JOURNAL READING

Ferawati

BENING PROSTATIC HYPERPLASIA

AND LOWER URINARY TRACT
SYMPTOMS: EVIDENCE AND
APPROACHES FOR BEST CASE
MANAGEMENT
by Jack Barkin, MD
The Canadian Journal of Urology

BACKGROUND

Age is the greatest risk factor for the presentation of

lower urinary tract symptoms (LUTS), and benign
prostatic hyperplasia (BPH) is one of the most
common cause of LUTS
50% of men over age 60 and almost 90% of men in
their 90s have symptoms from enlarged prostate
and need therapy for this

BACKGROUND

Almost 20 years ago, Michael J. Barry suggested that

by using simple questionnaire, which was later
validated , physician could quantify urine storage
and voiding symptoms in patients with BPH or LUTS
From this was born the International Prostate
Symptom Score (IPSS), which become the gold
standard outcome measurement for clinical trial that
assesed interventions for management of BPH

BACKGROUND

IPSS symptoms score range from 0 to 8 for mild

symptoms, 9 to 20 for moderate symptoms, and 21
to 35 for severe symptoms. Responses to quality of
life range from 0 (delighted) to 6 (terrible)
Clinical trials for the treatment of BPH and LUTS look
for symptoms response that is the change of the
IPSS score after measured at specified time after
therapy

BACKGROUND

The trials showed that to perceive a clinical benefit

from therapy, patients needed a minimum 3-point
improvement in IPSS score
Many reviews have shown that if BPH is untreated, it
often progresses, leading to worsening symptoms,
complications, the need for surgical intervention,
and poorer quality of life

BACKGROUND
The greatest predictable risk factors for progression of
BPH are:
Age older than 50,
Moderate prostate symptoms (IPSS 8), and
Prostate volume greater than 30 cc (or PSA 1,5
ng/mL, where PSA is a surrogate marker for prostate
volume)

BACKGROUND
The following parameters are signs of BPH progression:
Change in symptoms score (IPSS),
Increase in postvoid residual (PVR) urine volume,
Recurrent urinary tract infection,
Hematuria,
Renal failure,
Onset of urinary retention
The need for surgery

MANAGEMENT OF BPH

LIFESTYLE MODIFICATION

The first step in patient management is to determine

whether LUTS is caused by BPH causing bladder
outlet obstruction (BOO) or there is some other
cause
The physician can follow a relatively simple
diagnostic work up to assess patient who presents
with LUTS, that includes a complete patient history,
a focused physical examination, IPSS questionnaire,
urinalysis and serum prostate-spesific antigen (PSA)
test

LIFESTYLE MODIFICATION

For a patient with a small prostate and minimal

bother from symptoms, the recommended
treatment consists of watchful waiting and
patient education about lifestyle modification
These suggested lifestyle modification could
decrease symptoms, but they dont decrease the
size of the prostate or prevent prostate growth or
the progression of BPH

LIFESTYLE MODIFICATION

Example of lifestyle modification include:

Managing fluid intake during the day (decreasing
consumption of tea, coffee and alcohol)
Stop smoking
Decreasing use of drugs that affect bladde (e.g
decongestants and antihistamines)
Avoiding or treating constipation
Bladder training or pelvic-floor exercise

MEDICAL MANAGEMENT OF BPH

ALPHA BLOCKERS

The rationale of using an alpha blockers to treat BPH

is based on knowledge that stimulation of alpha
receptors in the smooth muscle fibers in the bladder
neck, prostatic urethra, and the prostate can
increase the smooth muscle tone
Thereby cause functional obstruction of the bladder
with symptoms of decreased urine flow, increased
frequency, nocturia and urgency

ALPHA BLOCKERS

The three main alpha receptor subtype are alpha 1A,

alpha 1B and alpha 1D. Alpha 1A receptors are found
in the smooth muscle of the bladder neck and
prostate, alpha 1B receptors are found in the smooth
muslce of peripheral vasculature, and aplha 1D
receptors are found in the spinal cord
Non-selective alpha blockers can block receptors
found in the body other than prostate. Recently,
uroselective alpha blockers that act specifically
became available

ALPHA BLOCKERS
These drug relieve LUTS through three proposed
mechanisms:
Relaxation of the smooth muscle tone in the prostate
stroma and bladder neck
Relaxation of bladder smooth muscle
Action on the central nervous system
In the most men, treatment with alpha blocker
provides fairly fast symptoms relieve (48 hours to 1
weeks), 30-50% improvement in symptoms compared
to plasebo

ALPHA BLOCKERS

However, patients who receive alpha blockers are

only likely to maintan the response for up to 4 years,
and do not prevent BPH progression, shrink the
prostate, or affect PSA level
All alpha blocker have very similar efficacies and
similar rates of potential side effects, including
postural hypotension (5%), dizziness (15%), nasal
congestion (5%), headache (5-10%), and asthenia
(5-10%)

5-ALPHA REDUCTASE INHIBITORS

Testosterone is broken down to its metabolite

dihydrotestosterone (DHT) by the action of enzyme
5-alpha reductase. DHT is absorbed in the prostate
cells and stimulates prostate cellular and stromal
growth
If the breakdown of testosterone to DHT is inhibited
by 5-ARI, DHT absorption into the prostate is
reduced and as a result, the prostate shrink and
symptoms caused by BPH will decrease

5-ALPHA REDUCTASE INHIBITORS

Two 5-ARIs finasteride and dutasteride are

currently available. Dutasteride inhibits both types of
5-alpha reductase isoenzymes, whereas finasteride
only inhibits the type 2 isoenzyme. As a result,
finasteride reduces DHT production by about 70%,
whereas dutasteride reduces it by more than 92%

5-ALPHA REDUCTASE INHIBITORS

In recent monotherapy trial, comparing the 5-ARIs to

placebo,
both
finasteride
and
dutasteride
demonstrated significant positive effects. In these
trials, men who received finasteride or dutasteride
had greater improvement in clinical symptoms after
6-12 months and their IPSS score were 15 to 30%
lower after 2 to 4 years, compared with men who
received placebo.
In another trial, finasteride was less effective than
alpha blockers in reducing LUTS and achieved the
same as placebo.

COMBINATION THERAPY

Based on the fact, that alpha blockers and 5-ARIs

have different mechanisms of action, long term
effects and efficacies (reduction of progression of
BPH), two large recent clinical trials were designed
to compare long term outcomes achieved by using
combination therapy (an alpha blocker and a 5-ARIs)
compared to monotherapy.

COMBINATION THERAPY

Earlier trials that compared combination therapy

with finasteride plus an alpha blocker versus placebo
concluded that this combination was no better that
placebo in treating symptoms of BPH. However the
reasons postulated for failure were that the trial
durations may have been too short (12 months) and
the inclusion criteria may have included prostates
that were too small.

COMBINATION THERAPY

After that, two large, longer term (4 or 5 year) trials

of combination therapy were performed. These trials
Medical Therapy of Prostate Symptoms (MTOPS)
and Combination of Avodart and Tamsulosin
(CombAT) investigated the effects of delivering
long term combination therapy to treat BPH.
The goal was to determine if signs of progression of
BPH were reduced in combination therapy compared
to monotherapy or placebo

COMBINATION THERAPY

In MTOPS, patients were randomized to one of the

four treatments arms: an alpha blocker (doxazosin)
alone; A 5-ARI (finasteride) alone; combination
therapy (finasteride plus doxazosin) and placebo
In CombAT, patients were randomized to an alpha
blocker (tamsulosin) alone or a 5-ARI (dutasteride)
alone and combination therapy (dutasteride plus
tamsulosin)

COMBINATION THERAPY

In MTOPS, included were patients had to be at least

age 50, have no clinical signs of prostate cancer,
and have an IPSS score at least 8, no minimum
requirement for prostate size.
In CombAT, the inclusion criteria were the same as
to predicts those at higher risk for progression of
BPH such as age 50, prostate volume 30 cc and
moderate IPSS ( 12). Placebo arm was excluded,
because the risk of disease progression after 4 years
was too high to justify withholding treatment

COMBINATION THERAPY

The primary endpoint in MTOPS was a composite

endpoint of clinical progression of BPH (ie renal
failure, urinary retention etc) at 4 years. At 1 year
the rate of clinical progression of BPH was not
significantly improved in the combination arm versus
placebo or monotherapy arm.
However, at 4 years the rate of clinical progression
of their BPH symptoms was significantly lower in the
combination arm versus the other arms

COMBINATION THERAPY

The primary endpoint of CombAT were improvement

in IPSS at 2 years and reduction in risk of acute
urinary retention (AUR) or surgery at 4 years.
In CombAT, up to 3 months, the slopes of the curves
of symptoms response over time were identical for
tamsulosin and for combination therapy.

COMBINATION THERAPY

Still in CombAT, as early as 15 months, however

patients treated with the 5-ARI dutasteride achieved
a better symptom response compared to patients
treated with tamsulosin (first time that trials showed
this kind of result)
At 4 years, symptom improvement for patients in the
combination arm was statistically superior to that of
patients with either of monotherpy arm (there is no
placebo arm)

COMBINATION THERAPY

Both trials also looked at the incidence of AUR, which

if not reversible, results in the need of surgery on the
prostate.
In MTOPS, McConell et al reported a 67% risk
reduction in AUR or the need for surgery at 4 years
in the combination arm compared to placebo arm.
The risk reduction for same endpoints in the CombAT
trial was virtually identical 66%.

COMBINATION THERAPY

Another very significant difference between alpha

blockers and 5-ARIs is that there is an expectation of
a 50% drop in PSA levels after a patient has been
taking a 5-ARI for at least 6 months, whereas there is
no impact on PSA if patient is taking an alpha
blockers.

CONCLUSION

Significant LUTS is very common in men over age 50.

After ruling out causes of LUTS other than BPH, it is
necessary and fairly easy for the primary care
physician to perform the patient workup to confirm
that BPH is causing the LUTS.
If the primary care physician determines that the
patient has moderate symptoms (IPSS 8),
moderate bother ( 3 on IPSS on bothersome
index question) and enlarged prostate ( 30 cc),
then the most effective, recommended treatment is
combination therapy with an alpha blocker and 5-ARI
from the outset.

CONCLUSION

This combination therapy will provide the most

dramatic, early symptom response and the most
durable prevention of the long term sequelae of BPH
progression AUR or the need for surgery.
If the patient complies with taking the combination
therapy, his PSA levels are expected to decline by
50%, and his symptom response is expected to
persist. If a patients PSA levels does not decline by
50%, or his symptom score does not improve, then
he should be referred to urologist.

THANK YOU FOR THE ATTENTION