- Email: [email protected]
Dilevalol compared with propranolol and placebo for systemic hypertension
Dilevalol Compared with Propranolol and Placebo for Systemic Hypertension James A. Schoenberger, MD, William H. Frishman, MD, J. David Wallin, MD, Jeffrey Gorwit, MD, Michael E. Davidov, MD, Eric L. Michelson, MD, Glen D. Bedsole, MD, Judith Cubbon, MD, and Marcia P. Poland, MA
Dilevalol is a new antihypertensive agent that is both a vasodilator, through its &-agonist action, and a nonselective ji antagonist. Two multicenter, double-blind studies were performed: study 1 compared dilevalol administered once-daily with either dilevalol or propranolol every 12 hours; study 2 compared dilevalol administered once daily with placeco. Both studies had a placebo run-in period to establish that the baseline supine diastolic blood pressures were consistent in the mild to moderate severity range (95 to 115 mm Hg) at 2 consecutive visits for study 1 and in the mild severity range (95 to 106 mm Hg) in study 2. Patients then were randomized to the double-blind titration phase, during whiih doses were titrated over a 9-week period to achieve a supine diastolic blood pressure of <90 mm Hg and a decrease from baseline of I10 mm Hg. Patients were then maintained on a fixed dose for 2 months (study 1) or for 1 month (study 2). Dilevalol given once daily was as effective in reducing supine diastolic blood pressure as dilevalol every 12 hours and propranolol every 12 hours (study 1) and was superior to placebo (p
From Rush Medical College, Chicago, Illinois; Albert Einstein College of Medicine, Bronx, New York; Tulane University Medical School, New Orleans, Louisiana; Escondido Cardiology Associates, Escondido, California; Georgetown University Medical Center, Washington, DC; Lankenau Medical Research Center, Philadelphia, Pennsylvania; Drug Research and Analyses, Montgomery, Alabama; and Schering-Plough Corporation, Kenilworth, New Jersey. Address for reprints: James A. Schoenberger, MD, Rush Medical College, 1725 West Harrison Street, Chicago, IL 60612.
he clinical usefulness of antihypertensive agents has been expanded by the availability of drugs that have selective antagonist activity at either pior &receptor sites. Newer drugs have, in addition, agonist activity at 1 or both sites and thus further increase therapeutic options. The combination of selective and nonselective antagonism with partial agonism at either preceptor site has given rise to the development of antihypertensive agents that differ in their pharmacologic actions.‘*2 These are likely to be clinically useful and important additions to current treatment methods. One of these newer agents is dilevalol hydrochloride. Its direct vasodilating properties mediated through selective ,&zagonism, combined with /3 antagonism, makes it a useful drug in the treatment of hypertension.3,4 In this report, 2 studies evaluating dilevalol’s antihypertensive efficacy are described. The first compares dilevalol administered once daily with dilevalol or propran0101administered every 12 hours in hypertension management. The second compares dilevalol’s ability to reduce blood pressure with that of placebo.
T
METHODS
Two double-blind multicenter studies were designed to assessdifferent aspects of dilevalol’s antihypertensive effects. Study 1 focused on patients with hypertension in the mild to moderate range of severity. It was designed to determine if dilevalol given once daily was as effective as when given every 12 hours daily, and how its antihypertensive effect compared with a reference standard-in this case, propranolol. The objective of study 2 was to demonstrate the antihypertensive effect of dilevalol administered once daily by comparing it with placebo therapy in patients with hypertension of mild severity. Study designs are shown in Figure 1. Both studies began with a placebo washout phase; in study 1, the placebo period was 3 weeks for previously untreated mild to moderate hypertensive patients and 4 weeks for those who had been receiving antihypertensive medication. Study 2 had a 4-week placebo washout phase. All study 2 subjects had mild hypertension. To qualify for randomization, a patient’s supine diastolic blood pressure (DBP) at the last 2 visits had to be within the limits shown in Figure 1. In both studies, doses were titrated over a 9week period to achieve a supine DBP of <90 mm Hg that was decreased by > 10 mm Hg from baseline at 2 consecutive visits. For each patient, the titration phase ended and the maintenance phase began when this therapeutic goal was reached. Patients who did not achieve goal even THE AMERICAN JOURNAL OF CARDIOLOGY JUNE 5.1989
45 I
A SYMPOStUM:
ANTIHYPE#TENSION
THERAPY
IN THE 9th
Phase I
Phase Ill
Phase II
\ Double-Blind
\\
Titration
\-
Goal: Supine DBP-zSO mmlig and 1210 mmHg from Baseline
Randomization into DoubleBlind Titration
.
Maintenance Fixed Dose
\Studv Propranolol
Dilevalol
~~~~ay~
Placebo
No. 1
2 Months
st[$
1 Study
No. 2
1 Month
\
4-----J N 16004801 8oo I I 3-4 Weeks
‘Readlng>95 “D~levalol
mmHg given
once
I
2-10 Weeks
u
at 1 of the 2 qualifying dally
placebo
given
in the evening
after administration of the highest dose (study l-l,600 mg; study 2-800 mg) could enter the maintenance phase if their supine DBP had decreased by 25 and was
The effects on blood pressure and heart rate were compared using: analysis of variance after the first week with 200 mg of dilevalol, 80 mg of propranolol, or with placebo; at the end of the titration period; and at the last maintenance dosing visit while the patient was taking the study drug alone. Fisher 2-tailed exact test was used to compare the proportion of patients reporting specific side effects judged at least possibly treatment-related by the investigator. RESULTS Patients:
A total of 223 patients were enrolled in study 1, but at the end of the washout period 50 failed to qualify for randomization (i.e., their supine DBP was outside the specific range, they had intercurrent medical problems, or they were noncompliant with visits or dosing). The remaining 173 patients were randomized to 46
1
\ L
dose
FIGURE 1. Study design. SuDBP = supine diistolii bbod pressure. bo given in the evening dose; same mber of capsules.
STATISTICAL
]
wits
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63
*Reading
195 mm Hg at 1 ad the 2 qualii
visitq
place-
dilevalol once daily (n = 54), dilevalol every 12 hours (n = 60) or propranolol every 12 hours (n = 59). One patient in the dilevalol once-daily group took a diuretic before the first titration visit and was therefore excluded from the efficacy analysis. An additional 4 patients (dilevalol = 3, propranolol = 1) were unable to meet the blood pressure criteria, but were randomized in error and terminated from the study. These 5 patients are included in the safety analysis. In study 2, 238 patients were enrolled, but during the washout period 105 were excluded before randomization, primarily because their supine DBP was above or below the entry criteria. The remaining 133 patients were randomized to dilevalol (n = 67) or placebo (n = 66) in a double-blind fashion. Five patients had at least 1 baseline blood pressure reading above the mild range and were excluded from the efficacy analysis. The demographic profiles of the patients in each study were similar, with no significant treatment group differences (Table I). Treatment groups were middle-aged, mostly men, and had a long history of hypertension. Study 1 comprised white patients who had either mild or moderate hypertension, whereas study 2 enrolled black and white patients, but restricted the severity of hypertension to mild. Blood pressure and heart rate: During the titration period, both studies contained at least 1 week of treatment with dilevalol, 200 mg. In study 1, blood pressures. decreased by 10/8 mm Hg with dilevalol(200 mg oncedaily), 9.5/8.1 mm Hg with dilevalol (100 mg every 12 hours) and 8.7/8.3 mm Hg with propranolol (40 mg every 12 hours) (Fig. 2). Blood pressure reductions of 13.7/7.3 mm Hg were found with dilevalol(200 mg oncedaily in study 2); these decreaseswere significantly greater (p <0.002) than the placebo response of 2.6/3 mm Hg. Further titration of the dose in study 1, followed by a maintenance period, resulted in further decrements in
TABLE
I Demographic
Profile
of the Patients
Randomized
in Study
1 and Study
2 Study 2
Study 1 Dilevalol Propranolol (Every 12 Hours)
Dilevalol (Once Daily)
(mean years) % 165 years Sex % Men Race % Black Weight (mean Ibs) Duration of hypertension (mean years) Severity of hypertension % Mild (SuDBP < 105 mm Hg) % Moderate (SuDBP > 105 mm Hg) SuDBP = supine diastolic
Dilevalol (Once Daily)
Placebo (Once Daily)
53 8
55 8
55 10
52
52
57
67
73
59
57
0
0
0
25
31
181
185
181
196
194
10.6
8.3 77 23
83 17
9.5
8.5
8.9
100
78 22
100
blood pressure.
blood pressure in these mild to moderate hypertensive patients. Daily dosages of dilevalol ranged from 200 to 1,600 mg, with a median dose of 600 mg given either once daily or split into a daily regimen of every 12 hours; the median dose of propranolol was 120 mg every 12 hours. In study 2, higher doses of dilevalol resulted in very little additional blood pressure reduction. Minimal placebo response seen after the second dose titration was diminished by the last visit of the study (from -2.6/-3 to +l/-2 mm Hg). Once again, the blood pressure-lowering effect of dilevalol was superior to that of placebo (p
dilevalol; this difference was statistically significant (p
n
FIGURE 2. Blood (W -s in stwly 1 (top) and hdy 2 (bottom). *patients who achieved ule the-fapeutic goal with dilsvald, 100 mg, &d not receivelhe2W-mgdose.
End Treatment
First
Week
of Rx
133 End Treatment
r
154/100
5
152/100
60
UJ 154IlOO
59
53
First
Week
of Rx
156199
46
154199
51
6 a CJ’I 156199
63
154199
65
N
THE AMERICAN
JOURNAL
OF CARDIOLOGY
JUNE 5.1989
47 I
A SYMPOSlUM:
ANYIHYPERYENSION
THERAPY
IN THE 90s
Terminations: In study 1, 10 of the 117 patients (8.5%) treated with dilevalol and 3 of the 60 (5%) treated with propranolol were unable to reach therapeutic goals. Fifty-five percent of placebo-treatedpatients in study 2 were unable to reach therapeutic goal, compared with 30% of those treated with dilevalol (p
TABLE
11 Incidence
(%) of Most
Frequent*
Adverse
Effects
tricular tachycardia that required intravenous verapamil therapy. Two other patients were withdrawn becauseof nonspecific chest pain; coronary artery diseasecould not be confirmed. Side effects: Fifty-live percent of the dilevalol- and propranolol-treated patients voiced at least 1 complaint during study 1. In study 2, a slightly higher proportion of patients--67% of the dilevalol-treated and 61% of the placebo-treatedpatients-reported at least 1 complaint. The most frequent (22%) adverseeffectsjudged possibly or probably related to treatment by the investigators are listed in Table II. The table doesnot include patients who had the samecomplaint during the placebowashout period, with severity of the complaint unchanged during active treatment. Three adverseeffects occurred significantly more of‘ten with propranolol dosing than with dilevalol: depression (p <0.04), fatigue (p <0.04) and bradycardiadefined as heart rate <50 beats/min (p <0.05). Diarrhea/loose stools occurred significantly more (p >0.05) with dilevalol than with propranolol. In study 2, there were no significant side-effectdifferencesbetweendileva101and placebo.The only adverseeffect that appearedto be clinically meaningful, but whose incidence was not statistically different from placebo, was dizziness;there was an 8% incidence associatedwith dilevalol dosing,
Judged
by Investigators
to be at Least Possibly
Dilevalol (n = 117)
l
2
Propranolol (n = 60)
I
JOURNAL
Placebo (n = 66)
2 2
3 2
-
-
3 5% 3 5 2 2
-
2 2 -
3 1’
2 5 -
3 7* 7 2 5
3
2
7 2 5
3 3 5
3 2 2 2
3 2
12% 2
-
5
2
2 2 8 2 3 3 8 3 2
2 3 2 2 5 6 6 -
3 2 7 3 7 9 8
10 5 3 23’ 5 3 -
1
2%.
THE AMERICAN
Dilevalol (n = 67)
1* 3
7 Percent rellects 1 man in each treatment group. * Dierence between treatment groups. P CO.05.
48
OF CARDIOLOGY
VOLUME
to Treatment
Study 2
Study 1
Autonomic nervous system Impotence+ Increased sweating Central nervous system Anorexia Depression Dreams (bad, vivid) Insomnia Somnolence Visual hallucination Gastrointestinal Abdominal cramps Diarrhea Dyspepsia Flatulence Nausea Heart rate and rhythm Bradycardia (50 beats/min) Palpitations Other systems Asthenia Chest pain Dizziness Dyspnea Edema Fatigue Headache Leg cramps Tremor
Related
63
compared to 2% with placebo. In study 1, the incidence of dizziness with dilevalol was 7% and with propranolol, 10%. DISCUSSION The studies reported in this paper were designed to extend the evidence for the usefulness of dilevalol in the treatment of hypertension. In study 1, dilevalol was found to be effective in reducing blood pressure in both mild and moderate hypertension. After 1 week of treatment with either dilevalol 200 mg administered once daily or 100 mg every 12 hours the reduction in blood pressure was comparable for patients with either mild or moderate hypertension. Continued treatment with increasing dose titration to a median dose of 600 mgjday resulted in further declines in blood pressure. At this median dose of 600 mg, 68% of patients achieved normal blood pressure with a once-a-day dose, and 70% with dosing every 12 hours. These results were comparable to those achieved with a median propranolol dose of 120 mg every 12 hours daily. In study 2, dilevalol was clearly more effective than placebo. Thus, dilevalol was effective in reducing mild to moderate hypertension in over two-thirds of the patients in these studies when given once daily. The once-daily administration of an antihypertensive drug has important advantages from the standpoint of compliance. Although the number of black patients in the second study were few, dilevalol appeared to be as effective in black as in white patients. In the elderly, normotension was achieved in 62% of patients who received dilevalol. Treatment failures occurred in 8.5% of dilevalol-treated patients compared with 5% of patients taking propran0101and 55% of placebo-treated patients. Adverse experiences requiring termination of the study were observed in
7 and 12% of patients treated with dilevalol and propran0101,respectively. Adverse effects considered to be probably or possibly related to treatment were uncommon in both the dilevalol and the propranolol groups. Depression was noted in 5%, fatigue in 23% and bradycardia in 12% of propranololtreated patients-all significantly greater values than were found in the dilevalol-treated patients. In contrast, 7% of dilevalol-treated patients reported diarrhea. In the second study, no significant difference in the incidence of adverse effects was noted when comparing dilevalol with placebo treatment. These results suggest that dilevalol was well tolerated, possibly more so than propranolol. The results of this clinical trial indicate, perhaps, dilevelol may be associated with better quality of life and greater likelihood of long-term adherence to treatment.5 Acknowledgment: Lankenau Medical Research Center wishes to thank Henry S. Sawin, Jr, MD, Collaborating Investigator; Susan A. Sabol, MS; and Colleen Long, RN, Study Coordinators.
REFERENCES 1. Lund-Johansen P. Hemodynamics of antihypertensive therapy. In Messerli FH, ed. The Heart and Hypertension. New York: Yorke Medical Books, 1987:27S-286. 2. Frishman WH. Pharmacodynamic and pharmacokinetic properties. In Frishman WH, ed. Clinical Pharmacology of the &Adrenoceptor Blocking Drugs. 2nd ed. Connecticut: Appleton-Century-Crofts, 1984:13-26. 3. Baum T, Watkins RW, Sybertz EJ, Vemulapalli S, F’ula KK, Eynon E, Nelson S, Vander Vliet G, Glennon~J, Moran RM. A&ihypertensive and hemodynamic actions of SCH 19927, the R,R-isomer of labetalol. J Pharmacol Exp Ther 1981:218:444-452. 4. Bugni WJ, Ayers CW, Ashby R, Bittle PA, Ram&z G. Effects of dilevalol on rest and supine exercise hemodynamics in mild to moderate systemic hypertension. Am J Cardiol 1989.63:452-4S6. 5. Croog SH, Levine S, Testa MA. The effects of antihypertensive therapy on quality of life. N Engl J Med 1986;314:1657m1664.
THE AMERICAN JOURNAL OF CARDIOLOGY JUNE 5.1989
49 I
Dilevalol is a new antihypertensive agent that is both a vasodilator, through its &-agonist action, and a nonselective ji antagonist. Two multicenter, double-blind studies were performed: study 1 compared dilevalol administered once-daily with either dilevalol or propranolol every 12 hours; study 2 compared dilevalol administered once daily with placeco. Both studies had a placebo run-in period to establish that the baseline supine diastolic blood pressures were consistent in the mild to moderate severity range (95 to 115 mm Hg) at 2 consecutive visits for study 1 and in the mild severity range (95 to 106 mm Hg) in study 2. Patients then were randomized to the double-blind titration phase, during whiih doses were titrated over a 9-week period to achieve a supine diastolic blood pressure of <90 mm Hg and a decrease from baseline of I10 mm Hg. Patients were then maintained on a fixed dose for 2 months (study 1) or for 1 month (study 2). Dilevalol given once daily was as effective in reducing supine diastolic blood pressure as dilevalol every 12 hours and propranolol every 12 hours (study 1) and was superior to placebo (p
From Rush Medical College, Chicago, Illinois; Albert Einstein College of Medicine, Bronx, New York; Tulane University Medical School, New Orleans, Louisiana; Escondido Cardiology Associates, Escondido, California; Georgetown University Medical Center, Washington, DC; Lankenau Medical Research Center, Philadelphia, Pennsylvania; Drug Research and Analyses, Montgomery, Alabama; and Schering-Plough Corporation, Kenilworth, New Jersey. Address for reprints: James A. Schoenberger, MD, Rush Medical College, 1725 West Harrison Street, Chicago, IL 60612.
he clinical usefulness of antihypertensive agents has been expanded by the availability of drugs that have selective antagonist activity at either pior &receptor sites. Newer drugs have, in addition, agonist activity at 1 or both sites and thus further increase therapeutic options. The combination of selective and nonselective antagonism with partial agonism at either preceptor site has given rise to the development of antihypertensive agents that differ in their pharmacologic actions.‘*2 These are likely to be clinically useful and important additions to current treatment methods. One of these newer agents is dilevalol hydrochloride. Its direct vasodilating properties mediated through selective ,&zagonism, combined with /3 antagonism, makes it a useful drug in the treatment of hypertension.3,4 In this report, 2 studies evaluating dilevalol’s antihypertensive efficacy are described. The first compares dilevalol administered once daily with dilevalol or propran0101administered every 12 hours in hypertension management. The second compares dilevalol’s ability to reduce blood pressure with that of placebo.
T
METHODS
Two double-blind multicenter studies were designed to assessdifferent aspects of dilevalol’s antihypertensive effects. Study 1 focused on patients with hypertension in the mild to moderate range of severity. It was designed to determine if dilevalol given once daily was as effective as when given every 12 hours daily, and how its antihypertensive effect compared with a reference standard-in this case, propranolol. The objective of study 2 was to demonstrate the antihypertensive effect of dilevalol administered once daily by comparing it with placebo therapy in patients with hypertension of mild severity. Study designs are shown in Figure 1. Both studies began with a placebo washout phase; in study 1, the placebo period was 3 weeks for previously untreated mild to moderate hypertensive patients and 4 weeks for those who had been receiving antihypertensive medication. Study 2 had a 4-week placebo washout phase. All study 2 subjects had mild hypertension. To qualify for randomization, a patient’s supine diastolic blood pressure (DBP) at the last 2 visits had to be within the limits shown in Figure 1. In both studies, doses were titrated over a 9week period to achieve a supine DBP of <90 mm Hg that was decreased by > 10 mm Hg from baseline at 2 consecutive visits. For each patient, the titration phase ended and the maintenance phase began when this therapeutic goal was reached. Patients who did not achieve goal even THE AMERICAN JOURNAL OF CARDIOLOGY JUNE 5.1989
45 I
A SYMPOStUM:
ANTIHYPE#TENSION
THERAPY
IN THE 9th
Phase I
Phase Ill
Phase II
\ Double-Blind
\\
Titration
\-
Goal: Supine DBP-zSO mmlig and 1210 mmHg from Baseline
Randomization into DoubleBlind Titration
.
Maintenance Fixed Dose
\Studv Propranolol
Dilevalol
~~~~ay~
Placebo
No. 1
2 Months
st[$
1 Study
No. 2
1 Month
\
4-----J N 16004801 8oo I I 3-4 Weeks
‘Readlng>95 “D~levalol
mmHg given
once
I
2-10 Weeks
u
at 1 of the 2 qualifying dally
placebo
given
in the evening
after administration of the highest dose (study l-l,600 mg; study 2-800 mg) could enter the maintenance phase if their supine DBP had decreased by 25 and was
The effects on blood pressure and heart rate were compared using: analysis of variance after the first week with 200 mg of dilevalol, 80 mg of propranolol, or with placebo; at the end of the titration period; and at the last maintenance dosing visit while the patient was taking the study drug alone. Fisher 2-tailed exact test was used to compare the proportion of patients reporting specific side effects judged at least possibly treatment-related by the investigator. RESULTS Patients:
A total of 223 patients were enrolled in study 1, but at the end of the washout period 50 failed to qualify for randomization (i.e., their supine DBP was outside the specific range, they had intercurrent medical problems, or they were noncompliant with visits or dosing). The remaining 173 patients were randomized to 46
1
\ L
dose
FIGURE 1. Study design. SuDBP = supine diistolii bbod pressure. bo given in the evening dose; same mber of capsules.
STATISTICAL
]
wits
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63
*Reading
195 mm Hg at 1 ad the 2 qualii
visitq
place-
dilevalol once daily (n = 54), dilevalol every 12 hours (n = 60) or propranolol every 12 hours (n = 59). One patient in the dilevalol once-daily group took a diuretic before the first titration visit and was therefore excluded from the efficacy analysis. An additional 4 patients (dilevalol = 3, propranolol = 1) were unable to meet the blood pressure criteria, but were randomized in error and terminated from the study. These 5 patients are included in the safety analysis. In study 2, 238 patients were enrolled, but during the washout period 105 were excluded before randomization, primarily because their supine DBP was above or below the entry criteria. The remaining 133 patients were randomized to dilevalol (n = 67) or placebo (n = 66) in a double-blind fashion. Five patients had at least 1 baseline blood pressure reading above the mild range and were excluded from the efficacy analysis. The demographic profiles of the patients in each study were similar, with no significant treatment group differences (Table I). Treatment groups were middle-aged, mostly men, and had a long history of hypertension. Study 1 comprised white patients who had either mild or moderate hypertension, whereas study 2 enrolled black and white patients, but restricted the severity of hypertension to mild. Blood pressure and heart rate: During the titration period, both studies contained at least 1 week of treatment with dilevalol, 200 mg. In study 1, blood pressures. decreased by 10/8 mm Hg with dilevalol(200 mg oncedaily), 9.5/8.1 mm Hg with dilevalol (100 mg every 12 hours) and 8.7/8.3 mm Hg with propranolol (40 mg every 12 hours) (Fig. 2). Blood pressure reductions of 13.7/7.3 mm Hg were found with dilevalol(200 mg oncedaily in study 2); these decreaseswere significantly greater (p <0.002) than the placebo response of 2.6/3 mm Hg. Further titration of the dose in study 1, followed by a maintenance period, resulted in further decrements in
TABLE
I Demographic
Profile
of the Patients
Randomized
in Study
1 and Study
2 Study 2
Study 1 Dilevalol Propranolol (Every 12 Hours)
Dilevalol (Once Daily)
(mean years) % 165 years Sex % Men Race % Black Weight (mean Ibs) Duration of hypertension (mean years) Severity of hypertension % Mild (SuDBP < 105 mm Hg) % Moderate (SuDBP > 105 mm Hg) SuDBP = supine diastolic
Dilevalol (Once Daily)
Placebo (Once Daily)
53 8
55 8
55 10
52
52
57
67
73
59
57
0
0
0
25
31
181
185
181
196
194
10.6
8.3 77 23
83 17
9.5
8.5
8.9
100
78 22
100
blood pressure.
blood pressure in these mild to moderate hypertensive patients. Daily dosages of dilevalol ranged from 200 to 1,600 mg, with a median dose of 600 mg given either once daily or split into a daily regimen of every 12 hours; the median dose of propranolol was 120 mg every 12 hours. In study 2, higher doses of dilevalol resulted in very little additional blood pressure reduction. Minimal placebo response seen after the second dose titration was diminished by the last visit of the study (from -2.6/-3 to +l/-2 mm Hg). Once again, the blood pressure-lowering effect of dilevalol was superior to that of placebo (p
dilevalol; this difference was statistically significant (p
n
FIGURE 2. Blood (W -s in stwly 1 (top) and hdy 2 (bottom). *patients who achieved ule the-fapeutic goal with dilsvald, 100 mg, &d not receivelhe2W-mgdose.
End Treatment
First
Week
of Rx
133 End Treatment
r
154/100
5
152/100
60
UJ 154IlOO
59
53
First
Week
of Rx
156199
46
154199
51
6 a CJ’I 156199
63
154199
65
N
THE AMERICAN
JOURNAL
OF CARDIOLOGY
JUNE 5.1989
47 I
A SYMPOSlUM:
ANYIHYPERYENSION
THERAPY
IN THE 90s
Terminations: In study 1, 10 of the 117 patients (8.5%) treated with dilevalol and 3 of the 60 (5%) treated with propranolol were unable to reach therapeutic goals. Fifty-five percent of placebo-treatedpatients in study 2 were unable to reach therapeutic goal, compared with 30% of those treated with dilevalol (p
TABLE
11 Incidence
(%) of Most
Frequent*
Adverse
Effects
tricular tachycardia that required intravenous verapamil therapy. Two other patients were withdrawn becauseof nonspecific chest pain; coronary artery diseasecould not be confirmed. Side effects: Fifty-live percent of the dilevalol- and propranolol-treated patients voiced at least 1 complaint during study 1. In study 2, a slightly higher proportion of patients--67% of the dilevalol-treated and 61% of the placebo-treatedpatients-reported at least 1 complaint. The most frequent (22%) adverseeffectsjudged possibly or probably related to treatment by the investigators are listed in Table II. The table doesnot include patients who had the samecomplaint during the placebowashout period, with severity of the complaint unchanged during active treatment. Three adverseeffects occurred significantly more of‘ten with propranolol dosing than with dilevalol: depression (p <0.04), fatigue (p <0.04) and bradycardiadefined as heart rate <50 beats/min (p <0.05). Diarrhea/loose stools occurred significantly more (p >0.05) with dilevalol than with propranolol. In study 2, there were no significant side-effectdifferencesbetweendileva101and placebo.The only adverseeffect that appearedto be clinically meaningful, but whose incidence was not statistically different from placebo, was dizziness;there was an 8% incidence associatedwith dilevalol dosing,
Judged
by Investigators
to be at Least Possibly
Dilevalol (n = 117)
l
2
Propranolol (n = 60)
I
JOURNAL
Placebo (n = 66)
2 2
3 2
-
-
3 5% 3 5 2 2
-
2 2 -
3 1’
2 5 -
3 7* 7 2 5
3
2
7 2 5
3 3 5
3 2 2 2
3 2
12% 2
-
5
2
2 2 8 2 3 3 8 3 2
2 3 2 2 5 6 6 -
3 2 7 3 7 9 8
10 5 3 23’ 5 3 -
1
2%.
THE AMERICAN
Dilevalol (n = 67)
1* 3
7 Percent rellects 1 man in each treatment group. * Dierence between treatment groups. P CO.05.
48
OF CARDIOLOGY
VOLUME
to Treatment
Study 2
Study 1
Autonomic nervous system Impotence+ Increased sweating Central nervous system Anorexia Depression Dreams (bad, vivid) Insomnia Somnolence Visual hallucination Gastrointestinal Abdominal cramps Diarrhea Dyspepsia Flatulence Nausea Heart rate and rhythm Bradycardia (50 beats/min) Palpitations Other systems Asthenia Chest pain Dizziness Dyspnea Edema Fatigue Headache Leg cramps Tremor
Related
63
compared to 2% with placebo. In study 1, the incidence of dizziness with dilevalol was 7% and with propranolol, 10%. DISCUSSION The studies reported in this paper were designed to extend the evidence for the usefulness of dilevalol in the treatment of hypertension. In study 1, dilevalol was found to be effective in reducing blood pressure in both mild and moderate hypertension. After 1 week of treatment with either dilevalol 200 mg administered once daily or 100 mg every 12 hours the reduction in blood pressure was comparable for patients with either mild or moderate hypertension. Continued treatment with increasing dose titration to a median dose of 600 mgjday resulted in further declines in blood pressure. At this median dose of 600 mg, 68% of patients achieved normal blood pressure with a once-a-day dose, and 70% with dosing every 12 hours. These results were comparable to those achieved with a median propranolol dose of 120 mg every 12 hours daily. In study 2, dilevalol was clearly more effective than placebo. Thus, dilevalol was effective in reducing mild to moderate hypertension in over two-thirds of the patients in these studies when given once daily. The once-daily administration of an antihypertensive drug has important advantages from the standpoint of compliance. Although the number of black patients in the second study were few, dilevalol appeared to be as effective in black as in white patients. In the elderly, normotension was achieved in 62% of patients who received dilevalol. Treatment failures occurred in 8.5% of dilevalol-treated patients compared with 5% of patients taking propran0101and 55% of placebo-treated patients. Adverse experiences requiring termination of the study were observed in
7 and 12% of patients treated with dilevalol and propran0101,respectively. Adverse effects considered to be probably or possibly related to treatment were uncommon in both the dilevalol and the propranolol groups. Depression was noted in 5%, fatigue in 23% and bradycardia in 12% of propranololtreated patients-all significantly greater values than were found in the dilevalol-treated patients. In contrast, 7% of dilevalol-treated patients reported diarrhea. In the second study, no significant difference in the incidence of adverse effects was noted when comparing dilevalol with placebo treatment. These results suggest that dilevalol was well tolerated, possibly more so than propranolol. The results of this clinical trial indicate, perhaps, dilevelol may be associated with better quality of life and greater likelihood of long-term adherence to treatment.5 Acknowledgment: Lankenau Medical Research Center wishes to thank Henry S. Sawin, Jr, MD, Collaborating Investigator; Susan A. Sabol, MS; and Colleen Long, RN, Study Coordinators.
REFERENCES 1. Lund-Johansen P. Hemodynamics of antihypertensive therapy. In Messerli FH, ed. The Heart and Hypertension. New York: Yorke Medical Books, 1987:27S-286. 2. Frishman WH. Pharmacodynamic and pharmacokinetic properties. In Frishman WH, ed. Clinical Pharmacology of the &Adrenoceptor Blocking Drugs. 2nd ed. Connecticut: Appleton-Century-Crofts, 1984:13-26. 3. Baum T, Watkins RW, Sybertz EJ, Vemulapalli S, F’ula KK, Eynon E, Nelson S, Vander Vliet G, Glennon~J, Moran RM. A&ihypertensive and hemodynamic actions of SCH 19927, the R,R-isomer of labetalol. J Pharmacol Exp Ther 1981:218:444-452. 4. Bugni WJ, Ayers CW, Ashby R, Bittle PA, Ram&z G. Effects of dilevalol on rest and supine exercise hemodynamics in mild to moderate systemic hypertension. Am J Cardiol 1989.63:452-4S6. 5. Croog SH, Levine S, Testa MA. The effects of antihypertensive therapy on quality of life. N Engl J Med 1986;314:1657m1664.
THE AMERICAN JOURNAL OF CARDIOLOGY JUNE 5.1989
49 I