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Therapeutics Letter, issue 58, January - March 2006

Benign Prostatic Hypertrophy

An update on drug therapy


Benign prostatic hypertrophy (BPH) is relatively common and potentially bothersome to aging men. See Therapeutics Letter # 19 (May/June 1997) for background information.1 This Letter updates the evidence of benefit and harm from alpha blockers and 5-α-reductase inhibitors.

The goals of drug therapy are symptom relief and prevention of complications. Symptoms are classified as irritative (frequency, nocturia, burning, urgency, or urge incontinence) or obstructive (hesitancy, weak stream, dribbling, incomplete voiding, or retention).

Many trials use the 35-point American Urological Association (AUA) symptom scale.1 When AUA scores were compared with patient perceptions, men who felt 'slightly improved' averaged a 3-pt reduction; those 'not improved' averaged a 0.7-pt reduction.8 Over 4 years, mean AUA scores fell by 5 points on placebo.5

Complications of BPH include infection, acute urinary retention (AUR) requiring catheterization, and urinary obstruction requiring surgery (partial or complete prostatectomy).

Alpha blockers

Five alpha blockers are available in Canada: alfuzosin, doxazosin, prazosin, tamsulosin, and terazosin.

Alpha blockers provide modest symptomatic benefit. Compared with placebo, on average terazosin reduced AUA score by 3 points,4 tamsulosin by 3 points,5 doxazosin by 3 points at 1 year6 and 2 points at 4 years,2 alfuzosin by 2 points short-term7 and 1 point at 2 years.3 Comparable data are not available for prazosin. Alpha blockers do not prevent BPH complications. Doxazosin was tested over 4 years vs. placebo (n=1493).2 Incidence of AUR (doxazosin 1%, placebo 2%) and surgery (doxazosin 3%, placebo 5%) did not differ. A 2-year trial of alfuzosin vs. placebo (n=1506) also found no difference in AUR or surgery.3

Only one trial longer than a year reports on serious adverse events (SAEs): alfuzosin 12%, placebo 11%.3 In the ALLHAT hypertension trial (no placebo arm), doxazosin increased congestive heart failure, angina and stroke vs. chlorthalidone. (see Therapeutics Letter 36)

The most frequent adverse effects of alpha blockers are dizziness, asthenia and postural hypotension. Tamsulosin's efficacy increases slightly with higher doses, but adverse effects are dose-related: dizziness 17% at 0.8mg, 9% at 0.4mg and 3% at 0.2mg.5 Average absolute risk increases for alpha blockers versus placebo are: dizziness 3-8%, postural hypotension 3-5%, and asthenia 5-6%, number needed to harm (NNH) 13-33.4, 5, 7, 9

No consistent evidence exists for a therapeutic advantage of one alpha blocker over another.

5-α-reductase inhibitors

Two 5-a-reductase inhibitors are available in Canada: finasteride and dutasteride.

Finasteride

Finasteride did not significantly reduce symptom scores vs. placebo in one 4-year trial.2 In a second 4-year trial, scores fell by a mean of 1.6 points.11

We meta-analyzed 16 randomized controlled trials (RCTs) (n=17,456; max 4 years) with at least one clinically important health outcome (Table 1).2, 6, 10-23 Since finasteride reduces AUR and surgery it is surprising that total SAEs are not also reduced. Published reports provide insufficient detail to assess rates of other SAEs.

During a 4-year trial, 4/1554 (0.3%) men on finasteride developed breast cancer (~ 200 times expected rate).2, 24 In a 7-year prostate cancer prevention trial (n=18,882) fewer men on finasteride vs. placebo developed tumours, 18.4% vs. 24.4%, but more men on finasteride had high-grade tumours with a worse prognosis: 6.4% vs. 5.1%. Mortality did not differ.25

Table 1: Benefits and Harms of Finasteride vs Placebo

Outcome N* Finasteride Placebo RR
(95% CI)
ARR/ARI NNT/NNH
Mortality 2,358 1.2% 0.7% 1.7
(0.7-4.1)
- -
Total SAEs 9,180 11.0% 11.4% 0.9
(0.7-1.1)
- -
Prostate Surgery 15,398 2.1% 4.8% 0.6
(0.4-0.8)
2.7% 37
Acute Urinary Retention 14,329 1.1% 3.1% 0.4
(0.3-0.6)
2.0% 50
Ejaculation Abnormality 14,396 2.7% 0.7% 3.6
(2.6-5.1)
2.0% 50
Erectile Dysfunction 15,839 8.1% 4.8% 1.8
(1.6-2.0)
3.3% 30
Decreased Libido 14,626 5.3% 3.4% 1.7
(1.4-2.0)
1.9% 53

*N = number of patients in trials with this outcome
RR = relative risk
CI = confidence interval
ARR = absolute risk reduction
ARI = absolute risk increase
NNT = number needed to treat to prevent one event
NNH = number needed to treat to cause one harmful event

Finasteride versus alpha blockers

Five RCTs (0.5 - 4 yrs) compared finasteride with an alpha blocker.2, 6, 10, 26, 27 Mortality,6, 10 SAEs 26, 27 and withdrawals due to adverse effects 6, 10, 26, 27 did not differ. Finasteride increased sexual dysfunction; alpha blockers increased dizziness, postural hypotension and asthenia. Surgery rates did not differ: finasteride 1.6%, doxazosin or terazosin 2.2%.2, 6, 10 In 4 studies alpha blockers reduced AUA symptom scores by 1-3 points more than finasteride.2, 6, 10, 27 Alfuzosin affected scores similarly to finasteride.26

Adding finasteride to an alpha blocker

Adding finasteride did not reduce mean symptom score as compared with an alpha-blocker alone in 0.5 - 1 year trials: difference = 0.3 points.6, 10, 26 In one 4-year RCT the mean symptom score fell by 0.8 points.2

Adding an alpha blocker to finasteride

Combination therapy reduced a combined outcome (“clinical progression”) largely driven by symptom scores vs. finasteride alone,2 but did not reduce AUR (0.4% vs. 0.7%)2, 6, 26 or surgery (1.0% vs. 1.6%).2, 6, 10

Dutasteride

Dutasteride has been tested less extensively. In 3 double-blind trials (combined n=4325), dutasteride reduced AUA scores by 1.3 points vs. placebo at 1 year. Dutasteride reduced AUR (1.8% vs. 4.2%) and need for surgery (2.2% vs. 4.1%), but increased impotence (7.3% vs. 4.0%), ejaculation disorder, gynecomastia and lowered libido.28 Mortality and SAE rates did not differ.29 A 6-month trial (n=399)30 and an unpublished 1-year trial (n=1630) vs. finasteride found no difference in efficacy or adverse events. Total SAEs and mortality were not reported.31-33

Table 2: Usual dose range, half-life and cost of drugs for BPH

Drug Brand name Dose range Half-life Daily cost
alfuzosin Xatral® 10 mg/d 5-10 hrs $1.14^
doxazosin Cardura®, generic 1-8 mg/d 22 hrs $0.35 - $1.09*
prazosin generic 1-5 mg BID 2-3 hrs $0.32 - $0.62*
tamsulosin Flomax® 0.4-0.8 mg/d 5-7 hrs $1.04 - $2.08*
terazosin Hytrin®, generic 1-10 mg/d 12 hrs $0.36 - $0.90*
dutasteride Avodart® 0.5 mg/d 5 weeks $1.96^
finasteride Proscar® 5 mg/d 6 hrs $1.78*

* = Average daily cost for the lowest priced formulation, calculated using 2005 BC PharmaCare data.
^ = Average price at local pharmacy in Vancouver, BC.

Conclusions

Clinical implications

Men with bothersome symptoms who wish a trial of alpha blocker therapy should set their own treatment goals and weigh the benefits (e.g. symptom relief) against side effects (e.g. postural hypotension, asthenia). Since all alpha blockers have relatively short half-lives (see Table 2), maximum concentrations and effect will occur within 4 days. A reasonable approach is to start with a low dose and assess for symptoms during a series of 1-week therapeutic trials at several doses. Neither finasteride nor dutasteride provide symptomatic benefit for most men. Patients considering long-term therapy to prevent complications should be informed of the magnitude of potential benefits and harms, as outlined above.


Addendum: saw palmetto extract
Letter #19 discussed saw palmetto (S.repens), a commonly used herbal treatment. A Cochrane review suggested a short term modest reduction in symptoms with saw palmetto.34 A new 1-year RCT comparing standardized doses (160 mg BID) with placebo showed no differences in symptom scores, urinary flow rates, quality of life measures, adverse effects or SAEs.35


The draft of this Therapeutics Letter was submitted for review to 40 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.

References

1.      Medical Management of Benign Prostatic Hyperplasia. Therapeutics Letter # 19 1997.

2.      McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349:2387-2398.

3.      Roehrborn CG; ALTESS Study Group. Alfuzosin 10 mg once daily prevents overall clinical progression of benign prostatic hyperplasia but not acute urinary retention: results of a 2-year placebo-controlled study. BJU Int 2006;97:734-741.

4.      Wilt TJ, Howe RW, Rutks IR, MacDonald R. Terazosin for benign prostatic hyperplasia. The Cochrane Database of Systematic Reviews 2000, Issue 1. Art. No.: CD003851. DOI: 10.1002/14651858.CD003851.

5.      Wilt TJ, MacDonald R, Rutks I. Tamsulosin for benign prostatic hyperplasia. The Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD002081. DOI: 10.1002/14651858.CD002081.

6.      Kirby RS, Roehrborn C, Boyle P, 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. Urology 2003;61:119-126.

7.      MacDonald R, Wilt TJ. Alfuzosin for treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia: a systematic review of efficacy and adverse effects. Urology 2005; 66:780-788.

8.      Barry MJ, Williford WO, Chang Y et al. Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association symptom index and the benign prostatic hyperplasia impact index is perceptible to patients? J Urol 1995;154:1770-1774.

9.      MacDonald R, Wilt TJ, Howe RW. Doxazosin for treating lower urinary tract symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and adverse effects. BJU Int 2004; 94:1263-1270.

10.  Lepor H; Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia.[see comment]. N Engl J Med 1996;335:533-539.

11.  McConnell JD; Finasteride Long-Term Efficacy and Safety Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia.[see comment]. N Engl J Med 1998;338:557-63.

12.  Gormley GJ; The Finasteride Study Group. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992;327:1185-91.

13.  Marberger MJ; PROWESS Study Group. Long-term effects of finasteride in patients with benign prostatic hyperplasia: a double-blind, placebo-controlled, multi-centre study. Urology 1998;51:677-86.

14.  Andersen JT; The Scandinavian BPH Study Group. Can finasteride reverse the process of benign prostatic hyperplasia? A two-year placebo-controlled study. Urology 1995;46:631-7.

15.  Nickel JC, Fradet Y, Boake RC, et al. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomized controlled trial (the PROSPECT Study). CMAJ 1996; 155:1251-59.

16.  Tenover JL ; Primary Care Investigator Study Group. Efficacy and tolerability of finasteride in benign prostatic hyperplasia: a primary care study.  Clin Ther 1997;19:243-58.

17.  Byrnes CA; CUSP Investigators. Community based study of Proscar.  Efficacy, tolerability and effect on health-related quality of life of finasteride versus placebo in men with symptomatic benign prostatic hyperplasia: a community based study. Clin Ther 1995;17:956-69.

18.  Beisland HO, Binkowitz B, Brekkan E et al.  Scandinavian clinical study of finasteride in the treatment of benign prostatic hyperplasia. Eur Urol 1992;22:271-77.

19.  The Finasteride Study Group. Finasteride (MK-906) in the treatment of benign prostatic hyperplasia. Prostate 1993;22:291-99.

20.  Stoner E; The Finasteride Study Group. The clinical effects of a 5 alpha- reductase inhibitor, finasteride, on benign prostatic hyperplasia. J Urol 1992;147:1298-1302.

21.  Lukkarinen O, Lehtonen T, Talja M, et al. Finasteride following baloon dilatation of the prostate. A double-blind, placebo-controlled, multicentre study.  Ann Chir Gynaecol 1999;88:299-303.

22.  Kirby RS, Bryan J, Eardley I, et al. Finasteride in the treatment of benign prostatic hyperplasia. A urodynamic evaluation. Br J Urol 1992;70:65-72.

23.  Yu HJ, Chiu TY, Lai MK. Therapeutic effects of finasteride in benign prostatic hyperplasia: a randomized double-blind controlled trial. J Formos Med Assoc 1995;94:37-41.

24.  Lee SC, Ellis RJ. Male breast cancer during finasteride therapy. J Natl Cancer Inst 2004;96:338-339.

25.  Thompson IM, Goodman PJ, Tangen CM et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215-24.

26.  Debruyne FM ; European ALFIN Study Group. Sustained-release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. Eur Urol 1998;34:169-175.

27.  Rigatti P, Bruasi M, Scarpa RM et al. A comparison of the efficacy and tolerability of tamsulosin and finasteride in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Prostate Cancer and Prostatic Dis 2003;6:315-323.

28.  Roehrborn CG; ARIA3001 ARIA3002 and ARIA3003 Study Investigators.  Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia.  Urology 2002; 60: 434-441.

29.  Benson GS, Hirsch MS. Center for Drug Evaluation and Research, US FDA. Medical Review. NDA 21-319. Oct 11, 2001. Available at: http://www.fda.gov/cder/foi/nda/2001/21319_Duagen_medr_P1.pdf. Accessed March 27, 2006.

30.  Clark RV, Hermann DJ, Cunningham GR et al. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5α-reductase inhibitor. J Clin Endocrinol Metab 2004; 89: 2179-2184.

31.  GlaxoSmithKline. A Multicentre, Randomised Double-Blind, Double-Dummy, Parallel-Group Study to Compare the Efficacy of Dutasteride/GI198745 0.5mg od Versus Finasteride 5 mg od for 12 Months in the Treatment of Subjects with Benign Prostatic Hyperplasia (BPH), Followed by an Optional 24 Months Open Label Phase. Study No: ARI40001 – Year 1. Available at: http://ctr.glaxowellcome.co.uk/summary/dutasteride/studylist.asp. Accessed March 27, 2006.

32.  Gilling PJ, Jacobi G, Tammela TL, Van Erps P. Efficacy of dutasteride and finasteride ofr the treatment of benign prostate hyperplasia: results of the 1-year enlarged prostate international comparator study (EPICS). BJU International 2005. [abstract] Annual Scientific Meeting of the Urological Society of Australasia 2/13/2005. Melbourne, Australia.

33.  Andriole GL, Kirby R. Safety and tolerability of the dual 5α-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia. European Urology 2003; 44:82-88.

34.  Wilt T, Ishani A, MacDonald R. Serenoa repens for benign prostatic hyperplasia. The Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD001423. DOI: 10.1002/14651858.CD001423.

35.  Bent S, Kane C, Shinohara K et al. Saw palmetto for benign prostatic hyperplasia. N Engl J Med 2006;354:557-566.


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