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 
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 
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