- Email: [email protected]
A long-term study of doxazosin in the treatment of mild or moderate essential hypertension in general medical practice
A long-term study of doxazosin in the treatment of mild or moderate essential hypertension in general medical practice This study assessed the long-term (54 weeks) antihypertensive efficacy and safety of doxarosin in the treatment of mild or moderate essential hypertension, defined as sitting and standing diastolic blood pressure of 95 to 114 mm Hg. Of the 153 patients who successfully completed an initial 14-week trial, 61 continued uninterrupted into a 40-week extension study. Optimal antihypertensive efficacy was achieved by week 12 and maintained in all patients for the duration of 1 year. The final mean sitting blood pressure was 148184 mm Hg and was reduced from a mean baseline level of 1731102 mm Hg. Occasional decreases in heart rate were observed, but these were not considered to be clinically relevant (1 to 3 beats/min). The mean final dose of doxazosin for patients evaluable for efficacy was 2.4 mg/day; 91.7% of patients were taking 14 mg/day. No increase in daily maintenance dose was observed from the initial phase to the long-term extension study. After 1 year of treatment, 93.3% of patients were considered a therapeutic success (sitting diastolic blood pressure 210 mm Hg reduction from baseline or z? 90 mm Hg with >5 mm Hg reduction). In no patients was there a worsening in the severity category of the hypertension. Total serum cholesterol concentrations were reduced significantly (6.6% p = 0.03) at the end of week 14. Reductions in total serum cholesterol levels persisted throughout the extension study, with a final reduction of 5.4%. Most side effects were mild or moderate and were well tolerated or disappeared with continued treatment. The investigators rated overall tolerance as excellent or good in 95% of patients during the l-year study period. (AM HEART J 1991;121:346-51.)
John Manos, MD Sandwich,
Kent, England
Doxazosin, a quinazoline derivative, is a selective postsynaptic al-adrenergic receptor inhibitor.‘, 2 By inhibiting postsynaptic al-adrenergic receptors, doxazosin produces a fall in peripheral vascular resistance, with little or no baroreceptor-induced reflex tachycardia.3 Clinical studies have demonstrated that doxazosin is an effective medication for the treatment of essential hypertension. An extended elimination half-life of between 1g4 and 22 hours5 provides the convenience of once-daily administration,6 and the good tolerance profile of doxazosin has been well established.7 This open study was designed to evaluate the long-term antihypertensive efficacy and safety of doxazosin in the treatment of essential hypertension in general practice. Patients who successfully completed an initial 14-week study continued uninterrupted into a 40-week extension study. Final efficacy
From the Medical Department, Pfizer Limited. Reprint requests: John Manes, MD, Medical Services Department, UK, Ramsgate Rd, Sandwich, Kent CT13 9N.J, England. 4/O/24881
346
Pfizer
parameters at week 54 were compared with baseline values obtained at the start of the initial study. METHODS Initial study: phase I (Fig. 1). Patients (n = 169) initially entered a 14.week trial with mild or moderate essential hypertension, defined as sitting and standing diastolic blood pressure (DBP) of 95 to 114 mm Hg. Both newly diagnosed and previously or currently treated patients with hypertension took part in the study. At entry, patients were allowed to take one or more concomitant antihypertensive agents including diuretics, P-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors provided that the dose was constant throughout the study. During a 2-week baseline period in phase I, sitting and standing blood pressure and heart rate were measured at three visits (0, 1, and 2 weeks); the mean value of the last two visits was taken as baseline. Patients with a sustained sitting and standing DBP of 95 to 114 mm Hg were eligible to proceed. Phase II. Doxazosin was initiated at 1 mg/day and adjusted at intervals of 2 weeks if required. Daily doses were increased sequentially to 2, 4, and 8 mg until one of the following occurred: control of blood pressure was achieved (sitting DBP 190 mm Hg), a maximum daily dose of 8 mg had been administered, or side effects precluded a
Volume 121 Number 1, Part 2
Table
Doxazosin
1. Demographic
data for the extension
Patients entered into study (n) Patients with mild hypertension (n)* Patient with moderate hypertension Mean age (yr) Range Mean duration of hypertension (yr)
on sitting
DBP:
extension
(n)*
mild, 95 to 104 mm Hg; moderate,
61 patients?
105 to 114 mm
Long-term
extension
study 1
I
further increase in dose. Patients continued to take the optimum adjusted dose until the end of the &week doseadjustment period and were monitored at biweekly intervals. Phase III. Patients (n = 153) who successfully completed the dose-adjustment. phase continued with their optimum dose for a 4-week maintenance period, during which they were evaluated at intervals of 2 weeks. Throughout the study, blood pressure was recorded as the mean of two consecutive measurements made after the patient had been sitting for 5 minutes and subsequently standing for 2 minutes. Therapy success in terms of blood pressure response was defined as a fall in sitting DBP to 190 mm Hg (“normalized”) with a decrease of 15 mm Hg, or a decrease in sitting DBP of ~10 mm Hg. Heart was
determined
immediately
before
the
measurement
blood pressure and side effects were recorded at each visit. Laboratory tests (hematology, liver and renal function, electrolytes, glucose, serum proteins, total serum cholesterol, and serum triglycerides) were performed at baseline and week 14. Extension study. Patients who successfully completed the initial 14-week trial continued uninterrupted into a 40-week extension study, dependent on patient consent and physician discretion. Baseline values for blood pressure, heart rate, and laboratory safety data obtained at the start of the 14-week study served as baseline for the 40-week extension study. Patients were evaluated at intervals of 8 weeks, corresponding to treatment weeks 22,30,38,46, and 54. At each visit
blood
pressure,
heart
rate,
and
body
weight
were
as-
sessed and side effects were recorded. Laboratory tests were repeated at week 54. In addition, the investigators provided an overall evaluation of the efficacy and tolerance of doxazosin in each patient at the end of the study. Statistical analysis. Final changes from baseline in blood pressure and heart rate were analyzed statistically by means of paired t tests. The percentage change from baseline in lipid parameters was derived from the difference of geometric means for final and baseline lipid values. RESULTS Initial study.
patients
347
169 patients (DBP 95-114 mm Hg)
study
Hp.
rate of
study
61 47 14 58.0 + 0.9 35-68 5.0 0.08-20 75.9 2 1.4 57-100
Range Mean weight (kg) Range *Based
long-term
In the initial 14-week study, 169 were treated with doxazosin. Sixteen (9 % )
14*+
22’
30.
46’
38’
1 54’+ weeks
Fig. 1. Study design.*Blood pressure and heart rate assessment.+Serum cholesterol assessment.xPatients who successfully completed the initial 14.week phase continued uninterrupted into the extension study. Entry criteria were based primarily on patient and physician consent and convenience.
Table
II. Summary
of concomitant
medications
No. of patients receiving concomitant medication at entry No. of concomitant medications No. of patients receiving antihypertensive therapy No. of patients beginning to take concomitant medication during the study No. of concomitant medications No. of patients beginning to take antihypertensive therapy
34 55 23 10 21 3
patients did not complete the study; 12 (7 % ) discontinued treatment because of side effects, mostly headache and dizziness, 2 (1% ) had an inadequate antihypertensive response and discontinued, 1 (0.5 % ) could not be followed up, and l(0.5 % ) did not comply with the treatment regimen. Of the 165 patients evaluable for efficacy, 139 (84.2 % ) were considered as therapeutic successes. Extension study. Sixty-one patients, 33 men and 28 women, continued uninterrupted into the extension study. Demographic data are given in Table I. A summary of the concomitant medication is given in Table II. Blood pressure response. Fig. 2 A, shows the mean changes in sitting systolic blood pressure @BP), DBP, and heart rate for all patients evaluable for efficacy throughout a l-year period of treatment with doxazosin. Mean baseline sitting and standing blood pressures were 173/102 and 170/102 mm Hg, respectively. Doxazosin produced a statistically significant
348
Manos
American
Therapy week
January 1991 Heart Journal
Therapy week
Fig. 2. Mean changes (+ SEM) in sitting SBP, DBP, and heart rate in (A) all patients evaluable for efficacy (n = 60), (B) patients receiving doxazosin monotherapy (n = 37), and (C) patients receiving doxazosin in combination with another antihypertensive agent (n = 23). *p < 0.05, statistically significantly different from baseline.
Table
III. Final dose summary for patients evaluable for efficacy All patients Efficacy eualuable
Final dose (mg/day) 1 2 4 a Total (n) Final mean dose
46.7 26.7 la.3 a.3
601 2.4
Monotherapy
(X)
patients
(YO)
Combination
Success*
Normalizedj
Efficacy eualuable
Success*
Normalizedf
Efficacy eualuable
50.0 25.0 17.9 7.1 56 2.3
51.9 25.9 la.5 3.7 54 2.1
54.1 16.2 21.6 a.1 371 2.4.
58.8 14.7 20.6 5.9 34 2.2
60.6 15.2 21.2 3.0 33 2.0
34.8 43.5 13.0 a.7 23 2.4
therapy
patients
((‘0)
Success*
Normalizedf
36.4 40.9 13.6
38.1 42.9 14.3 4.8 ‘21 2.2
9.1
22 2.5
(mg/day)
TSitting DBP 590 mm Hg with 25 mm Hg reduction +Sitting DBP 590 mm Hg with 25 mm Hg reduction iOne patient was considered not evaluable for efficacy of the extension study.
from baseline or 210 mm Hg reduction from from baseline. because concomitant antihypertensive therapy
(p < 0.05) reduction in mean blood pressure throughout the entire study, with the final mean sitting and standing blood pressures being 148/84 and 144/83 mm Hg, respectively. Optimal antihypertensive efficacy was achieved by week 12 and maintained in all patients for the duration of 1 year. Occasionally, statistically significant decreases in heart rate were ob-
baseline. was added
before
the first
regularly
scheduled
visit
served, but no trend was established and the changes (1 to 3 beats/min) were not clinically significant. Fig. 2, B and C, shows the mean changes in sitting SBP, DBP, and heart rate for the subgroup analysis of patients who received doxazosin either as monotherapy or in combination with other antihypertensive agents, respectively. In patients who
“O,“me 121 Number 1, Part 2
Doxazosin
Table IV. Therapeutic success rates patients treated with doxazosin All patients (n = SO)
Therapy successes Normalized r10mmHg reduction Therapeutic failures Dose adjusted to maximum Dose not adjusted to maximum
for
Doxazosin monotherap> (n = 37)
all evaluable
IL
n
“;I
n
“;
56 54 2
93.3 90.0 3.3
34 33 1
91.9 89.2 2.7
22 21 1
95.7 91.3 4.3
4 1
6.7
3
8.1
1
4.3
1.7
1
2.7
3
5.0
2
5.4
1
4.3
extension
Doxazosin monotherapy (n = 37)
All patients (n = 60)
Improved severity category of hypertension No change in severity category
Table
duration
of therapy,
Combination therapy (n = 23)
“0
II
“<
n
c;,
55
91.7
34
91.9
21
91.3
5
8.3
3
8.1
2
8.7
-
received doxazosin monotherapy, mean sitting and standing blood pressures were reduced from 1721 103 to 147/85 mm Hg and from 169/102 to 143/83 mm Hg, respectively. When doxazosin was added to prior antihypertensive medication, mean sitting and standing blood pressures were reduced from 174/102 to 148/84 mm Hg and from 172/102 to 146/84 mm Hg, respectively. The reductions in blood pressure for the group receiving combined therapy can be attributed to doxazosin, because the doses of concomitant medications were constant throughout the study. evaluability,
349
n
VI. Changes
in total
serum cholesterol Baseline fn = 27)
Efficacy
study
Table V. Changes in the severity category of hypertension in patients evaluable for efficacy from baseline to final visit
Combination therapy (n = 23)
n
long-term
and dose.
Patients were considered evaluable for efficacy if they had completed the initial 14-week study, met the inclusion criteria, and completed at least one regularly scheduled active drug visit in the extension study. Patients in whom the dose or type of concomitant antihypertensive therapy changed during the course of the study were considered not evaluable for efficacy at subsequent visits. The mean duration of treatment for all 60 patients evaluable for efficacy was 396.2 days; in the subgroups of doxazosin monotherapy and combination therapy the mean duration of treatment was 382.7 and 417.8 days, respectively. The mean final dose of doxazosin for all patients evaluable for efficacy was 2.4 mglday; at the final study visit 91.7 % of patients were taking 14 mg doxazosin once daily. A dose summary for the different patient groups is given in Table III. Therapeutic success rate. At the completion of the initial 14-week study, 54 of 60 (90.0 % ) patients were considered as therapeutic successes at a mean daily dose of 2.2 mg; 6 (10.0%) of the patients continuing into the extension study were regarded as therapeutic failures. All patients continued into the extension
Mean total serum cholesterol mmol/L mg/dl Mean Y’;$ change from baseline
6.66
257.1
Week 14 (n = 27)
6.23 240.5 -6.56
levels Final visit (n = 27)
6.30 243.2 -5.43
study at the discretion of the investigators, because treatment was seen to be beneficial. After 1 year of doxazosin therapy, 56 (93.3%) patients were considered as therapeutic successes, with a mean daily dose of 2.3 mg. Fifty-four (90.0%) patients achieved normalized blood pressures (sitting DBP 190 mm Hg with a ~5 mm Hg reduction from baseline) and two had a reduction in DBP of 210 mm Hg from baseline. Only four (6.7 % ) patients were regarded as treatment failures: in one the dose of doxazosin was adjusted to the maximum 8 mg/day, in two (3.3%) the maximum dose was not adjusted because of side effects (one possibly related and one not related to treatment), and in one patient the dose of doxazosin was not increased for unexplained reasons. Table IV gives the therapeutic success and failure rates for all patients receiving doxazosin monotherapy and doxazosin in combination with other antihypertensive agents. Severity of hypertension. The changes in severity of hypertension (based on mean sitting DBP) are presented in Table V. In no patient was there a worsening in the severity category of the hypertension. Laboratory variables. A total of 5880 individual parameters was analyzed and 17 abnormal test results were reported. In most cases the laboratory safety data remained unchanged after treatment, or minor changes were considered insignificant and related to concomitant medications or disease. No trends with
350
Manos
Table
VII. Summary of tolerance
American
Total no. of patients Patients with side effects (n/f;) Patients discontinued because Patients with dose of doxazosin
monotherapy
of side effects (n/O; ) reduced (n/Z’ )
61 9h4.8 l/1.6 l/1.6
Table VIII. Investigators’ global assessment of efficacy and
tolerance
Efficacy Excellent Good Fair Tolerance Excellent Good Fair Poor
All patients (5%) (n = 60)
Dorazosin monotherapy (%) (n = 37)
Combination therapy (70) (n = 23)
72 23 5
68 24 8
78 22 0
75 20 3 2
73 22 3 3
78 17 4 0
regard to organ systems or correlations with doxazosin dose and duration of therapy were apparent. Serum lipids. Lipid data analyses identified a significant 6.6% (p = 0.03) reduction from baseline in total serum cholesterol levels at the end of week 14. Reductions in total serum cholesterol levels persisted throughout the extension study, reaching a final reduction of 5.4% from baseline (Table VI). There were variable, nonsignificant changes in serum triglyceride levels that, by final visit, were not significantly different from baseline (0.3% final reduction). Tolerance. An overall summary of tolerance is given in Table VII. The majority of side effects (dizziness [n = 4; 6.6%], dyspnea [n = 3; 4.9%], fatigue [n = 2; 3.3%], somnolence [n = 2; 3.3% 1, and headache [n = 2; 3.3 % ] were mild or moderate and were tolerated or disappeared with continued treatment. One patient with a history of angina who was receiving concomitant isosorbide dinitrate and nitroglycerin trinitrate had a myocardial infarction after 327 days of therapy; the incident was judged to be unrelated to doxazosin treatment. No apparent differences were noted between the nature or number of side effects occurring in the subgroups receiving doxazosin monotherapy and combination therapy. Overall clinical evaluation. At the end of the extension study, efficacy and tolerance were rated as excellent or good for 95 % of patients and fair for 5 % . A summary of these data and the results for the
January 1991 Heart Journal
and combined groups is given in Table
VIII. DISCUSSION
The objective of this open, noncomparative study was to evaluate the long-term antihypertensive efficacy and safety of doxazosin when administered in a general medical practice to patients with mild or moderate essential hypertension. Patients who received doxazosin as monotherapy and in combination with other antihypertensive agents were assessed. Of the 169 patients who began the original 14-week study, 153 (91% ) completed the full course of treatment; 165 were evaluable for efficacy and 139 (84.2 %) were considered as therapeutic successes at a mean daily dose of 2.8 mg. Twelve (7 % ) of the 169 patients discontinued treatment because of side effects; headache and dizziness were the most commonly reported events. To address the long-term effects of doxazosin, the physicians were allowed to extend treatment from the original 14-week trial. The decision to continue uninterrupted into the 40-week extension study was based primarily on patient consent and physician discretion, because only 61 (39.9%) of the 153 patients who completed the 14-week study continued. Of the 60 evaluable patients who entered the extension study, 54 (90.0 % ) were considered as therapeutic successes at 2.2 mglday at the end of the original 14-week study. Indeed, six (10.0% ) patients who continued into the extension study were regarded as treatment failures in the initial study, although in all patients there was some reduction in blood pressure (range, 4 to 9 mm Hg from baseline). The long-term (54 weeks) treatment results demonstrated the sustained antihypertensive efficacy of doxazosin. There was no suggestion that the antihypertensive effects of doxazosin were diminished after 1 year of treatment (mean, 396.2 days). It is important that, from baseline to final visit, dosages of doxazosin and blood pressure reductions were similar after 14 and 54 weeks. In fact, in a few of the patients who were regarded as therapeutic failures after 14 weeks of therapy blood pressures were controlled successfully with long-term treatment. The long-term success rate in this study is attributable to doxazosin because there were changes in concomitant antihypertensive medications in only three patients during the study; all subsequent blood pressure and heart rate values for these patients were not included in the efficacy analysis. Minor changes in heart rate were observed during the course of the study and, although some mean changes attained
Volume 121 Number 1. Part 2
statistical significance, there were no clinically important alterations. Lipid data analyses identified a significant 6.6% (p < 0.05) reduction from baseline in total serum cholesterol levels at the end of week 14. Reductions in cholesterol levels persisted at 5 % to 6 % throughout the long-term study. Triglyceride levels differed at various time points; the reasons for the apparent inconsistent changes in triglyceride levels could be the result of effects of recent food and/or alcohol consumption. However, the lipid results alone should be interpreted prudently based on the relatively small number of patients with evaluable data (n = 27 cholesterol; n = 23 triglycerides). During the 54 weeks of treatment, 9 (14.8 % ) of the 61 patients reported side effects. The most common were dizziness (n = 4; 6.6%), dyspnea (n = 3; 4.9%), somnolence, fatigue, and headache (each n = 2, 3.3 % ). The occurrence and profile of side effects were similar to those reported at the end of 14 weeks of treatment in the larger group. No new or unexpected adverse events developed during the long-term extension period. Laboratory safety data were basically unchanged after long-term treatment. There were a few apparently random abnormal values that might have been the result of treatment; however, no trends with regard to organ systems or correlations with dose and duration were apparent. None of the ab-
Doxazosin
long-term
extension
study
351
normal values were grossly outside the normal control range. The investigators’ overall assessment of both efficacy and tolerance was excellent or good in 95% of the patients who received long-term doxazosin therapy. In conclusion, the results from this 54-week treatment period demonstrate that doxazosin exerts a well-tolerated and sustained antihypertensive effect when administered as monotherapy or with other antihypertensive agents in the long-term treatment of mild or moderate essential hypertension. 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:S145&51. 2. Alabaster VA, Davey MJ. The alpha-adrenoceptor antagonist profile of doxazosin: pre-clinical pharmacology. Br J Clin Pharmacol 1986;21:98-178. 3. Lund-Johansen P, Omvik P, Haughland H. Acute and chronic haemodynamic effects of doxazosin in hypertension at rest and during exercise. Br J Clin Pharmacol 1986;21:458-548. 4. Cubeddu LX, Fuenmayor N, Caplan N, Ferry D. Clinical pharmacology of doxazosin in patients with essential hypertension. Clin Pharmacol Ther 1987;41:439-49. 5. Elliott HL, Meredith PA, Reid JL. Pharmacokinetic overview of doxazosin. Am J Cardiol 1987;59:78G-81G. 6. Conrad KA, Fagan TC, Mackie MJ, et al. Doxazosin in patients with hypertension. Eur J Clin Pharmacol 1988:35: __ 21-4. 7. Hayduk K. Efficacy and safety of doxazosin in hypertension therapy. Am J Cardiol 1987;59:35G-9G.
John Manos, MD Sandwich,
Kent, England
Doxazosin, a quinazoline derivative, is a selective postsynaptic al-adrenergic receptor inhibitor.‘, 2 By inhibiting postsynaptic al-adrenergic receptors, doxazosin produces a fall in peripheral vascular resistance, with little or no baroreceptor-induced reflex tachycardia.3 Clinical studies have demonstrated that doxazosin is an effective medication for the treatment of essential hypertension. An extended elimination half-life of between 1g4 and 22 hours5 provides the convenience of once-daily administration,6 and the good tolerance profile of doxazosin has been well established.7 This open study was designed to evaluate the long-term antihypertensive efficacy and safety of doxazosin in the treatment of essential hypertension in general practice. Patients who successfully completed an initial 14-week study continued uninterrupted into a 40-week extension study. Final efficacy
From the Medical Department, Pfizer Limited. Reprint requests: John Manes, MD, Medical Services Department, UK, Ramsgate Rd, Sandwich, Kent CT13 9N.J, England. 4/O/24881
346
Pfizer
parameters at week 54 were compared with baseline values obtained at the start of the initial study. METHODS Initial study: phase I (Fig. 1). Patients (n = 169) initially entered a 14.week trial with mild or moderate essential hypertension, defined as sitting and standing diastolic blood pressure (DBP) of 95 to 114 mm Hg. Both newly diagnosed and previously or currently treated patients with hypertension took part in the study. At entry, patients were allowed to take one or more concomitant antihypertensive agents including diuretics, P-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors provided that the dose was constant throughout the study. During a 2-week baseline period in phase I, sitting and standing blood pressure and heart rate were measured at three visits (0, 1, and 2 weeks); the mean value of the last two visits was taken as baseline. Patients with a sustained sitting and standing DBP of 95 to 114 mm Hg were eligible to proceed. Phase II. Doxazosin was initiated at 1 mg/day and adjusted at intervals of 2 weeks if required. Daily doses were increased sequentially to 2, 4, and 8 mg until one of the following occurred: control of blood pressure was achieved (sitting DBP 190 mm Hg), a maximum daily dose of 8 mg had been administered, or side effects precluded a
Volume 121 Number 1, Part 2
Table
Doxazosin
1. Demographic
data for the extension
Patients entered into study (n) Patients with mild hypertension (n)* Patient with moderate hypertension Mean age (yr) Range Mean duration of hypertension (yr)
on sitting
DBP:
extension
(n)*
mild, 95 to 104 mm Hg; moderate,
61 patients?
105 to 114 mm
Long-term
extension
study 1
I
further increase in dose. Patients continued to take the optimum adjusted dose until the end of the &week doseadjustment period and were monitored at biweekly intervals. Phase III. Patients (n = 153) who successfully completed the dose-adjustment. phase continued with their optimum dose for a 4-week maintenance period, during which they were evaluated at intervals of 2 weeks. Throughout the study, blood pressure was recorded as the mean of two consecutive measurements made after the patient had been sitting for 5 minutes and subsequently standing for 2 minutes. Therapy success in terms of blood pressure response was defined as a fall in sitting DBP to 190 mm Hg (“normalized”) with a decrease of 15 mm Hg, or a decrease in sitting DBP of ~10 mm Hg. Heart was
determined
immediately
before
the
measurement
blood pressure and side effects were recorded at each visit. Laboratory tests (hematology, liver and renal function, electrolytes, glucose, serum proteins, total serum cholesterol, and serum triglycerides) were performed at baseline and week 14. Extension study. Patients who successfully completed the initial 14-week trial continued uninterrupted into a 40-week extension study, dependent on patient consent and physician discretion. Baseline values for blood pressure, heart rate, and laboratory safety data obtained at the start of the 14-week study served as baseline for the 40-week extension study. Patients were evaluated at intervals of 8 weeks, corresponding to treatment weeks 22,30,38,46, and 54. At each visit
blood
pressure,
heart
rate,
and
body
weight
were
as-
sessed and side effects were recorded. Laboratory tests were repeated at week 54. In addition, the investigators provided an overall evaluation of the efficacy and tolerance of doxazosin in each patient at the end of the study. Statistical analysis. Final changes from baseline in blood pressure and heart rate were analyzed statistically by means of paired t tests. The percentage change from baseline in lipid parameters was derived from the difference of geometric means for final and baseline lipid values. RESULTS Initial study.
patients
347
169 patients (DBP 95-114 mm Hg)
study
Hp.
rate of
study
61 47 14 58.0 + 0.9 35-68 5.0 0.08-20 75.9 2 1.4 57-100
Range Mean weight (kg) Range *Based
long-term
In the initial 14-week study, 169 were treated with doxazosin. Sixteen (9 % )
14*+
22’
30.
46’
38’
1 54’+ weeks
Fig. 1. Study design.*Blood pressure and heart rate assessment.+Serum cholesterol assessment.xPatients who successfully completed the initial 14.week phase continued uninterrupted into the extension study. Entry criteria were based primarily on patient and physician consent and convenience.
Table
II. Summary
of concomitant
medications
No. of patients receiving concomitant medication at entry No. of concomitant medications No. of patients receiving antihypertensive therapy No. of patients beginning to take concomitant medication during the study No. of concomitant medications No. of patients beginning to take antihypertensive therapy
34 55 23 10 21 3
patients did not complete the study; 12 (7 % ) discontinued treatment because of side effects, mostly headache and dizziness, 2 (1% ) had an inadequate antihypertensive response and discontinued, 1 (0.5 % ) could not be followed up, and l(0.5 % ) did not comply with the treatment regimen. Of the 165 patients evaluable for efficacy, 139 (84.2 % ) were considered as therapeutic successes. Extension study. Sixty-one patients, 33 men and 28 women, continued uninterrupted into the extension study. Demographic data are given in Table I. A summary of the concomitant medication is given in Table II. Blood pressure response. Fig. 2 A, shows the mean changes in sitting systolic blood pressure @BP), DBP, and heart rate for all patients evaluable for efficacy throughout a l-year period of treatment with doxazosin. Mean baseline sitting and standing blood pressures were 173/102 and 170/102 mm Hg, respectively. Doxazosin produced a statistically significant
348
Manos
American
Therapy week
January 1991 Heart Journal
Therapy week
Fig. 2. Mean changes (+ SEM) in sitting SBP, DBP, and heart rate in (A) all patients evaluable for efficacy (n = 60), (B) patients receiving doxazosin monotherapy (n = 37), and (C) patients receiving doxazosin in combination with another antihypertensive agent (n = 23). *p < 0.05, statistically significantly different from baseline.
Table
III. Final dose summary for patients evaluable for efficacy All patients Efficacy eualuable
Final dose (mg/day) 1 2 4 a Total (n) Final mean dose
46.7 26.7 la.3 a.3
601 2.4
Monotherapy
(X)
patients
(YO)
Combination
Success*
Normalizedj
Efficacy eualuable
Success*
Normalizedf
Efficacy eualuable
50.0 25.0 17.9 7.1 56 2.3
51.9 25.9 la.5 3.7 54 2.1
54.1 16.2 21.6 a.1 371 2.4.
58.8 14.7 20.6 5.9 34 2.2
60.6 15.2 21.2 3.0 33 2.0
34.8 43.5 13.0 a.7 23 2.4
therapy
patients
((‘0)
Success*
Normalizedf
36.4 40.9 13.6
38.1 42.9 14.3 4.8 ‘21 2.2
9.1
22 2.5
(mg/day)
TSitting DBP 590 mm Hg with 25 mm Hg reduction +Sitting DBP 590 mm Hg with 25 mm Hg reduction iOne patient was considered not evaluable for efficacy of the extension study.
from baseline or 210 mm Hg reduction from from baseline. because concomitant antihypertensive therapy
(p < 0.05) reduction in mean blood pressure throughout the entire study, with the final mean sitting and standing blood pressures being 148/84 and 144/83 mm Hg, respectively. Optimal antihypertensive efficacy was achieved by week 12 and maintained in all patients for the duration of 1 year. Occasionally, statistically significant decreases in heart rate were ob-
baseline. was added
before
the first
regularly
scheduled
visit
served, but no trend was established and the changes (1 to 3 beats/min) were not clinically significant. Fig. 2, B and C, shows the mean changes in sitting SBP, DBP, and heart rate for the subgroup analysis of patients who received doxazosin either as monotherapy or in combination with other antihypertensive agents, respectively. In patients who
“O,“me 121 Number 1, Part 2
Doxazosin
Table IV. Therapeutic success rates patients treated with doxazosin All patients (n = SO)
Therapy successes Normalized r10mmHg reduction Therapeutic failures Dose adjusted to maximum Dose not adjusted to maximum
for
Doxazosin monotherap> (n = 37)
all evaluable
IL
n
“;I
n
“;
56 54 2
93.3 90.0 3.3
34 33 1
91.9 89.2 2.7
22 21 1
95.7 91.3 4.3
4 1
6.7
3
8.1
1
4.3
1.7
1
2.7
3
5.0
2
5.4
1
4.3
extension
Doxazosin monotherapy (n = 37)
All patients (n = 60)
Improved severity category of hypertension No change in severity category
Table
duration
of therapy,
Combination therapy (n = 23)
“0
II
“<
n
c;,
55
91.7
34
91.9
21
91.3
5
8.3
3
8.1
2
8.7
-
received doxazosin monotherapy, mean sitting and standing blood pressures were reduced from 1721 103 to 147/85 mm Hg and from 169/102 to 143/83 mm Hg, respectively. When doxazosin was added to prior antihypertensive medication, mean sitting and standing blood pressures were reduced from 174/102 to 148/84 mm Hg and from 172/102 to 146/84 mm Hg, respectively. The reductions in blood pressure for the group receiving combined therapy can be attributed to doxazosin, because the doses of concomitant medications were constant throughout the study. evaluability,
349
n
VI. Changes
in total
serum cholesterol Baseline fn = 27)
Efficacy
study
Table V. Changes in the severity category of hypertension in patients evaluable for efficacy from baseline to final visit
Combination therapy (n = 23)
n
long-term
and dose.
Patients were considered evaluable for efficacy if they had completed the initial 14-week study, met the inclusion criteria, and completed at least one regularly scheduled active drug visit in the extension study. Patients in whom the dose or type of concomitant antihypertensive therapy changed during the course of the study were considered not evaluable for efficacy at subsequent visits. The mean duration of treatment for all 60 patients evaluable for efficacy was 396.2 days; in the subgroups of doxazosin monotherapy and combination therapy the mean duration of treatment was 382.7 and 417.8 days, respectively. The mean final dose of doxazosin for all patients evaluable for efficacy was 2.4 mglday; at the final study visit 91.7 % of patients were taking 14 mg doxazosin once daily. A dose summary for the different patient groups is given in Table III. Therapeutic success rate. At the completion of the initial 14-week study, 54 of 60 (90.0 % ) patients were considered as therapeutic successes at a mean daily dose of 2.2 mg; 6 (10.0%) of the patients continuing into the extension study were regarded as therapeutic failures. All patients continued into the extension
Mean total serum cholesterol mmol/L mg/dl Mean Y’;$ change from baseline
6.66
257.1
Week 14 (n = 27)
6.23 240.5 -6.56
levels Final visit (n = 27)
6.30 243.2 -5.43
study at the discretion of the investigators, because treatment was seen to be beneficial. After 1 year of doxazosin therapy, 56 (93.3%) patients were considered as therapeutic successes, with a mean daily dose of 2.3 mg. Fifty-four (90.0%) patients achieved normalized blood pressures (sitting DBP 190 mm Hg with a ~5 mm Hg reduction from baseline) and two had a reduction in DBP of 210 mm Hg from baseline. Only four (6.7 % ) patients were regarded as treatment failures: in one the dose of doxazosin was adjusted to the maximum 8 mg/day, in two (3.3%) the maximum dose was not adjusted because of side effects (one possibly related and one not related to treatment), and in one patient the dose of doxazosin was not increased for unexplained reasons. Table IV gives the therapeutic success and failure rates for all patients receiving doxazosin monotherapy and doxazosin in combination with other antihypertensive agents. Severity of hypertension. The changes in severity of hypertension (based on mean sitting DBP) are presented in Table V. In no patient was there a worsening in the severity category of the hypertension. Laboratory variables. A total of 5880 individual parameters was analyzed and 17 abnormal test results were reported. In most cases the laboratory safety data remained unchanged after treatment, or minor changes were considered insignificant and related to concomitant medications or disease. No trends with
350
Manos
Table
VII. Summary of tolerance
American
Total no. of patients Patients with side effects (n/f;) Patients discontinued because Patients with dose of doxazosin
monotherapy
of side effects (n/O; ) reduced (n/Z’ )
61 9h4.8 l/1.6 l/1.6
Table VIII. Investigators’ global assessment of efficacy and
tolerance
Efficacy Excellent Good Fair Tolerance Excellent Good Fair Poor
All patients (5%) (n = 60)
Dorazosin monotherapy (%) (n = 37)
Combination therapy (70) (n = 23)
72 23 5
68 24 8
78 22 0
75 20 3 2
73 22 3 3
78 17 4 0
regard to organ systems or correlations with doxazosin dose and duration of therapy were apparent. Serum lipids. Lipid data analyses identified a significant 6.6% (p = 0.03) reduction from baseline in total serum cholesterol levels at the end of week 14. Reductions in total serum cholesterol levels persisted throughout the extension study, reaching a final reduction of 5.4% from baseline (Table VI). There were variable, nonsignificant changes in serum triglyceride levels that, by final visit, were not significantly different from baseline (0.3% final reduction). Tolerance. An overall summary of tolerance is given in Table VII. The majority of side effects (dizziness [n = 4; 6.6%], dyspnea [n = 3; 4.9%], fatigue [n = 2; 3.3%], somnolence [n = 2; 3.3% 1, and headache [n = 2; 3.3 % ] were mild or moderate and were tolerated or disappeared with continued treatment. One patient with a history of angina who was receiving concomitant isosorbide dinitrate and nitroglycerin trinitrate had a myocardial infarction after 327 days of therapy; the incident was judged to be unrelated to doxazosin treatment. No apparent differences were noted between the nature or number of side effects occurring in the subgroups receiving doxazosin monotherapy and combination therapy. Overall clinical evaluation. At the end of the extension study, efficacy and tolerance were rated as excellent or good for 95 % of patients and fair for 5 % . A summary of these data and the results for the
January 1991 Heart Journal
and combined groups is given in Table
VIII. DISCUSSION
The objective of this open, noncomparative study was to evaluate the long-term antihypertensive efficacy and safety of doxazosin when administered in a general medical practice to patients with mild or moderate essential hypertension. Patients who received doxazosin as monotherapy and in combination with other antihypertensive agents were assessed. Of the 169 patients who began the original 14-week study, 153 (91% ) completed the full course of treatment; 165 were evaluable for efficacy and 139 (84.2 %) were considered as therapeutic successes at a mean daily dose of 2.8 mg. Twelve (7 % ) of the 169 patients discontinued treatment because of side effects; headache and dizziness were the most commonly reported events. To address the long-term effects of doxazosin, the physicians were allowed to extend treatment from the original 14-week trial. The decision to continue uninterrupted into the 40-week extension study was based primarily on patient consent and physician discretion, because only 61 (39.9%) of the 153 patients who completed the 14-week study continued. Of the 60 evaluable patients who entered the extension study, 54 (90.0 % ) were considered as therapeutic successes at 2.2 mglday at the end of the original 14-week study. Indeed, six (10.0% ) patients who continued into the extension study were regarded as treatment failures in the initial study, although in all patients there was some reduction in blood pressure (range, 4 to 9 mm Hg from baseline). The long-term (54 weeks) treatment results demonstrated the sustained antihypertensive efficacy of doxazosin. There was no suggestion that the antihypertensive effects of doxazosin were diminished after 1 year of treatment (mean, 396.2 days). It is important that, from baseline to final visit, dosages of doxazosin and blood pressure reductions were similar after 14 and 54 weeks. In fact, in a few of the patients who were regarded as therapeutic failures after 14 weeks of therapy blood pressures were controlled successfully with long-term treatment. The long-term success rate in this study is attributable to doxazosin because there were changes in concomitant antihypertensive medications in only three patients during the study; all subsequent blood pressure and heart rate values for these patients were not included in the efficacy analysis. Minor changes in heart rate were observed during the course of the study and, although some mean changes attained
Volume 121 Number 1. Part 2
statistical significance, there were no clinically important alterations. Lipid data analyses identified a significant 6.6% (p < 0.05) reduction from baseline in total serum cholesterol levels at the end of week 14. Reductions in cholesterol levels persisted at 5 % to 6 % throughout the long-term study. Triglyceride levels differed at various time points; the reasons for the apparent inconsistent changes in triglyceride levels could be the result of effects of recent food and/or alcohol consumption. However, the lipid results alone should be interpreted prudently based on the relatively small number of patients with evaluable data (n = 27 cholesterol; n = 23 triglycerides). During the 54 weeks of treatment, 9 (14.8 % ) of the 61 patients reported side effects. The most common were dizziness (n = 4; 6.6%), dyspnea (n = 3; 4.9%), somnolence, fatigue, and headache (each n = 2, 3.3 % ). The occurrence and profile of side effects were similar to those reported at the end of 14 weeks of treatment in the larger group. No new or unexpected adverse events developed during the long-term extension period. Laboratory safety data were basically unchanged after long-term treatment. There were a few apparently random abnormal values that might have been the result of treatment; however, no trends with regard to organ systems or correlations with dose and duration were apparent. None of the ab-
Doxazosin
long-term
extension
study
351
normal values were grossly outside the normal control range. The investigators’ overall assessment of both efficacy and tolerance was excellent or good in 95% of the patients who received long-term doxazosin therapy. In conclusion, the results from this 54-week treatment period demonstrate that doxazosin exerts a well-tolerated and sustained antihypertensive effect when administered as monotherapy or with other antihypertensive agents in the long-term treatment of mild or moderate essential hypertension. 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:S145&51. 2. Alabaster VA, Davey MJ. The alpha-adrenoceptor antagonist profile of doxazosin: pre-clinical pharmacology. Br J Clin Pharmacol 1986;21:98-178. 3. Lund-Johansen P, Omvik P, Haughland H. Acute and chronic haemodynamic effects of doxazosin in hypertension at rest and during exercise. Br J Clin Pharmacol 1986;21:458-548. 4. Cubeddu LX, Fuenmayor N, Caplan N, Ferry D. Clinical pharmacology of doxazosin in patients with essential hypertension. Clin Pharmacol Ther 1987;41:439-49. 5. Elliott HL, Meredith PA, Reid JL. Pharmacokinetic overview of doxazosin. Am J Cardiol 1987;59:78G-81G. 6. Conrad KA, Fagan TC, Mackie MJ, et al. Doxazosin in patients with hypertension. Eur J Clin Pharmacol 1988:35: __ 21-4. 7. Hayduk K. Efficacy and safety of doxazosin in hypertension therapy. Am J Cardiol 1987;59:35G-9G.