are to be attained in most patients with mild to moderate hypertension.
References 1. Lindholm L. Hypertension and its risks. Epidemiological studies in Swedish primary he&h care. Thesis, University of Lund, 1984. 2. Isles CG, Walker LM. Beevers GD, Brown I, Cameron HL. Clarke J, Hawthorne V. Hole D. Lever AF. Robertson IWK. Waoshaw IA. Mortolitv in patients of the Glasgow blood pressure clinic. J Hypertens’1986;4:141-i56. 3. Samuelsson 0. Hypertension in middle-aged men. Acto Med Stand 1986;suppl 702:1-79. 4. Hansson L, Robertson JIS. Is hypertension treated adequately? A report from the 1986 North Cope Meeting. r Hypertens 1986. in press. 5. Hof HP, Scholtysik G, Loutzenhiser R. Vuorela HJ, Neumann P. PN 200. 110.o new calcium antagonist: electrophysiologicol. inotropic. and chronotropit effects on guinea pig myocardial tissue and effects on contraction and calcium uptake of rabbit aorta. J Cardiovasc Phormacol 1984;6:399-406. 6. Hof RP, Hof A, Scholtysik G, Menninger K. Effects of the new calcium ontugonist PN 200-110on the myocordium and the regional peripheral circulation in anesthetized cats and dogs. r Cordiovosc Pharmacol1984;6:407-416. 7. Wada Y, Satoh K. Taira N. Separation of the coronary vasodilator from the cord& effects of PN 200-110, o new dihydropyridine calcium antagonist, in the dog heart. J Cardiovasc Phormacol 1985;7:190-196.