textbook campbell chapter 92

8/10/2019 Textbook Campbell chapter 92

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CHAPTER 92

ASSESSING THE EFFECTIVENESS

AND SAFETY OF MEDICAL THERAPY

P R E S E N T E D B Y :

D R . A L D I L L A W A H Y U R A H M A D I A N

Textbook ReadingCampbell-Walsh Urology 10thEdition


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Predict and control Adverse Events

Determine Proper Sample Size

Encourage Bias Elimination

Determine Quantitative Outcome Measure

Determine Clinical End Points


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(Shapiro and Lepor, 1995).

1. Determine Clinical End Points in BPH Therapy

Relieving LUTSDecreasing

BOO

Improving

bladder

emptying

Ameliorating

detrusor

instability

Reversing

renal

insufficiency

Preventing diseaseprogression

Deterioration of symptomsFuture episodes of gross hematuria

UTI

AUR

Need for surgical intervention


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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 andafter 3 months of treatment were reported by Barry and colleagues

(1995). The group mean changes in AUASI for subjects rating theirimprovement 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 urinaryperformances measure of BOO.

The reporting of PFR has been standardized but the clinical significance ofthe changes in PFR cannot be defined, owing to the lack of correlationswith relevant clinical, physiologic, or biochemical outcomes. (Abrams etal, 2003)


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(contd 2/3)

3. Bladder emptying performance; measuring PVR volumeusing TAUS

Majority of BPH clinical trials exclude subjects with high baseline PVR

amount (>300 mL) because of the potential risks of randomization to aplacebo or ineffective treatment group

Insignificant baseline PVR urine volumes potentially undermining therelevance 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 ata bladder volume less than 300 mL (Jepsen and Bruskewitz, 2000).

The presence of an OAB does not reliably predict response to medical orsurgical treatment. Therefore improvement of an OAB is not a standardoutcome measure in clinical trials.


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(contd 3/3)

5. Presence of UTI and Hematuria; measuring clinicalappearance 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 andnondiseasespecific events in the aging male population, it would be extremelydifficult to design a prospective study to determine whether any BPH treatment

prevents these events in an unselected cohort of men.


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The only mechanism to ensure that the potential biasof the subject and the investigator does not influencethe outcome is a randomized, placebo-controlled,doubleblind design.

Trials should therefore include a placebo run-inperiod before recording baseline values. Ideally a 4-week placebo run-in period before initiation oftreatment should be included in any trial design.

the statistical concept of regression toward meanshould also be taken into account in trial design

3. Encourage Bias Elimination


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It is a general misconception that the validity of a clinicaltrial is directly proportional to the number of subjectsenrolled

Enrolling an excessive number of subjects may result in an

overpowered study; that is, a small and clinicallyinsignificant difference may be statistically significant.

Enrolling insufficient numbers of subjects may result in anunderpowered study; that is, a large and clinicallysignificant difference may not be statistically significant.

The larger the number of subjects enrolled in a study, thesmaller is the change that is required to achieve statisticalsignificance

4. Determine Proper Sample Size


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5. Predict And Control Adverse Events

Drug entering clinical investigation in humans must beno significant chemical, behavioral, physiologic,teratogenic, mutagenic, or carcinogenic effects in atleast two animal models

adverse events captured in a clinical trial includephysical findings, laboratory results, and complaints.

The majority of clinical trials are powered based onoutcome measures and not adverse events.

serious adverse events that may therefore only showup

later in postmarketing surveillance studies


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Watchful Waiting or Self-Help

Watchful waiting is often the patient-driven treatment of choice in the absence ofabsolute indications for intervention. Of 670 consecutive men with BPH referred to39 urologists in the Netherlands, 41% elected watchful waiting (Stoevelaar et al,1999).

556 subjects with moderate symptoms of BPH randomized to TURP versuswatchful waiting (Wasson et al, 1995). The changes in all outcome measures weresignificantly greater in the TURP group. A relevant outcome for patients selectingwatchful waiting is disease progression. During 3 years of follow-up, treatmentfailure was observed in 23 (8.2%) and 47 (17%) of subjects randomized to TURPand watchful waiting, respectively.

One hundred forty men were randomized between standard care and self-management, which comprised hree small group sessions of relevant urinaryeducation and lifestyle advice. Self-management significantly reduced thefrequency of treatment failure and reduced urinary symptoms. Because of thelarge observed benefit of self-management, these investigators suggested a largemulticenter trial to confirm whether self-management could be considered asfirst-line treatment for men with LUTS.


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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 partcaused by BOO, which is mediated by 1-adrenergic receptors associatedwith prostatic smooth muscle (Caine, 1986)

The importance of this dynamic obstruction was supported bymorphometric studies demonstrating that smooth muscle is one of the

dominant cellular constituents of BPH, accounting for 40% of the areadensity of the hyperplastic prostate (Shapiro et al, 1992). Caine andcoworkers (1975) reported that the human prostate contracts in thepresence of the -adrenergic agonist norepinephrine.

Several investigators subsequently demonstrated that the tension ofprostate 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 humanprostate using radioligand binding studies. These investigatorssubsequently reported that 98% of the 1 receptors are localized to theprostatic stroma (Kobayashi et al, 1994).


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immunohistochemical (Walden et al, 1997) techniques, the 1A and1B receptors are predominant in the human stroma andepithelium, respectively. Prostate smooth muscle tension has beenshown 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 1Breceptor and no selectivity for the 1A versus the 1D receptor(Foglar et al, 1995).

The pharmaceutical industry has developed 1 antagonists that are1000-fold selective for the 1A receptor versus 1B/1D (Forray etal, 1994).

Recently, silodosin (Rapaflo) has been introduced. This agent shows162:1 selectivity for 1A versus 1B adrenoceptors and is achievingpromising results.


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Multicenter, randomized, double-blind,placebocontrolled studies have examined the safetyand efficacy of the long-acting -adrenergic blockers

Terazosin

Doxazosin

Tamsulosin

(SR) alfuzosin

Subjects enrolled in these studies generally presentedwith moderate to severe symptoms, PVR less than300 mL, and no absolute indications for surgicalintervention

textbook campbell chapter 92

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