- Email: [email protected]
Clinical experience with doxazosin in general medical practice in New Zealand
Clinical experience with doxazosin medical practice in New Zealand
in general
This study investigated the safety and efficacy of doxazosin treatment in a large population of patients (n = 336) with essential hypertension and assessed the effect of doxazosin on the serum lipid profile and the calculated risk of developing coronary heart disease. Patients were assigned to two groups: those with a baseline diastolic blood pressure 295 mm Hg (group 1) and those with a baseline diastolic blood pressure <95 mm Hg (group 2) that was controlled by previous antihypertensive therapy. Doxazosin treatment (monotherapy in 76.2% of patients) significantly (p < 0.05) reduced the blood pressure of patients in group 1 (-231-17 mm Hg) after 10 weeks and maintained the control of blood pressure for patients in group 2. Heart rate was essentially unchanged in both groups. Mean final daily doses of 3.6 and 3.2 mg were achieved in groups 1 and 2, respectively. Treatment with doxarosin improved the severity category of hypertension for 66.4% of patients in group 1; 87.3% of patients were considered a therapy success. Doxazosin had a favorable effect on the serum lipid profile in both groups of patients. The majority of lipid changes achieved statistical significance and resulted In a significant 27% decrease in the calculated risk of developing coronary heart disease. Doxarosin was well tolerated; only 24.1% of patients had side effects that were related or possibly related to treatment. In nine (2.7%) patients the dose of doxazosin was reduced and 26 (7.7%) patients withdrew from doxazosin therapy because of side effects. (AM HEART J 1991;121:323-8.)
Andrew H. Maslowski,
MBChB,
FRACP,
Auckland,
Antihypertensive therapy tailored to individual patient requirements has replaced the step-care approach of the early 1980s. The selection of agents is now based on their effects on other parameters over and above that of their effect on blood pressure for individual patients. Given the importance of lipid levels in the context of ischemic heart disease,l, 2 antihypertensive medication that produces a favorable change in the serum lipid profile clearly presents a major advantage over alternative agents. Doxazosin, an effective antihypertensive agent, is a selective (piadrenoceptor inhibitor that has been shown to increase the high-density lipoprotein (HDL)/total cholesterol ratio by 9 2%.3 This article presents the results of a postmarketing surveillance study designed to assess the effect of doxazosin in a general practice setting. In an open study during a lo-week period the end points of the study were changes in blood pressure, changes in serum lipid levels, and toleration of doxazosin. The report summarizes data received to date on 336 of an expected 500 patients in New Zealand, as part of a From Reprint Health
Middlemore
Hospital.
requests: Andrew Board, Middlemore
4/O/24888
H. Maslowski, MBChB, FRACP, Auckland Area Hospital, Otahuhu, Auckland 6, New Zealand.
New Zealand
multicountry study ultimately 10,000 patients.
to cover more than
METHODS Patient selection. Eligible men and women had an established diagnosis of essential hypertension, which was defined for the purposes of this study as sitting diastolic blood pressure (DBP) 295 mm Hg without antihypertensive medication. Previously treated and untreated patients could be included. Excluded from the study were patients with malignant or secondary hypertension, pregnant or lactating women, patients with documented or suspected serious drug reactions or sensitivity to al-inhibitors in general and quinazolines in particular, patients with orthostatic hypotension, and patients with any other medical condition that could interfere with completion of the study. Women were advised not to use oral contraceptives and to avoid pregnancy for 6 months after entry to the study. Study design. Patients were treated for 10 weeks with doxazosin, after an optional 2-week baseline phase during which existing antihypertensive medication could be discontinued and baseline blood pressure established. If possible, patients were evaluated twice during the baseline phase, at the end of weeks 1 and 2. Patients continued into the treatment phase if mean sitting DBP was 295 mm Hg, with no greater than 10 mm Hg difference between the two baseline measurements. A third baseline week was allowed if DBP had not stabilized. Some investigators elected to 323
324 Table
Maslowski I. Baseline
American
characteristics
of the study population
No. of patients Male/female Mean age (yr) Range Mean duration of hypertension (yr) Range No. of patients with? Mild hypertension Moderate hypertension Severe hypertension Gross hypertension No. of patients With previous antihypertensive treatment Discontinued before doxazosint: Continued during study Patients treated with one prestudy drug (n/Z) Patients treated with two or more prestudy drugs (n/T>) No. of patients with no prior therapy
Group 1 fsitting DBP 295 mm Hg)
Group 2 (sitting DBP <95 mm Hg)
276* 150/125 55.4 20-82 6.8 0.08-30
60 37123 58.4 36-76 8.6 0.17-22
TOtid
336 1871148 5.5.9 20-8’ 7.1 0.08-30
162 80 32 2 170 99
71 140/82.4 30/17.6 106
165
80 3” 2 58 51 7 41/70.7 17129.3
228 150
78 18U79.4
47120.6
2
*Sex not stated for one patient. tBased on sitting DBP of 91 to 104 mm Hg mild, 105 to 114 mm Hg moderate, 115 to 129 mm Hg severe, and ,130 mm Hg gross. tOf the 150 patients changing to doxazosin monotherapy, 104 (69.3”Fm) had been receiving one previous drug; 46 (30.7’, ) had been receiving
Table
II. Study
treatment
status
Group 1 (sitting DBP 295 mm Hg)
Doxazosin monotherapy Doxazosin plus prior therapy
January 1991 Heart Journal
Group 2 (sitting DBP <9S mm Hg)
Total
n
%
n
%
205
74.3
53
88.3
258 76.8
71
25.7
7
11.7
78 23.2
n
7’0
treat a group of previously treated patients with doxazosin monotherapy, without a washout phase. The objective was to determine whether doxazosin monotherapy would maintain the same blood pressure control as prior antihypertensive treatment. If there was no 2-week baseline phase, the initial screening visit was considered baseline. Treatment with doxazosin was initiated at 1 mg/day. The dose was increased, if required, at intervals of 1 to 4 weeks, until one of the following occurred: (1) sitting DBP 190 mm Hg was achieved, (2) the maximum daily dose of 16 mg had been taken for 2 consecutive weeks, or (3) significant side effects precluded a further increase in dose. The defined dose titration schedule was 1, 2, 4, 8, and 16 mg, once daily; a decrease in dose was permitted if side effects became evident. Once the optimum dose had been reached, assessments were scheduled at 4-week intervals. Assessments. Patients were evaluated 2 to 12 hours af-
108
two or more
ter drug administration at each review visit. Blood pressure was determined after the patient had been sitting for 5 minutes and was the mean of two consecutive measurements. Heart rate was recorded immediately before the blood pressure measurement. Blood samples for serum lipid assessment (total cholesterol, HDL cholesterol, HDL/total cholesterol ratio, and triglycerides) were taken after the last baseline blood pressure measurement and at the final visit. Plasma samples were obtained after an overnight fast before drug administration. Routine laboratory tests were carried out only when clinically indicated. If patients demonstrated clinically relevant abnormalities in laboratory parameters, they were monitored until the condition returned to prestudy status or resolution of the problem was achieved. Side effects were recorded at each visit in terms of onset date, duration, severity, drug relation, and outcome. Information regarding concomitant illnesses and medications was also listed. At the end of the doxazosin treatment period, the investigator gave an overall assessment of efficacy and toleration for each patient, on a scale of excellent, good, fair, or poor. Data analysis. Mean changes in blood pressure and heart rate were analyzed with a paired t test (two tailed), at a significance level of 5%, Qualitative changes in blood pressure in hypertensive patients (group 1) were categorized as follows: (1) sitting DBP 5 90 mm Hg with at least a 5 mm Hg reduction (“normalized”), (2) sitting DBP reduction ~10 mm Hg but not reaching a sitting DBP 190
Volume 121 Number 1. Part 2
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/
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easelme
2
4
Time (weeks)
III. Duration
and dose of doxazosin
Mean duration of therapy (days) Range Patients with duration >90 days (n/Y; Mean final dose (mg/day) Patients taking final dose of (nl“c ) 1 mglday 2 mglday 4 mglday
practice
stud-v
325
I 8
12
Final
Time (weeks)
Fig. 1. Doxazosin-induced changes in sitting blood pressure (BP) and heart rate (HR) for patients in group 1 (baseline sitting DBP 295 mm Hg). SBP, Systolic blood pressure.
Table
general
Fig. 2. Doxazosin-induced changes in sitting blood pressure (BP) and heart rate (HR) for patients in group 2 (baseline sitting DBP <95 mm Hg). SBP, Systolic blood pressure.
treatment Group 1 (sitting DBP 295 mm Hg)
Group 2 (sitting DBP <95 mm Hg)
TOM
107.5 4-340 “01/72.8 3.6
116.8 24-348 38/63.3 3.2
109.2 4-348 239171.1 3.5
62122.5 82f29.7 83/30.1
n/20.0 26/43.3 12/20.0 416.7 l/1.7
74122.0 108/32.1 9U28.3 3018.9 912.7
)
8 mg/day 16 mglday
mm Hg, and (3) reduction in sitting DBP 510 mm Hg (“failures”). Patients in the first two categories were regarded as therapy successes. For the subgroup of patients whose baseline blood pressure was “normotensive” (group 2), therapy successes were: (1) from baseline sitting DBP of 91 to 95 mm Hg to 190 mm Hg or (2) from baseline sitting DBP of <90 mm Hg that remained at < 90 mm Hg. Mean changes in serum lipid levels were also analyzed with a paired t test (two tailed). The significance of between-group difference was assessed with the Wilcoxon two sample test. Lipid determinations were used in conjunction with blood pressure, smoking status, evidence of left ventricular hypertrophy, and glucose intolerance to evaluate the probability of developing coronary heart disease (CHD) in 10 years according to the Framingham equation.4 Each patient’s calculated risk score was determined at baseline and after treatment with doxazosin. Mean changes from baseline were assessed by applying a log-odds transformation and a within-group t test.
2619.4 812.9
RESULTS Population
status. The study population was divided into two groups for efficacy analysis: group 1, those patients with a baseline sitting DBP 195 mm Hg (n = 276) and group 2, those patients with a baseline sitting DBP <95 mm Hg (n = 60). The majority (57/60) of patients in group 2 had a baseline DBP <90 mm Hg. All 336 patients except one in group 2 were evaluable for efficacy. Baseline characteristics of the study population are given in Table I and the study treatment status is shown in Table II. Duration and dose of doxazosin treatment. Although the protocol specified a lo-week doxazosin treatment period, most patients received the drug for 12 weeks or more. The mean duration of treatment for all patients was 109.2 days and the mean final daily dose was 3.5 mg; 277 (82.4%) patients were taking a final daily dose ~4 mg. The majority of patients (76.8%) were treated with doxazosin monotherapy. This was
326
Mzslowski Table
t p < 0.05 between grou/x Wilcoxon
Z-sample
test
from
V. Changes baseline
sitting
DBP
in the severity
to final
visit
[
IV. Efficacy
outcome
of evaluable
Patients evaluable for efficacy (ni Therapy successes (n/“;, I Control achieved* 210 mm Hg reduction Therapy failures (n/Y) Inadequate response at maximum dose Not titrated to maximum dose For any apparent reason Lost to follow-up Limited by side effectst
Graup 1 (sitting DBP ~9.5 mm Hg)
Group 2 (sitting DRP <95 mm Hg)
276 241/87.3 210176.1 31/11.2 35112.7 10/3.6
59 46/78.0
15/5.4 110.4 913.3
7h1.9 111.7
*Reduction in sitting DBP to 590 mm Hg. tIncludes patients with dose reduced hecause
13122.0 l/1.7
416.8
of side effects.
particularly true for group 2, in which 88.3% of patients received doxazosin monotherapy. Data for groups 1 and 2 are given in Table III. Doxazosin-induced Blood pressure response. changes in blood pressure for patients in groups 1 and 2 are shown in Figs. 1 and 2, respectively. Doxazosin produced a significant reduction in blood pressure at each visit in the patients in group 1, from a mean baseline level of 167/104 mm Hg to a final measurement of 144/87 mm Hg. In group 2 in patients whose blood pressures were controlled by previous antihypertensive therapy, blood pressures were essentially unchanged after treatment with doxazosin (baseline, 151/87 mm Hg; final, 146/85 mm Hg). No significant changes in heart rate were seen in both groups of patients. Of the 276 patients in group 1, in 210 (76.1%) blood pressure was normalized after treatment with dox-
1 (baseline
severity
(n)
Mild
Moderate
Normal Mild Moderate
0 134 .55
0 23 21
0 5 3
0 0 0
0 0 1
20
10
2
0
0
1
0
0
0
c55
10
0
1
1 210
Severe
Total in)
Gross
0 162 80 32
2 276
Table VI. Changes in the severity category of hypertension from baseline to final visit for patients in group 2 (baseline sitting DBP <95 mm Hg) Final
patients
of hypertension
in group
Normal
Gross Total
Table
category
patients
Baseline secwrit\,
Severe
Fig. 3. Doxazosin-induced changes in serum lipid profile for patients in group 1 (baseline sitting DBP 195 mm Hg) and group 2 (baseline sitting DBP <95 mm Hg).
for
295 mm Hg) Final
Trlglycendes
January 1991 Heart Journal
American
Baseline sewrit> Normal Mild Total
seoerity
Cn)
Normal
Mild
Total (nl
45
11
66
1
2
3
46
13
59
azosin; in 31 (11.2 % ) there was a reduction in sitting DBP ~10 mm Hg, and the remaining 35 patients (12.7%) were regarded as therapy failures. In group 2, 46 patients (78.0% ) were considered a therapy success; 13 (22.0%) were therapy failures. A summary of efficacy is presented in Table IV. In group 1, 244 patients (88.4%) showed an improvement in the severity category of their hypertension; in 134 (82.7 % ) patients with mild hypertension blood pressure was normalized, in 76 (95.1%) patients with moderate hypertension blood pressure was normalized or became mild hypertension, and 30 (93.8 % ) patients with severe hypertension became either mildly hypertensive or their blood pressure was normalized (Table V). In group 2, in the majority of patients (47; 79.7 % ), there was no change in the severity category of hypertension (Table VI). Antihypertensive efficacy as a function of prestudy therapy. In group 1, 241 patients (87.3%) were con-
sidered therapy successes after treatment with doxazosin; 94 patients (88.7%) with no previous antihypertensive therapy achieved success and 23 patients (76.7 % ) who had taken two or more antihypertensive agents were therapy successes when changed to doxazosin monotherapy. In group 2, 46 patients (78.0%) were considered therapy successes. Forty-two patients (82.3 % ) whose blood pressures were controlled by prior therapy
Volume 121 Number 1, Part 2
Table
New Zealand
VII. Antihypertensive
Patients with no prior therapy No. of patients Mean baseline blood pressure (mm Mean final blood pressure (mm Hg) Mean reduction from baseline (mm Mean final dose (mg/day) Patients with one or more prior drugs* No. of patients Mean baseline blood pressure (mm Mean final blood pressure (mm Hg) Mean reduction from baseline (mm Mean final dose (mg/day) Patients with two or more prior drugs* No. of patients Mean baseline blood pressure (mm Mean final blood pressure (mm Hg) Mean reduction from baseline (mm Mean final dose (mg/day) withdrawn
before
doxazosin
study
327
efficacy and dose of doxazosin as a function of prestudy therapy (sitting
*Therapy
general practice
Group 1 DBP 295 mm
Hg)
(sitting
Group 2 DBP <95 mm Hg)
106
Hg) Hg)
1671105 143187 24.1/18.0 3.4
-
99 161/102 142187 19.7D5.5 3.1
51 152187
Hg)
30 164/104 145188
Hg)
19.2/15.9
16 147186 144187 3.41-0.3 3.4
Hg) Hg)
145185 6.8/2.1
3.0
4.4
administration.
achieved therapy success when changed to doxazosin monotherapy, and 12 patients (75.0%) who had received two or more antihypertensive agents achieved success with doxazosin monotherapy. Changes in blood pressure and final mean daily doses for the aforementioned subgroups are presented in Table VII. Change in serum lipid profile. One hundred twentyfive patients in group 1 and 21 patients in group 2 were included in the lipid analysis. Seven patients were excluded because they were taking concomitant antilipemic agents, and the remaining patients had missing or inevaluable baseline or follow-up data. At baseline, between-group differences (group 1 vs group 2) were found for both triglyceride levels (199.3 vs 137.3 mg/dl; 2.25 vs 1.55 mmol/L) and the ratio of HDL/total cholesterol (0.16 vs 0.20). Fig. 3 illustrates the doxazosin-induced changes in serum lipid levels in groups 1 and 2. Doxazosin produced a favorable improvement in the serum lipid profile in both groups, the majority of lipid changes from baseline to final visit achieving statistical significance. The total serum cholesterol level was reduced significantly @ < 0.01) by 5.9% and 6.7 % in groups 1 (n = 153) and 2 (n = 26), respectively. Triglyceride levels were reduced by 6.8 % in group 1 and 14.3 % in group 2, the former achieving statistical significance 0, < 0.05). HDL cholesterol levels were increased by 1.0% and 7.4% (p < 0.05) in groups 1 and 2, respectively, and the ratio of HDL/total cholesterol increased by 6.2 % and 16.4% (both p < 0.01). The increase in the ratio
Table
VIII. Doxazosin-induced change in calculated CHD
risk
No. of patients Mean baseline risk* Mean final risk* Mean % change from p Value *Probability of developing the Framingham equation). iCalculated from log-odds
baseline?
CHD
Group 1 (sitting DBP 295 mm Hg)
GFOU~ 2 (sitting DBP <95 mm Hg)
94 21.6 17.2 -27
14 29.0 23.8 -27
in 10 years in chances
per 100 (based
on
ratio.
of HDL/total cholesterol was significantly greater (p < 0.05) in patients in group 2 than in patients in group 1. Reduction in calculated CHD risk. As a result of the favorable changes in blood pressure and the lipid profile, the calculated probability of developing CHD in 10 years was reduced by 27% in groups 1 and 2 (Table VIII). Tolerance. Of the 336 patients studied, 81 (24.1% ) reported one or more side effects that had a definite, possible, uncertain, or unknown relationship to doxazosin treatment; on a scale of mild, moderate, and severe, 14 (11.1%) side effects were classified as severe. In nine (2.7 % ) patients the dose of doxazosin was reduced, and 26 (7.7 % ) patients were withdrawn from doxazosin therapy because of side effects (Ta-
328
Maslowski
Table
IX. Summary
American
of tolerance
No. of patients evaluated Patient-days of drug exposure Patients with one or more side effects (nl? No. of side effects No. of severe side effects? Patients with dose of doxazosin reduced because of side effects (n/Y;‘) Patients discontinued because of side effects tnl?) *Considered by investigator to have definite, known relationship to doxazosin. ton a scale of mild, moderate. or severe.
possible,
I*
336 36,150 81124.1 126 14 912.7 26/1.1
uncertain,
or un-
ble IX). The most frequently reported side effects were dizziness (n = 18; 5.4%), headache (n = 15; 4.5%), fatigue (n = 10; 3.0%), malaise (n = 7; 2.1%), palpitation (n = 7; 2.1%), nausea (n = 6; 1.8%), and edema (n = 5; 1.5%). Three cases of syncope were recorded; in each case the patient continued treatment without further incidence of fainting. Overall impression of efficacy and tolerance. At the end of the doxazosin treatment period, the investigators rated overall efficacy as excellent or good in 274 of 322 (85.1% ) patients; in group 1 efficacy was considered to be excellent or good in 228 of 265 (86.4%) patients and in group 2 the efficacy of doxazosin was excellent or good in 46 of 58 (79.3 % ) patients. Toleration was considered to be excellent or good in 282 of 321 (87.9%) patients; toleration was rated as excellent or good in 233 of 263 (88.6%) patients in group 1 and 49 of 58 (84.5%) patients in group 2. DISCUSSION
This study confirms the efficacy of doxazosin as once-daily monotherapy for hypertension. Doxazosin
January 1991 Heart Journal
significantly reduced blood pressure in those patients who had baseline pressures 295 mm Hg and effectively maintained the blood pressure control in patients whose blood pressure was previously controlled by an alternative antihypertensive agent. Heart rate was essentially unchanged. Side effects, related or possibly related to treatment, were noted by 81 (24.1%) patients. The favorable effects on lipid levels with doxazosin represent a fall in total cholesterol values of approximately 6%. The HDL/total cholesterol ratio increased by 6% (group 1) and 16% (group 2), which was consistent with findings of previous studies.5s 6 Such a modification in the serum lipid profile, if sustained, would be expected to lead to a reduction in CHD mortality rates in the context of treated hypertension. However, this remains to be demonstrated and the results are awaited of a long-term study currently in progress.7 REFERENCES
1. Castelli WP. Epidemiology of coronary heart disease: the Framingham Study. Am J Med 1984;76(suppl 2A):4-12. 2. Martin MJ, Hulley SA, Browner WS, Kuller LH, Wentworth D. Serum cholesterol, blood pressure and mortality: implications from a cohort of 361,622 men. Lancet 1986;2:933-6. 3. Cox DA, Leader JP, Milson JA, Singleton W. The antihypertensive effects of doxazosin: a clinical overview. Br J Clin Pharmacol 1986;21(suppl 1):83S-90s. 4. Lew D. Wilson PWF. Anderson KM. Castelli WP. Stratifvine the patient at risk from coronary disease: new insights from the Framingham Heart Study. AM HEART J 1990;119:712-7. 5. Pool J. Plasma lipid lowering effects of doxazosin, a new selective alpha-l adrenergic inhibitor for systemic hypert,ension. Am J Cardiol 1987;59:46G-50G. 6. Pool JL, Addison AA, Nelson EB. Review of the effects of doxazosin, a new selective alpha-l adrenergic inhibitor, on lipoproteins in patients with essential hypertension. Am J Med 1989;87(suppl 2A):57-61. I. Stamler J, Prineas RJ, Neaton JD, et al. Background and design of the new U.S. trial on diet and drug treatment of “mild” hypertension (TOMHS). Am J Cardiol 1987;59:51G-60G.
in general
This study investigated the safety and efficacy of doxazosin treatment in a large population of patients (n = 336) with essential hypertension and assessed the effect of doxazosin on the serum lipid profile and the calculated risk of developing coronary heart disease. Patients were assigned to two groups: those with a baseline diastolic blood pressure 295 mm Hg (group 1) and those with a baseline diastolic blood pressure <95 mm Hg (group 2) that was controlled by previous antihypertensive therapy. Doxazosin treatment (monotherapy in 76.2% of patients) significantly (p < 0.05) reduced the blood pressure of patients in group 1 (-231-17 mm Hg) after 10 weeks and maintained the control of blood pressure for patients in group 2. Heart rate was essentially unchanged in both groups. Mean final daily doses of 3.6 and 3.2 mg were achieved in groups 1 and 2, respectively. Treatment with doxarosin improved the severity category of hypertension for 66.4% of patients in group 1; 87.3% of patients were considered a therapy success. Doxazosin had a favorable effect on the serum lipid profile in both groups of patients. The majority of lipid changes achieved statistical significance and resulted In a significant 27% decrease in the calculated risk of developing coronary heart disease. Doxarosin was well tolerated; only 24.1% of patients had side effects that were related or possibly related to treatment. In nine (2.7%) patients the dose of doxazosin was reduced and 26 (7.7%) patients withdrew from doxazosin therapy because of side effects. (AM HEART J 1991;121:323-8.)
Andrew H. Maslowski,
MBChB,
FRACP,
Auckland,
Antihypertensive therapy tailored to individual patient requirements has replaced the step-care approach of the early 1980s. The selection of agents is now based on their effects on other parameters over and above that of their effect on blood pressure for individual patients. Given the importance of lipid levels in the context of ischemic heart disease,l, 2 antihypertensive medication that produces a favorable change in the serum lipid profile clearly presents a major advantage over alternative agents. Doxazosin, an effective antihypertensive agent, is a selective (piadrenoceptor inhibitor that has been shown to increase the high-density lipoprotein (HDL)/total cholesterol ratio by 9 2%.3 This article presents the results of a postmarketing surveillance study designed to assess the effect of doxazosin in a general practice setting. In an open study during a lo-week period the end points of the study were changes in blood pressure, changes in serum lipid levels, and toleration of doxazosin. The report summarizes data received to date on 336 of an expected 500 patients in New Zealand, as part of a From Reprint Health
Middlemore
Hospital.
requests: Andrew Board, Middlemore
4/O/24888
H. Maslowski, MBChB, FRACP, Auckland Area Hospital, Otahuhu, Auckland 6, New Zealand.
New Zealand
multicountry study ultimately 10,000 patients.
to cover more than
METHODS Patient selection. Eligible men and women had an established diagnosis of essential hypertension, which was defined for the purposes of this study as sitting diastolic blood pressure (DBP) 295 mm Hg without antihypertensive medication. Previously treated and untreated patients could be included. Excluded from the study were patients with malignant or secondary hypertension, pregnant or lactating women, patients with documented or suspected serious drug reactions or sensitivity to al-inhibitors in general and quinazolines in particular, patients with orthostatic hypotension, and patients with any other medical condition that could interfere with completion of the study. Women were advised not to use oral contraceptives and to avoid pregnancy for 6 months after entry to the study. Study design. Patients were treated for 10 weeks with doxazosin, after an optional 2-week baseline phase during which existing antihypertensive medication could be discontinued and baseline blood pressure established. If possible, patients were evaluated twice during the baseline phase, at the end of weeks 1 and 2. Patients continued into the treatment phase if mean sitting DBP was 295 mm Hg, with no greater than 10 mm Hg difference between the two baseline measurements. A third baseline week was allowed if DBP had not stabilized. Some investigators elected to 323
324 Table
Maslowski I. Baseline
American
characteristics
of the study population
No. of patients Male/female Mean age (yr) Range Mean duration of hypertension (yr) Range No. of patients with? Mild hypertension Moderate hypertension Severe hypertension Gross hypertension No. of patients With previous antihypertensive treatment Discontinued before doxazosint: Continued during study Patients treated with one prestudy drug (n/Z) Patients treated with two or more prestudy drugs (n/T>) No. of patients with no prior therapy
Group 1 fsitting DBP 295 mm Hg)
Group 2 (sitting DBP <95 mm Hg)
276* 150/125 55.4 20-82 6.8 0.08-30
60 37123 58.4 36-76 8.6 0.17-22
TOtid
336 1871148 5.5.9 20-8’ 7.1 0.08-30
162 80 32 2 170 99
71 140/82.4 30/17.6 106
165
80 3” 2 58 51 7 41/70.7 17129.3
228 150
78 18U79.4
47120.6
2
*Sex not stated for one patient. tBased on sitting DBP of 91 to 104 mm Hg mild, 105 to 114 mm Hg moderate, 115 to 129 mm Hg severe, and ,130 mm Hg gross. tOf the 150 patients changing to doxazosin monotherapy, 104 (69.3”Fm) had been receiving one previous drug; 46 (30.7’, ) had been receiving
Table
II. Study
treatment
status
Group 1 (sitting DBP 295 mm Hg)
Doxazosin monotherapy Doxazosin plus prior therapy
January 1991 Heart Journal
Group 2 (sitting DBP <9S mm Hg)
Total
n
%
n
%
205
74.3
53
88.3
258 76.8
71
25.7
7
11.7
78 23.2
n
7’0
treat a group of previously treated patients with doxazosin monotherapy, without a washout phase. The objective was to determine whether doxazosin monotherapy would maintain the same blood pressure control as prior antihypertensive treatment. If there was no 2-week baseline phase, the initial screening visit was considered baseline. Treatment with doxazosin was initiated at 1 mg/day. The dose was increased, if required, at intervals of 1 to 4 weeks, until one of the following occurred: (1) sitting DBP 190 mm Hg was achieved, (2) the maximum daily dose of 16 mg had been taken for 2 consecutive weeks, or (3) significant side effects precluded a further increase in dose. The defined dose titration schedule was 1, 2, 4, 8, and 16 mg, once daily; a decrease in dose was permitted if side effects became evident. Once the optimum dose had been reached, assessments were scheduled at 4-week intervals. Assessments. Patients were evaluated 2 to 12 hours af-
108
two or more
ter drug administration at each review visit. Blood pressure was determined after the patient had been sitting for 5 minutes and was the mean of two consecutive measurements. Heart rate was recorded immediately before the blood pressure measurement. Blood samples for serum lipid assessment (total cholesterol, HDL cholesterol, HDL/total cholesterol ratio, and triglycerides) were taken after the last baseline blood pressure measurement and at the final visit. Plasma samples were obtained after an overnight fast before drug administration. Routine laboratory tests were carried out only when clinically indicated. If patients demonstrated clinically relevant abnormalities in laboratory parameters, they were monitored until the condition returned to prestudy status or resolution of the problem was achieved. Side effects were recorded at each visit in terms of onset date, duration, severity, drug relation, and outcome. Information regarding concomitant illnesses and medications was also listed. At the end of the doxazosin treatment period, the investigator gave an overall assessment of efficacy and toleration for each patient, on a scale of excellent, good, fair, or poor. Data analysis. Mean changes in blood pressure and heart rate were analyzed with a paired t test (two tailed), at a significance level of 5%, Qualitative changes in blood pressure in hypertensive patients (group 1) were categorized as follows: (1) sitting DBP 5 90 mm Hg with at least a 5 mm Hg reduction (“normalized”), (2) sitting DBP reduction ~10 mm Hg but not reaching a sitting DBP 190
Volume 121 Number 1. Part 2
New
2 r”
6OJ
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/
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easelme
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4
Time (weeks)
III. Duration
and dose of doxazosin
Mean duration of therapy (days) Range Patients with duration >90 days (n/Y; Mean final dose (mg/day) Patients taking final dose of (nl“c ) 1 mglday 2 mglday 4 mglday
practice
stud-v
325
I 8
12
Final
Time (weeks)
Fig. 1. Doxazosin-induced changes in sitting blood pressure (BP) and heart rate (HR) for patients in group 1 (baseline sitting DBP 295 mm Hg). SBP, Systolic blood pressure.
Table
general
Fig. 2. Doxazosin-induced changes in sitting blood pressure (BP) and heart rate (HR) for patients in group 2 (baseline sitting DBP <95 mm Hg). SBP, Systolic blood pressure.
treatment Group 1 (sitting DBP 295 mm Hg)
Group 2 (sitting DBP <95 mm Hg)
TOM
107.5 4-340 “01/72.8 3.6
116.8 24-348 38/63.3 3.2
109.2 4-348 239171.1 3.5
62122.5 82f29.7 83/30.1
n/20.0 26/43.3 12/20.0 416.7 l/1.7
74122.0 108/32.1 9U28.3 3018.9 912.7
)
8 mg/day 16 mglday
mm Hg, and (3) reduction in sitting DBP 510 mm Hg (“failures”). Patients in the first two categories were regarded as therapy successes. For the subgroup of patients whose baseline blood pressure was “normotensive” (group 2), therapy successes were: (1) from baseline sitting DBP of 91 to 95 mm Hg to 190 mm Hg or (2) from baseline sitting DBP of <90 mm Hg that remained at < 90 mm Hg. Mean changes in serum lipid levels were also analyzed with a paired t test (two tailed). The significance of between-group difference was assessed with the Wilcoxon two sample test. Lipid determinations were used in conjunction with blood pressure, smoking status, evidence of left ventricular hypertrophy, and glucose intolerance to evaluate the probability of developing coronary heart disease (CHD) in 10 years according to the Framingham equation.4 Each patient’s calculated risk score was determined at baseline and after treatment with doxazosin. Mean changes from baseline were assessed by applying a log-odds transformation and a within-group t test.
2619.4 812.9
RESULTS Population
status. The study population was divided into two groups for efficacy analysis: group 1, those patients with a baseline sitting DBP 195 mm Hg (n = 276) and group 2, those patients with a baseline sitting DBP <95 mm Hg (n = 60). The majority (57/60) of patients in group 2 had a baseline DBP <90 mm Hg. All 336 patients except one in group 2 were evaluable for efficacy. Baseline characteristics of the study population are given in Table I and the study treatment status is shown in Table II. Duration and dose of doxazosin treatment. Although the protocol specified a lo-week doxazosin treatment period, most patients received the drug for 12 weeks or more. The mean duration of treatment for all patients was 109.2 days and the mean final daily dose was 3.5 mg; 277 (82.4%) patients were taking a final daily dose ~4 mg. The majority of patients (76.8%) were treated with doxazosin monotherapy. This was
326
Mzslowski Table
t p < 0.05 between grou/x Wilcoxon
Z-sample
test
from
V. Changes baseline
sitting
DBP
in the severity
to final
visit
[
IV. Efficacy
outcome
of evaluable
Patients evaluable for efficacy (ni Therapy successes (n/“;, I Control achieved* 210 mm Hg reduction Therapy failures (n/Y) Inadequate response at maximum dose Not titrated to maximum dose For any apparent reason Lost to follow-up Limited by side effectst
Graup 1 (sitting DBP ~9.5 mm Hg)
Group 2 (sitting DRP <95 mm Hg)
276 241/87.3 210176.1 31/11.2 35112.7 10/3.6
59 46/78.0
15/5.4 110.4 913.3
7h1.9 111.7
*Reduction in sitting DBP to 590 mm Hg. tIncludes patients with dose reduced hecause
13122.0 l/1.7
416.8
of side effects.
particularly true for group 2, in which 88.3% of patients received doxazosin monotherapy. Data for groups 1 and 2 are given in Table III. Doxazosin-induced Blood pressure response. changes in blood pressure for patients in groups 1 and 2 are shown in Figs. 1 and 2, respectively. Doxazosin produced a significant reduction in blood pressure at each visit in the patients in group 1, from a mean baseline level of 167/104 mm Hg to a final measurement of 144/87 mm Hg. In group 2 in patients whose blood pressures were controlled by previous antihypertensive therapy, blood pressures were essentially unchanged after treatment with doxazosin (baseline, 151/87 mm Hg; final, 146/85 mm Hg). No significant changes in heart rate were seen in both groups of patients. Of the 276 patients in group 1, in 210 (76.1%) blood pressure was normalized after treatment with dox-
1 (baseline
severity
(n)
Mild
Moderate
Normal Mild Moderate
0 134 .55
0 23 21
0 5 3
0 0 0
0 0 1
20
10
2
0
0
1
0
0
0
c55
10
0
1
1 210
Severe
Total in)
Gross
0 162 80 32
2 276
Table VI. Changes in the severity category of hypertension from baseline to final visit for patients in group 2 (baseline sitting DBP <95 mm Hg) Final
patients
of hypertension
in group
Normal
Gross Total
Table
category
patients
Baseline secwrit\,
Severe
Fig. 3. Doxazosin-induced changes in serum lipid profile for patients in group 1 (baseline sitting DBP 195 mm Hg) and group 2 (baseline sitting DBP <95 mm Hg).
for
295 mm Hg) Final
Trlglycendes
January 1991 Heart Journal
American
Baseline sewrit> Normal Mild Total
seoerity
Cn)
Normal
Mild
Total (nl
45
11
66
1
2
3
46
13
59
azosin; in 31 (11.2 % ) there was a reduction in sitting DBP ~10 mm Hg, and the remaining 35 patients (12.7%) were regarded as therapy failures. In group 2, 46 patients (78.0% ) were considered a therapy success; 13 (22.0%) were therapy failures. A summary of efficacy is presented in Table IV. In group 1, 244 patients (88.4%) showed an improvement in the severity category of their hypertension; in 134 (82.7 % ) patients with mild hypertension blood pressure was normalized, in 76 (95.1%) patients with moderate hypertension blood pressure was normalized or became mild hypertension, and 30 (93.8 % ) patients with severe hypertension became either mildly hypertensive or their blood pressure was normalized (Table V). In group 2, in the majority of patients (47; 79.7 % ), there was no change in the severity category of hypertension (Table VI). Antihypertensive efficacy as a function of prestudy therapy. In group 1, 241 patients (87.3%) were con-
sidered therapy successes after treatment with doxazosin; 94 patients (88.7%) with no previous antihypertensive therapy achieved success and 23 patients (76.7 % ) who had taken two or more antihypertensive agents were therapy successes when changed to doxazosin monotherapy. In group 2, 46 patients (78.0%) were considered therapy successes. Forty-two patients (82.3 % ) whose blood pressures were controlled by prior therapy
Volume 121 Number 1, Part 2
Table
New Zealand
VII. Antihypertensive
Patients with no prior therapy No. of patients Mean baseline blood pressure (mm Mean final blood pressure (mm Hg) Mean reduction from baseline (mm Mean final dose (mg/day) Patients with one or more prior drugs* No. of patients Mean baseline blood pressure (mm Mean final blood pressure (mm Hg) Mean reduction from baseline (mm Mean final dose (mg/day) Patients with two or more prior drugs* No. of patients Mean baseline blood pressure (mm Mean final blood pressure (mm Hg) Mean reduction from baseline (mm Mean final dose (mg/day) withdrawn
before
doxazosin
study
327
efficacy and dose of doxazosin as a function of prestudy therapy (sitting
*Therapy
general practice
Group 1 DBP 295 mm
Hg)
(sitting
Group 2 DBP <95 mm Hg)
106
Hg) Hg)
1671105 143187 24.1/18.0 3.4
-
99 161/102 142187 19.7D5.5 3.1
51 152187
Hg)
30 164/104 145188
Hg)
19.2/15.9
16 147186 144187 3.41-0.3 3.4
Hg) Hg)
145185 6.8/2.1
3.0
4.4
administration.
achieved therapy success when changed to doxazosin monotherapy, and 12 patients (75.0%) who had received two or more antihypertensive agents achieved success with doxazosin monotherapy. Changes in blood pressure and final mean daily doses for the aforementioned subgroups are presented in Table VII. Change in serum lipid profile. One hundred twentyfive patients in group 1 and 21 patients in group 2 were included in the lipid analysis. Seven patients were excluded because they were taking concomitant antilipemic agents, and the remaining patients had missing or inevaluable baseline or follow-up data. At baseline, between-group differences (group 1 vs group 2) were found for both triglyceride levels (199.3 vs 137.3 mg/dl; 2.25 vs 1.55 mmol/L) and the ratio of HDL/total cholesterol (0.16 vs 0.20). Fig. 3 illustrates the doxazosin-induced changes in serum lipid levels in groups 1 and 2. Doxazosin produced a favorable improvement in the serum lipid profile in both groups, the majority of lipid changes from baseline to final visit achieving statistical significance. The total serum cholesterol level was reduced significantly @ < 0.01) by 5.9% and 6.7 % in groups 1 (n = 153) and 2 (n = 26), respectively. Triglyceride levels were reduced by 6.8 % in group 1 and 14.3 % in group 2, the former achieving statistical significance 0, < 0.05). HDL cholesterol levels were increased by 1.0% and 7.4% (p < 0.05) in groups 1 and 2, respectively, and the ratio of HDL/total cholesterol increased by 6.2 % and 16.4% (both p < 0.01). The increase in the ratio
Table
VIII. Doxazosin-induced change in calculated CHD
risk
No. of patients Mean baseline risk* Mean final risk* Mean % change from p Value *Probability of developing the Framingham equation). iCalculated from log-odds
baseline?
CHD
Group 1 (sitting DBP 295 mm Hg)
GFOU~ 2 (sitting DBP <95 mm Hg)
94 21.6 17.2 -27
14 29.0 23.8 -27
in 10 years in chances
per 100 (based
on
ratio.
of HDL/total cholesterol was significantly greater (p < 0.05) in patients in group 2 than in patients in group 1. Reduction in calculated CHD risk. As a result of the favorable changes in blood pressure and the lipid profile, the calculated probability of developing CHD in 10 years was reduced by 27% in groups 1 and 2 (Table VIII). Tolerance. Of the 336 patients studied, 81 (24.1% ) reported one or more side effects that had a definite, possible, uncertain, or unknown relationship to doxazosin treatment; on a scale of mild, moderate, and severe, 14 (11.1%) side effects were classified as severe. In nine (2.7 % ) patients the dose of doxazosin was reduced, and 26 (7.7 % ) patients were withdrawn from doxazosin therapy because of side effects (Ta-
328
Maslowski
Table
IX. Summary
American
of tolerance
No. of patients evaluated Patient-days of drug exposure Patients with one or more side effects (nl? No. of side effects No. of severe side effects? Patients with dose of doxazosin reduced because of side effects (n/Y;‘) Patients discontinued because of side effects tnl?) *Considered by investigator to have definite, known relationship to doxazosin. ton a scale of mild, moderate. or severe.
possible,
I*
336 36,150 81124.1 126 14 912.7 26/1.1
uncertain,
or un-
ble IX). The most frequently reported side effects were dizziness (n = 18; 5.4%), headache (n = 15; 4.5%), fatigue (n = 10; 3.0%), malaise (n = 7; 2.1%), palpitation (n = 7; 2.1%), nausea (n = 6; 1.8%), and edema (n = 5; 1.5%). Three cases of syncope were recorded; in each case the patient continued treatment without further incidence of fainting. Overall impression of efficacy and tolerance. At the end of the doxazosin treatment period, the investigators rated overall efficacy as excellent or good in 274 of 322 (85.1% ) patients; in group 1 efficacy was considered to be excellent or good in 228 of 265 (86.4%) patients and in group 2 the efficacy of doxazosin was excellent or good in 46 of 58 (79.3 % ) patients. Toleration was considered to be excellent or good in 282 of 321 (87.9%) patients; toleration was rated as excellent or good in 233 of 263 (88.6%) patients in group 1 and 49 of 58 (84.5%) patients in group 2. DISCUSSION
This study confirms the efficacy of doxazosin as once-daily monotherapy for hypertension. Doxazosin
January 1991 Heart Journal
significantly reduced blood pressure in those patients who had baseline pressures 295 mm Hg and effectively maintained the blood pressure control in patients whose blood pressure was previously controlled by an alternative antihypertensive agent. Heart rate was essentially unchanged. Side effects, related or possibly related to treatment, were noted by 81 (24.1%) patients. The favorable effects on lipid levels with doxazosin represent a fall in total cholesterol values of approximately 6%. The HDL/total cholesterol ratio increased by 6% (group 1) and 16% (group 2), which was consistent with findings of previous studies.5s 6 Such a modification in the serum lipid profile, if sustained, would be expected to lead to a reduction in CHD mortality rates in the context of treated hypertension. However, this remains to be demonstrated and the results are awaited of a long-term study currently in progress.7 REFERENCES
1. Castelli WP. Epidemiology of coronary heart disease: the Framingham Study. Am J Med 1984;76(suppl 2A):4-12. 2. Martin MJ, Hulley SA, Browner WS, Kuller LH, Wentworth D. Serum cholesterol, blood pressure and mortality: implications from a cohort of 361,622 men. Lancet 1986;2:933-6. 3. Cox DA, Leader JP, Milson JA, Singleton W. The antihypertensive effects of doxazosin: a clinical overview. Br J Clin Pharmacol 1986;21(suppl 1):83S-90s. 4. Lew D. Wilson PWF. Anderson KM. Castelli WP. Stratifvine the patient at risk from coronary disease: new insights from the Framingham Heart Study. AM HEART J 1990;119:712-7. 5. Pool J. Plasma lipid lowering effects of doxazosin, a new selective alpha-l adrenergic inhibitor for systemic hypert,ension. Am J Cardiol 1987;59:46G-50G. 6. Pool JL, Addison AA, Nelson EB. Review of the effects of doxazosin, a new selective alpha-l adrenergic inhibitor, on lipoproteins in patients with essential hypertension. Am J Med 1989;87(suppl 2A):57-61. I. Stamler J, Prineas RJ, Neaton JD, et al. Background and design of the new U.S. trial on diet and drug treatment of “mild” hypertension (TOMHS). Am J Cardiol 1987;59:51G-60G.