A double-blind comparative study of doxazosin and prazosin in the treatment of essential hypertension Two hundred sixty-six patients took part in a multicenter comparative study of doxazosin and prazosin. Both drugs produced a significant reduction (p < 0.001) in blood pressure and no increase in heart rate. Blood pressure was considered “markedly decreased” or “decreased” in 70.6% of patients treated with doxazosin and 70.0% of patients treated with prazosin. No statistically significant between-group differences in antihypertensive efficacy were observed. Both doxarosin and prazosin were well tolerated; seven patients (5.6%) in each group had the therapy withdrawn.(Au HEART J 1991;121:317-22.)
Koshiro Fukiyama, MD, Teruo Omae, MD, Osamu Iimura, MD, Kaoru Yoshinaga, MD, Shigeru Yagi, MD, Yoshiaki Inagaki, MD, Masao Ishii, MD, Yoshihiro Kaneko, MD, Kazuo Yamada, MD, Hamao Ijichi, MD, Tadanao Takeda, MD, Morio Kuramochi, MD, Tatsuo Kokubu, MD, Akio Ebihara, MD, and Mituyoshi Nakashima, MD Okinawa, Japan Doxazosin is a new selective al-inhibitor with a mechanism of action similar to that of praz0sin.l The antihypertensive action has been demonstrated in various animal models of hypertension and in humans, where there is evidence that doxazosin is a more selective agent than prazosin,2 with a longer duration of action. Studies on diurnal variations of blood pressure in Japanese patients with primary hypertension showed that once-daily administration of doxazosin produced an effective decrease in mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) during 24 hours without significant changes in standard deviations of blood pressure and diurnal differences.3 An open-label, prospective, multicenter trial of doxazosin indicated that treatment with doxazosin was effective at a dose of 0.5 to 4 mg once a day.4 To date, however, Japanese studies have not compared the effect of doxazosin with that of prazosin, the most widely used of the q-inhibitors in Japan. This article presents the results of a randomized, double-blind comparison of doxazosin and prazosin in the treatment of mild or moderate essential hypertension. From the Cooperative Study Group on Doxazosin in Japan. Reprint requests: Koshiro Fukiyama. MD, Third Department of Internal Medicine, University of Ryukyus, School of Medicine, 207 Uehara, Nishihara-cho, Okinawa, Japan 903-01. 4/o/24900
METHODS Subjects. This study was an Whospital cooperative, randomized, double-blind clinical trial. It was initiated in November 1986 and concluded in November 1987. Hypertensive men and women from 30 to 69 years of age were entered into the trial after giving appropriate informed consent if they met the criteria. The baseline blood pressure was defined as the median of three blood pressure readings taken in the sitting position with a mercury manometer. Patients not currently receiving treatment for hypertension were accepted in the trial if DBP was 95 to 119 mm Hg with SBP higher than 160 mm Hg. Patients under treatment for hypertension were also accepted if their blood pressure met previous inclusion criteria after 4 weeks of washout. Patients were excluded if they had a severe complication of hypertension, DBP >120 mm Hg, secondary hypertension, or a contraindication to treatment with any of the study drugs. Patients were excluded if they had a history of congestive heart failure, cerebrovascular disease, or myocardial infarction within the past 6 months, severe angina pectoris, a severe complication of diabetes mellitus, hepatic disease, or ulcerative diseases of the digestive tract. Patients were also excluded if they were pregnant or nursing. Study design. An initial 4-week placebo phase was followed by a E-week treatment phase with doxazosin once daily or prazosin three times a day (Fig. 1). Patients were considered eligible for randomization if they were compliant at two consecutive visits at which the blood pressure was 1160 mm Hg (systolic) and 295 mm Hg (diastolic). The baseline blood pressure was defined as the average of
317
318
Fukiyama
et al.
American
January 1991 Heart Journal
Placebo
Placebo
1
2
4
a
6
10
12
14
Weeks
Fig.
Table
I. Criteria
Administration
1.
for the assessment
schedule
of antihypertensive
Systolic Diastolic Mean Score *Japanese
guidelines
Decreased
Slightly decreased
1215
1 29-20 1 14-10
119-10 1 9-5
1 220
1 19-13
1
2
1 12-7 3
1 230
for the clinical
evaluation
of antihypertensive
and prazosin.
efficacy* Blood
Markedly decreased
for doxazosin
pressure
change
Unchanged it9 l? 4 it 6 4 drugs,
pressures at the randomization visit and the visit immediately preceding. Blood pressure and heart rate were measured every 2 weeks during the study period. At the end of the control (week 4) and treatment periods (week 16), laboratory tests were carried out and the Schelong test to examine blood pressure response to postural change from supine to upright position was determined. The dose of doxazosin or prazosin was increased at weeks 6, 8, and 10 if (1) sitting blood pressure was >150 mm Hg (systolic) and >90 mm Hg (diastolic), (2) if a reduction in blood pressure >20 mm Hg (systolic) and >lO mm Hg (diastolic) was not achieved, or (3) if mean blood pressure was not reduced by more than 13 mm Hg. The dose of drug could be reduced if excessive reduction in blood pressure was observed. Treatment could be withdrawn if an excessive increase in blood pressure was observed, if symptoms worsened with or without appearance of either side effects or complications, or at the patient’s request. The concomitant use of any drug that would affect the antihypertensive effects of either doxazosin or prazosin was avoided (e.g., diuretics, sympatholytic agents, angiotensin-
(mm
Hg) Slightlr increased
Increased
t 10-19 t 5-9 t 7-12
t 20-29 t 10-14 t 13-19
5
6
Marked13 increased ’ r30 " 215 ’ 220 7
1979.
converting enzyme inhibitors, calcium channel blockers, vasodilators, @-blockers, and a-blockers). Concomitant use of drugs such as sedatives, tranquilizers, or hypnotics was also avoided in principle, but when inevitable they were administered continuously throughout the study period with no change in dose. An attending physician noted subjective symptoms and recorded any side effects or complications by means of physical examination at each visit. Subjective symptoms were evaluated according to five grades: none, slightly improved, improved, no change, or worse. Those symptoms that appeared during the treatment period were considered side effects except when a cause and effect relationship with the drug could not be established. Severity of side effects was classified as mild (continued administration possible without changing the dose), moderate (necessary to reduce the dose or treat the symptom), and severe (necessary to withdraw the drug). Cardiovascular diseases or adventitious diseases appearing during the treatment period were considered complications. Laboratory tests performed were urinalysis, ECG, chest x-rays, and blood tests including red blood cell counts, white blood cell counts with fractions, platelet count, he-
Volume 121 Number 1, Part 2
Comparison
200 180 53
of doxazosin
and prazosin
3 19
llT
160
(113) (110) L 0
(110) (104) / 2
(106) (104) I 4
Treatment
(109) (101) 1 6
(99) (93) 1 8
period (weeks)
Fig. 2. Effects of doxazosin and prazosin on sitting systolic, diastolic, in parentheses indicate number of patients. *p < 0.001.
moglobin, hematocrit, aspartate aminotransferease, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, blood urea nitrogen, creatinine, uric acid, fasting blood glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, sodium, potassium, and chloride. When an abnormality was found in these test results at the end of the trial, follow-up examinations were carried out and the relationship to the drugs used was investigated. Antihypertensive efficacy, overall safety, and overall clinical usefulness were evaluated. Antihypertensive efficacy was assessed according to the criteria in Table I. Assessment was made by both SBP and DBP, and if a discrepancy was found mean blood pressure was evaluated. Overall safety was assessed by the total score of side effects, complications, and disorder of laboratory tests and was made on a scale of no problem (score 0) to great problem (score 7). Overall clinical usefulness was evaluated by the total score of antihypertensive efficacy and overall safety as very useful (score 0 or l), useful (score 2), slightly useful (score 3), useless (score 4 to 6), should not be used (score 7), and unevaluable. Statistics. The data were computer analyzed at the Japanese Institute of Science and Technology with the SAS statistical package. In a between-group comparison of the background characteristics and efficacy, the Mann-Whitney U test, x2 test, and Fisher direct probability method were used as nonparametric methods. Variations in blood pressure, heart rate, and laboratory data were analyzed by
-"(ooxazosi") " r?rarosln)
(84) (88) I 12
(92) (87) 1 10
Table
Il. Number
Registered Excluded Evaluated Voluntarily Withdrawn
and mean arterial
of patients
discontinued
pressure.
enrolled
Figures
in the study
Dorazosin group
Prazosin
Total 266 14 252 42 18
133 5 126 22 9
135 9 126 20 9
group
the parametric Student paired t test. In a between-group comparison of changes in blood pressure and heart rate, an analysis of variance of repeated measurements over time was used. Numeric values were expressed as the mean 2 SD. A p value CO.05 was considered to be statistically significant. RESULTS Of the total of 266 patients, 14 were excluded from analysis because of protocol violation; 252 patients were evaluated for efficacy and tolerance. Data were
analyzed in each of 126 patients of the doxazosin group and the prazosin group. Discontinuation of the therapy occurred in 42 cases, mainly at the patient’s own request, and in 18 cases because of either side effects or complications (Table II). There was no sig-
320
Fukiyama
et al.
American
January 1991 Heart Journal
-.=J-
__------
+-----m *------E------rlL--(109)
(101)
(1041
(102)
(100)
I 0
I 2
I 4
Treatment Fig. 3. Effects of patients. U,
(106)
(98)
“----2 (90)
(81)
n poxarosin)
(94)
(91)
(86)
(86)
n,~iaros~ni
I 6
I
a
of doxazosin and prazosin on sitting heart rate. Figures in parentheses Doxazosin group; O--O, prazosin group. *p < 0.05.
Doxazosin
4.
indicate
number
Diastolic
group
Effect of posture on blood pressure, before and after treatment with antihypertensive therapy. *p < 0.05.
nificant difference in the background characteristics of the patients in the doxazosin group and the prazosin group. The daily maintenance dose of doxazosin was 0.5 mg in 34 patients, 1 mg in 23 patients, 2 mg in 33 patients, and 4 mg in 36 patients; the average was 1.98 mg. The daily maintenance dose of prazosin was 1.5 mg in 31 patients, 3 mg in 30 patients, 4.5 mg in 30 patients, and 6 mg in 35 patients; the average was 3.82 mg. Figs. 2 and 3 illustrate the effects of doxazosin and prazosin on blood pressure and heart rate. In both groups a significant reduction in blood pressure was obtained 2 weeks after the treatment was started. The blood pressure decreased further thereafter and achieved stability at 8 weeks of treatment. SBP and DBP at baseline were 170.9 + 11.7/102.3 + 6.4 mm Hg in the doxazosin group and 171.3 -+ lO.O/ 102.5 +- 6.5 mm Hg in the prazosin group. After 12 weeks of treatment, blood pressure decreased significantly to 145.9 + 13.8/88.5 + 7.3 mm Hg and 147.4 f 15.2/89.1 & 98mmHg (p < 0.001) withdoxazosin and prazosin, respectively. Heart rate showed
J 12
period (weeks)
T
Fig.
I 10
Prazosin
group
with doxazosin
or prazosin.
Cl,
a significant decrease only after 10 weeks in the prazosin group; no significant change was obtained at any other visit with either doxazosin or prazosin. An analysis of variance indicated no significant betweengroup difference in the changes in SBP (p = 0.5756), DBP (p = 0.9882), mean blood pressure (p = 0.7826)) and heart rate (p = 0.9402). Fig. 4 shows the effect of postural change on blood pressure from supine to upright position. A decrease in SBP after postural change at baseline was -1.3 + 8.8 mm Hg in the doxazosin group and -1.0 +- 8.7 mm Hg in the prazosin group, and it was augmented significantly (p < 0.05) after 12 weeks of therapy to -4.0 & 9.8 mm Hg and -3.7 i 9.9 mm Hg, respectively. The increase in DBP in the doxazosin group was +2.9 f 5.7 mm Hg at baseline and +1.5 +- 6.4 mm Hg after treatment, which was not statistically significant, whereas in the prazosin group it was suppressed significantly @ < 0.05) from +3.0 + 5.5 mm Hg at baseline to +l.l& 7.4 mm Hg after treatment. The increase in heart rate in response to postural change was not affected by treatment with either doxazosin or prazosin.
Volume 121 Number 1, Part 2
III. Antihypertensive doxazosin and prazosin
Table
efficacy and evaluation for
Markedly decreased (n/‘, Decreased (nl”(‘) Slightly decreased (n) Unchanged (n) Slightly increased (n) Increased (n) Markedly increased (n) Unevaluable (n 1 Total (n) U test X test Efhcacy rate (‘( )* decreased
Table
IV. An evaluation
of
and prazosin
1
and decreased/evaluable
Prazosin group
58/51.3 22119.5 20 9 3 1 0 13 126
53148.2 24/21.8 24 9 0 0 0 16 126 NS NS
70.8
70.0
groups.
The antihypertensive efficacy rate (“markedly decreased” plus “decreased”/evaluable patients; Table III) was 70.8 % in the doxazosin group and 70.0 % in the prazosin group, and blood pressure was normalized to a level below 150/90 mm Hg in 39.8% of the doxazosin group and 42.7 % of the prazosin group. There was no significant difference in antihypertensive efficacy between the groups. Adverse effects occurred in 15.1% of the doxazosin group and 15.9% of the prazosin group, and in each 5.6% of them discontinued the trial. The main adverse effects were drowsiness, headache, dizziness, palpitations, shortness of breath, and gastrointestinal symptoms (Table IV). Two patients in the doxazosin group withdrew from the trial for complications of food poisoning and elevation of blood pressure. Two patients in the prazosin group withdrew because of angina pectoris and ineffectiveness of the treatment. Laboratory values at the end of the trial were compared with those at baseline. Red b!ood cell count, hemoglobin, hematocrit, platelet count, aspartate aminotransferase, and alanine aminotransferase were slightly but significantly decreased after treatment with either doxazosin or prazosin. In the doxazosin group there was also a decrease in alkaline phosphatase and serum potassium levels and an increase in serum chloride values. In the prazosin group the white blood cell count decreased. No significant change was observed in serum sodium, blood urea nitrogen, serum creatinine, serum uric acid, and fasting blood sugar values in both groups. Seven incidences in six patients in the doxazosin group and nine incidences in seven patients in the prazosin group were considered to be laboratory abnormali-
No. of patients evaluated Patients with side effects in/‘< 1 No. of side effects observed Patients discontinued because of side effects (nl’; 1 Categorization of side effects by organ system (n/‘c’) Central nervous system (headache, dizziness, etc) Respiratory or circulatory system (palpitation, shortness of breath. chest discomfort) Gastrointestinal (nausea, stomach discomfort, gastric pain, etc) Other (rash, tiredness, shoulder stiffness, etcl
Table
V. Overall
clinical
group
126 19/15.1 23 715.6
126 2Oh5.9 32 715.6
10/7.9
1118.7
211.6
917.1
6/4.8
614.8
514.0
614.8
usefulness
Very useful (n/c’cl ) Useful (nlCc ) Slightly useful (n) Useless (n) Should not be used (n) Unevaluable (n 1 Total (n) U test X test Usefulness rate (“c )* useful and useful/evaluahle
1
Prazosin
group
Doxazosin group
*Very
32
tolerance Doxazosin
Doxazosin group
*Markedly
of doxazosin
Comparison
Prazosin group
54149.5 22120.2 20 11 2
45142.9 27125.7 17 11 5 21 126 NS NS
69.7
68.8
groups
ties. None of these abnormalities resulted in termination of the study. Total cholesterol values were decreased significantly from 205.7 ? 36.7 mg/dl (5.33 ? 0.95 mmol/ L) to 199.6 f 31.7 mg/dl(5.17 + 0.82 mmol/L) in the doxazosin group and from 206.0 k 40.4 mg/dl (5.34 * 1.05 mmol/L) to 196.8 * 36.8 mg/dl (5.10 +0.95 mmol/L) in the prazosin group. No significant decrease was found in triglyceride levels in both groups. HDL cholesterol levels showed no significant increase with doxazosin and a slight decrease with prazosin. The overall safety evaluation was obtained by totaling the scores for side effects, complications and adventitious diseases, and abnormal laboratory findings. Patients with a score of 0 (“no problem”) accounted for 85.1% in the doxazosin group and 78.9 % in the prazosin group. There was no significant difference between the groups.
322
Fukiyarnu
et al.
Attending physicians evaluated the usefulness of the treatment (Table V). A rating of “very useful” or “useful” was obtained in 69.7% of the doxazosin group and in 68.6% of the prazosin group. DISCUSSION
The results of this study show that doxazosin, 0.5 to 4.0 mg once daily, is similar in efficacy to prazosin, 1.5 to 6 mg three times daily, the dose recommended in Japan for the reduction of blood pressure in hypertensive patients. Significant reductions in SBP and DBP were obtained 2 weeks after treatment started and were maintained during the 12-week trial period with both drugs. The reductions achieved by doxazosin were slightly but not significantly greater than those observed with prazosin. However, the antihypertensive efficacy of doxazosin was achieved at a lower daily dose than that of prazosin (1.98 mg vs 3.82 mg). There was no increase in heart rate with either doxazosin or prazosin during the 12-week treatment period, suggesting that these agents caused no reflex tachycardia and no inhibition of presynaptic al-adrenergic receptors.2 Doxazosin and prazosin were well tolerated, with insignificant differences in side effects observed between the two groups. Seven patients (5.6 % ) withdrew from each group because of side effects, and four patients, two from each group, discontinued the trial because of either complications or ineffectiveness of treatment. Postural hypotension and dizziness, which are potentially the most troublesome effect of al-inhibitors, were rarely observed. The documented first-dose phenomenon of prazosin5 was readily prevented by initiation of therapy at a low dose. A slight decrease in blood cell count and hemoglobin and hematocrit values was observed in both groups, which may be attributed to hemodilution caused by fluid retention.6 At present much interest is focused on antihyper-
American
January 1991 Heart Journal
tensive agents with a long duration of action. Thus doxazosin may prove to be more useful than prazosin in the management of hypertension. We thank the attending physicians in the 88 institutions. The participation of the following central committee members is also greatly acknowledged: Dr. 0. Iimura, Second Department of Internal Medicine, Sapporo Medical College; Dr. K. Yoshinaga, Second Department of Internal Medicine, Tohoku University School of Medicine; Dr. S. Yagi, Cardiovascular Department of Internal Medicine, Dokkyo Medical College; Dr. Y. Inagaki, Third Department of Internal Medicine, Chiba University School of Medicine; Dr. M. Ishii, Second Department of Internal Medicine, University of Tokyo School of Medicine; Dr. Y. Kaneko, Second Department of Internal Medicine, Yokohama City University School of Medicine; Dr. K. Yamada, Department of Internal Medicine, Meitetsu Hospital; Dr. H. Ijichi, Second Department of Internal Medicine, Kyoto Prefectural Medical College; Dr. T. Takeda, First Department of Internal Medicine, Osaka City University School of Medicine; Dr. M. Kuramoto, Department of Internal Medicine, National Cardiovascular Centre: Dr. T. Kokuhu, Second Department of Internal Medicine, Ehime University School of Medicine; and Dr. A. Ebihara. Department of Clinical Pharmacology, Oita Medical College.
REFERENCES
1. Singleton W, Saxton CAPD, Hernandez J, Prichard BNC. Postjunctional selectivity of alpha-blockade with prazosin, trimazosin and UK-33,274 in man. J Cardiovasc Pharmacol 1982;4(suppl l):S145-51. 2. Alabaster VA, Davey MJ. The alphai-adrenoceptor antagonist profile of doxazosin: preclinical pharmacology. Br J Clin Pharmacol 1986;21:S9-17. 3. Yoshinaga K, Miura Y, Omae T, et al. Effects of doxazosin on diurnal variation of blood pressure in patients with essential hypertension (in Japanese). Igaku Yakugaku 1988;20:117-26. 4. Yoshinaga K, Miura Y, Omae T, et al. Clinical effects of doxazosin in the treatment of essential hypertension: results of an open-labelled multicenter trial in Japan (in Japanese). Igaku Yakugaku 1988;20:141-66. 5. Stokes GS, Graham RM, Gain JM, Davis PR. Influence of dosage and dietary sodium on the first-dose effects of prazosin. Br Med J 1977;2:1507-8. 6. Letcher RL, Chien S, Laragh JH. Change in blood viscosity accompanying the response to prazosin in patients with essential hypertension. J Cardiovasc Pharmacol 1979;lfsuppl 6):S8-20.
Koshiro Fukiyama, MD, Teruo Omae, MD, Osamu Iimura, MD, Kaoru Yoshinaga, MD, Shigeru Yagi, MD, Yoshiaki Inagaki, MD, Masao Ishii, MD, Yoshihiro Kaneko, MD, Kazuo Yamada, MD, Hamao Ijichi, MD, Tadanao Takeda, MD, Morio Kuramochi, MD, Tatsuo Kokubu, MD, Akio Ebihara, MD, and Mituyoshi Nakashima, MD Okinawa, Japan Doxazosin is a new selective al-inhibitor with a mechanism of action similar to that of praz0sin.l The antihypertensive action has been demonstrated in various animal models of hypertension and in humans, where there is evidence that doxazosin is a more selective agent than prazosin,2 with a longer duration of action. Studies on diurnal variations of blood pressure in Japanese patients with primary hypertension showed that once-daily administration of doxazosin produced an effective decrease in mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) during 24 hours without significant changes in standard deviations of blood pressure and diurnal differences.3 An open-label, prospective, multicenter trial of doxazosin indicated that treatment with doxazosin was effective at a dose of 0.5 to 4 mg once a day.4 To date, however, Japanese studies have not compared the effect of doxazosin with that of prazosin, the most widely used of the q-inhibitors in Japan. This article presents the results of a randomized, double-blind comparison of doxazosin and prazosin in the treatment of mild or moderate essential hypertension. From the Cooperative Study Group on Doxazosin in Japan. Reprint requests: Koshiro Fukiyama. MD, Third Department of Internal Medicine, University of Ryukyus, School of Medicine, 207 Uehara, Nishihara-cho, Okinawa, Japan 903-01. 4/o/24900
METHODS Subjects. This study was an Whospital cooperative, randomized, double-blind clinical trial. It was initiated in November 1986 and concluded in November 1987. Hypertensive men and women from 30 to 69 years of age were entered into the trial after giving appropriate informed consent if they met the criteria. The baseline blood pressure was defined as the median of three blood pressure readings taken in the sitting position with a mercury manometer. Patients not currently receiving treatment for hypertension were accepted in the trial if DBP was 95 to 119 mm Hg with SBP higher than 160 mm Hg. Patients under treatment for hypertension were also accepted if their blood pressure met previous inclusion criteria after 4 weeks of washout. Patients were excluded if they had a severe complication of hypertension, DBP >120 mm Hg, secondary hypertension, or a contraindication to treatment with any of the study drugs. Patients were excluded if they had a history of congestive heart failure, cerebrovascular disease, or myocardial infarction within the past 6 months, severe angina pectoris, a severe complication of diabetes mellitus, hepatic disease, or ulcerative diseases of the digestive tract. Patients were also excluded if they were pregnant or nursing. Study design. An initial 4-week placebo phase was followed by a E-week treatment phase with doxazosin once daily or prazosin three times a day (Fig. 1). Patients were considered eligible for randomization if they were compliant at two consecutive visits at which the blood pressure was 1160 mm Hg (systolic) and 295 mm Hg (diastolic). The baseline blood pressure was defined as the average of
317
318
Fukiyama
et al.
American
January 1991 Heart Journal
Placebo
Placebo
1
2
4
a
6
10
12
14
Weeks
Fig.
Table
I. Criteria
Administration
1.
for the assessment
schedule
of antihypertensive
Systolic Diastolic Mean Score *Japanese
guidelines
Decreased
Slightly decreased
1215
1 29-20 1 14-10
119-10 1 9-5
1 220
1 19-13
1
2
1 12-7 3
1 230
for the clinical
evaluation
of antihypertensive
and prazosin.
efficacy* Blood
Markedly decreased
for doxazosin
pressure
change
Unchanged it9 l? 4 it 6 4 drugs,
pressures at the randomization visit and the visit immediately preceding. Blood pressure and heart rate were measured every 2 weeks during the study period. At the end of the control (week 4) and treatment periods (week 16), laboratory tests were carried out and the Schelong test to examine blood pressure response to postural change from supine to upright position was determined. The dose of doxazosin or prazosin was increased at weeks 6, 8, and 10 if (1) sitting blood pressure was >150 mm Hg (systolic) and >90 mm Hg (diastolic), (2) if a reduction in blood pressure >20 mm Hg (systolic) and >lO mm Hg (diastolic) was not achieved, or (3) if mean blood pressure was not reduced by more than 13 mm Hg. The dose of drug could be reduced if excessive reduction in blood pressure was observed. Treatment could be withdrawn if an excessive increase in blood pressure was observed, if symptoms worsened with or without appearance of either side effects or complications, or at the patient’s request. The concomitant use of any drug that would affect the antihypertensive effects of either doxazosin or prazosin was avoided (e.g., diuretics, sympatholytic agents, angiotensin-
(mm
Hg) Slightlr increased
Increased
t 10-19 t 5-9 t 7-12
t 20-29 t 10-14 t 13-19
5
6
Marked13 increased ’ r30 " 215 ’ 220 7
1979.
converting enzyme inhibitors, calcium channel blockers, vasodilators, @-blockers, and a-blockers). Concomitant use of drugs such as sedatives, tranquilizers, or hypnotics was also avoided in principle, but when inevitable they were administered continuously throughout the study period with no change in dose. An attending physician noted subjective symptoms and recorded any side effects or complications by means of physical examination at each visit. Subjective symptoms were evaluated according to five grades: none, slightly improved, improved, no change, or worse. Those symptoms that appeared during the treatment period were considered side effects except when a cause and effect relationship with the drug could not be established. Severity of side effects was classified as mild (continued administration possible without changing the dose), moderate (necessary to reduce the dose or treat the symptom), and severe (necessary to withdraw the drug). Cardiovascular diseases or adventitious diseases appearing during the treatment period were considered complications. Laboratory tests performed were urinalysis, ECG, chest x-rays, and blood tests including red blood cell counts, white blood cell counts with fractions, platelet count, he-
Volume 121 Number 1, Part 2
Comparison
200 180 53
of doxazosin
and prazosin
3 19
llT
160
(113) (110) L 0
(110) (104) / 2
(106) (104) I 4
Treatment
(109) (101) 1 6
(99) (93) 1 8
period (weeks)
Fig. 2. Effects of doxazosin and prazosin on sitting systolic, diastolic, in parentheses indicate number of patients. *p < 0.001.
moglobin, hematocrit, aspartate aminotransferease, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, blood urea nitrogen, creatinine, uric acid, fasting blood glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, sodium, potassium, and chloride. When an abnormality was found in these test results at the end of the trial, follow-up examinations were carried out and the relationship to the drugs used was investigated. Antihypertensive efficacy, overall safety, and overall clinical usefulness were evaluated. Antihypertensive efficacy was assessed according to the criteria in Table I. Assessment was made by both SBP and DBP, and if a discrepancy was found mean blood pressure was evaluated. Overall safety was assessed by the total score of side effects, complications, and disorder of laboratory tests and was made on a scale of no problem (score 0) to great problem (score 7). Overall clinical usefulness was evaluated by the total score of antihypertensive efficacy and overall safety as very useful (score 0 or l), useful (score 2), slightly useful (score 3), useless (score 4 to 6), should not be used (score 7), and unevaluable. Statistics. The data were computer analyzed at the Japanese Institute of Science and Technology with the SAS statistical package. In a between-group comparison of the background characteristics and efficacy, the Mann-Whitney U test, x2 test, and Fisher direct probability method were used as nonparametric methods. Variations in blood pressure, heart rate, and laboratory data were analyzed by
-"(ooxazosi") " r?rarosln)
(84) (88) I 12
(92) (87) 1 10
Table
Il. Number
Registered Excluded Evaluated Voluntarily Withdrawn
and mean arterial
of patients
discontinued
pressure.
enrolled
Figures
in the study
Dorazosin group
Prazosin
Total 266 14 252 42 18
133 5 126 22 9
135 9 126 20 9
group
the parametric Student paired t test. In a between-group comparison of changes in blood pressure and heart rate, an analysis of variance of repeated measurements over time was used. Numeric values were expressed as the mean 2 SD. A p value CO.05 was considered to be statistically significant. RESULTS Of the total of 266 patients, 14 were excluded from analysis because of protocol violation; 252 patients were evaluated for efficacy and tolerance. Data were
analyzed in each of 126 patients of the doxazosin group and the prazosin group. Discontinuation of the therapy occurred in 42 cases, mainly at the patient’s own request, and in 18 cases because of either side effects or complications (Table II). There was no sig-
320
Fukiyama
et al.
American
January 1991 Heart Journal
-.=J-
__------
+-----m *------E------rlL--(109)
(101)
(1041
(102)
(100)
I 0
I 2
I 4
Treatment Fig. 3. Effects of patients. U,
(106)
(98)
“----2 (90)
(81)
n poxarosin)
(94)
(91)
(86)
(86)
n,~iaros~ni
I 6
I
a
of doxazosin and prazosin on sitting heart rate. Figures in parentheses Doxazosin group; O--O, prazosin group. *p < 0.05.
Doxazosin
4.
indicate
number
Diastolic
group
Effect of posture on blood pressure, before and after treatment with antihypertensive therapy. *p < 0.05.
nificant difference in the background characteristics of the patients in the doxazosin group and the prazosin group. The daily maintenance dose of doxazosin was 0.5 mg in 34 patients, 1 mg in 23 patients, 2 mg in 33 patients, and 4 mg in 36 patients; the average was 1.98 mg. The daily maintenance dose of prazosin was 1.5 mg in 31 patients, 3 mg in 30 patients, 4.5 mg in 30 patients, and 6 mg in 35 patients; the average was 3.82 mg. Figs. 2 and 3 illustrate the effects of doxazosin and prazosin on blood pressure and heart rate. In both groups a significant reduction in blood pressure was obtained 2 weeks after the treatment was started. The blood pressure decreased further thereafter and achieved stability at 8 weeks of treatment. SBP and DBP at baseline were 170.9 + 11.7/102.3 + 6.4 mm Hg in the doxazosin group and 171.3 -+ lO.O/ 102.5 +- 6.5 mm Hg in the prazosin group. After 12 weeks of treatment, blood pressure decreased significantly to 145.9 + 13.8/88.5 + 7.3 mm Hg and 147.4 f 15.2/89.1 & 98mmHg (p < 0.001) withdoxazosin and prazosin, respectively. Heart rate showed
J 12
period (weeks)
T
Fig.
I 10
Prazosin
group
with doxazosin
or prazosin.
Cl,
a significant decrease only after 10 weeks in the prazosin group; no significant change was obtained at any other visit with either doxazosin or prazosin. An analysis of variance indicated no significant betweengroup difference in the changes in SBP (p = 0.5756), DBP (p = 0.9882), mean blood pressure (p = 0.7826)) and heart rate (p = 0.9402). Fig. 4 shows the effect of postural change on blood pressure from supine to upright position. A decrease in SBP after postural change at baseline was -1.3 + 8.8 mm Hg in the doxazosin group and -1.0 +- 8.7 mm Hg in the prazosin group, and it was augmented significantly (p < 0.05) after 12 weeks of therapy to -4.0 & 9.8 mm Hg and -3.7 i 9.9 mm Hg, respectively. The increase in DBP in the doxazosin group was +2.9 f 5.7 mm Hg at baseline and +1.5 +- 6.4 mm Hg after treatment, which was not statistically significant, whereas in the prazosin group it was suppressed significantly @ < 0.05) from +3.0 + 5.5 mm Hg at baseline to +l.l& 7.4 mm Hg after treatment. The increase in heart rate in response to postural change was not affected by treatment with either doxazosin or prazosin.
Volume 121 Number 1, Part 2
III. Antihypertensive doxazosin and prazosin
Table
efficacy and evaluation for
Markedly decreased (n/‘, Decreased (nl”(‘) Slightly decreased (n) Unchanged (n) Slightly increased (n) Increased (n) Markedly increased (n) Unevaluable (n 1 Total (n) U test X test Efhcacy rate (‘( )* decreased
Table
IV. An evaluation
of
and prazosin
1
and decreased/evaluable
Prazosin group
58/51.3 22119.5 20 9 3 1 0 13 126
53148.2 24/21.8 24 9 0 0 0 16 126 NS NS
70.8
70.0
groups.
The antihypertensive efficacy rate (“markedly decreased” plus “decreased”/evaluable patients; Table III) was 70.8 % in the doxazosin group and 70.0 % in the prazosin group, and blood pressure was normalized to a level below 150/90 mm Hg in 39.8% of the doxazosin group and 42.7 % of the prazosin group. There was no significant difference in antihypertensive efficacy between the groups. Adverse effects occurred in 15.1% of the doxazosin group and 15.9% of the prazosin group, and in each 5.6% of them discontinued the trial. The main adverse effects were drowsiness, headache, dizziness, palpitations, shortness of breath, and gastrointestinal symptoms (Table IV). Two patients in the doxazosin group withdrew from the trial for complications of food poisoning and elevation of blood pressure. Two patients in the prazosin group withdrew because of angina pectoris and ineffectiveness of the treatment. Laboratory values at the end of the trial were compared with those at baseline. Red b!ood cell count, hemoglobin, hematocrit, platelet count, aspartate aminotransferase, and alanine aminotransferase were slightly but significantly decreased after treatment with either doxazosin or prazosin. In the doxazosin group there was also a decrease in alkaline phosphatase and serum potassium levels and an increase in serum chloride values. In the prazosin group the white blood cell count decreased. No significant change was observed in serum sodium, blood urea nitrogen, serum creatinine, serum uric acid, and fasting blood sugar values in both groups. Seven incidences in six patients in the doxazosin group and nine incidences in seven patients in the prazosin group were considered to be laboratory abnormali-
No. of patients evaluated Patients with side effects in/‘< 1 No. of side effects observed Patients discontinued because of side effects (nl’; 1 Categorization of side effects by organ system (n/‘c’) Central nervous system (headache, dizziness, etc) Respiratory or circulatory system (palpitation, shortness of breath. chest discomfort) Gastrointestinal (nausea, stomach discomfort, gastric pain, etc) Other (rash, tiredness, shoulder stiffness, etcl
Table
V. Overall
clinical
group
126 19/15.1 23 715.6
126 2Oh5.9 32 715.6
10/7.9
1118.7
211.6
917.1
6/4.8
614.8
514.0
614.8
usefulness
Very useful (n/c’cl ) Useful (nlCc ) Slightly useful (n) Useless (n) Should not be used (n) Unevaluable (n 1 Total (n) U test X test Usefulness rate (“c )* useful and useful/evaluahle
1
Prazosin
group
Doxazosin group
*Very
32
tolerance Doxazosin
Doxazosin group
*Markedly
of doxazosin
Comparison
Prazosin group
54149.5 22120.2 20 11 2
45142.9 27125.7 17 11 5 21 126 NS NS
69.7
68.8
groups
ties. None of these abnormalities resulted in termination of the study. Total cholesterol values were decreased significantly from 205.7 ? 36.7 mg/dl (5.33 ? 0.95 mmol/ L) to 199.6 f 31.7 mg/dl(5.17 + 0.82 mmol/L) in the doxazosin group and from 206.0 k 40.4 mg/dl (5.34 * 1.05 mmol/L) to 196.8 * 36.8 mg/dl (5.10 +0.95 mmol/L) in the prazosin group. No significant decrease was found in triglyceride levels in both groups. HDL cholesterol levels showed no significant increase with doxazosin and a slight decrease with prazosin. The overall safety evaluation was obtained by totaling the scores for side effects, complications and adventitious diseases, and abnormal laboratory findings. Patients with a score of 0 (“no problem”) accounted for 85.1% in the doxazosin group and 78.9 % in the prazosin group. There was no significant difference between the groups.
322
Fukiyarnu
et al.
Attending physicians evaluated the usefulness of the treatment (Table V). A rating of “very useful” or “useful” was obtained in 69.7% of the doxazosin group and in 68.6% of the prazosin group. DISCUSSION
The results of this study show that doxazosin, 0.5 to 4.0 mg once daily, is similar in efficacy to prazosin, 1.5 to 6 mg three times daily, the dose recommended in Japan for the reduction of blood pressure in hypertensive patients. Significant reductions in SBP and DBP were obtained 2 weeks after treatment started and were maintained during the 12-week trial period with both drugs. The reductions achieved by doxazosin were slightly but not significantly greater than those observed with prazosin. However, the antihypertensive efficacy of doxazosin was achieved at a lower daily dose than that of prazosin (1.98 mg vs 3.82 mg). There was no increase in heart rate with either doxazosin or prazosin during the 12-week treatment period, suggesting that these agents caused no reflex tachycardia and no inhibition of presynaptic al-adrenergic receptors.2 Doxazosin and prazosin were well tolerated, with insignificant differences in side effects observed between the two groups. Seven patients (5.6 % ) withdrew from each group because of side effects, and four patients, two from each group, discontinued the trial because of either complications or ineffectiveness of treatment. Postural hypotension and dizziness, which are potentially the most troublesome effect of al-inhibitors, were rarely observed. The documented first-dose phenomenon of prazosin5 was readily prevented by initiation of therapy at a low dose. A slight decrease in blood cell count and hemoglobin and hematocrit values was observed in both groups, which may be attributed to hemodilution caused by fluid retention.6 At present much interest is focused on antihyper-
American
January 1991 Heart Journal
tensive agents with a long duration of action. Thus doxazosin may prove to be more useful than prazosin in the management of hypertension. We thank the attending physicians in the 88 institutions. The participation of the following central committee members is also greatly acknowledged: Dr. 0. Iimura, Second Department of Internal Medicine, Sapporo Medical College; Dr. K. Yoshinaga, Second Department of Internal Medicine, Tohoku University School of Medicine; Dr. S. Yagi, Cardiovascular Department of Internal Medicine, Dokkyo Medical College; Dr. Y. Inagaki, Third Department of Internal Medicine, Chiba University School of Medicine; Dr. M. Ishii, Second Department of Internal Medicine, University of Tokyo School of Medicine; Dr. Y. Kaneko, Second Department of Internal Medicine, Yokohama City University School of Medicine; Dr. K. Yamada, Department of Internal Medicine, Meitetsu Hospital; Dr. H. Ijichi, Second Department of Internal Medicine, Kyoto Prefectural Medical College; Dr. T. Takeda, First Department of Internal Medicine, Osaka City University School of Medicine; Dr. M. Kuramoto, Department of Internal Medicine, National Cardiovascular Centre: Dr. T. Kokuhu, Second Department of Internal Medicine, Ehime University School of Medicine; and Dr. A. Ebihara. Department of Clinical Pharmacology, Oita Medical College.
REFERENCES
1. Singleton W, Saxton CAPD, Hernandez J, Prichard BNC. Postjunctional selectivity of alpha-blockade with prazosin, trimazosin and UK-33,274 in man. J Cardiovasc Pharmacol 1982;4(suppl l):S145-51. 2. Alabaster VA, Davey MJ. The alphai-adrenoceptor antagonist profile of doxazosin: preclinical pharmacology. Br J Clin Pharmacol 1986;21:S9-17. 3. Yoshinaga K, Miura Y, Omae T, et al. Effects of doxazosin on diurnal variation of blood pressure in patients with essential hypertension (in Japanese). Igaku Yakugaku 1988;20:117-26. 4. Yoshinaga K, Miura Y, Omae T, et al. Clinical effects of doxazosin in the treatment of essential hypertension: results of an open-labelled multicenter trial in Japan (in Japanese). Igaku Yakugaku 1988;20:141-66. 5. Stokes GS, Graham RM, Gain JM, Davis PR. Influence of dosage and dietary sodium on the first-dose effects of prazosin. Br Med J 1977;2:1507-8. 6. Letcher RL, Chien S, Laragh JH. Change in blood viscosity accompanying the response to prazosin in patients with essential hypertension. J Cardiovasc Pharmacol 1979;lfsuppl 6):S8-20.
