1. Benign Prostatic Hyperplasia: Trends in Medical Management
08/22/98
Benign Prostatic Hyperplasia: Trends in Medical Management
I’d like to present the case of R.F., a 32 year old man with a right testicular mass.
Jonathan Wu, M.D.
Stanford University 1

2. BPH Definitions Symptoms Medical options for treatment BPH progression
Alpha blockers
5 alpha reductase inhibitors
BPH progression

3. What is BPH?
Microscopic (BPH): histological changes, nodular overgrowth of normal prostatic glands
Macroscopic (BPE): palpable enlargement of the prostate (or measurable by ultrasound)
Clinical (BOO): Lower Urinary Tract Symptoms (LUTS) are not necessarily due to obstruction

4. Anatomy of BPH Normal BPH BLADDER Hypertrophied detrusor muscle
PROSTATE
URETHRA
Obstructed urinary flow
Kirby RS et al. Benign prostatic hyperplasia. Health Press, 1995.

5. Schematic transverse section of enlarged prostate
Urethra
Transitional zone
Central zone
Peripheral zone
Typical location of benign nodular hyperplasia in the transitional zone
Posterior displacement of both peripheral and central zones

6. OVERVIEW OF BPH

7. Autopsy Prevalence of BPH

8. OVERVIEW OF BPH

9. The Culprit: Dihydrotestosterone
Dihydrotestosterone (DHT) is the main androgen responsible for prostate growth
Two isoenzymes of 5-reductase
have been identified
5-reductase
inhibitors
suppress DHT
formation
Adapted from Kirby R et al (Eds).
Shared Care for Prostatic Diseases 1995

10. OVERVIEW OF BPH

11. OVERVIEW OF BPH

12. TREATING BPH

13. TREATING BPH

15. Alpha1 Blockade for BPH Nonselective (a1 & a2) Phenoxybenzamine
Prazosin
Long-Acting Selective a1
Terazosin
Doxazosin
Long-Acting a1 Subtype Selective (IA)
Tamsulosin HCl
Slide 6.
The earliest studies demonstrating the effectiveness of alpha blockade in relieving BPH were done with phenoxybenzamine, a nonselective alpha blocker with a troublesome side effects profile. The development of prazosin, an alpha blocker with improved tolerance, led to the concept of selective alpha1 blockade. Terazosin is structurally similar to prazosin and exhibits similar selectivity, but is long-acting. Prazosin and its analogues are vasodilators, however, and cause a significant decrease in blood pressure.

16. TREATING BPH

17. TREATING BPH

18. TREATING BPH

19. Uroselective Alpha blocker
Prostatic smooth muscle represents 75% of total alpha1- adrenoreceptor population
Theoretically will improve LUTS but have no cardiovascular effects
Tamsulosin (Flomax) has 7 to 38-fold greater affinity for a1a receptor vs a1b

20. TREATING BPH

21. Uroselective Alpha-blockade
Pros
Cons
No need for titration
Lack of interaction with other antihypertensive medications
No effect on BP
Increased incidence of retrograde ejaculation

22. TREATING BPH

23. Finasteride Adverse Effects
Side effects are uncommon outside of expense
erectile dysfunction 4%
ejaculatory dysfunction 3%
hair growth
decrease in PSA

24. The Evidence: MTOPS
Double blind, placebo controlled trial of 3047 men >50 yrs with moderate-severe LUTS and peak flow of 4-15 mL/s randomized to placebo, doxazosin 8 mg/d, finasteride 5 mg/d or combination with mean followup of 4.5 yrs
Primary endpoint was first occurrence of clinical progression (i.e. IPSS, AUR, kidney failure, UTI)

25. The Evidence: MTOPS
Total of 17% in placebo group had clinical progression in 4 yrs with IPSS accounting for 79% of events (vs 5% required AUR BPH-surgery)
Combo therapy most effective in reducing progression and improving LUTS (Doxazosin 39% risk reduction (RR), finasteride 34% RR, combination 66% RR
Combination treatment superior to either single agent for improvement in symptom scores

26. The Evidence: MTOPS

27. Cumulative Incidence of AUR
Finasteride responsible for the entirety of the risk reduction
3.0
Placebo
2.5
Doxazosin
P =
2.0
Patients With Event (%)
1.5
Finasteride
1.0
Finasteride alone, but not doxazosin alone, reduced the risk of acute urinary retention. The combination of doxazosin and finasteride was slightly more effective at reducing the risk of AUR than was either medication administered alone.
Compared with placebo, finasteride was associated with a 68% reduction in the relative risk for AUR and combination therapy was associated with an 81% reduction in relative risk. Although doxazosin delayed the time to AUR, it did not significantly reduce the cumulative incidence of AUR.
Reference
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.
0.5
Combination . 5 1 . 1 . 5 2 . 2 . 5 3 . 3 . 5 4 . 4 . 5 5 . 5 . 5
Years From Randomization
McConnell JD, et al. N Engl J Med. 2003;349:23872398.

28. The Evidence: ALTESS
Double blind, placebo controlled trial of of alfuzosin 10 mg/d vs placebo in men over 2 years
Mean age 66.5, mean IPSS 19.2, mean prostate size 47 g, Qmax 9 mL/s
Endpoints: occurrence of AUR and need for BPH-related surgery, IPSS

29. The Evidence: CombAT
Alfuzosin had 26% risk reduction of any clinical progression event
Did NOT reduce risk of AUR or BPH-related surgery

30. The Evidence: CombAT
Randomized, double blinded study of 4844 men comparing dutasteride vs tamsulosin vs combo
3195 (66%) completed 4 year followup
Primary end point: AUR or BPH related surgery

31. The Evidence: CombAT
Combo therapy RR of AUR by 67.6% and BPH surgery by 70.6% compared to tamsulosin alone
Combo therapy RR of AUR by 18.3% and BPH surgery by 31.1% compared to dutasteride alone

32. The Evidence: CombAT

33. The Evidence: CombAT

34. TREATING BPH
Avodart