Effect of dutasteride on clinical progression of benign prostatic hyperplasia in asymptomatic men with enlarged prostate: a post hoc analysis of the REDUCE study

Dear Sirs

We have been interested in the points raised by post hoc analysis of data from the REDUCE study involving a 5-Alpha Reductase Inhibitor and Prostate Cancer development (1).

The progression of BPH (Benign Prostatic Hyperplasia) is an important consideration with men presenting with Lower Urinary Tract Symptoms (LUTS). Quantifying progression is difficult and relies on various end points and disease development. These have been outlined in other studies and incorporate similar compounds and combination studies with Alpha -1 blockers (2,3).

We highlight three points for discussion. Firstly, the incidence of LUTS (Lower Urinary Tract Symptoms) classified as ‘Mild’ or ‘None’ is common. Data from the Olmsted County Study of Urinary Symptoms showed that 66% of 40-79 year old white men had either none or mild urinary symptoms based on the International Prostate Symptom Score (IPSS) (4). The suggestion is that treatment should be offered to these men as a preventive treatment or screened opportunistically, in similar ways that Hypertension. The benefit and acceptability of the side effect profile of such treatments, such as on sexual function, may not be acceptable among these asymptomatic men.

Secondly, the lack of a timescale is noticeable. Similar studies have referred to a risk reduction of over a fixed time point. It is unclear the time over which this risk reduction would occur and whether this is a gradual or step-wide reduction.

Thirdly, the absence of alpha blockers in the post hoc analysis may have shown that combination therapy in this group is more efficacious in preventing BPH progression, compared to a monotherapy, as was shown in the COMBAT trial data (5).

To suggest that we treat large numbers of men with ‘mild’ LUTS in preventing progression may not be practical or economically viable (6). Analysis of trial data examining this previously has suggested that $40,000 per QALY is achieved with all patients on combination therapy. It is unclear as to how long such treatment should continue or alternatively if combination or alternative therapy with alpha blockers is more efficacious.

A further analysis might be to analyse the cost of events related to progression (Acute Urinary Retention, Surgery, Treatment of Urinary Tract Infections). Offsetting this to the cost of 5 Alpha Reductase Inhibitor treatment in larger numbers of men might then allow a more informed choice for healthcare commissioning.

Yours Sincerely

.

References
1. J Urol. 2011 Jan;185(1):126-31. The effect of dutasteride on the usefulness of prostate specific antigen for the diagnosis of high grade and clinically relevant prostate cancer in men with a previous negative biopsy: results from the REDUCE study.
Andriole GL, Bostwick D, Brawley OW, Gomella L, Marberger M, Montorsi F, Pettaway C, Tammela TL, Teloken C, Tindall D, Freedland SJ, Somerville MC, Wilson TH, Fowler I, Castro R, Rittmaster RS; REDUCE Study Group.

2. N Engl J Med. 2003 Dec 18;349(25):2387-98.
The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia.
McConnell JD, Roehrborn CG, Bautista OM, Andriole GL Jr, Dixon CM, Kusek JW, Lepor H, McVary KT, Nyberg LM Jr, Clarke HS, Crawford ED, Diokno A, Foley JP, Foster HE, Jacobs SC, Kaplan SA, Kreder KJ, Lieber MM, Lucia MS, Miller GJ, Menon M, Milam DF, Ramsdell JW, Schenkman NS, Slawin KM, Smith JA; Medical Therapy of Prostatic Symptoms (MTOPS) Research Group.

3. Eur Urol. 1998 Sep;34(3):169-75.
Sustained-release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. European ALFIN Study Group.
Debruyne FM, Jardin A, Colloi D, Resel L, Witjes WP, Delauche-Cavallier MC, McCarthy C, Geffriaud-Ricouard C.

4. J Urol. 1999 Oct;162(4):1301-6.
Treatment for benign prostatic hyperplasia among community dwelling men: the Olmsted County study of urinary symptoms and health status.
Jacobsen SJ, Jacobson DJ, Girman CJ, Roberts RO, Rhodes T, Guess HA, Lieber MM.

5.Eur Urol. 2010 Jan;57(1):123-31. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study.
Roehrborn CG, Siami P, Barkin J, Damião R, Major-Walker K, Nandy I, Morrill BB, Gagnier RP, Montorsi F; CombAT Study Group.

6. Can J Urol. 2004 Aug;11(4):2327-40.
An economic evaluation of doxazosin, finasteride and combination therapy in the treatment of benign prostatic hyperplasia.
McDonald H, Hux M, Brisson M, Bernard L, Ni