Mark Helfand, MD, MPH, FACP

Staff Physician

Portland VA Medical Center

Portland, OR

Tara Muzyk, Pharm.D.

Clinical Pharmacist

VA Southern Nevada Healthcare System

Las Vegas, NV

Mark Garzotto, MD

Staff Physician, Urology Section 

Portland VA Medical Center

Portland, OR

Evidence Synthesis Pilot Program 

Benign Prostatic Hyperplasia (BPH) 

Management in Primary Care – 

Screening and Therapy

Comparative Effectiveness Review

Department of Veterans Affairs

Health Services Research & Development Service

Final Report

February 2007

The purpose of this report is to make available information regarding the comparative effectiveness and safety 

profiles of different drugs within pharmaceutical classes. 

Reports are not usage guidelines, nor should they be 

read as an endorsement of, or recommendation for, any 

particular drug, use or approach. 

Portland VA Medical Center does not recommend or 

endorse any guideline or recommendation developed by 

users of these reports.
TABLE OF CONTENTS 

EXECUTIVE SUMMARY.................................................................................................................................. 3

INTRODUCTION................................................................................................................................................ 5

CURRENT VA GUIDANCE ................................................................................................................................... 6

AUA GUIDELINES .............................................................................................................................................. 6

SCOPE AND KEY QUESTIONS .............................................................................................................................. 8

ELIGIBILITY CRITERIA........................................................................................................................................ 8

METHODS ........................................................................................................................................................... 9

RESULTS.............................................................................................................................................................. 9

OVERVIEW.......................................................................................................................................................... 9

KEY QUESTION 1:

For patients with BPH, what are the comparative benefits, harms, and efficacy of combination therapy with a 

5-alpha-reductase inhibitor plus an alpha blocker versus either treatment alone?............................................. 9

KEY QUESTION 2:

In head-to-head trials, for patients with benign prostatic hyperplasia (BPH), do the different alpha-1-

adrenergic antagonists differ in efficacy or adverse events? ........................................................................... 17

KEY QUESTION 3:

Are there subgroups of patients based on demographics (age, racial groups, and gender), other medications, 

or co-morbidities for which one treatment is more effective or associated with fewer adverse events? ......... 19

SUMMARY......................................................................................................................................................... 21

REFERENCES ................................................................................................................................................... 22

APPENDIX A: METHODS FOR EVIDENCE SYNTHESIS ........................................................................ 27

LITERATURE SEARCH ....................................................................................................................................... 27

STUDY SELECTION ........................................................................................................................................... 27

DATA ABSTRACTION ........................................................................................................................................ 27

QUALITY ASSESSMENT..................................................................................................................................... 28

EVIDENCE SYNTHESIS ...................................................................................................................................... 29

DATA PRESENTATION....................................................................................................................................... 29

APPENDIX B: TRIALS COMPARING ALPHA ANTAGONISTS ............................................................. 30

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 2 
EXECUTIVE SUMMARY 

Background 

Benign prostatic hyperplasia (BPH) causes urinary hesitancy and intermittency, weak urine 

stream, nocturia, frequency, urgency, and the sensation of incomplete bladder emptying. 

These symptoms, collectively called “lower urinary tract symptoms,” or LUTS, can 

significantly reduce quality of life. Men with no symptoms or mild symptoms (AUA 

Symptom Index [SI] score of <7 points), and those who tolerate moderate symptoms well, 

may be managed without pharmacotherapy (“watchful waiting”). For those who have 

moderate or severe symptoms, medical treatments include alpha-1-selective adrenergic 

receptor (a-1-AR) antagonists, 5-alpha-reductase inhibitors (5-aRIs), or a combination 

therapy with one drug from each of these classes. 

This report addresses the following questions about treatment for BPH: 

1. For patients with BPH, what are the comparative benefits, harms, and efficacy of 

combination therapy with a 5-alpha-reductase inhibitor plus an alpha blocker versus 

either treatment alone? 

2. What are the comparative efficacy and harms of alpha-1-adrenergic antagonists? 

3. Are there subgroups of patients based on demographics (age, racial groups), other 

medications, or co-morbidities for which one treatment is more effective or associated 

with fewer adverse events? 

Results 

Combination therapy versus an alpha blocker or 5-ARI alone. 

In the first year of treatment, alpha blockers are more effective than finasteride in improving 

symptoms. Combination therapy and an alpha blocker alone have similar effects on quality 

of life in the first year and a half of treatment. 

For men who have BPH and have a large prostate or a high PSA at baseline, combination 

therapy can prevent about 2 episodes of clinical progression per 100 men per year over 4 

years of treatment. There is no additional benefit within the first year of treatment. Most 

men who take combination therapy will have no additional benefit, and about 4 additional 

patients per 100 will become impotent who would not have taking an alpha blocker alone. 

Combination therapy can also be instituted after clinical progression occurs, but this strategy, 

while used widely, has not been studied. 

There is considerable uncertainty about how best to monitor PSA in whom to choose to take 

finasteride or combination therapy and who are otherwise candidates for PSA screening. 

Candidates for combination therapy—patients who have large prostates and at least moderate 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 3 
symptoms—tend to have higher PSA levels than other patients who have BPH. Finasteride 

reduces prostate size and PSA levels, making detection of prostate cancer more difficult. 

Alpha-blockers do not affect PSA levels. Expanding access to combination therapy as an 

initial option would require higher utilization of ultrasound and PSA testing in BPH patients 

to assess the risk of progression. The consequences of such a program in a primary care 

setting have not been studied. 

Choice of Alpha Blocker. 

Previous, good-quality systematic reviews found that the alpha blockers, including alfuzosin 

prolonged-release and doxazosin GITS, have similar efficacy in improving symptoms and 

urinary flow rate. Observational studies of doxazosin, terazosin, and tamsulosin in selected 

patients indicate that in most patients who respond to an alpha blocker and who tolerate it 

well initially, the drug continues to work and to be well-tolerated for many years. 

Head-to-head trials of alpha-blockers are few, small, and have serious limitations. They do 

not adequately test commonly held beliefs about differences in the side effect profiles of the 

alpha blockers. Specifically, they do not prove that, when used in practice, tamsulosin causes 

fewer cardiovascular adverse effects than other alpha-blockers because it does not reduce 

blood pressure. In placebo-controlled trials, tamsulosin caused higher rates of sexual 

ejaculation abnormalities than other alpha blockers. The placebo-controlled trials do not 

adequately test the hypothesis that use of tamsulosin as initial therapy reduces the risk of 

symptomatic hypotension. 

For combination therapy, doxazosin is the best-studied alpha blocker. 

Treatment of BPH in subgroups of patients. 

Long-term observational studies establish that BPH can be treated safely with alpha blockers 

in patients taking other medications for hypertension. Alpha blockers should not be used as 

initial treatment for patients with hypertension, even those with BPH, because they are 

associated with poorer long-term outcomes than other choices. Data on the safety of alpha 

blockers in patients taking erectile dysfunction drugs are sparse. 

Recently, the FDA issued a notice that intraoperative Floppy Iris Syndrome (IFIS) has been 

observed during phacoemulsification cataract surgery in some patients currently or recently 

treated with tamsulosin. 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 4 
INTRODUCTION 

Benign prostatic hyperplasia (BPH) causes urinary hesitancy and intermittency, weak urine 

stream, nocturia, frequency, urgency, and the sensation of incomplete bladder emptying. 

These symptoms, collectively called “lower urinary tract symptoms,” or LUTS, can 

significantly reduce quality of life. Approximately 50% of men who have BPH develop 

moderate to severe symptoms. BPH is the 4th most commonly diagnosed disease among 

patients ≥50 years, after coronary disease and hyperlipidemia; hypertension; and type 2 

diabetes. Among men over 50 years the prevalence of diagnosed BPH in the community is 

13.5%. 

Reducing symptoms is the main reason to treat BPH. Men with no symptoms or mild 

symptoms (AUA Symptom Index [SI] score of <7 points), and those who tolerate moderate 

symptoms well, may be managed without pharmacotherapy (“watchful waiting”). Medical 

treatments include alpha-1-selective adrenergic receptor (a-1-AR) antagonists, and 5-alphareductase inhibitors (5-aRIs). 

Several reasons to choose one treatment instead of another have been suggested. A clinician 

may consider several factors in choosing a treatment:

• expeditious relief of the presenting symptoms and quality of life 

• quality of life related to adverse effects of medications such as sexual dysfunction, 

dizziness, and asthenia 

• preventing or delaying progression (especially acute urinary retention) in the longterm 

• the risk of developing cancer 

• the effect of treatment on hypertension, diabetes, post-traumatic stress disorder, and 

other conditions common among veterans. 

Combination therapy with an alpha blocker plus a 5-aRIs, finasteride, has become 

increasingly popular [1, 2] since December, 2003, when the NIH-funded Medical Therapy of 

Prostatic Symptoms (MTOP) trial [3] was published. The trial found that the patients taking 

a combination of finasteride and doxazosin were less likely to develop acute urinary retention 

(AUR), an increase in symptom score greater than 4 points on the AUA/IPSS scale, or 

invasive therapy for BPH. 

Wider use of combination therapy raises several issues for the VA: 

1. Should the VA change its clinical practice guidelines to increase access to 

combination therapy? 

2. Should the VA increase access to combination therapy by allowing primary care 

physicians to prescribe it? 

3. How should patients taking finasteride or combination therapy be monitored for 

prostate cancer? 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 5 
Current VA Guidance 

In September, 2004, the VHA Pharmacy Benefits Management Strategic Healthcare Group 

and the Medical Advisory Panel published guidelines for the use of combination therapy. 

This guideline recommended combination therapy in two groups of patients: (A) those who 

had persistence or clinical progression of BPH symptoms while taking maximal doses of an 

alpha-blocker and (B) those who present with an AUA score ≥ 12 and have a prostate size 

>40 ml (see Figure 1). They did not offer specific guidance for PSA testing in patients taking 

finasteride, but some facilities recommend annual testing. 

Figure 1. PBM-MAP Guidance on Combination Therapy. 

The PBM/MAP has also recommended against the addition of dutasteride and alfuzosin to the 

National VA Formulary. 

AUA Guidelines 

The American Urological Association published guidelines for management of BPH in 2003. 

It is described as having been updated in 2006, but it is not clear what material was updated. 

The AUA’s main findings regarding the choice of drug therapies are: 

• Alpha blockers are more effective than finasteride in improving symptoms 

• Finasteride is not an appropriate treatment for patients who do not have prostate 

enlargement 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 6 
• Finasteride is an appropriate treatment for patients who have LUTS and a large 

prostate 

• The combination of an alpha-adrenergic receptor blocker and a 5 alpha-reductase 

inhibitor (combination therapy) is an appropriate and effective treatment for patients 

who have a high baseline risk of progression, but a specific threshold of risk cannot be 

determined. 

• Alfuzosin, doxazosin, tamsulosin and terazosin have similar effectiveness 

o While side effect profiles differ, none of these drugs had a clear advantage as 

initial therapy. 

The AUA guidelines also state that “Data are insufficient to support a recommendation for 

the use of prazosin.” However, data on prazosin were not analyzed in developing the 

guidelines (page 3-13).

Advocates of wider use of combination therapy argue that “moderate to severely symptomatic 

patients with larger glands and higher serum PSA levels, however, are best served with 

combination therapy, as they benefit from the disease modification induced by the 5 alpha 

reductase inhibitors in addition to the symptomatic improvement due to the alpha blockers.” 

[4] The AUA guidelines do not specify a threshold risk of progression above which 

combination therapy is the treatment of choice, but imply that there is such a threshold. 

Based on the guidance in Figure 1, in the VA combination therapy is an option for initial 

treatment in men who have at least moderate symptoms and a large prostate; however, within 

the VA there is no group for which combination therapy is described as the treatment of 

choice. 

The purpose of this review is to compare finasteride in combination with an alpha-blocker to 

finasteride alone or to an alpha blocker alone, and to compare the efficacy and safety of 

different alpha-blockers (listed in Table 1). Combination therapy is used variably, within 

VHA. The balance of benefits and harms of finasteride, and its complex effects on detection 

of prostate cancer, and on the natural history of cancer, make it important that the VA 

implement evidence-based approach to treating BPH. 

Table 1. Drug Indications and Dosing

Starting Drug Dosage Maintenance 

Dosage 

On VA 

Formulary 

Alfuzosin extended release 10 mg daily 10 mg qd No 

Doxazosin – Cardura®, generic 1 mg daily 2 to 8 mg daily Yes 

Doxazosin Gastro-Intestinal 

Therapeutic System 

4 mg daily 8 mg qd No 

Prazosin 1 mg daily 2 to 10 mg Yes 

Tamsulosin – Flomax® 

(Boehringer Ingelheim) 

0.4 mg daily 0.4 or 0.8 mg No 

Terazosin – Hytrin®, generic 1 mg daily 2 to 10 mg Yes 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 7 
Scope and Key Questions 

Key Question 1: For patients with BPH, what are the comparative benefits, harms, and 

efficacy of combination therapy with a 5-alpha-reductase inhibitor plus an alpha blocker 

versus either treatment alone? 

Key Question 2: what are the comparative efficacy and harms of alpha-1-adrenergic 

antagonists? 

Key Question 3: Are there subgroups of patients based on demographics (age, racial 

groups), other medications, or co-morbidities for which one treatment is more effective or 

associated with fewer adverse events? 

Eligibility Criteria 

Population(s): Adult patients in outpatient settings with the following diagnosis:

1. Benign prostatic hyperplasia (BPH) 

2. Lower urinary tract symptoms (LUTS) 

Interventions 

1. Terazosin 

2. Doxazosin 

3. Tamsulosin 

4. Prazosin 

5. Finasteride 

6. Combination of an alpha blocker and a 5-alpha-reductase inhibitor 

Efficacy outcomes 

1. Reduction in BPH or LUTS symptoms 

o Improvement in maximum flow rate (Qmax) 

o Reduction in International Prostate Symptom Score (IPSS or AUA score) 

o Reduction in irritative or obstructive symptoms 

2. Delaying progression to acute urinary retention, worsening symptoms, or invasive therapy 

Safety and related outcomes 

1. Adverse drug reactions 

2. Withdrawals due to adverse drug reactions 

3. Hypertension, hypotension, sexual dysfunction 

4. detection of prostate cancer 

Study designs 

For efficacy outcomes 

1. controlled clinical trials that directly compared 2 or more of the interventions listed above 

2. systematic reviews 

3. placebo-controlled trials if they addressed outcomes not adequately addressed in direct 

comparison studies 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 8 
For safety outcomes 

1. controlled clinical trials and good-quality systematic reviews 

2. cohort studies of a defined population 

Trials were excluded if they 

o evaluated phytotherapeutic agents or drugs that are not available on the VA National 

Formulary 

o were not available in English 

o had less than 30 days of follow up 

METHODS see Appendix.

RESULTS 

Overview 

Searches identified 10 relevant systematic reviews. [5-14] We also identified 41 articles 

reporting 7 observational studies relevant to Key Question 1, including 11 about the risk for 

progression of BPH; 12 about prostate cancer detection or the incidence of cancer on 

treatment; and 18 about the comparative efficacy and/or safety of combination therapy, 

finasteride alone, and an alpha blocker alone. For comparisons of different alpha blockers 

(Key Question 2), we relied on relevant systematic reviews, [6, 9-13] supplemented by trials 

and observational studies published since 2003. For Key Question 3, we identified 11 

publications of the use of alpha blockers or finasteride in the elderly or in patients with 

comorbid conditions, most commonly hypertension. [14-24] 

Key Question 1: For patients with BPH, what are the comparative benefits, 

harms, and efficacy of combination therapy with a 5-alpha-reductase inhibitor plus an 

alpha blocker versus either treatment alone? 

In the first year of treatment, alpha blockers are more effective than finasteride in improving 

symptoms. [25] Alpha blockers are equally effective in relieving symptoms in men with 

large prostate glands and those with normal-sized prostate glands. [26, 27] Finasteride is 

more effective than placebo in relieving symptoms only in men with prostate size >40 cc and 

is less effective than an alpha blocker in the first year of therapy regardless of prostate size. 

[25, 28] 

Because it has no advantage in the short-term, the main potential advantage of finasteride 

therapy or combination therapy is preventing or delaying progression of disease in the longterm. [29] Progression of BPH is usually defined as any of the following events: 1) an 

episode of acute, spontaneous urinary retention, 2) an increase in AUA symptom score of 4 or 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 9 
more points, or 3) surgery for BPH. Some definitions of progression include other events. 

For example, in the Veterans Affairs Cooperative Study of transurethral resection vs. 

watchful waiting in 591 veterans (mean AUA score 14.1), 47 patients (17%) in the watchful 

waiting group experienced treatment failure, defined asthe occurrence of any of the following 

events during 3 years of follow-up: death; repeated or intractable urinary retention; a residual

urinary volume over 350 ml; the development of a bladder calculus; new, persistent 

incontinence requiring the use of a pad, penile clamp, or condom; a symptom score of 24 or 

higher at one visit or scores of 21 or higher at two consecutive visits; or a doubling of the 

base-line serum creatinine concentration.[30] In the TUR group, 23/280 (8%) failed 

treatment. 

In judging the need for finasteride or combination therapy, it is important to consider several 

factors: 

• How serious a threat to health and well-being are progression events?

• What is the risk of progression?

• By how much does finasteride or combination therapy reduce the risk?

• What are the risks and bother from side effects of finasteride or combination 

therapy? 

Smaller trials, and those with a duration of one year or less, accrue too few progression events 

to compare the longer term balance of benefits and risks of alpha-blocker therapy to 

finasteride alone or to combination therapy. For this reason, the evidence base for comparing 

combination therapy to single-drug therapy is limited to a few well-known trials. [3, 25, 31-

33] 

How serious is progression? 

AUR or advancing symptoms cause significant expense and reduce the quality of life, but 

they are treatable conditions with a good prognosis. Most men who present with AUR will 

eventually require surgery, but transurethral resection as well as other effective treatment 

options are available for patients who progress. 

What is the risk of progression? 

Population-based cohort studies as well as the control groups of randomized trials of 

treatments for LUTS provide information about the risk of progression. 

About 60% of first episodes of acute urinary retention (AUR) occur in men who have a 

diagnosis of BPH. Table 2 shows annual rates of AUR, symptom progression, and surgery for 

some large cohort studies and trials. The 2nd line of data from Olmsted County indicates that 

men in Olmsted County who met the inclusion criteria for the MTOPs trial had substantially 

higher rates of events than the MTOPs sample. [34] This result means that the MTOPS 

results may not represent results in other practice settings. 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 10 
Table 2. Progression Events per 1,000 men. 

Type of progression event Æ

Acute 

Urinary 

Retention 

Symptom 

Progression Surgery All 

Cohorts 

Health Professionals Study 

(AUA score 8-19) 

11.1 

Health Professionals Study 

(AUA score >20) 

14.3 

Olmsted County (all) 8.5 97 6.6 105 

Olmsted County (similar to MTOPS) 18.3 86.5 16.8 109 

Placebo groups 

MTOPS 6 36 45* 

PREDICT 15 11 

PLESS 10 25 

Data from [29, 34] [35-37] 

*Included UTI and incontinence. 

Predicting the risk of progression. 

Older age, prostate size, and PSA, high increasing symptom severity, a poor maximum 

urinary flow rate (Qmax), and a high post void residual urine volume (PVR) are established 

predictors of progression. [38, 39] Most studies of these risk factors, including analyses of 

the placebo groups of Proscar Long-Term Efficacy and Safety Study (PLESS)[40, 41] and 

MTOPs [42], confirm that the traditional risk factors are associated with progression, but fail 

to combine the factors into a sensitive, specific clinical prediction rule. In the “Olmsted 

County Study of Urinary Symptoms in Men” the relative risk of acute urinary retention in 

patients with prostate volumes >30 mL was three times greater than that in patients with a 

prostate volume of <30 mL. [38] 

In the MTOPs trial, 128 of 737 men (17%) in the placebo group progressed over 4 years. [42] 

About 80% of the progression events were an increase in symptoms of 4 or more AUA points 

from baseline. A PSA≥1.6 ng/mL was associated with a higher risk of progression. After 4 

years, 22% of men who had a PSA≥1.6 ng/mL vs. 12% of men who had a PSA<1.6 ng/mL 

progressed. This difference can be expressed as approximately 22 additional cases per 1000 

men per year (52 vs. 30 per 1000 men each year). Higher prostate volume (≥ 31 mL vs. <31 

ml) lower Qmax (≥ 10.6 mL/sec vs. <10.6 mL/s), and higher post-void residual volume (≥39 

mL vs. <39 mL) were also associated with progression. 

Similarly, in PLESS, over 4 years 99 of 3,040 men (6.6%) experienced AUR. Half of these 

episodes of AUR were spontaneous; the others were precipitated by surgery or other 

interventions. The incidence of spontaneous acute urinary retention increased with increasing 

prostate volume divided into tertiles (14 to 41 mL; 42 to 57 mL; >57 mL) from 0% to 1.7% 

and 6.0%, respectively, over a 4-year period. [43] The incidence of combined, spontaneous, 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 11 
and precipitated acute urinary retention increased from 4.4% to 14.0%, from the smallest to 

the largest volume tertile. In the placebo-controlled finasteride trials generally, the 2-year 

incidence of spontaneous AUR was 4.2% in men with prostate volume>40 ml vs. 1.6% in the 

<40 ml group. [44] Higher baseline PSA was associated with a higher risk of progression, 

defined as acute urinary retention or the need for surgery. [43] A PSA≥3.2 ng/mL was 

associated with an 18% risk of progression, versus 12% for 1.4≤PSA<3.2 ng/mL and 7% for 

PSA<1.4 ng/dL. 

It is not known whether the additional risk related to a higher PSA or prostate volume is 

additive, or whether there is a more complicated relationship among factors. In MTOPs, for 

example, higher prostate volume was not associated with age or baseline symptom scores, but 

was highly correlated with post-void residual and PSA results. [31] In fact, the risk for a 

patient who has none of these risk factors, or more than one of them, has not been reported. 

As noted in the AUA guidelines, the lack of a validated prediction rule makes it difficult to 

specify a threshold for initial treatment with combination therapy. [45] 

By how much does finasteride or combination therapy reduce the risk of progression? 

Characteristics of the subjects of the major long-term trials of combination therapy are 

summarized in Table 3, Part 1. The VA Cooperative trial and Prospective European 

Doxazosin and Combination Therapy (PREDICT) were well-designed, one-year trials. Both 

found that an alpha blocker was better than finasteride for relieving symptoms. [25, 32, 33] 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 12 
The Medical Therapy of Prostatic Symptoms trial was designed to test whether, with a longer 

follow up, finasteride and combination therapy, but not an alpha-blocker alone, would prevent or 

delay progression of BPH. [3] The mean patient age at randomization was 62.6 years (±7.3 years). 

Patients were Caucasian (82%), African American (9%), Hispanic (7%), Asian (1%) or Native 

American (<1%). The mean duration of BPH symptoms was 4.7 years (±4.6 years). Patients had 

moderate to severe BPH symptoms at baseline with a mean AUA symptom score of approximately 

17 out of 35 points. Mean maximum urinary flow rate was 10.5 mL/sec (±2.6 mL/sec). The mean 

prostate volume as measured by transrectal ultrasound was 36.3 mL (±20.1 mL). Prostate volume 

was ≤20 mL in 16% of patients, ≥50 mL in 18% of patients and between 21 and 49 mL in 66% of 

patients. 

The main results of MTOPs are shown in Table 3, Part 2. Overall, for every 22 patients treated 

with combination therapy instead of doxazosin alone, one instance of progression would be 

prevented over 4 years. 

AUR. In the MTOPs trial, the cumulative incidence of acute urinary retention at 4 years in the 

finasteride and placebo groups was 0.8% and 2.4%, respectively, so if 100 men were treated for 4 

years only 2 cases of AUR would be prevented. Alpha blockers alone do not appear to affect rates 

of AUR. 

Recent meta-analyses of studies of finasteride vs. placebo provide the best available estimates of 

its effects on progression (Table). [5, 7] In PLESS, if 100 men were started on finasteride instead 

of placebo, by 4 years four men would avoid AUR. In the placebo controlled finasteride trials 

generally, in men who had a prostate size >40 ml, finasteride reduced the 2-year incidence of AUR 

from 4.2% to 1.8%. In men who had a prostate size <40 ml, the 2-year incidence in the placebo 

group was only 1.6%. [44] Similarly, finasteride reduced AUR incidence more in patients who 

had a PSA>1.4 ng/ml (from 3.9% to 1.6% over 2 years) than in those with a PSA<1.4 ng/ml (from 

0.5% to 0.024%). 

Symptomatic Progression. 

About 75% of progression events are due to an increase in symptom score rather than a dramatic 

event such as AUR. Alpha blockers as well as finasteride reduce the risk of symptomatic 

progression. MTOPs found that doxazosin alone and finasteride alone reduced the risk of clinical 

progression to a similar degree, [3] but not as much as combination therapy. The event rates 

shown below, from MTOPs, reflect symptomatic progression rates. Compared with doxazosin 

alone, combination therapy prevented 1 symptomatic progression for every 20 patients treated for 

4 years. (Conversely, 19 of 20 patients treated for 4 years did not benefit symptomatically from 

combination therapy.) 

Surgery. 

Among the major trials, and across time, rates of surgery vary widely, most likely due to practice 

styles rather than patient characteristics. In MTOPs, 26 (3%) of 756 patients assigned to doxazosin 

required invasive therapy by 4 years, versus 14 (2%) per 768 finasteride patients and 12 (1%) of 

786 combination therapy patients. 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 13 
Table 3. Part 2. With permission from Bandolier. [46] 

Placebo Doxazosin Finasteride Combination 

Number of patients 737 756 768 786 

Outcome Percent Percent NNT

(95% CI) Percent NNT(95% CI) Percent NNT(95% CI) 

Any clinical BPH 

progression 17 9.7 15 (10 to 27) 10 16 (10 to 34) 5.3 9 (7 to 12) 

Symptom score 

increase ≥4 points 13 7.3 17 (11 to 35) 8.5 21 (13 to 64) 4.6 12 (9 to 17) 

Acute retention 2.4 1.2 NS 0.8 60 (34 to 260) 0.5 52 (32 to 140) 

Invasive BPH 

therapy 5.0 3.4 NS 1.8 31 (20 to 74) 1.5 27 (19 to 59) 

MTOPS was reported in 2003, but results for subjects with different prostate gland sizes did not 

become available until early 2006. [31] Table 3, Part 2 compares the results of combination 

therapy in patients with a small, medium, or large gland. For men with a prostate size over 40 ml, 

initial therapy with finasteride plus doxazosin instead of doxazosin alone prevented one 

progression event for every 13 men treated for four years. It should be noted again that nearly 

80% of these events were an increase in symptoms rather than less common, more serious events 

(AUR and invasive treatment). 

Table 3, Part 3, Expected numbers of events per 1,000 men over 4 years by prostate 

size. Based on MTOPs. [31] 

All progression events Prostate Size (percent 

of sample)* Doxazosin 

Alone 

Finasteride 

Alone 

Combination 

Therapy 

NNT (Comb 

vs. Dox alone) 

<25 ml (31%) 77 102 54 43 

25 to 40 ml (28%) 106 102 55 20 

>40 ml (31%) 148 147 71 13 

*Total sample 3,047. Bold=statistically significant for doxazosin vs. combination. 

Effect on Quality of Life. 

After 16 months of treatment, combination therapy and an alpha blocker alone have similar effects 

on quality of life. (Figure, Copyright © 2003 American Urological Association Education and 

Research, Inc.) 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 14 
What are the risks of combination therapy (that is, of alpha blocker+finasteride) vs. alpha blocker 

alone? 

Discontinuation rates in MTOPs were low relative to most other studies. Adverse event rates in 

MTOPs (Table 4) show that combination therapy caused a higher frequency of dizziness and 

sexual side effects than doxazosin alone, but was similar otherwise. 

Table 4: Adverse events (% of men) in MTOPS over four years. 

With permission from Bandolier. [46] 

Adverse event Placebo Doxazosin Finasteride Combination

Discontinuation -- 27 24 18 

Dizziness 2.3 4.4 2.3 5.4 

Postural hypotension 2.3 4.0 2.6 4.3 

Asthenia 2.1 4.1 1.6 4.2 

Peripheral edema 0.7 0.9 0.7 1.3 

Dyspnea 0.6 0.9 0.6 1.2 

Erectile dysfunction 3.3 3.6 4.5 5.1 

Decreased libido 1.4 1.6 2.4 2.5 

Abnormal ejaculation 0.8 1.1 1.8 3.1 

What other factors influence the balance of benefits and harms? 

Risk of developing cancer 

The Prostate Cancer Prevention Trial (PCPT) studied the long-term effect of finasteride on cancer 

rates. Other large, long-term prostate cancer prevention trials are currently in the enrollment 

phase, including the REDUCE trial, a study undertaken by GlaxoSmithKline involving the drug 

dutasteride. [47] 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 15 
Patients recruited into the PCPT were expected to have a lifetime incidence of 16.7% and a rate of 

death from prostate cancer of 3% to 4%. In the PCPT finasteride decreased the 7-year period 

incidence of prostate cancer vs. placebo (18.4% vs. 24.4%), but high-grade (Gleason score 7-10) 

tumors were significantly more common in the finasteride group. [48] Put differently, over 7 

years, for every 1000 patients, finasteride was associated with 7 fewer low-grade cancers, 61 fewer 

intermediate-grade cancers, 6 fewer ungraded cancers, and 14 additional high-grade ones for a net 

reduction of 61 cancers. (Finasteride does not have an FDA indication for chemoprophylaxis of 

prostate cancer.) 

The meaning of these results has been debated extensively. A notable recent finding is that, over 

the course of the study, the rate of PSA increase for high-grade cancers was similar in finasteridetreated patients and in placebo-treated patients, suggesting the increase in high-grade cancers is 

likely to be real rather than artifactual. [49, 50] At any rate, even those experts who argue that this 

increase in high-grade tumors is artifactual agree that “the role of 5ARIs for prostate cancer 

chemoprevention needs further examination before it can be considered for wide 

recommendation.” [51] 

PSA Testing 

There is considerable uncertainty about how best to monitor PSA in whom to choose to take 

finasteride or combination therapy and who are otherwise candidates for PSA screening. 

Candidates for combination therapy—patients who have large prostates and at least moderate 

symptoms—tend to have higher PSA levels than other patients who have BPH. Finasteride 

reduces prostate size and PSA levels, making detection of prostate cancer more difficult. Alphablockers do not affect PSA levels. [52] 

The best strategy for monitoring is unclear. The “doubling” rule—performing a biopsy if twice the 

PSA level exceeds the threshold for biopsy—is a typical protocol. It is based on analysis of PSA 

data in the PLESS trial, which had four years of follow up and which found that the performance 

(sensitivity and specificity) of the doubled PSA for detecting prostate cancer in the finasteride 

patients was at least as good as the actual PSA level was in the placebo control group. [53] 

New strategies, while based on a careful analysis of data from several trials, have not been applied 

in practice, and their influence on the frequency of biopsies or the overall detection of cancers is 

unknown. A new analysis of data from PLESS, PCPT, and trials of dutasteride found that PSA 

decreases gradually over the first year of treatment with finasteride.[54] Before one year of 

treatment has been completed, doubling the PSA can overestimate PSA, resulting in a high false 

positive rate and more biopsies. Because of the difficulty of interpreting PSA They recommended 

not obtaining biopsies until one year of therapy is complete. At that time and thereafter, instead of 

using an adjustment factor (such as doubling), a biopsy should be done when an annual PSA test is 

higher by 0.3 ng/ml or more than the lowest PSA level obtained during treatment (the nadir.) 

Alternatively , analysis of PSA data in the 7-year Prostate Cancer Prevention Trial (PCPT) 

suggests that the adjustment factor gradually increased from 2 (doubling) to 2.5 after 7 years of 

treatment. [49] During the trial, the PCPT finasteride arm was adjusted to 2.3 at study year 4 to try 

to achieve a rate of biopsies closer to that of the placebo group. 

High utilization of tests 

In primary care, the use of combination therapy as an initial treatment option would require routine 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 16 
use of ultrasound to determine prostate size and PSA to identify men at high risk of progression. 

In current primary care practice, these tests are rarely if ever used to choose an initial therapy for 

BPH, although PSA is of course used frequently to screen for prostate cancer. An alternative 

approach would be to obtain only a PSA and, after appropriate screening for prostate cancer, offer 

men who have severe symptoms and a PSA level above 4 ng/mL combination therapy. This 

strategy—intended to avoid wider ultrasound testing in primary care—has not been examined in a 

formal study. For every 1000 patients with BPH seen in primary care, this approach would result 

in obtaining 1000 PSA tests to identify perhaps 70 candidates for combination therapy. Of these, 

if 50 accepted combination treatment, 10 would discontinue therapy (mostly because of adverse 

events), while treating the remaining 40 men for 4 years would prevent 4 episodes of progressive 

symptoms and 1 episode of acute urinary retention or invasive therapy. 

How does a stepped approach compare with those of initial combination therapy? 

As mentioned above, adding finasteride after progression has occurred on an alpha blocker is an 

alternative to initial treatment with combination therapy. The stepped approach has the advantage 

of avoiding finasteride therapy in those patients (approximately 19 of 20) who would not 

experience a benefit over four years compared with an alpha blocker alone. 

Unfortunately, there is no evidence about the strategy of instituting combination therapy after 

progression occurs. Comparing the effectiveness of these different approaches in patients 

considered candidates for initial combination therapy might be a high priority for the VA. 

Key Question 2: In head-to-head trials, for patients with benign prostatic hyperplasia 

(BPH), do the different alpha-1-adrenergic antagonists differ in efficacy or adverse 

events?

Previous, good-quality systematic reviews found that the alpha blockers, including alfuzosin 

prolonged-release and doxazosin GITS, have similar efficacy in improving symptoms and urinary 

flow rate. [5, 6, 9, 13] [10-12] The GITS formulation is not available at the VA. 

The review articles primarily summarize placebo-controlled trials. This is because only a few 

head-to-head trials of different alpha-blockers have been done (Table 5). [55-60] The head-tohead studies ranged from 4 weeks to 3 months in duration. Four of the 5 studies were conducted in 

Asian men. These trials are summarized in Appendix 2 (Evidence Table). 

Table 5. Head to head trials of alpha blockers. 

Doxazosin Prazosin Tamsulosin Terazosin 

Doxazosin X 0 0 1 

Prazosin 1 1 

Tamsulosin 3 

Terazosin 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 17 
Because they are few, small, and have serious limitations, the head-to-head trials do not adequately 

test commonly held beliefs about differences in the side effect profiles of the alpha blockers. 

Specifically, they do not prove that, when used in practice, tamsulosin causes fewer cardiovascular 

adverse effects than other alpha-blockers because it does not reduce blood pressure. 

The most extensive meta-analysis comparing side effects of alpha-blockers in trials was conducted 

by the American Urological Association. Results of these analyses are shown in Table 6. Except 

for a higher rate of asthenia with doxazosin and a higher rate of sexual side effects with 

tamsulosin, none of the differences are statistically significant. More recent uncontrolled or 

placebo-controlled trials [22, 61, 62] do not change these findings. 

Table 6. Meta-analysis of side effects of alpha blockers. 

Outcomes of medical therapies: estimates of occurrence of adverse events 

Median Percentage (95% CI) 

Acute 

Urinary 

Retention 

Asthenia Breast Cardiovascular 

CardiovascularPeripheral 

Edema 

Cardiovascular, 

Serious 

Dizziness GI 

Systems Headache 

Alpha Blockers 

Alfuzosin 4 (1-10) 1 (0-4) 0 (0-1) 5 (1-12) 10 (6-15) 5 (3-9 

Doxazosin 0 (0-1) 15 (13-18) 2 (1-4) 1 (1-3) 13 (9-19) 10 (6-15) 8 (4-12) 

Tamsulosin 4 (1-8) 7 (3-12) 8 (2-18) 12 (8-17) 11 (6-18) 12 (6-19) 

Terazosin 4 (1-8) 12 (10-13) 2 (1-3) 4 (2-6) 0 (0-0) 15 (12-20) 5 (3-9) 7 (5-10) 

Hormonal

Finasteride 2 (1-2) 2 (1-4) 1 (0-2) 5 (2-10) 1 (0-3) 5 (2-10) 6 (3-10) 4 (2-6) 

Combination

Alfuzosin/ 

finasteride 0 (0-1) 1 (0-2) 0 (0-1) 2 (1-4) 2 (1-3) 

Doxazosin/ 

finasteride 0 (0-1) 13 (9-17) 2 (1-4) 14 (11-19) 8 (6-12) 9 (6-13) 

Terazosin/ 

finasteride 14 (11-18) 21 (17-26) 5 (3-8) 

Placebo 3 (2-5) 4 (3-5) 2 (0-5) 4 (2-7) 1 (1-2) 1 (1-1) 5 (4-7) 6 (4-9) 5 (4-7) 

From AUA Guideline with permission. [45] 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 18 
Table 6 (cont.). Meta-analysis of side effects of alpha blockers. 

Outcomes of medical therapies: estimates of occurrence of adverse events (continued) 

Median Percentage (95% CI) 

Hypotension

Asymptomatic 

Hypotension 

Symptomatic 

Hypotension

Symptomatic 

Postural 

Hypotension

Symptomatic 

Syncope 

RespiratoryNasal 

Congestion 

SexualEjaculation SexualErectile 

Problems 

Sexual 

Libido 

Alpha Blockers 

Alfuzosin 1 (0-3) 1 (0-3) 6 (1-15) 3 (1-6) 1 (0-4) 

Doxazosin 5 (3-10) 4 (1-9) 0 (0-2) 8 (1-25) 0 (0-2) 4 (1-8) 3 (2-6) 

Tamsulosin 7 (2-15) 3 (1-6) 1 (0-1) 11 (4-23) 10 (6-15) 4 (1-8) 

Terazosin 8 (2-18) 3 (1-8) 6 (3-11) 1 (1-3) 6 (4-10) 1 (1-2) 5 (3-8) 3 (1-5) 

Hormonal 

Finasteride 4 (1-12) 2 (1-3) 1 (0-3) 9 (2-22) 4 (3-5) 8 (6-11) 5 (4-7) 

Combination 

Alfuzosin/ 

finasteride 8 (6-11) 1 (0-2) 1 (0-2) 8 (5-11) 2 (1-4) 

Doxazosin/ 

finasteride 3 (1-5) 3 (1-5) 2 (1-3) 18 (14-23) 3 (2-6) 10 (7-14) 3 (1-5) 

Terazosin/ 

finasteride 9 (6-12) 2 (1-4) 10 (7-14) 7 (5-10) 9 (1-13) 5 (3-8) 

Placebo 2 (1-3) 2 (0-5) 1 (1-2) 1 (0-1) 6 (3-10) 1 (1-1) 4 (3-5) 3 (3-4) 

From AUA Guideline with permission. [45] 

A limitation of the AUA analysis is that it did not separate out rates of side effects by dose. While 

all alpha blockers have higher rates of adverse effects at high doses, the increase is particularly 

marked for tamsulosin. In head-to-head trials, tamsulosin 0.2 mg had lower rates of withdrawal 

due to side effects than terazosin at various doses. [55, 56, 58, 60] Across trials of tamsulosin, 

however, the overall rate of withdrawals increased from 6.5% for tamsulosin 0.2 mg to 16.3% for 

tamsulosin 0.8 mg. [11] Similarly, “any adverse event” was reported by 5% of men receiving 

tamsulosin 0.2 mg and by 75% of men receiving tamsulosin 0.8 mg. [11] Rates of dizziness were 

0% for 0.2 mg, 7% for 0.4 mg, and 18% for 0.8 mg. Tamsulosin is not available as 0.2 mg 

capsules in the United States. 

Observational studies of doxazosin, terazosin, and tamsulosin in selected patients indicate that in 

most patients who respond to an alpha blocker and who tolerate it well initially, the drug continues 

to work and to be well-tolerated for many years. [63-68] [69] 

Key Question 3: Are there subgroups of patients based on demographics (age, racial 

groups, and gender), other medications, or co-morbidities for which one treatment is more 

effective or associated with fewer adverse events?

Hypertension. 

The one-year-long Hytrin Community Assessment Study is the largest, best-conducted evaluation 

the safety of an alpha blocker in patients with hypertension and BPH. [21] [70] In the trial, 555 of 

2084 subjects had hypertension, some of whom were treated with other classes of medication. 

Terazosin lowered blood pressure significantly in untreated (by 5.3 mm Hg) and treated patients 

(6.7 mm Hg). It lowered blood pressure by about 12 mm Hg in patients who actually had high 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 19 
blood pressure at baseline (that is, who were not adequately controlled on their other blood 

pressure medications). The incidences of blood pressure-related side effects in patients on 

terazosin were comparable between untreated (13.5%) and treated patients (14.3%), as were 

premature withdrawal rates, with 4.2% of untreated patients and 4.5% of treated patients 

withdrawing due to blood pressure-related side effects. Overall rates of side effects and of 

withdrawal due to side effects were similar in patients with and without hypertension. Terazosin 

may be less effective for BPH symptoms in patients who have uncontrolled hypertension than in 

normotensive or well-controlled patients,[23]but it is not yet clear whether terazosin differs from 

other alpha blockers in this respect. 

Three long-term observational studies have evaluated the use of doxazosin in patients with 

hypertension. In two of these, doxazosin was used primarily to treat BPH but was also used as 

therapy for high blood pressure. [17, 18] In the other, ALLHAT, doxazosin was the primary 

treatment for hypertension in patients who did not have BPH. ALLHAT found that, compared 

with other choices for initial blood pressure control, doxazosin treatment resulted in a higher rate 

of heart failure among patients at risk for that condition. Probably no alpha blocker should be used 

as initial treatment for patients with hypertension who are at risk of developing heart failure. 

We identified one long-term follow up study of tamsulosin that evaluated side effects in patients 

with various comorbidities. [71] The study had 19,365 patients identified through post-marketing 

surveillance. It found that tamsulosin was well tolerated in patients with hypertension and other 

conditions, but the study was confined to patients who had been on the medication for some time, 

so patients who had dropped out early because of side effects would have been missed. 

Tadalafil, Vardenafil and sildenafil. 

All alpha blockers can cause hypotension and priapism, raising concern that alpha blockers might 

cause serious side effects when administered with drugs for erectile dysfunction. Erectile 

dysfunction drugs and prazosin, terazosin, or alfuzosin should be given at least 4 hours apart. In a 

small (22 patient) placebo-controlled study of starting vardenafil in patients already taking 

tamsulosin 0.4 or 0.8 mg, 2 placebo patients and 1 vardenafil 10-mg patient had a drop of 20 mm 

Hg or more in standing DBP; and 1 vardenafil 10-mg patient had a standing SBP drop of 30 mm 

Hg or more; and 3 patients receiving vardenafil 20 mg/tamsulosin 0.4 mg reported dizziness. [16] 

While the authors concluded that combining the two drugs is safe, the sample is too small to be 

conclusive evidence that more serious adverse events would not occur in a larger study. 

Cataracts. 

Recently, the FDA issued a notice that intraoperative Floppy Iris Syndrome (IFIS) has been 

observed during phacoemulsification cataract surgery in some patients currently or recently treated 

with tamsulosin (Flomax®). 

Age. 

Finasteride appears to be equally effective in older and younger patients who have BPH. [15] 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 20 
SUMMARY 

For men who have BPH and have a large prostate or a high PSA at baseline, combination therapy 

can prevent about 2 episodes of clinical progression per 100 men per year over 4 years of 

treatment. There is no additional benefit within the first year of treatment. Most men who take 

combination therapy will have no additional benefit, and about 4 additional patients per 100 will 

become impotent who would not have taking an alpha blocker alone. Combination therapy can 

also be instituted after clinical progression occurs, but this strategy, while used widely, has not 

been studied. 

Expanding access to combination therapy as an initial option would require higher utilization of 

ultrasound and PSA testing in BPH patients to assess the risk of progression. The consequences of 

such a program in a primary care setting has not been studied. 

Alpha blockers have similar effectiveness and safety. For combination therapy, doxazosin is the 

best-studied alpha blocker. 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 21 
REFERENCES 

1. Fitzpatrick, J.M. and R.S. Kirby, Two-drug therapy is best for symptomatic prostate 

enlargement: could a combination of doxazosin and finasteride change clinical practice?

BJU International, 2004. 93(7): p. 914-5. 

2. McDonald, H., et al., An economic evaluation of doxazosin, finasteride and combination 

therapy in the treatment of benign prostatic hyperplasia. Canadian Journal of Urology, 

2004. 11(4): p. 2327-40. 

3. McConnell, J.D., et al., The long-term effect of doxazosin, finasteride, and combination 

therapy on the clinical progression of benign prostatic hyperplasia. New England Journal 

of Medicine, 2003. 349(25): p. 2387-98. 

4. Roehrborn, C.G., Drug treatment for LUTS and BPH: New is not always better. European 

Urology, 2006. 49(1): p. 5-7. 

5. Benign Prostatic Hypertrophy: An update on drug therapy, in Therapeutics Letter. 2006. 

6. Clifford, G.M. and R.D. Farmer, Medical therapy for benign prostatic hyperplasia: a 

review of the literature. European Urology, 2000. 38(1): p. 2-19. 

7. Edwards, J.E. and M.R. A., Finasteride in the treatment of clinical benign prostatic 

hyperplasia: a systematic review of randomised trials. BMC Urol, 2002. 2: p. 1–17. 

8. Andersen, J., et al., Finasteride significantly reduces acute urinary retention and need for 

surgery in patients with symptomatic benign prostatic hyperplasia. Urology, 1997. 49: p. 

839-845. 

9. Milani, S. and B. Djavan, Lower urinary tract symptoms suggestive of benign prostatic 

hyperplasia: latest update on alpha1-adrenoceptor antagonists. BJU International, 2005. 

95 (Suppl4): p. 29-36. 

10. Wilt, T.J., W. Howe, and R. MacDonald, Terazosin for treating symptomatic benign 

prostatic obstruction: a systematic review of efficacy and adverse effects. BJU 

International, 2002. 89(3): p. 214-25. 

11. Wilt, T.J., R. MacDonald, and D. Nelson, Tamsulosin for treating lower urinary tract 

symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and 

adverse effects. Cochrane Database of Systematic Reviews, 2002(4). 

12. MacDonald, R., T.J. Wilt, and R.W. Howe, Doxazosin for treating lower urinary tract 

symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and 

adverse effects. BJU International, 2004. 94(9): p. 1263-70. 

13. Djavan, B. and M. Marberger, A Meta-Analysis on the Efficacy and Tolerability of alpha1-

Adrenoceptor Antagonists in Patients with Lower Urinary Tract Symptoms Suggestive of 

Benign Prostatic Obstruction. Eur Urol 1999. 36: p. 1-13. 

14. Barendrecht, M.M., et al., Treatment of lower urinary tract symptoms suggestive of benign 

prostatic hyperplasia: the cardiovascular system. BJU International, 2005. 95 Suppl 4: p. 

19-28. 

15. Kaplan, S.A., et al., Comparison of the efficacy and safety of finasteride in older versus 

younger men with benign prostatic hyperplasia. Urology, 2001 57: p. 1073-7. 

16. Auerbach, S.M., et al., Simultaneous administration of vardenafil and tamsulosin does not 

induce clinically significant hypotension in patients with benign prostatic hyperplasia.

Urology, 2004. 64(5): p. 998-1003; discussion 1003-4. 

17. Fawzy, A., et al., Long-term (4 year) efficacy and tolerability of doxazosin for the 

treatment of concurrent benign prostatic hyperplasia and hypertension. International 

Journal of Urology, 1999. 6(7): p. 346-54. 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 22 
18. Guthrie, R.M. and R.L. Siegel, A multicenter, community-based study of doxazosin in the 

treatment of concomitant hypertension and symptomatic benign prostatic hyperplasia: the 

Hypertension and BPH Intervention Trial (HABIT). Clinical Therapeutics, 1999. 21(10): p. 

1732-48. 

19. Kirby, R.S., Terazosin in benign prostatic hyperplasia: effects on blood pressure in 

normotensive and hypertensive men. British Journal of Urology, 1998. 82(3): p. 373-9. 

20. Lowe, F.C., Coadministration of tamsulosin and three antihypertensive agents in patients 

with benign prostatic hyperplasia: pharmacodynamic effect. Clinical Therapeutics, 1997. 

19(4): p. 730-42. 

21. Lowe, F.C., P.J. Olson, and R.J. Padley, Effects of terazosin therapy on blood pressure in 

men with benign prostatic hyperplasia concurrently treated with other antihypertensive 

medications. Urology, 1999. 54(1): p. 81-5. 

22. Muzzonigro, G., Tamsulosin in the treatment of LUTS/BPH: an Italian multicentre trial.

Archivio Italiano di Urologia, Andrologia, 2005. 77(1): p. 13-7. 

23. Sugaya, K., et al., Influence of hypertension on lower urinary tract symptoms in benign 

prostatic hyperplasia. International Journal of Urology, 2003. 10(11): p. 569-74; discussion 

575. 

24. Suzuki, H., Treatment of benign prostatic hyperplasia and hypertension in elderly 

hypertensive patients. British Journal of Urology, 1998. 81 Suppl 1: p. 51-5. 

25. Lepor, H., et al., The impact of medical therapy on bother due to symptoms, quality of life 

and global outcome, and factors predicting response. Veterans Affairs Cooperative Studies 

Benign Prostatic Hyperplasia Study Group. Journal of Urology, 1998. 160(4): p. 1358-67. 

26. Becopoulos, T., D. Mitropoulos, and I. Christofis, Influence of prostate size on terazosin 

efficacy. International Journal of Urology, 1997. 4(4): p. 358-61. 

27. Boyle, P., et al., Meta-analysis of randomized trials of terazosin in the treatment of benign 

prostatic hyperplasia. Urology, 2001. 58(5): p. 717-22. 

28. Boyle, P., A.L. Gould, and C. Roehrborn, Prostate volume predicts outcome of treatment of 

benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials.

Urology, 1996. 48: p. 398-405. 

29. McConnell, J.D., et al., The effect of finasteride on the risk of acute urinary retention and 

the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride 

Long-Term Efficacy and Safety Study Group. N Engl J Med. , 1998 338: p. 557-63. 

30. Wasson, J.H., D. Reda, J, and R.C. Bruskewitz, A comparison of transurethal surgery with 

watchful waiting for moderate symptoms of benign prostatic hyperplasia. N Engl J Med., 

1995. 332: p. 75-79. 

31. Kaplan, S.A., et al., Combination therapy with doxazosin and finasteride for benign 

prostatic hyperplasia in patients with lower urinary tract symptoms and a baseline total 

prostatic volume of 25 Ml or greater. Journal of Urology, 2006. 175: p. 217-21. 

32. Lepor, H., et al., The efficacy of terazosin, finasteride, or both in benign prostatic 

hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study 

Group. New England Journal of Medicine, 1996. 335(8): p. 533-9. 

33. Kirby, R.S., et al., Efficacy and tolerability of doxazosin and finasteride, alone or in 

combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective 

European Doxazosin and Combination Therapy (PREDICT) trial.[see comment]. Urology, 

2003. 61(1): p. 119-26. 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 23 
34. Roberts, R.O., et al., Limitations of using outcomes in the placebo arm of a clinical trial of 

benign prostatic hyperplasia to quantify those in the community. Mayo Clinic Proceedings, 

2005. 80(6): p. 759-64. 

35. Meigs, J.B., et al., Incidence rates and risk factors for acute urinary retention: the Health 

Professionals Followup Study. Journal of Urology, 1999. 162: p. 376-82. 

36. Roehrborn, C., et al., Urinary retention in patients with BPH treated with finasteride or 

placebo over 4 years. The PLESS study group. European Urology, 2000. 37(5): p. 528-36. 

37. Roehrborn, C.G., Reporting of acute urinary retention in BPH treatment trials: importance 

of patient follow-up after discontinuation and case definitions. Urology, 2002. 59(6): p. 

811-5. 

38. Jacobsen, S.J., C.J. Girman, and M.M. Lieber, Natural history of benign prostatic 

hyperplasia. Urology, 2001. 58(6 Suppl 1): p. 5-16; discussion 16. 

39. Hong, S.J., et al., Identification of baseline clinical factors which predict medical treatment 

failure of benign prostatic hyperplasia: an observational cohort study. European Urology, 

2003. 44(1): p. 94-9; discussion 99-100. 

40. Roehrborn, C.G., et al., Storage (irritative) and voiding (obstructive) symptoms as 

predictors of benign prostatic hyperplasia progression and related outcomes. European 

Urology, 2002. 42: p. 1-6. 

41. Roehrborn, C.G., et al., Clinical predictors of spontaneous acute urinary retention in men 

with LUTS and clinical BPH: A comprehensive analysis of the pooled placebo groups of 

several large clinical trials. Urology, 2001. 58: p. 210-6. 

42. Crawford, E.D., et al., Baseline factors as predictors of clinical progression of benign 

prostatic hyperplasia in men treated with placebo. Journal of Urology, 2006. 175(4): p. 

1422-6; discussion 1426-7. 

43. Roehrborn, C., et al., Serum prostate-specific antigen concentrations are a powerful 

predictor of acute urinary retention and need for surgery in men with clinical benign 

prostatic hypertrophy. Urology, 1999. 53: p. 473-80. 

44. Marberger, M., et al., Prostate volume and serum prostate-specific antigen as predictors of 

acute urinary retention. European Urology, 2000. 38: p. 563-8. 

45. Roehrborn, C., et al., AUA Guideline on the management of benign prostatic hyperplasia. 

American Urological Association Education and Research, Inc., (2003). Updated 2006 

<http://auanet.org/guidelines/bph.cfm>. (10/28/04). 2006. 

46. Bandolier, Long-term BPH treatment. 2004. 

47. Andriole, G., et al., Chemoprevention of prostate cancer in men at high risk: rationale and 

design of the reduction by dutasteride of prostate cancer events (REDUCE) trial. J Urol:, 

2004. 172: p. 1314. 

48. Thompson, I., et al., The influence of finasteride on the development of prostate cancer.

New England Journal of Medicine, 2003. 349: p. 215-224. 

49. Etzioni, R.D., et al., Long-term effects of finasteride on prostate specific antigen levels: 

results from the prostate cancer prevention trial. J Urol:, 2005. 174(3): p. 877-81. . 

50. Walsh, P.C., Re: Long-term effects of finasteride on prostate specific antigen levels: results 

from the Prostate Cancer Prevention Trial.[comment]. Journal of Urology, 2006. 176(1): 

p. 409-10; author reply 410. 

51. Andriole, G., et al., The effects of 5alpha-reductase inhibitors on the natural history, 

detection and grading of prostate cancer: current state of knowledge. Journal of Urology, 

2005. 174(6): p. 2098-104. 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 24 
52. Roehrborn, C.G., et al., Serial prostate-specific antigen measurements in men with 

clinically benign prostatic hyperplasia during a 12-month placebo-controlled study with 

terazosin. HYCAT Investigator Group. Hytrin Community Assessment Trial. Urology, 

1997. 50(4): p. 556-61. 

53. Andriole, G.L., et al., Treatment with finasteride preserves usefulness of prostate-specific 

antigen in the detection of prostate cancer: results of a randomized, double-blind, placebo 

controlled clinical trial. PLESS Study Group. Proscar Long-Term Efficacy and Safety 

Study. Urology, 1998. 52: p. 195. 

54. Marks, L.S., et al., The Interpretation of Serum Prostate Specific Antigen in Men Receiving 

5[alpha]-Reductase Inhibitors: A Review and Clinical Recommendations. The Journal of 

Urology, 2006. 176(3): p. 868-874. 

55. Lee, E. and C. Lee, Clinical comparison of selective and non-selective alpha 1Aadrenoreceptor antagonists in benign prostatic hyperplasia: studies on tamsulosin in a 

fixed dose and terazosin in increasing doses. British Journal of Urology, 1997. 80(4): p. 

606-11. 

56. Na, Y.J., Y.L. Guo, and F.L. Gu, Clinical comparison of selective and non-selective alpha 

1A-adrenoceptor antagonists for bladder outlet obstruction associated with benign 

prostatic hyperplasia: studies on tamsulosin and terazosin in Chinese patients. The 

Chinese Tamsulosin Study Group. Journal of Medicine, 1998. 29(5-6): p. 289-304. 

57. Narayan, P., M.P. O'Leary, and G. Davidai, Early efficacy of tamsulosin versus terazosin in 

the treatment of men with benign prostatic hyperplasia: a randomized, open-label trial. . J 

Appl Res, 2005. 5: p. 237-245. 

58. Okada, H., et al., A comparative study of terazosin and tamsulosin for symptomatic benign 

prostatic hyperplasia in Japanese patients. BJU International, 2000. 85(6): p. 676-81. 

59. Samli, M.M. and C. Dincel, Terazosin and doxazosin in the treatment of BPH: results of a 

randomized study with crossover in non-responders. Urologia Internationalis, 2004. 73(2): 

p. 125-9. 

60. Tsujii, T., Comparison of prazosin, terazosin and tamsulosin in the treatment of 

symptomatic benign prostatic hyperplasia: a short-term open, randomized multicenter 

study. BPH Medical Therapy Study Group. Benign prostatic hyperplasia. International 

Journal of Urology, 2000. 7(6): p. 199-205. 

61. Flannery, M.T., et al., Efficacy and safety of tamsulosin for benign prostatic hyperplasia: 

clinical experience in the primary care setting. Current Medical Research & Opinion, 

2006. 22(4): p. 721-30. 

62. Chung, B.H., S.J. Hong, and M.S. Lee, Doxazosin for benign prostatic hyperplasia: an 

open-label, baseline-controlled study in Korean general practice. International Journal of 

Urology, 2005. 12(2): p. 159-65. 

63. Narayan, P., C.P. Evans, and T. Moon, Long-term safety and efficacy of tamsulosin for the 

treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia.

Journal of Urology, 2003. 170(2 Pt 1): p. 498-502. 

64. Narayan, P. and H. Lepor, Long-term, open-label, phase III multicenter study of tamsulosin 

in benign prostatic hyperplasia. Urology, 2001. 57(3): p. 466-70. 

65. Dutkiewicz, S., Long-term treatment with doxazosin in men with benign prostatic 

hyperplasia: 10-year follow-up. International Urology & Nephrology, 2004. 36(2): p. 169-

73. 

66. Ichioka, K., et al., Long-term treatment outcome of tamsulosin for benign prostatic 

hyperplasia. International Journal of Urology, 2004. 11(10): p. 870-5. 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 25 
67. Palacio, A., et al., Long-term study to assess the efficacy of tamsulosin in the control of 

symptoms and complications developed in patients with symptomatic benign prostatic 

hyperplasia (OMNICONTROL study): first-year follow-up report. Archivos Espanoles de 

Urologia, 2004. 57(4): p. 451-60. 

68. Schulman, C.C., et al., Tamsulosin: 3-year long-term efficacy and safety in patients with 

lower urinary tract symptoms suggestive of benign prostatic obstruction: analysis of a 

European, multinational, multicenter, open-label study. European Tamsulosin Study 

Group. European Urology, 1999. 36(6): p. 609-20. 

69. Lepor, H., Long-term evaluation of tamsulosin in benign prostatic hyperplasia: placebocontrolled, double-blind extension of phase III trial. Tamsulosin Investigator Group.

Urology, 1998. 51(6): p. 901-6. 

70. Roehrborn, C.G., et al., The Hytrin Community Assessment Trial study: a one-year study of 

terazosin versus placebo in the treatment of men with symptomatic benign prostatic 

hyperplasia. HYCAT Investigator Group. Urology, 1996. 47(2): p. 159-68. 

71. Michel, M.C., et al., Tamsulosin treatment of 19,365 patients with lower urinary tract 

symptoms: does co-morbidity alter tolerability? J Urol:, 1998. 160: p. 784-91. 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 26 
APPENDIX A: Methods for Evidence Synthesis 

Literature Search 

To identify relevant citations, we searched Ovid MEDLINE (1966 to July 2006.) For Key 

Question #1 we used the following search strategy: 

1. exp Adrenergic alpha-Antagonists/ad, ae, cl, tu, ct, du [Administration & Dosage, Adverse 

Effects, Classification, Therapeutic Use, Contraindications, Diagnostic Use] 

2. exp Prostatic Hyperplasia/mo, cl, co, di, pc, dh, dt, ep, su, th, ge [Mortality, Classification, 

Complications, Diagnosis, Prevention & Control, Diet Therapy, Drug Therapy, 

Epidemiology, Surgery, Therapy, Genetics] 

3. 1 and 2 

4. limit 3 (humans and male and "all adult (19 plus years)" and (clinical trial, phase i or 

clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or clinical trial or 

controlled clinical trial or evaluation studies or multicenter study or randomized controlled 

trial or technical report)) 

5. explode Finasteride 

6. 3 and 5 

For Key Questions #2 and #3, we used steps 1 to 4 of the same search string. We searched the 

Cochrane Database of Systematic Reviews (2nd quarter, 2006) but did not identify any additional 

systematic reviews. 

All citations were imported into an electronic database (EndNote 9.0).

Study Selection 

One reviewer assessed abstracts of citations identified from literature searches for inclusion, using 

the criteria described above. Full-text articles of potentially relevant abstracts were retrieved and a 

second review for inclusion was conducted by reapplying the inclusion criteria. 

Data Abstraction 

The following data were abstracted from included trials: study design, setting, population 

characteristics (including sex, age, ethnicity, diagnosis), eligibility and exclusion criteria, 

interventions (dose and duration), comparisons, numbers screened, eligible, enrolled, and lost to 

follow-up, method of outcome ascertainment, and results for each outcome. We recorded 

intention-to-treat results when reported. In cases where only per-protocol results were reported, 

we calculated intention-to-treat results if the data for these calculations were available. In trials 

with crossover, outcomes for the first intervention were recorded if available. This was because of 

the potential for differential withdrawal prior to crossover biasing subsequent results and the 

possibility of either a “carryover effect” (from the first treatment) in studies without a washout 

period, or “rebound” effect from withdrawal of the first intervention. 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 27 
Data abstracted from observational studies included design, eligibility criteria duration, 

interventions, concomitant medication, assessment techniques, age, gender, ethnicity, number of 

patients screened, eligible, enrolled, withdrawn, or lost to follow-up, number analyzed, and results. 

Quality Assessment 

We assessed the internal validity (quality) of trials based on the predefined criteria listed in 

Appendix B. These criteria are based on the U.S. Preventive Services Task Force and the National 

Health Service Centre for Reviews and Dissemination (U.K.) criteria.22, 23 We rated the internal 

validity of each trial based on the methods used for randomization, allocation concealment, and 

blinding; the similarity of compared groups at baseline; maintenance of comparable groups; 

adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to followup; and the use of intention-to-treat analysis. Trials that had a fatal flaw in one or more categories 

were rated “poor-quality”; trials that met all criteria were rated “good-quality”; the remainder were 

rated “fair-quality.” A fatal flaw occurs when there is evidence of bias or confounding in the trial, 

for example when randomization and concealment of allocation of random order are not reported 

and baseline characteristics differ significantly between the groups. In this case, randomization 

has apparently failed and for one reason or another bias has been introduced. 

As the fair-quality category is broad, studies with this rating vary in their strengths and 

weaknesses: the results of some fair-quality studies are likely to be valid, while others are only 

probably valid. Those studies considered only probably valid are indicated as such using a “fairpoor” rating. A poor-quality trial is not valid—the results are at least as likely to reflect flaws in 

the study design as the true difference between the compared drugs. External validity of trials was 

assessed based on whether the publication adequately described the study population, how similar 

patients were to the target population in whom the intervention will be applied, and whether the 

treatment received by the control group was reasonably representative of standard practice. We 

also recorded the role of the funding source. 

Appendix B also shows the criteria we used to rate observational studies. These criteria reflect 

aspects of the study design that are particularly important for assessing adverse event rates. We 

rated observational studies as good-quality for adverse event assessment if they adequately met six 

or more of the seven predefined criteria, fair-quality if they met three to five criteria and poorquality if they met two or fewer criteria. 

Included systematic reviews were also rated for quality based on pre-defined criteria (see 

Appendix B), based on a clear statement of the questions(s), inclusion criteria, adequacy of search 

strategy, validity assessment and adequacy of detail provided for included studies, and 

appropriateness of the methods of synthesis. 

Overall quality ratings for the individual study were based on internal and external validity ratings 

for that trial. A particular randomized trial might receive two different ratings: one for 

effectiveness and another for adverse events. The overall strength of evidence for a particular key 

question reflects the quality, consistency, and power of the set of studies relevant to the question. 

HSR&D Evidence Synthesis Pilot Program – 

Benign Prostatic Hyperplasia 28 
HSR&D Evidence Synthesis Pilot

Benign Prostatic Hyperplasia

 Program – 

 29 

Evidence Synthesis 

An evidence report pays particular attention to the generalizability of efficacy studies performed in 

controlled or academic settings. Efficacy studies provide the best information about how a drug 

performs in a controlled setting that allow for better control over potential confounding factors and 

bias. However, efficacy studies have some limitations, as the results are not always applicable to 

many, or to most, patients seen in everyday practice. This is because most efficacy studies use 

strict eligibility criteria which may exclude patients based on their age, sex, medication 

compliance, or severity of illness. For many drug classes severely impaired patients are often 

excluded from trials. Often, efficacy studies also exclude patients who have “comorbid” diseases, 

meaning diseases other than the one under study. Efficacy studies may also use dosing regimens 

and follow up protocols that may be impractical in other practice settings. They often restrict 

options, such as combining therapies or switching drugs, that are of value in actual practice. They 

often examine the short-term effects of drugs that, in practice, are used for much longer periods of 

time. Finally, they tend to use objective measures of effect that do not capture all of the benefits 

and harms of a drug or do not reflect the outcomes that are most important to patients and their 

families. 

Data Presentation 

We constructed evidence tables showing the study characteristics, quality ratings, and results for 

all included studies. Studies that evaluated one macrolide against another provided direct evidence 

of comparative benefits and harms. Outcomes of changes in symptom measured using scales or 

tools with good validity and reliability are preferred over scales or tools with low 

validity/reliability or no reports of validity/reliability testing. Where possible, head-to-head data 

are the primary focus of the synthesis. No meta-analyses were conducted in this review due to 

heterogeneity in treatment regimens, use of concomitant medications, outcome reporting and 

patient populations. 

In theory, trials that compare these drugs to other interventions or placebos can also provide 

evidence about effectiveness. This is known as an indirect comparison and can be difficult to 

interpret for a number of reasons, primarily issues of heterogeneity between trial populations, 

interventions, and assessment of outcomes. Indirect data are used to support direct comparisons, 

where they exist, and are also used as the primary comparison where no direct comparisons exist. 

Such indirect comparisons should be interpreted with caution. 
Appendix B: Trials comparing alpha antagonists 

Clinical Trial Inclusion Criteria/Pt. 

Population 

Intervention Results Safety/Com

Cam et al 2003 Prospective clinical study 178 patients doxazosin 4 mg 24 months no financial disclosure Turkish 

Men > 50 years old IPSS 18-35 Attendance to a urology department due to: -LUTS -age > 50 -unremarkable medical hx in terms of LUTS -no definitive need for surgery 

Doxazosin 1 mg titrated to 4 mg 

Reduction in symptom scores from 24 (SD 

+7.4) before medication to 17 (SD 

+8.4) after 

3 months of treatment 

In the patients reporting doxazosin as ineffective, no change, or effective, 93%, 59% and 15% respectively underwent surgery. Of the 178 patients enrolled 47% underwent surgery. 

Evaluation determined regarding ttreatment i

Ichioka et al 2004 Prospective 123 patients 43 months Tamsulosin (n = 123) No financial disclosure Japanese 

Men 53-88 years old Dx BPH Treated with tamsulosin >12 months 

Tamsulosin 0.2 mg titrated up to 0.4 mg as needed to relieve sx. 

Predictive for treatment failure: baseline IPSS 

> 15, months 0-12 lowest IPSS 

> 13, lowest 

QoL score of 

> 3 and lowest BPH impact 

score of 

> 4. 

Roehrborn et al 1996 Prospective, placebo controlled, randomized, double-blinded 2084 patients 1 year (Terazosin n = 1053 Placebo n = 1031) Funding: Abbot Labratorie American 

Men 

> 55 years old 

Moderate-severe BPH AUA-Symptom Score (SS) 

>

13 

AUA-Bother Score (BS) 

> 8 

PUF 

< 15 mL/sec. 

Voided volume = 150 mL 

Terazosin 1 mg x 3 days, 2 mg x 25 days, ↑

5 mg or 10 mg as tolerated 

Placebo 

Statistically superior improvements were observed in regard to AUA-BS, BPH impact index and the QoL score in terazosin-treated patients. PUF improved Treatment failure was higher in placebo 

Withdraw in terazosin 

HSR&D Evidence Synthesis Pilot Program – Benign Prostatic Hyperplasia 30 
Okada et al 

2000 Single-blind, randomized 61 patients 4 weeks Japanese 

Symptomatic BPH Terazosin 1-2 mg 

Tamsulosin 0.2 mg 

Both meds significantly improved the total IPSS, irritative and obstructive symptom score, and quality of life. There was no significant difference for these variables between groups. There was no significant improvements between groups. 

Incidence odifferent beNeither mediastolic bl

Lee et al 1997 Single-blind 98 patients randomized 8 weeks Korean 

Moderate to severe BPH Tamsulosin 0.2 mg 

Terazosin 1 mg ↑ 5 mg 

Both medications similarly improved IPSS and Increased Qmax 

Terazosin: -systolic ansignificant-dizziness, 

Tsuiji et al 2000 Open-label 105 patietns Randomized (Prazosin n= 32, Terazosin n=35, Tamsulosin n=38) 4 weeks 

LUTS associated with BPH Prazosin 1 mg ↑ 2 mg 

Terazosin 1 mg ↑ 2 mg Tamsulosin 0.1 mg ↑ 0.2 mg 

All significantly reduced subjective symptom scores from baseline. Terazosin significantly better improvement than Tamsulosin in 4 of 9 symptom scores (urgency, sense of residual urine, prolonged micturition, intermittency) Significant increase in flow with prazosin 

ADR whicPrazosin = Terazosin = Tamsulosin 

Na et al 1998 Single-blinded, randomized 212 Patients Randomized 4 weeks Chinese 

BPH Terazosin 2 mg 

Tamsulosin 0.2 mg 

Tamsulosin and terazosin: significant improvement in IPSS, Qmax and average urinary flow rate from baseline 

Dizziness, more frequ

HSR&D Evidence Synthesis Pilot Program – Benign Prostatic Hyperplasia 31