Objective A one-year prospective, randomized, placebo-controlled study was carried out to evaluate the efficacy and safety of doxazosin, finasteride or both in the treatment of symptomatic benign prostatic hyperplasia (BPH).
Patients and Methods This study included 187 patients with BPH randomized into 4 treatment groups: doxazosin group (49 patients), finasteride group (47 patients), combination therapy group (46 patients) and placebo group (45 patients). Primary efficacy assessments included the International Prostate Symptom Score (IPSS) and the maximum urinary flow rate (Qmax). Safety assessments included the incidence of acute urinary retention (AUR) and transurethral resection of the prostate (TURP).
Results At the end point, the mean decrease in IPSS was 6.8 in the doxazosin group, 4.9 in the finasteride group, 7.1 in the

combination therapy group and 2.8 in the placebo group. The mean increase in Qmax was 3.3 ml/s in the doxazosin group, 2.2 ml/s in the finasteride group, 3.6 ml/s in the combination therapy group and 1.6 ml/s in the placebo group. AUR occurred in 2.1% in the finasteride group and in 4.4% of the placebo group, while TURP was required for 2% in the doxazosin group, 4.3% in the finasteride group, 0% in the combination therapy group and 13.3% in the placebo group.
Conclusion Doxazosin and the combination therapy improved IPSS and Qmax significantly compared to finasteride (p<0.05) and placebo (p<0.001). The combination of doxazosin and finasteride was not more effective than doxazosin alone.
Key Words BPH, doxazosin, finasteride, combination therapy

INTRODUCTION

Benign prostatic hyperplasia (BPH) is common in aging men. It is characterized by obstructive and irritative symptoms that inter-fere with normal activities and reduce the quality of life1. It can also be progressive, with a risk of urinary retention, bladder infection, bladder calculi and renal failure2. Although many men with mild-to-moderate symptoms do well without therapy, others have gradually increasing symptoms and require medical therapy or surgery3.

Although the pathophysiology of BPH and its symptoms are poorly understood, it has been postulated that both a static and a dynamic component are responsible for the infravesical obstruction and development of

symptoms. The static component results from hyperplasia of the glandular and stromal tissue which impinges on and narrows the urethral tract while the dynamic component results from the activity of smooth muscle cells in the prostatic adenoma, prostatic capsule, urethra and bladder neck. Smooth muscle tone is regulated by the sympathetic nervous system via a1- receptors located in these structures4-6.

Medical management of BPH should be regarded as an option in its own right, rather than merely an interim measure in patients waiting for surgery. Five a-reductase inhibitors, like finasteride, act by inhibiting the enzyme 5a-reductase which converts testosterone to dihydrotestosterone. Administration of these drugs results in reduction in the size of the prostate and improvement in urinary symp-

toms. These drugs address the static com-ponent of obstruction in BPH7. Selective a1-adrenoceptor blockers, such as prazosin, indoramin, alfuzosin, as well as more recently, the longer acting agents terazosin, doxazosin, and tamsulosin act by blocking a1-adreno-ceptors in the prostatic smooth muscles and in the bladder neck, thus reducing outflow obstruction without adversely affecting detrusor contractility. These drugs address the dynamic component of obstruction in BPH8.

The purpose of the present study was to evaluate the efficacy and safety of doxazosin, finasteride, the combination of both drugs, and placebo in treating men with symptomatic BPH.

PATIENTS AND METHODS

Between January 1998 and October 2000, a total of 187 patients with symptomatic BPH were enrolled in this study after informed consent. Their age ranged from 51 to 76 years with a median age of 65 years (mean 64.8 ± 5.1 years). All patients were evaluated before starting the treatment protocol by careful history taking, thorough physical examination including digital rectal examination, laboratory investigations (urinalysis, urine culture, serum electrolytes, creatinine, complete blood count, and prostate specific antigen levels), plain and intravenous urography, completion of a stan-dard International Prostate Symptom Score (IPSS) questionnaire9, uroflometry using a Dantec Urodyne 5000 machine (Dantec

Medical, Inc., Santa Clara, Calif., USA), post-void residual urine (PVR) measurements by ultrasound, and transrectal ultrasound (TRUS) measurement of the prostate size.

Selection criteria for patients entering this study included an IPSS of more than 6, a maximum urinary flow rate (Qmax) between 5 and 15 ml/s for a voided volume of at least 150 ml, a residual urine volume of less than 200 ml, and a serum prostate specific antigen (PSA) concentration of less than 4 ng/ml. No thre-shold level for the prostate size was specified. Exclusion criteria included treatment with a-adrenergic blockers or antiandrogens within the preceeding three months, treatment with medications that could interfere with normal detrusor or sphincter activity, a history of myo-cardial infarction or cerebrovascular accident within two months prior to the study, insulin–dependent diabetes mellitus, a history of ortho-static hypotension, a history of prostate cancer, pelvic irradiation, urethral stricture, surgery for benign prostatic hyperplasia or bladder neck obstruction, neurogenic bladder dysfunction, bladder stones, large bladder diverticulum, chronic prostatitis, recurrent urinary tract infec-tions, cystoscopy within two weeks of study entry, clinically important renal or hepatic impairment, and a serum PSA concentration of more than 10 ng/ml.

The patients were randomly classified into 4 treatment groups: (1) the doxazosin group (n = 49 patients) where doxazosin was admi-nistered at a dose of 1 mg once daily at bedtime for one week, 2 mg at bedtime for

another week, then 4 mg at bedtime for one year, (2) the finasteride group (n = 47 patients) where finasteride was administered at a dose of 5 mg once daily at bedtime for one year, (3) the combination therapy group (n=46 patients) where doxazosin and finasteride were admi-nistered together at the same previous doses for one year and (4) the placebo group (n = 45 patients) where patients received placebo me-dication once daily at bedtime for one year. The study medication was discontinued in the event of a serious adverse effect attributed to finasteride or a serious adverse effect that persisted despite a reduction in the dose of doxazosin. Patients were re-evaluated after 2 weeks and after 1, 3, 6 and 12 months of therapy. Primary efficacy criteria were sympto-matic improvement (reduction in the IPSS and improvement in the Qmax). Safety assessment included the incidence of acute urinary retention (AUR) and transurethral resection of the prostate (TURP). At each visit, vital signs (including blood pressure and heart rate measurements) were monitored and any spon-taneously reported adverse events during the

The results were expressed as mean ± standard deviation (SD). The main analysis was an endpoint analysis of mean changes from baseline. With the baseline value used as the covariate in an analysis of covariance model, all data were studied and compared statistically using the student's t- test and chi-square test.

RESULTS

This study included 187 patients with clinical BPH randomized into 4 treatment groups (doxazosin group, n = 49, finasteride group, n=47, combination therapy group, n=46, and placebo group, n =45). The duration of symptoms ranged from 2 to 16 months (mean 9.5 ± 4.8). Mild (IPSS = 7), moderate (IPSS 8-19), and severe (IPSS = 20) symptoms were reported in 2 (1.1%), 141(75.4%) and 44

(23.5%) patients, respectively. Demographic and baseline patient characteristics in the 4 treatment groups are shown in Table 1. There were no significant differences between the treatment groups with regard to any of these characteristics. During the one–year study, 36 patients (19.3%) discontinued the treatment while 151 patients (80.7%) completed the treatment period. The reasons for discontinua-tion of treatment are shown in Table 2.

At the end point, the mean decrease in the IPSS in the 4 treatment groups was: 6.8 points in the doxazosin group, 4.9 points in the finasteride group, 7.1 points in the combination therapy group, and 2.8 points in the placebo group. There was a statistically significant reduction in the symptom scores in both the doxazosin and the combination therapy groups compared to the finasteride group (p < 0.05) and the placebo group (p < 0.001).

The mean increase in the Qmax at the end point in the 4 treatment groups was: 3.3 ml/s in the doxazosin group, 2.2 ml/s in the finasteride group, 3.6 ml/s in the combination therapy group, and 1.6 ml/s in the placebo group. There was a statistically significant improve-ment in the Qmax in both the doxazosin and the combination therapy groups compared to the finasteride group (p< 0.05) and the placebo group (p<0.001).

There was essentially no difference between the four treatment groups in the
either the doxazosin or placebo group (p<0.001).

The reported drug-related adverse events are summarized in Table 4. Adverse events occurred in 53.0%, 46.8%, 73.9% and 28.8% of patients in the doxazosin, finasteride, combination therapy and placebo groups, respectively. Dizziness, asthenia and postural hypotension were significantly more frequent with doxazosin, alone or in combination, than with finasteride or placebo. Conversely, impo-tence, decreased libido, ejaculatory disorders and breast tenderness were significantly more frequent with finasteride, alone or in com-bination, than with doxazosin or placebo.

The mean change in the systolic blood pressure from the baseline at the end of one year was a decrease by – 4.2 mmHg, – 2.1 mmHg, – 4.1 mmHg and – 1.2 mmHg in the doxazosin, finasteride, combination therapy and placebo groups, respectively. The mean change in the diastolic blood pressure was a decrease by – 3.6 mmHg, – 1.9 mmHg, – 3.5 mmHg, and – 0.9 mmHg in the doxazosin, finasteride, combination therapy, and placebo groups, respectively. The reduction in both the systolic and diastolic blood pressure was significantly higher with doxazosin, alone or in combination, than with finasteride or placebo (p < 0.01). There were no clinically significant changes in the heart rate between the four treatment groups.

DISCUSSION

There is no standard treatment of BPH that is appropriate for all patients. Between watch-ful waiting and surgery, there is now a place for medical treatment of BPH. To be acceptable, medical treatment of BPH should be asso-ciated with a minimal morbidity and should not alter the patient’s quality of life10.

This prospective study was designed to directly compare the efficacy and safety of doxazosin, finasteride, the combination of both drugs, and placebo in men with symptomatic BPH. The symptomatic response of the patients to these medications over 12 months, when expressed as a percent change from baseline, was a decrease in the IPSS by 42.7%, 30.0%, 42.5% and 17.8% together with an increase in the Qmax by 33.0%, 22.2%, 35.6% and 15.2% in the doxazosin, finasteride, combination therapy and placebo The prostate size has been suggested as a treatment outcome predictor for finasteride14. A meta-analysis of six randomized clinical trials comparing finasteride and placebo in the treatment of BPH suggested that finasteride was more effective in men with larger pro-states, i.e. > 60 ml. It seems reasonable to assume that larger prostates respond more favourably to treatments aimed at shrinking their size than do small prostates. Whether the results of our study would have been different in a pre-selected population with larger pro-state glands (over 60 cm3) remains to be demonstrated.

The present study confirmed a good safety profile of doxazosin. Quantitative and quail-tative distribution of adverse events was similar to that previously observed in placebo-controlled studies15,16. Although clinically signi-ficant reductions in blood pressure were documented in hypertensive patients, only smaller, clinically insignificant reductions were seen in normotensive patients. These findings are consistent with those previously reported by other investigators17. Finasteride was well tolerated with a satisfactory safety profile. The overall frequency of adverse events was si-milar to that reported by other placebo-controlled studies18,19. One potential concern with finasteride is that it reduces the level of serum PSA. However, there is no unequivocal evidence that this reduction in serum PSA limits the effectiveness of PSA as a cancer detection tool.

In conclusion, this comparative study de-monstrated that the differences between doxazosin and finasteride were statistically significant in favour of doxazosin with regard to both primary efficacy parameters, symptom scores and urinary flow rate, and the com-bination of both drugs added no benefit over doxazosin alone. The combined rapid onset of clinical effectiveness, ease of once-daily dos-ing, and sustained therapeutic efficacy over the long term make doxazosin a very attractive initial treatment option for BPH.

REFERENCES

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2. Jacobsen SJ, Jacobsen DJ, Girman CJ. Natural history of prostatism: risk factors for acute urinary retention. J Urol 1997, 158:481.
18. Stoner E. Three-year safety and efficacy data on the use of finasteride in the treatment of benign prostatic hyperplasia. Urology 1994, 43:284.

All correspondence to be sent to:

M. Adel Omar, M.D.
Department of Urology
Tanta University Hospital
Tanta
Egypt

improvement in postvoid residual urine volume measured by transabdominal ultrasonography at any time. Acute urinary retention (AUR) occurred in one patient (2.1%) in the fina-steride group and in 2 patients (4.4%) in the placebo group. Transurethral resection of the prostate (TURP) was required in one patient (2.0%) in the doxazosin group, in 2 patients (4.3%) in the finasteride group, and in 6 pa-tients (13.3%) in the placebo group (Table 3).

The mean change in prostate size from the baseline at the end of one year was an increase of 2.1 cm3 in the doxazosin group (5.1%), a decrease of 6.1cm3 in the finasteride group (15.3%), a decrease of 6.4 cm3 in the combination therapy group (15.9%), and an increase of 2.2 cm3 in the placebo group (5.2%). The changes in the mean prostate size were significantly higher in both the finasteride and combination therapy groups compared to either the doxazosin or placebo group (p<0.001).

The mean change in serum PSA concentrations from the baseline at the end of one year was an increase of 0.2 ng/ml in the doxazosin group (6.8%), a decrease of 0.7 ng/ml in the finasteride group (26.9%), a de-crease of 0.8 ng/ml in the combination therapy group (29.6%) and an increase of 0.3 ng/ml in the placebo group (6.9 %). The changes in the mean serum PSA concentration were statis-tically significant for both the finasteride and combination therapy groups compared to groups, respectively. Analysis of the pooled data showed that doxazosin produced a significantly greater improvement than fina-steride with regard to both primary efficacy parameters, symptom scores and urinary flow rate. The clinical improvement associated with doxazosin therapy occurred as early as 1 week of treatment with doses as low as 1 mg. This is in contrast to the treatment with finasteride, which required several months for clinical efficacy to be apparent. Not only has doxa-zosin been shown to have a rapid onset of efficacy, but its beneficial effects are main-tained over the long term. The combination therapy for BPH with an a1-adrenoceptor blocker and a 5a-reductase inhibitor appears attractive due to the potential additive effects on symptom reduction resulting from their different mechanisms of action. This one-year study showed no clinical benefits in combining the two agents. The incidence of AUR and TURP was more common in the placebo group than in the doxazosin, finasteride or combina-tion therapy groups.

Three direct comparative trials between finasteride, a1-adrenoceptor blockers and their combination are now available. The Veterans’ Administration Cooperative Study (VA study) compared the efficacy and safety of terazosin, finasteride, combination therapy and placebo in patients with clinical BPH and found that the a1-blocker was more effective over 1 year than finasteride, but caused more side effects, particularly dizziness11. Moreover, improve-ment was no better in patients who received the combined treatment than when the a1-blocker was given alone. The European ALFIN Study Group evaluated the comparative efficacy and safety of sustained release (SR) alfuzosin, finasteride and the combination of both drugs for the treatment of BPH and found that SR alfuzosin was more effective over 6 months than finasteride, with no additional benefit in combining both drugs12. Lastly, the PREDICT trial (Prospective European Doxa-zosin and Combination Therapy) assessed the long-term efficacy and safety of doxazosin, finasteride, combination of both drugs and placebo for one-year in patients with symp-tomatic BPH and reported that doxazosin was more effective than finasteride and the combination of both drugs added no benefit over doxazosin alone13. Our data showed similar results to those prior studies in that doxazosin was more effective than finasteride with the combination achieving no better re-sults than doxazosin alone.
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