International Journal of Urology (1999) 6, 346–354

Original Article

Long-term (4 year) efficacy and tolerability of doxazosinfor the treatment of concurrent benign prostatichyperplasia and hypertension

AHMED FAWZY, ANGELA HENDRY, EILEEN COOK AND FRANCISCO GONZALEZUrologic Institute of New Orleans and Department of Nephrology, Louisiana State UniversityMedical Center, New Orleans, Louisiana, USA

Abstract Background: The a1-adrenoceptor antagonist doxazosin has proved successful in treating patients

with concurrent benign prostatic hyperplasia (BPH) and hypertension in short-term studies.However, both conditions are chronic and may worsen over time. The aim of this study was,therefore, to examine the tolerability and efficacy of doxazosin in the long-term treatment ofconcurrent BPH and hypertension.Methods: This study was a longitudinal extension of earlier double-blind trials. Patients wereenrolled into the study on a rolling basis. From a total of 178 BPH patients with hypertensionenrolled into the study, 28 had reached 48 months of open-label treatment with doxazosin at thetime of the final data cutoff.Results: Treatment with doxazosin resulted in sustained benefits for BPH patients over the wholestudy period, with significant improvements in the severity (12.2%, P < 0.001) and bothersomeness(13.2%, P < 0.001) of BPH symptoms, and in the maximum urinary flow rate (26.6%, P < 0.05)from baseline to the end of the 4-year period. There was also a significant and sustained reductionin diastolic blood pressure. The efficacy of doxazosin treatment for both BPH and hypertensionwas maintained over the 4-year period, despite the tendency of these conditions to worsen withtime. Comparison of adverse events in patients with long- and short-term hypertension and BPHdemonstrates that the safety of doxazosin is not altered during long-term therapy.Conclusions: This study demonstrates that doxazosin appears to be well tolerated and efficaciousin the long-term management of concurrent BPH and hypertension.

Key words a1-adrenoceptor antagonists, benign prostatic hyperplasia, doxazosin, hypertension.

Introduction

Benign prostatic hyperplasia (BPH) is an increasinglycommon age-related disorder causing significant dis-comfort and morbidity.1 Benign prostatic hyperplasiaincreases in prevalence with advancing age, as shownby autopsy data and symptom surveys.2–4 Fifty per-

cent of prostate glands removed post-mortem frommen > 60 years old showed histologic signs of BPH,rising to 88% of prostates from men aged > 80 years,compared with none from men < 30 years old.2 Thispattern is supported by evidence from symptomsurveys which also showed an increased prevalence inthe older population. A survey of men aged 40–79years in Minnesota found moderate–severe urinarysymptoms in 13% of men aged 40–49 years, rising to28% in men aged > 70 years.3 A similar survey inScotland found an even higher prevalence: 13.8% inmen aged 40–49 years and 43% in those aged 60–69years.4 These symptoms can interfere significantly withthe patient’s quality of life. More than 50% of menwith undiagnosed BPH experienced disruption with at

Correspondence: Dr Ahmed Fawzy, Urologic Institute ofNew Orleans, 2600 Belle Chasse Hwy., Gretna, LA 70056,USA. Email: <afawzy@iAmerica.net>

Received 27 August 1997; revision 1998; accepted 6October 1998.

Long-term doxazosin therapy 347

least one activity of daily life as a result of urinarydysfunction and 75% reported at least one symptom asbothering them.1

Hypertension is also a common disease in Westernsocieties. Although estimates of its prevalence varyaccording to the exact definition used, 60–70% of the United States’ male population > 60 years old have some degree of hypertension (blood pressure > 140/90 mmHg)5 and like BPH, its prevalence alsoincreases with age.6,7 The increased life-expectancy ofpopulations in the developed world has led to anincreasing prevalence of age-related disorders such ashypertension and BPH.

Benign prostatic hyperplasia and hypertension oftenoccur concurrently. It is estimated that a quarter ofmen in the United States will undergo treatment forBPH by the age of 80 years and a similar proportionwill be diagnosed as having essential hypertension bythe time they are 60 years old. Even disregarding thepossibility of a shared etiology (described below) andassuming the risk factors for each condition areindependent, it is estimated that at least one in eightmen over the age of 60 years could develop con-comitant BPH and hypertension.8

In addition to their frequent coexistence, BPH andhypertension may have a common etiology in thesympathetic nervous system. Increased sympatheticnoradrenergic activity is a key pathophysiologiccomponent of both BPH (increased prostatic andurethral smooth muscle tone) and hypertension(elevated peripheral vascular resistance). Blockade ofa

1-adrenoceptors opposes the effect of increased

sympathetic activity on prostatic and vascular smoothmuscle, decreasing both the dynamic component ofurinary outflow obstruction in BPH and high bloodpressure. Consequently, a

1-adrenoceptor antagonists

are effective in controlling both BPH and hyper-tension. They are already an established therapy forhypertension and recent studies show a

1-adrenoceptor

antagonists are becoming established as the treatmentof choice for BPH. The effective control of the twoconditions with one drug is therefore possible using anon-subtype-specific a

1-adrenoceptor antagonist such

as doxazosin whose actions are not localized to theprostate.

Doxazosin is a selective a1-adrenoceptor antagonist

with a balanced action on all a1-adrenoceptor sub-

types. It is an established first-line therapy for hyper-tension and has proven efficacy in relieving symptomsof BPH in both normotensive and hypertensivepatients.9–13 In 3–4-month double-blind studies, doxa-zosin, in addition to improving BPH symptoms, wasclinically effective in reducing blood pressure in hyper-

tensive patients but had only minimal effects in nor-motensive patients.11

Once a patient begins to manifest symptoms ofBPH and/or hypertension, long-term medical treatmentmay be required, as these tend to be chronic conditionsthat increase in severity with time; and so, thesustained efficacy of medical treatment is of keyimportance. In this paper we have, therefore, addressedthe long-term efficacy and tolerability of doxazosin inthe treatment of concurrent BPH and hypertension. Atfinal data cut-off, 28 hypertensive men with BPH hadbeen treated with doxazosin for 4 years; at this timepoint the study was terminated and all remainingpatients were discontinued from study treatment.Results are reported from these 28 hypertensive menwho were treated with doxazosin for 4 years.

Methods

This was a long-term, open-label extension of pre-vious double-blind, placebo-controlled studies ofdoxazosin in normotensive and hypertensive men withsymptomatic BPH.12–14 Four hundred and fifty patients,of whom 272 (60%) were normotensive and 178 (40%)were hypertensive, entered the extension study within2 weeks (normotensives) or 1 week (hypertensives) of completing the earlier double-blind studies. Theduration of this study was planned to be 4 years.

Patients

All the hypertensive patients (n = 178) were previouslyentered in a double-blind, placebo-controlled study.12

On entry into the original double-blind study, thehypertensive subjects were outpatients ≥ 45 years ofage with symptoms of BPH and outflow obstruction:maximum urinary flow rate of 5–15 mL/sec in a voidedvolume of 150–500 mL, a postvoid residual volumeless than < 200 mL, a daytime micturition frequency ≥ 4 and a nocturia ≥ 2; and a sitting diastolic bloodpressure of 90–114 mmHg.

Patients were excluded from the study if they hadany non-BPH conditions giving rise to urinarysymptoms or a reduced urinary flow rate; if they hadhad previous prostate surgery; a prostate specificantigen level > 10 ng/mL; acute urinary retention;recent catheterization for outflow obstruction; orprostate malignancy. Other exclusion criteria includedpatients with diabetes, secondary hypertension,significant hepatic, renal or cardiovascular dysfunction,or any other serious concurrent disease, malignancy orobesity; or intolerance/insensitivity to quinazoline

348 A Fawzy et al.

derivatives. Patients were also excluded if they werereceiving any anti-hypertensive drug therapy or anytreatment known to affect vesico-urethral function.

Hypertensive patients entered the open-label phaseafter completion of all appropriate evaluations fromthe final visit of the preceding double-blind study andwithin 1 week of terminating their participation in the double-blind study. On day 1 of the open-labelstudy, blood pressure, heart rate, adverse experiences,concurrent medications and concurrent illnesses wereevaluated prior to the first dose of open-labeldoxazosin (1 mg). Patients remained in the clinic for a2–6 h postdose evaluation of blood pressure, heart rateand adverse events. All patients received open-labeldoxazosin, once daily, with the dosage titrated atbiweekly intervals over 8 weeks to obtain maximumbenefit (maximum efficacy or maximum toleration if limiting adverse experiences occurred) up to amaximum of 12 mg once daily. During the dose-titration phase, patients were evaluated at biweeklyintervals in the clinic, 24 h after the previous day’sself-medicated dose, and remained in the clinic afterdosing for evaluation of blood pressure, heart rate andadverse events. After four consecutive weeks on theirestablished optimal dose and provided that they neededno further dose-adjustment during four consecutiveweeks, the patients entered the stable-dose efficacyphase of the study. During this phase, patients wereevaluated clinically at 1 month and then at quarterlyintervals during the first year of the study (1, 3, 6, 9and 12 months) and twice each year thereafter.

Efficacy and safety evaluations

Efficacy parameters

At each visit, maximum and average urinary flow rate(mL/sec) and voided volume (mL) were measured witha Dantec Urodyn 1000 Flowmeter. Post-void residualvolume (mL) was measured using a DiagnosticUltrasound Bladder Scan BVI 2000 unit immediatelyafter the urodynamic evaluations. Repeat evaluationswere made for safety reasons 2–6 h after the in-clinicdosing during the titration phase. Adverse events,blood pressure, heart rate and concurrent illnesses andmedications were also evaluated.

Patient assessment of symptoms

Benign prostatic hyperplasia symptom bothersomenessand severity was assessed by questionnaire, using amodified form of the nine-symptom Boyarsky index.15

This was completed by hypertensive patients at 1, 3,

6, 9 and 12 months and twice each year thereafter. The questionnaire measured both the quantitativeaspects (frequency/severity) and the qualitative aspects (bothersomeness) of BPH symptoms. The self-administered questionnaire rated four irritativesymptoms (nocturia, daytime urinary frequency,urgency and burning sensation) and five obstructivesymptoms (hesitancy, intermittency, dribbling,impairment in size and force of stream, and sensationof incomplete emptying of the bladder). The questionsrelating to severity had a range in possible total scoreof 7–39 points, with a lower score indicating morefrequent symptoms. For bothersomeness, the rangewas 9–45, again with a lower score indicating a greaterdegree of bothersomeness of the symptoms. Benignprostatic hyperplasia symptoms were also evaluated bythe investigator.

Safety parameters

Patients underwent a complete physical examinationincluding 12-lead electrocardiogram (ECG), medicalhistory and clinical laboratory evaluation, before enter-ing and upon completion of the preceding double-blindstudies. Electrocardiogram and clinical laboratoryanalyses, including hematology; serum biochemicalanalysis; serum lipids; urinalysis; and prostate specificantigen, were conducted every 6 months during theextension study and a full physical examinationincluding rectal examination was performed once ayear.

At each clinic visit, both sitting and standing bloodpressure and heart rate were measured. The average of two measurements taken before and 2–6 h afterdosing was recorded for each parameter. Observed and reported adverse events were recorded by theinvestigator throughout the study and categorizedusing World Health Organization terminology.

Statistical methods

The baseline value for all trough (24 h) efficacyvariables was taken as the mean of the measurementstaken at two consecutive weeks during the single-blindplacebo run-in phase prior to the double-blind phase in the original studies. For the analysis of the peakurodynamic and blood pressure measurements (i.e. 2–6 h after dosing) only values obtained at week 1were used for the baseline, as the week 2 peakmeasurements were obtained after the administrationof the first dose of double-blind medication. Changesfrom the baseline value at each timepoint wereanalyzed by Student’s paired t-test.

Long-term doxazosin therapy 349

Results

Demographics

This study was a longitudinal extension of earlierdouble-blind trials with patients being enrolled into thestudy on a ‘rolling’ basis. From a total of 178 BPHpatients with hypertension enrolled into the study, 28had reached 48 months of open-label treatment withdoxazosin at the time of the final data cutoff; the studywas stopped at this time. The mean age of thesepatients was 64.5 years (range 43.6–73.4 years). Onentry to the study, the mean duration of their hyper-tension was 10.5 years (range 1–35 years) and theyhad experienced symptomatic BPH for a mean of 5.2years (range 4 months to 20 years).

The mean end-point total daily dose (TDD) for thecohort of 28 hypertensives who were entered into the study for 45–48 months was 7.9 mg (range 4–16 mg/day). Nine patients (32%) received doxazosin4 mg/day, one (4%) 6 mg/day, 10 (36%) 8 mg/day,seven (25%) 12 mg/day and one (4%) 16 mg/day. Incomparison, the mean TDD for all 178 long-term hypertensive patients was 6.4 mg/day (range 1–16 mg/day).14 Forty-nine (28%) of these patientsreceived either 1 or 2 mg doxazosin/day (i.e. less thanthe lowest dose of the long-term hypertensives). Forty-five (25%) patients received 4 mg/day, one (1%) 6mg/day, 37 (21%) 8 mg/day, 39 (22%) 12 mg/day andseven (4%) 4 mg/day. The mean duration of therapy forall 178 hypertensives was 807 days (range 7–1593days), whereas the subset of 28 long-term patients, bydefinition, received doxazosin for approximately 4years (1461 days).

On entry into the open-label study, the baselineurodynamic values and symptom scores for the 4-yearcohort of hypertensive BPH patients were similar tothose of the hypertensive patients as a whole (Tables 1and 2).

Efficacy

Doxazosin produced significant improvements inmaximum urinary flow rate (Q

max) and residual urinary

volume, which were sustained over 4 years (Table 1,Fig. 1). The Q

maxincreased from 9.9 mL/sec at baseline

to 12.6 mL/sec at 4 years (P < 0.05), an increase of27%. The Q

maxand mean urinary flow rate (Q

mean) are

shown over the whole 4 years in Fig. 1. Residualurinary volume decreased from 73.9 mL at baseline to 38.7 mL at 4 years (P < 0.01), a decrease of 48%.For all the hypertensive patients in the study, Q

maxincreased by 14% (P < 0.001) and residual volume

decreased by 24% (P < 0.01) as assessed at a meanend-point of 807 days (Table 1).

Doxazosin reduced total BPH symptom severity andbothersomeness significantly over the whole 4 years (P < 0.05–0.001; Table 2, Figs 2 and 3). The modifiedBoyarsky symptom severity score improved from 26.5 at baseline to 29.8 at 4 years (P < 0.001), animprovement of 12%. The bothersomeness scoreimproved by 13% from 34.4 at baseline to 39.0 at 4years (P < 0.001). This compares with improvements atthe end-point of treatment of 14 and 12%, respectively,for all hypertensives (P < 0.001 for both symptomseverity and bothersomeness; Table 2). The obstructive

Table 1 Urodynamic baseline and end-point values

Parameter All hypertensives 4-year hypertensives(n = 153) (n = 28)

Max flow rate Qmax

(mL/sec)Baseline 10.45 9.94End-point 11.88 12.58% Change 13.6 26.6Significance P < 0.001 P < 0.05

Mean flow rate Qmean

(mL/sec)Baseline 5.23 5.02End-point 6.08 6.57% Change 16.3 30.9Significance P < 0.001 NS

Void volume (mL)Baseline 252.6 262.8End-point 217.3 213.4% Change -14 -18.8Significance P < 0.01 P < 0.01

Residual volume (mL)Baseline 66.55 73.87End-point 50.37 38.63% Change -24.3 -47.8Significance P < 0.01 P < 0.01

NS, not significant.

Table 2 Baseline and end-point symptom scores

Parameter All hypertensives 4-year hypertensives (n = 144) (n = 28)

Symptom severityBaseline 25.56 26.54Endpoint 29.07 29.77% Change 13.7 12.2Significance P < 0.001 P < 0.001

Symptom bothersomenessBaseline 33.15 34.44Endpoint 37.08 38.99% Change 11.9 13.2Significance P < 0.001 P < 0.001

350 A Fawzy et al.

and irritative subscores for severity and bother-someness also improved significantly (Figs 2 and 3).

Doxazosin produced a significant reduction indiastolic blood pressure (10 mmHg at < 2 months; P < 0.001) which was sustained throughout the 4 years(Table 3). Sitting diastolic blood pressure was reducedfrom 97 mmHg at baseline to 89 mmHg at 4 years (P < 0.001).

Safety

Even after 4 years of treatment and despite therelatively high mean dose of doxazosin (7.9 mg per dayvs 6.4 mg per day in all hypertensives), 43% (12/28) of the long-term hypertensive BPH patients hadexperienced no drug-related adverse events (Table 4).

Over the 4-year period, the most frequent adverseevents were dizziness, experienced by eight patients(28.6%) and fatigue, experienced by four patients(14.3%). When considered on a per year basis, theoverall incidence rate of adverse events was notincreased in the long term group of patients relative toall hypertensives (Table 4).

The incidence rate of drug-related adverse events innormotensive patients was approximately half the rateof that seen in hypertensive patients (6.6% per year innormotensives compared with 12.4% per year in allhypertensives and 14.3% per year in the long termcohort). This is likely to be due to the fact that thehypertensive patients could be titrated to higher dosesof doxazosin (up to 16 mg) if necessary for treatmentof their hypertension. The maximum permitted dosefor normotensives was 8 mg; half the maximum dosepermissible for hypertensives. Drug-related adverseevents appear to be less common in older than inyounger patients (Fig. 4). This appears to be the casefor both groups of hypertensive patients (long-termand all hypertensives).

Of the 178 hypertensive patients, 123 (69.1%)experienced adverse events compared with 174/272(64.0%) normotensive patients. However, a slightlygreater percentage of adverse events per year was seenfor normotensive patients (31.4 vs 35.0%, respectively)despite the fact that the permitted dose was 2-fold higherin hypertensive patients. The incidence of severe adverseevents was comparable in both groups with 28 (15.7%,at a rate of 7.1% per year) hypertensive patients,compared with 33 (12.1%, at a rate of 6.6% per year)normotensive patients having this severity of event.Forty-nine (27.5%) of the hypertensive patients had

Table 3 Blood pressure and heart rate after 4 years (n = 16)

Parameter Sitting Standing

Systolic blood pressure (mmHg)Baseline 149.6 148.3End-point 147.5 147.6Change -2.1 -0.8Significance NS NS

Diastolic blood pressure ( mmHg)Baseline 97.0 99.4End-point 89.2 90.1Change -7.8 -9.3Significance P < 0.001 P < 0.001

Heart rate (beats per minute)Baseline 71.1 77.1End-point 72.6 75.6Change 1.5 - 1.4Significance NS NS

NS, not significant.

Fig. 1 Change from baseline in (a) maximum and (b)mean urinary flow rate in long-term hypertensive BPHpatients (n = 28). Data shown are mean ± SEM. *P < 0.05,**P < 0.01 compared with baseline.

Long-term doxazosin therapy 351

Fig. 2 Percentage improvementin (a) total, (c) obstructive and (e)irritative symptom severity in all hypertensive BPH patients and in (b) total, (d) obstructiveand (f) irritative symptomseverity in long-term hypertensiveBPH patients (n = 28). Datashown are mean ± SEM. *P <0.05, **P < 0.01, ***P < 0.001compared with baseline.

Table 4 Drug-related adverse events*

All hypertensives (n = 178) 4-year hypertensives (n = 28)n % % per year n % % per year

Total patients 49 27.5 12.4 16 57.1 14.3Dizziness 26 14.6 6.6 8 28.6 7.1Fatigue 8 4.5 2.0 4 14.3 3.6Headache 6 3.4 1.5 2 7.1 1.8Postural hypotension 5 2.8 1.3 2 7.1 1.8Somnolence 4 2.2 1.0 2 7.1 1.8

*Drug-related adverse events occurring at a percentage-per-year rate of ≥ 1%. For all hypertensive patients, other adverseevents (n) reported included: impotence (3), dyspnea (2), ejaculation failure (2), flushing (2) and tinnitus (2). Of theseadverse events, there was one report of impotence in the 4-year hypertensives group.

events that were deemed to be drug-related comparedwith 43 (15.8%) normotensive patients.

Thirty-four out of 178 (19.1%) hypertensive patientsdiscontinued due to adverse events, compared with41/272 (15.1%) normotensives. Discontinuations peryear were no different (8.6 vs 8.3%). Discontinuations in

the older subgroup of hypertensives were slightly higherthan in the younger subgroup (10.3% per year vs 6.8%per year); however, this is perhaps not surprising.

Twenty-four out of 178 (13.5%) hypertensivepatients discontinued due to lack of efficacy, comparedwith 18/272 (6.6%) normotensive patients.

352 A Fawzy et al.

Discussion

Double-blind trials have shown that doxazosin, alreadyused widely for the treatment of hypertension, isbeneficial in the treatment of BPH.10,12,13 The datareported in the current 4-year study show that theefficacy of doxazosin therapy is clearly maintained in the long term in patients with concomitant hyperten-sion and BPH, despite the fact that the disease pro-cesses worsen over time. Improvements in urodynamic

parameters and in symptomatology, which are seenwithin weeks,7,16 persisted throughout the 4 yearsstudied in this analysis. Furthermore, doxazosin pro-duced a significant 10 mmHg reduction in diastolicblood pressure in hypertensive patients, which was also sustained throughout the 4 years. Generally, theincidence of adverse events was low, as has beenreported in other studies;10,12–14,17 adverse events werehigher in hypertensives compared with normotensives,although this may be explained by the fact that thepermitted dose for hypertensives was twice that ofnormotensives. Importantly, there was no increasedincidence of adverse events over 4 years, even thoughthe mean dose for the long-term cohort of hypertensivepatients was higher than that for all hypertensives.

Twenty-eight hypertensive BPH patients werestudied over 4 years in this longitudinal prospectivestudy. These patients are a subset of 178 hypertensivepatients originally enrolled over time into a double-blind study12 and then entered into the open-labelphase on the completion of the double-blind protocols.

Fig. 3 Percentage improvement in (a) total, (b)obstructive and (c) irritative symptom bothersomeness in long-term hypertensive BPH patients (n = 28). Datashown are mean ± SEM. *P < 0.05, **P < 0.01, ***P <0.001 compared with baseline.

Fig. 4 Drug-related adverse events by age in hyper-tensive patients. (a) All hypertensive (n = 178); h, < 65 years old (n = 86); j, > 65 years old (n = 92). (b)Four-year hypertensives (n = 28). h, < 65 years old; j, > 65 years old (n = 17).

Long-term doxazosin therapy 353

The 28 patients reported in the current analysis werethe first and only cohort to reach 4 years. Despite thefact that only 28 reached 4 years, the data clearly showthat efficacy is maintained in the long term. Therewere very few withdrawals due to adverse events(16.7% for all 450 normotensive and hypertensivepatients; 19.1% for the 178 hypertensive patients).

Doxazosin produced sustained improvements in boththe symptoms of BPH and in Q

maxover 4 years in patients

with hypertension. This benefit was not eroded over thelong-term; the change from baseline after 4 years beingsimilar to that after only a few months of treatment.Although doxazosin did increase Q

maxsignificantly, it is

the symptoms of BPH rather than problems with urinaryflow per se that drive patients to seek medical attention.18

It is interesting to note in this regard that doxazosinproduced a greater and more consistent improvement insymptoms throughout the 4 years (P < 0.001). It is alsoof interest that doxazosin is most effective in thosepatients with more severe symptoms.19

These results compare favorably with previouslypublished long-term studies of doxazosin10,14 andterazosin,20 and show that a

1-adrenoceptor antagonists

such as doxazosin, with a balanced action on a1-

adrenoceptor subtypes, are especially beneficial in thetreatment of concomitant BPH and hypertension. Thismeans that a single drug can be used, which is valuablein an older population who may already be on multiplemedications for other diseases. There is also theprobability of fewer adverse events with a singlemedication than with multiple therapies. The sustainedlong-term efficacy and safety of doxazosin, as shown in the present study, is of importance as BPH andhypertension are chronic and progressive and there-fore, require patients to stay on medication for a longperiod of time. The low incidence of adverse events and the sustained efficacy of doxazosin may encouragegreater compliance. Moreover, male patients treatedwith doxazosin have been shown to have a lowerincidence of erectile dysfunction compared with otherclasses of antihypertensives,21 a major concern in termsof compliance with antihypertensive medications.

Conclusion

Doxazosin produced sustained improvements in theseverity and bothersomeness of BPH symptoms (total,obstructive and irritative) and in Q

maxover 4 years in

BPH patients with hypertension. The benefit was noteroded over the long-term, the change from baselineafter 4 years being similar to that after only a few monthsof treatment. As expected, there is a significant reduction

in blood pressure in hypertensive patients. Doxazosinappears to be effective and well tolerated as a long-termtreatment in BPH, with no increase in the incidence ofadverse events with prolonged treatment.

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