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, dox- azosin produces a fall in peripheral vascular resis- tance, 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 administra- tion,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 com- pleted an initial 14-week study continued uninter- rupted into a 40-week extension study. Final efficacy

From the Medical Department, Pfizer Limited. Reprint requests: John Manes, MD, Medical Services Department, Pfizer UK, Ramsgate Rd, Sandwich, Kent CT13 9N.J, England. 4/O/24881

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 di- agnosed 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

346

Volume 121 Number 1, Part 2 Doxazosin long-term extension study 347

Table 1. Demographic data for the extension study 169 patients (DBP 95-114 mm Hg)

Patients entered into study (n) 61 Patients with mild hypertension (n)* 47

Patient with moderate hypertension (n)* 14 Mean age (yr) 58.0 + 0.9

Range 35-68 Mean duration of hypertension (yr) 5.0

Range 0.08-20 Mean weight (kg) 75.9 2 1.4

Range 57-100

*Based on sitting DBP: mild, 95 to 104 mm Hg; moderate, 105 to 114 mm

Hp.

further increase in dose. Patients continued to take the optimum adjusted dose until the end of the &week dose- adjustment period and were monitored at biweekly inter- vals.

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 rate was determined immediately before the measurement of blood pressure and side effects were recorded at each visit. Laboratory tests (hematology, liver and renal func- tion, 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 pres- sure, 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, corre- sponding 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 base- line in lipid parameters was derived from the difference of geometric means for final and baseline lipid values.

RESULTS Initial study. In the initial 14-week study, 169

patients were treated with doxazosin. Sixteen (9 % )

61 patients?

I Long-term extension study

1

1

14*+ 22’ 30. 38’ 46’ 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 con- venience.

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 % ) discon- tinued 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 ef- ficacy throughout a l-year period of treatment with doxazosin. Mean baseline sitting and standing blood pressures were 173/102 and 170/102 mm Hg, respec- tively. Doxazosin produced a statistically significant

348 Manos January 1991

American Heart Journal

Therapy week Therapy week

Fig. 2. Mean changes (+ SEM) in sitting SBP, DBP, and heart rate in (A) all patients evaluable for ef- ficacy (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 (X) Monotherapy patients (YO) Combination therapy patients ((‘0)

Efficacy Efficacy Efficacy eualuable Success* Normalizedj eualuable Success* Normalizedf eualuable Success* Normalizedf

Final dose (mg/day) 1 46.7 50.0 51.9 54.1 58.8 60.6 34.8 36.4 38.1 2 26.7 25.0 25.9 16.2 14.7 15.2 43.5 40.9 42.9 4 la.3 17.9 la.5 21.6 20.6 21.2 13.0 13.6 14.3 a a.3 7.1 3.7 a.1 5.9 3.0 a.7 9.1 4.8 Total (n) 601 56 54 371 34 33 23 22 ‘21

Final mean 2.4 2.3 2.1 2.4. 2.2 2.0 2.4 2.5 2.2

dose (mg/day)

TSitting DBP 590 mm Hg with 25 mm Hg reduction from baseline or 210 mm Hg reduction from baseline. +Sitting DBP 590 mm Hg with 25 mm Hg reduction from baseline. iOne patient was considered not evaluable for efficacy because concomitant antihypertensive therapy was added before the first regularly scheduled visit of the extension study.

(p < 0.05) reduction in mean blood pressure through- served, but no trend was established and the changes out the entire study, with the final mean sitting and (1 to 3 beats/min) were not clinically significant. standing blood pressures being 148/84 and 144/83 Fig. 2, B and C, shows the mean changes in mm Hg, respectively. Optimal antihypertensive ef- sitting SBP, DBP, and heart rate for the subgroup ficacy was achieved by week 12 and maintained in all analysis of patients who received doxazosin either patients for the duration of 1 year. Occasionally, sta- as monotherapy or in combination with other an- tistically significant decreases in heart rate were ob- tihypertensive agents, respectively. In patients who

“O,“me 121 Number 1, Part 2 Doxazosin long-term extension study 349

Table IV. Therapeutic success rates for all evaluable patients treated with doxazosin

Doxazosin Combination All patients monotherap> therapy

(n = SO) (n = 37) (n = 23)

n IL n “;I n “;

Therapy successes 56 93.3 34 91.9 22 95.7 Normalized 54 90.0 33 89.2 21 91.3 r10mmHg 2 3.3 1 2.7 1 4.3

reduction Therapeutic failures 4 6.7 3 8.1 1 4.3

Dose adjusted to 1 1.7 1 2.7 - maximum

Dose not adjusted 3 5.0 2 5.4 1 4.3 to maximum

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 con- stant throughout the study.

Baseline Week 14 Final visit fn = 27) (n = 27) (n = 27)

Mean total serum cholesterol mmol/L 6.66 6.23 6.30

mg/dl 257.1 240.5 243.2

Mean Y’;$ change from baseline -6.56 -5.43

study at the discretion of the investigators, because treatment was seen to be beneficial.

Efficacy evaluability, duration of therapy, and dose. Patients were considered evaluable for efficacy if they had completed the initial 14-week study, met the in- clusion 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 effi- cacy at subsequent visits.

After 1 year of doxazosin therapy, 56 (93.3%) pa- tients were considered as therapeutic successes, with a mean daily dose of 2.3 mg. Fifty-four (90.0%) pa- tients 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.

The mean duration of treatment for all 60 patients evaluable for efficacy was 396.2 days; in the sub- groups 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.

Only four (6.7 % ) patients were regarded as treat- ment 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 dox- azosin in combination with other antihypertensive agents.

Severity of hypertension. The changes in severity of hypertension (based on mean sitting DBP) are pre- sented in Table V. In no patient was there a worsen- ing in the severity category of the hypertension.

Therapeutic success rate. At the completion of the initial 14-week study, 54 of 60 (90.0 % ) patients were

Laboratory variables. A total of 5880 individual pa- rameters was analyzed and 17 abnormal test results

considered as therapeutic successes at a mean daily dose of 2.2 mg; 6 (10.0%) of the patients continuing

were reported. In most cases the laboratory safety data remained unchanged after treatment, or minor

into the extension study were regarded as therapeu- changes were considered insignificant and related to tic failures. All patients continued into the extension concomitant medications or disease. No trends with

Table V. Changes in the severity category of hypertension in patients evaluable for efficacy from baseline to final visit

Doxazosin Combination All patients monotherapy therapy

(n = 60) (n = 37) (n = 23)

n “0 II “< n c;,

Improved severity 55 91.7 34 91.9 21 91.3 category of hypertension

No change in 5 8.3 3 8.1 2 8.7 severity category

Table VI. Changes in total serum cholesterol levels

350 Manos January 1991

American Heart Journal

Table VII. Summary of tolerance

Total no. of patients 61 Patients with side effects (n/f;) 9h4.8 Patients discontinued because of side effects (n/O; ) l/1.6 Patients with dose of doxazosin reduced (n/Z’ ) l/1.6

Table VIII. Investigators’ global assessment of efficacy and tolerance

Dorazosin Combination All patients monotherapy therapy (5%) (n = 60) (%) (n = 37) (70) (n = 23)

Efficacy Excellent Good Fair

Tolerance Excellent Good Fair Poor

72 68 78 23 24 22

5 8 0

75 73 78 20 22 17

3 3 4 2 3 0

regard to organ systems or correlations with dox- azosin dose and duration of therapy were apparent.

Serum lipids. Lipid data analyses identified a sig- nificant 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 per- sisted throughout the extension study, reaching a final reduction of 5.4% from baseline (Table VI). There were variable, nonsignificant changes in se- rum triglyceride levels that, by final visit, were not significantly different from baseline (0.3% final re- duction).

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 concom- itant 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 be- tween 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 exten- sion 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

monotherapy and combined groups is given in Table VIII.

DISCUSSION

The objective of this open, noncomparative study was to evaluate the long-term antihypertensive effi- cacy and safety of doxazosin when administered in a general medical practice to patients with mild or moderate essential hypertension. Patients who re- ceived 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 treat- ment; 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; head- ache 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 pa- tients who completed the 14-week study continued.

Of the 60 evaluable patients who entered the extension study, 54 (90.0 % ) were considered as ther- apeutic 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 re- garded as treatment failures in the initial study, al- though 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 dem- onstrated the sustained antihypertensive efficacy of doxazosin. There was no suggestion that the antihy- pertensive effects of doxazosin were diminished after 1 year of treatment (mean, 396.2 days). It is impor- tant that, from baseline to final visit, dosages of dox- azosin 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 attrib- utable 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 Doxazosin long-term extension study 351

statistical significance, there were no clinically im- portant alterations.

Lipid data analyses identified a significant 6.6% (p < 0.05) reduction from baseline in total serum cho- lesterol 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 in- consistent changes in triglyceride levels could be the result of effects of recent food and/or alcohol con- sumption. However, the lipid results alone should be interpreted prudently based on the relatively small number of patients with evaluable data (n = 27 cho- lesterol; 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 ex- tension 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-

normal values were grossly outside the normal con- trol range. The investigators’ overall assessment of both efficacy and tolerance was excellent or good in 95% of the patients who received long-term dox- azosin therapy.

In conclusion, the results from this 54-week treat- ment 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.

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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 hyper- tension. Clin Pharmacol Ther 1987;41:439-49.

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