Here we review some of the landmark trials in the medical management of BPH.
Tamsulosin Investigator GroupAlpha-Blocker Trial
Lepor H. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group. Urology. 1998 Jun;51(6):892-900.
765 men randomized to placebo, 0.4mg or 0.8mg of tamsulosin with the inclusion criteria: age >45, AUA symptom score >13, urinary flow rate (Qmax) 4-15mL/second and post-void residual (PVR) <300cc. At the study endpoint, improvement in AUA-SS was 5.5, 8.3 and 9.6 points in the placebo, 0.4mg and 0.8mg groups respectively. This correlated to a 25% AUA-SS improvement in 51%, 70% and 74% of patients. Urinary flow rates (Qmax) improved by 0.5, 1.75 and 1.78; corresponding to a 30% Qmax improvement in 21%, 31% and 36% of men.
North American Finasteride Trial5-Alpha Reductase Inhibitor Trial
Gormley GJ, Stoner E, Bruskewitz RC, et al: The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992;327:1185-1191.
Proscar Long-term Efficacy and Safety Study (PLESS)
Dutasteride ARIA Studies5-Alpha Reductase Inhibitor Trial
Roehrborn CG, Boyle P, Nickel JC, et al: 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.
Roehrborn CG,Marks LS, Fenter T, et al: Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia. Urology 2004;63:709-715.
Veterans Affairs Cooperative Study 359Combination Alpha-Blocker / 5ARI Trial
This was the first trial directly comparing an alpha-blocker and 5ARI, and the first time combination therapy was explored. 1,229 men were randomized to terazosin, finasteride, combination or placebo for 1 year. This study failed to demonstrate an improvement in finasteride when compared to placebo with respect to symptom scores or urinary flow rates. However, the average prostate size in this study was only 37cc and when subset analyses were performed, it was confirmed that the improvement due to terazosin was independent of prostate volume while finasteride was most effective in larger prostates.
Barry MJ1, Williford WO, Chang Y, Machi M, Jones KM, Walker-Corkery E, Lepor H. 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 Nov;154(5):1770-4.
In this analysis of the VA359 study, Dr. Barry and colleagues defined slight, moderate and marked improvement in AUA-SS as 3, 5 and 8 points respectively.
Medical Therapy of Prostate Symptoms (MTOPS)Combination Alpha-Blocker / 5ARI Trial
McConnell JD1, 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.The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia.N Engl J Med. 2003 Dec 18;349(25):2387-98.
The MTOPS Trial was a prospective, multi-center, randomized, double-blind trial where 3047 patients randomized to doxazosin, finasteride or both versus placebo. Mean prostate volume was 36cc, mean IPSS 16.7 and Qmax ranged from 4-15mL/s. Over an average follow-up of 4.5 years, the risk reduction for progression (increase in IPSS of 4, acute urinary retention or surgery) was 39% for doxazosin, 34% for finasteride, and 67% for combination therapy compared with placebo. The risk of acute urinary retention did not change for patients on doxazosin (although time to AUR was longer), but was reduced 68% for men on finasteride and 81% for patients on combination-therapy. Similarly, there was no difference in surgical rates for patients on doxazosin, but a 64% and 67% reduction for men on finasteride or combination therapy respectively. Importantly, the MTOPS trial also demonstrated a dramatic reduction in hematuria for patients on finasteride (63% hematuria recurrence on placebo, 14% recurrence in finasteride).
Combination of Avodart and Tamsulosin Trial (CombAT)Combination Alpha-Blocker / 5ARI Trial
In summary, we can draw the following conclusions from these studies:
- Significant improvements in AUA-SS are considered greater than 3 points.
- Alpha blockers can begin working as quickly as 8 hours.
- The effects of 5ARI may not be felt for 2 weeks to 2 months, and may take 6-12 months to reach their maximum benefit.
- 5ARIs reduces the risk of acute urinary retention and surgical treatment associated with BPH.
- 5ARIs are effective only on men with larger prostates (>40g).
This blog was written by Mark W. Ball, MD, urology resident at the Brady Urological Institute at Johns Hopkins.