CHAPTER 92

ASSESSING THE EFFECTIVENESS

AND SAFETY OF MEDICAL THERAPY

PRESENTED BY:
DR. ALDI LLA WAHYU RAHMADI AN
Textbook Reading
Campbell-Walsh Urology 10
th
Edition

Predict and control Adverse Events
Determine Proper Sample Size
Encourage Bias Elimination
Determine Quantitative Outcome Measure
Determine Clinical End Points
(Shapiro and Lepor, 1995).
1. Determine Clinical End Points in BPH Therapy
Relieving LUTS
Decreasing
BOO
Improving
bladder
emptying
Ameliorating
detrusor
instability
Reversing
renal
insufficiency
Preventing disease
progression
Deterioration of symptoms
Future episodes of gross hematuria
UTI
AUR
Need for surgical intervention
2. Determine Quantitative Outcome Measure
(contd 1/3)
1. Degree of Symptoms; measuring LUTS using IPSS/AUASI
The clinical significance of changes in the AUASI score at baseline and
after 3 months of treatment were reported by Barry and colleagues
(1995). The group mean changes in AUASI for subjects rating their
improvement as markedly, moderately, or slightly improved, unchanged,
or worse.
2. Degree of BOO; measuring PFR using Uroflowmetry
Uroflowmetry is a noninvasive, inexpensive, indirect indicator of urinary
performances measure of BOO.
The reporting of PFR has been standardized but the clinical significance of
the changes in PFR cannot be defined, owing to the lack of correlations
with relevant clinical, physiologic, or biochemical outcomes. (Abrams et
al, 2003)
2. Determine Quantitative Outcome Measure
(contd 2/3)
3. Bladder emptying performance; measuring PVR volume
using TAUS
Majority of BPH clinical trials exclude subjects with high baseline PVR
amount (>300 mL) because of the potential risks of randomization to a
placebo or ineffective treatment group
Insignificant baseline PVR urine volumes potentially undermining the
relevance of most trials to real world practice.
4. Presence of Bladder Overactivty; measuring detrussors
contraction instability
Definition : development of a detrusor contraction exceeding 15 cm H2O at
a bladder volume less than 300 mL (Jepsen and Bruskewitz, 2000).
The presence of an OAB does not reliably predict response to medical or
surgical treatment. Therefore improvement of an OAB is not a standard
outcome measure in clinical trials.
2. Determine Quantitative Outcome Measure
(contd 3/3)
5. Presence of UTI and Hematuria; measuring clinical
appearance and urinalysis
There is no convincing evidence that UTI in the aging male population is
associated with either PVR urine or BOO.
Hematuria may be associated with prostatic vascularity and may
sometimes respond to medical therapy with a 5-reductase inhibitor.
6. Degree of Renal Insufficiency; measuring renal function
It is reasonable to assume that renal insufficiency occurs secondary to
urinary retention if renal failure is reversed after catheter drainage.
Incidences of UTI, renal insufficiency, and hematuria are relatively uncommon and
nondiseasespecific events in the aging male population, it would be extremely
difficult to design a prospective study to determine whether any BPH treatment
prevents these events in an unselected cohort of men.
The only mechanism to ensure that the potential bias
of the subject and the investigator does not influence
the outcome is a randomized, placebo-controlled,
doubleblind design.
Trials should therefore include a placebo run-in
period before recording baseline values. Ideally a 4-
week placebo run-in period before initiation of
treatment should be included in any trial design.
the statistical concept of regression toward mean
should also be taken into account in trial design
3. Encourage Bias Elimination
It is a general misconception that the validity of a clinical
trial is directly proportional to the number of subjects
enrolled
Enrolling an excessive number of subjects may result in an
overpowered study; that is, a small and clinically
insignificant difference may be statistically significant.
Enrolling insufficient numbers of subjects may result in an
underpowered study; that is, a large and clinically
significant difference may not be statistically significant.
The larger the number of subjects enrolled in a study, the
smaller is the change that is required to achieve statistical
significance
4. Determine Proper Sample Size
5. Predict And Control Adverse Events
Drug entering clinical investigation in humans must be
no significant chemical, behavioral, physiologic,
teratogenic, mutagenic, or carcinogenic effects in at
least two animal models
adverse events captured in a clinical trial include
physical findings, laboratory results, and complaints.
The majority of clinical trials are powered based on
outcome measures and not adverse events.
serious adverse events that may therefore only show
up
later in postmarketing surveillance studies
Watchful Waiting or Self-Help
Watchful waiting is often the patient-driven treatment of choice in the absence of
absolute indications for intervention. Of 670 consecutive men with BPH referred to
39 urologists in the Netherlands, 41% elected watchful waiting (Stoevelaar et al,
1999).
556 subjects with moderate symptoms of BPH randomized to TURP versus
watchful waiting (Wasson et al, 1995). The changes in all outcome measures were
significantly greater in the TURP group. A relevant outcome for patients selecting
watchful waiting is disease progression. During 3 years of follow-up, treatment
failure was observed in 23 (8.2%) and 47 (17%) of subjects randomized to TURP
and watchful waiting, respectively.
One hundred forty men were randomized between standard care and self-
management, which comprised hree small group sessions of relevant urinary
education and lifestyle advice. Self-management significantly reduced the
frequency of treatment failure and reduced urinary symptoms. Because of the
large observed benefit of self-management, these investigators suggested a large
multicenter trial to confirm whether self-management could be considered as
first-line treatment for men with LUTS.

Medical Therapy:
1. - Adrenergic blocker
The rationale for -adrenergic blockers in the treatment of BPH is based
on the hypothesis that the pathophysiology of clinical BPH is in part
caused by BOO, which is mediated by 1-adrenergic receptors associated
with prostatic smooth muscle (Caine, 1986)
The importance of this dynamic obstruction was supported by
morphometric studies demonstrating that smooth muscle is one of the
dominant cellular constituents of BPH, accounting for 40% of the area
density of the hyperplastic prostate (Shapiro et al, 1992). Caine and
coworkers (1975) reported that the human prostate contracts in the
presence of the -adrenergic agonist norepinephrine.
Several investigators subsequently demonstrated that the tension of
prostate smooth muscle is mediated by the 1 receptor (Hieble et al,
1985; Lepor et al, 1988; Gup et al, 1989). Lepor and colleagues (1988)
were the first investigators to characterize the 1 receptor in the human
prostate using radioligand binding studies. These investigators
subsequently reported that 98% of the 1 receptors are localized to the
prostatic stroma (Kobayashi et al, 1994).
immunohistochemical (Walden et al, 1997) techniques, the 1A and
1B receptors are predominant in the human stroma and
epithelium, respectively. Prostate smooth muscle tension has been
shown to be mediated by the 1A receptor (Forray et al, 1994).
Tamsulosin is a once-daily administered 1 antagonist that exhibits
some modest degree of selectivity for the 1A versus the 1B
receptor and no selectivity for the 1A versus the 1D receptor
(Foglar et al, 1995).
The pharmaceutical industry has developed 1 antagonists that are
1000-fold selective for the 1A receptor versus 1B/1D (Forray et
al, 1994).
Recently, silodosin (Rapaflo) has been introduced. This agent shows
162:1 selectivity for 1A versus 1B adrenoceptors and is achieving
promising results.

Multicenter, randomized, double-blind,
placebocontrolled studies have examined the safety
and efficacy of the long-acting -adrenergic blockers
Terazosin
Doxazosin
Tamsulosin
(SR) alfuzosin
Subjects enrolled in these studies generally presented
with moderate to severe symptoms, PVR less than
300 mL, and no absolute indications for surgical
intervention