Campbell Evaluation and Nonsurgical Management of BPH Flashcards
The main goal of the baseline interview
of any patient is ____.
to identify potential causes of LUTS so as to
further address the diagnostic and therapeutic decision-making process with a more patient-tailored approach
The DRE has a double aim: (2)
Obtain baseline estimation of prostate volume.
Exclude palpable nodules or any increased consistency, that may signal the presence of PCA.
** The sensitivity of DRE in detecting PCa is low, with historical
series showing PCa detection rates on biopsy as low as 40% to
50% in the era before prostate-specific antigen (PSA) testing among
patients with positive DRE findings
International clinical guidelines advise that _____ should be used during the basic evaluation of
patients with prevalent storage LUTS or nocturia
FVCs (or their derived forms)
*** Frequency-volume charts (FVCs), recording the voided volume
and the time of each micturition during day and night hours for
24 hours
VS.
*** Bladder diaries, recording the time of micturition, voided volume,
and additional information such as fluid intake, incontinence
episodes, degree of incontinence, pad usage, and degree of urgency
The use of a _____ is suggested in all patients complaining of LUTS
as a part of the baseline evaluation
dipstick test and/or the microscopic evaluation of urine samples
_____ should always be requested in men with severe
storage symptoms and dysuria, especially if they have a smoking
history.
Urine cytology
The value of PSA testing among patients presenting for LUTS is
multiple: _____ (3)
assess the risk and eventually rule out the presence of
PCa;
estimate PV;
and predict BPH-related outcomes.
Current international clinical guidelines suggest measurement of PSA if
_____, excluding, for instance, those ______.
a diagnosis of PCa will change LUTS management,
men with a life expectancy of less than 10 years
PSA level at which there is a 65-70% chance of detection of prostate volume > 40 mL at a specific age.
PSA level at which there is a 65-70% chance of detection of prostate volume > 40 mL at a specific age.
- 6 ng/mL = 50s
- 0 ng/mL = 60s
- 3 ng/mL = 70s
Caution should be paid in patients treated with 5α-reductase inhibitors (5ARIs), given that serum PSA level is reduced by ____
40% to 50% after 12 months of treatment
TRUE or FALSE
The assessment of renal function based on serum creatinine level
or estimated glomerular filtration rate is not routinely suggested in patients with LUTS.
TRUE
The assessment of renal function based on serum creatinine level
or estimated glomerular filtration rate is NOT routinely suggested
in patients with LUTS.
As a whole, AUA guidelines no longer recommend a routine renal function assessment but EAU guidelines suggest assessment of serum creatinine level if renal impairment is suspected on the basis of medical history or when surgical treatment is considered.
PVR volume is defined as _____ . Currently, there is no standardized
definition for a normal PVR volume.
In clinical practice, a PVR volume of ____ is usually considered nonsignificant, whereas PVR volume ____ could be regarded as important.
the volume (mL) of urine left in the bladder at the end of micturition
less than 30 mL (nonsignificant)
persistently greater than 50 mL (important)
ICS Urodynamics Committee for correct assessment of PVR Volume:
• The interval between voiding and PVR volume measurement
should be of short duration.
• Although transurethral catheterization is considered the gold
standard to assess PVR volume, it could be associated with patient
discomfort and the risk for UTIs and urinary tract trauma.
• The ultrasound bladder volume measurement should be used
to assess PVR volume and can be performed with either a
real-time transabdominal ultrasound scanner or a portable
bladder scanner.
The presence of an abnormal PVR volume is [HIGHLY or NOT HIGHLY] correlated with BOO.
not highly
Indeed, an abnormal PVR volume could be the consequence of either BOO or DUA. In this context, the diagnostic accuracy of PVR volume measurement has a positive predictive value of 63% and a negative predictive value of 52% to detect BOO
PVR volume assessment is suggested both during _____.
Men with significant PVR volume should be _____.
basic workup and during the follow-up of patients with LUTS.
monitored closely if they elect to have nonsurgical therapy
Uroflow measurement: _____
The main parameters provided by uroflowmetry: (3)
Electronic recording of the free urinary flow rate throughout the course of micturition.
Qmax (or peak urinary flow rate [PFR]): inaccurate if the voided volume is less than 125 to 150 mL
Voided volume
Flow pattern
*** Average flow rate is considered less accurate than Qmax to detect
BOO
*** There is substantial within-subject variation in terms of uroflowmetry
results among measurements taken either on the same
day or on consecutive days
According to expert opinion, a PFR cutoff of _____ could be used to define outlet obstruction in clinical practice.
15 mL/s
*** a PFR of less than 15 mL/s does not differentiate between obstruction and bladder decompensation.
International clinical guidelines consider uroflowmetry as an _____ test in the assessment of patients with LUTS, although its use is recommended _____.
OPTIONAL
before any active treatment
The invasive urodynamic test is the gold standard for the assessment of LUTS pathophysiology and it is used to identify _______.
Two distinct evaluations investigating the storage
and voiding phase of micturition: _____ and ______.
DO, DUA, low bladder compliance, and BOO.
the filling cystometry and the pressure-flow study (PFS).
videourodynamics refers to the use of ______.
This test allows one to obtain ______.
synchronous radiographic imaging and filling the bladder with contrast medium while cystometry and a PFS are performed.
additional anatomic information by showing the presence of eventual alteration of the bladder profile (diverticula, trabeculation), of vesicoureteral reflux, or of alterations of the pelvic floor activity.
** No clear recommendation is currently provided regarding the use
of videourodynamics
Cystometry allows the assessment of the _____.
It is characterized by _____
storage phase.
a continuous fluid filling of the bladder through a transurethral catheter, with a concomitant measurement of intravesical and abdominal pressure and the display of the detrusor pressure
Cystometry: In patients with LUTS suggestive of BOO, the main goal of this test ____.
is the detection of involuntary detrusor contractions, which may identify DO.
*** The diagnosis of DO could be useful to identify patients who
may benefit from the use of anticholinergic drugs either alone or
in combination with other treatments.
PFS allows assessment of the ____.
It is defined as the measurement of the ______ while
uroflowmetry is performed with a transurethral catheter in place
The joint evaluation of detrusor pressure and flow
rate allows the diagnosis of either _____ or _____.
BOO (characterized by impaired flow rate along with an increased detrusor pressure)
or
DUA
(characterized by the impairment of both flow rate and detrusor
pressure).
As invasive diagnostic modalities, both the European and the American guideline panels do NOT routinely suggest the use of urodynamic tests to assess men with LUTS.
However, PFS is suggested before invasive treatments in some specific scenarios:
• Patients with previously unsuccessful invasive treatments for
LUTS
• Patients who cannot void more than 150 mL
• Patients with PVR volume greater than 300 mL
• Patients older than 80 years of age with predominantly voiding
LUTS
• Patients younger than 50 years of age with predominantly
voiding LUTS
ALSO, AUA: PFS may be performed in patients with a Qmax greater than 10 mL/s before
surgical treatment is considered
TRUE or FALSE
The routine assessment of the upper tract with ultrasonography is NOT recommended in patients with LUTS.
TRUE
** In a population of 6102 patients evaluated in 25 studies by intravenous urography
before prostate surgery, only 7.6% were found to have hydronephrosis.
*** imaging assessment of the upper tract is currently suggested for patients with LUTS
combined with an elevated serum creatinine level or large PVR volumes.
patients with a history of hematuria, UTI, urolithiasis, or prior urinary tract surgery should also be assessed with abdominal ultrasonography
Candidates for treatment with 5ARIs should be evaluated for ____.
PV, as treatment outcomes have been related to the baseline gland volume
*** The PV estimated by TRUS imaging was a predictor of BPH progression and invasive treatment in the MTOPS trial
*** Similarly, data from the placebo arm of the ALTESS showed that men with a PV greater than 49 mL had a 3.2% risk for AUR compared with those with a PV of 49 mL or less
Ultrasound-based estimation of PV (either suprapubic or TR) should be routinely performed before _____.
any BPH surgery so as to help the physician in choosing the most appropriate technique
** Moreover, the detection of a third prostate lobe protruding into the bladder could guide the
choice of treatment in patients scheduled for minimally invasive approaches
Intravesical prostatic protrusion (IPP) is defined as _____, can be assessed by suprapubic ultrasound imaging in the ____.
Should be estimated with a volume of ____ of urine in the bladder.
In a cohort of 2115 men with LUTS, a high ______ was associated with a higher
probability of ____.
the distance from the tip of the protruding prostate to the base at the circumference of the bladder.
sagittal plane
100 to 200 mL
IPP grade (>10 mm)
medical treatment over time
TRUE or FALSE
There is currently no clear recommendation for using IPP as a noninvasive alternative to PFS to diagnose BOO.
TRUE
Cystourethroscopy can provide information regarding the ____.
However, cystourethroscopy is neither useful for the diagnosis of BOO nor to determine
the need for treatment.
Clinical guidelines suggest the use of cystourethroscopy in: ______
morphology of the prostate and bladder neck, and the detection of detrusor trabeculation at the level of the bladder wall or the presence of diverticula.
the case of reported gross hematuria,
history of bladder cancer,
history of recurrent UTIs or urethral injury (to rule out urethral stenosis),
or in the case of previous surgery of the prostate or urethra.
WW is based on ____.
If patients choose WW as the preferred management, they
should be: _____
reassurance and education of the patient, lifestyle interventions, and periodic monitoring of the disease.
followed up yearly to detect any progression in terms of symptoms or the occurrence of complications, which should prompt a more aggressive treatment approach
** Data from longitudinal community-based studies show that unfavorable outcomes such as AUR and BPH-related surgery are relatively uncommon throughout the natural history of BPH patients, reporting a cumulative incidence of 1% to 2.7% for AUR and 3% for surgery
** recent 15-year longitudinal study, 50% of included patients showed stable symptom scores over the time frame investigated
Lifestyle and Dietary Modifications: Education and reassurance: (3)
• Discuss the causes of LUTS, including normal prostate and
bladder function.
• Discuss the natural history of BPH and LUTS, including the
expected future symptoms.
• Reassure the patient that no evidence of detectable PCa has
been found.
Lifestyle and Dietary Modifications: Fluid Management (4)
Fluid Management
• Advise a daily fluid intake of 1500 to 2000 mL (minor adjustments
may be made for climate and activity).
• Avoid inadequate or excessive fluid intake on the basis of an
FVC.
• Advise fluid restriction when symptoms are most inconvenient
(e.g., during long journeys or when out in public).
• Advise evening fluid restriction for nocturia (no fluid for 2
hours before retiring).
Lifestyle and Dietary Modifications: Caffeine and Alcohol (3)
Caffeine and Alcohol
• Avoid caffeine by replacing caffeine with alternatives (e.g.,
decaffeinated or caffeine-free drinks).
• Avoid alcohol in the evening if nocturia is bothersome.
• Replace large-volume alcoholic drinks (e.g., pint of beer) with
small-volume alcoholic drinks (e.g., wine or spirits).
Lifestyle and Dietary Modifications: Concurrent Medication (2)
• Adjust the time when medication with an effect on the urinary
system is taken to reduce LUTS at times of greatest inconvenience
(e.g., during long journeys and when out in public).
• Replace antihypertensive diuretics with suitable alternatives
with fewer urinary effects (via the patient’s general practitioner).
Lifestyle and Dietary Modifications: Types of Toileting and Bladder Retraining (3)
• Advise men to double-void (spending extra time on the toilet
to try to empty the bladder completely).
• Advise urethral milking for men with postmicturition dribbling.
• Advise bladder retraining. With use of distraction techniques
(predetermined mind exercise, perineal pressure, or pelvic floor
exercises), aim to increase the minimum time between voids
to 3 hours (daytime) and/or the minimum voided volume to
between 200 and 400 mL (daytime). The urge to void should
be suppressed for 1 minute, then 5 minutes, then 10 minutes,
and so on, increasing on a weekly basis. Use FVCs to monitor
progress.
Medical therapy is the first-line treatment for patients _______.
bothered by LUTS without imperative indications for surgery, such as the occurrence of AUR, recurrent UTIs, renal insufficiency, bladder stones, and recurrent gross hematuria
Drug therapy should be tailored to the patient’s symptoms:
In a patient with predominantly voiding symptoms: _____
predominant storage symptoms: _____
In a patient with predominantly voiding symptoms: α1-blockers, 5ARIs and PDE5Is may be all valid treatment options
predominant storage symptoms: muscarinic receptor antagonists or β3-agonists
The goals of LUTS medical treatment may include: ______ (6)
relieving symptoms,
decreasing BOO,
improving bladder emptying,
ameliorating DO,
reversing renal insufficiency, and
preventing disease progression, defined as symptom deterioration and/or the occurrence
of complications requiring surgical treatment.
_______ , are considered the gold standard to quantify the impact of therapeutic interventions on LUTS.
The mean changes in the AUASI score for patients rating their symptoms
as markedly, moderately or slightly relieved, unchanged, or worse: _____
A minimum of a ____ change in terms of the symptom score appears perceptible to patients.
Changes in patients’ symptoms, as assessed with validated tools such as the AUASI or the IPSS
markedly relieved: −8.8 moderately relieved: −5.1 slightly relieved: −3.0 unchanged: −0.7 worse: +2.7
3-point change = perceptible
_____ are the gold standard for the assessment and quantification of BOO;
however, as an invasive test, this modality is not suggested for the evaluation of treatment outcomes in clinical practice.
PFSs
Several studies used uroflowmetry parameters to compare the efficacy of different
LUTS treatments; of those, _____ is considered an indirect measure of BOO
PFR (Qmax)
An urodynamic profile characterized by _____ suggests DO, which may be spontaneous or provoked
involuntary detrusor contractions during the filling phase
** Of clinical relevance, urodynamically demonstrated DO is not
invariably associated with OAB syndrome
There is an important placebo effect in LUTS outcome measures.
Ideally a _____ period before initiation of treatment
should be included in any trial design; this would allow the
incorporation of a baseline placebo effect before any comparison
is made.
4-week placebo run-in
Total of nine AR subtypes: the ____ plays a major role in the pathophysiology of LUTS and is the target of α1-blockers.
α1-AR subfamily
MOA of α1-ARs: _____
Noradrenaline-mediated contraction of the smooth muscle via the binding with α1-ARs (mainly α1a subtype) at the level of the bladder neck, the proximal urethra, and the prostate is responsible for the dynamic component of BOO in patients with BPH;
therefore, the blockade of α1-ARs leads to the relaxation of smooth muscle tissue at both sites, with a decrease of the sympathetic baseline muscle tone and the consequent relief of symptoms.
** The effect of α1-blockers on bladder detrusor function has not yet been clarified.
Phenoxybenzamine: Non-selective α1-blocker outcomes: ____
nonselectivity of the molecule, blocking both α1 and α2 receptor subtypes, serious cardiovascular AEs were observed, and the drug was no longer used to treat LUTS/BPH.
____ was the first selective α1-AR antagonist investigated for LUTS treatment. Resulted in a significant increase in urinary flow rates and better tolerated than phenoxybenzamine.
Short serum elimination half-life, requires administration at least ___ daily.
Prazosin
Twice
____ are defined as uroselective drugs and have a higher affinity for the α1a and α1d receptor subtypes than for the α1b subtype.
Tamsulosin, alfuzosin, silodosin, and naftopidil
Lepor et al., 1992: TERAZOSIN
Phase III Multicenter Trial
285 patients with LUTS suggestive of BOO randomized to
receive placebo or 2 mg, 5 mg, or 10 mg terazosin once daily for a
12-week treatment period
RESULTS: _____
AEs: _____
- 4% reduction in symptom score (Boyarsky symptom scale) in favor of the treatment
group.
Moreover, patients treated with terazosin had a significant increase in PFRs and mean urinary flow rates.
Both effects were dose dependent, with better results with 10 mg terazosin.
Overall, AEs were minor and reversible in all four terazosin treated groups.
Dizziness and asthenia were the most commonly reported AEs in the terazosin group (26% and 14%, respectively);
Hytrin Community Assessment Trial (HYCAT)
2084 men with an AUASI score of 13 or greater and a PFR of less
than 15 mL/s
Patients were randomized to receive placebo or terazosin;
the dose was titrated from 1 mg to 5 mg or 10 mg according
to the clinical response
RESULTS: ____
AEs: ____
The symptom score decreased by 37.8% in the terazosin group and by 18.4% in the placebo group (P < 0.001)
similarly treatment with terazosin significantly improved urinary flow parameters.
AEs: Of note, 19.7% of patients discontinued use of terazosin because of AEs.
terazosin dose titration is recommended to minimize the risk for____. Patients should be counseled to start treatment with _____.
First-dose hypotension and syncope
1 mg terazosin taken at bedtime, further increasing up to 5 or 10 mg
Fawzi et al., 1995: DOXAZOSIN
16-week, double-blind, multicenter trial, 100 patients were randomized to receive doxazosin or placebo
symptomatic BPH with an AUASI score of 10 or greater, PFR of 5 to 15 mL/s, and PVR volume of 125 to 500 mL; dose titration was applied to 2, 4, or 8 mg once daily (88% of patients reached the 8-mg dose)
RESULTS: ____
AEs: _____
The symptom score decreased significantly by 39% in the treatment group compared with 17% in the placebo group (P < 0.001);
similarly, PFR increased by a mean of 2.9 mL/s with doxazosin compared with 0.7 mL/s with placebo
hypotension was reported by 8% of patients
Gillenwater et al., 1995. DOXAZOSIN
larger multicenter RCT including 248 hypertensive patients randomized to
16-week therapy with doxazosin or placebo
Efficacy and safety were investigated for 2, 4, 8, and 12 mg doxazosin doses, with titration to
a fixed-dose approach
RESULTS: _____
AEs: _____
significant reduction of symptom severity ONLY for doxazosin at doses of 4 and 8 mg over
placebo. Small number of patients in each dosing group may be responsible for the lack of significance compared with placebo for the other doses.
AEs: Maximum average decrease in systolic blood pressure of
17.4 mm Hg in the standing position. These data confirmed the
significant impact of doxazosin on blood pressure, at least in
hypertensive men
DOXAZOSIN alone: MTOPs
Findings from the MTOPS trial showed that doxazosin alone reduced the risk for clinical progression of BPH by 39% as compared with placebo (P < 0.001).
Doxazosin GITS therapy showed a pattern of ____ compared with the doxazosin standard formulation;
This finding was related to the possibility to start the therapy at a higher dose (4 mg), with no need for dose titration for the SR formulation.
Doxazosin SR is recommended at the initial dose of _____
earlier onset of symptom relief and increase in flow rates
4 mg taken at breakfast
ALFUZOSIN: Higher selectivity ratio toward prostate tissue over vascular tissue, therefore: _____
This pharmacokinetic profile is reflected in a high efficacy for relieving LUTS, along with a lower
rate of cardiovascular AEs (postural hypotension, syncope, vertigo, and dizziness) or CNS AEs (somnolence, asthenia)
ALFUZOSIN: ____ alfuzosin is an effective and safe compound with no need for dose titration. Alfuzosin should be taken _____
10 mg once-daily
After the same meal each day
TAMSULOSIN is a ______.
Lepor 1998. Phase III multicenter trial, 756 patients with BPH were randomized to receive either tamsulosin (0.4 vs. 0.8 mg/day) or placebo for 13 weeks.
RESULTS:_____
AEs: ______
uroselective α1-blocker with higher affinity for the α1a and α1d receptor subtypes.
RESULTS: PFR increased within 4 to 8 hours after a single 0.4-mg dose, and symptom relief was evident after 1 week of treatment.
AEs: AE incidence was comparable after treatment with the 0.4-mg dose and placebo, but was greater for the 0.8-mg dose. Mean changes in systolic and diastolic blood pressure did not
differ between placebo and tamsulosin in both hypertensive and normotensive patients.
TAMSULOSIN
Wilt et al., 2003: meta-analysis of RCTs assessing the efficacy
of tamsulosin versus placebo
RESULTS: ______
showed a percentage reduction in symptom score ranging from 20% to 48% and a mean change in PFR ranging from 1.2 to 4 mL/s after tamsulosin therapy
Symptomatic relief was slightly greater with 0.8 mg tamsulosin compared with 0.4 mg tamsulosin;
rates of AEs and treatment withdrawal were dose dependent, and therefore
0.4 mg tamsulosin emerged as the formulation of choice for LUTS treatment.
SILODOSIN: As a uroselective α1-blocker, silodosin has demonstrated the _____.
Chapple et al., 2011: _____
DOSAGE:
highest selectivity for the α1a-AR subtype
Chapple: three-arm European registration trial: confirmed the good efficacy of 8 mg silodosin as compared with placebo and the noninferiority compared with 0.4 mg tamsulosin
DOSAGE: Silodosin is recommended at the daily dose of 8 mg taken with a meal
SILODOSIN:
Ding et al., 2013 and Novara et al., 2013: meta-analyses of phase III RCTs
RESULTS: _______
mean change in terms of IPPS storage symptoms score (–0.85; 95% CI, –1.11 to –0.59),
IPPS voiding symptoms score (–1.81; 95% CI, –2.21 to –1.42),
and QoL score (–0.42; 95% CI, –0.71 to –0.13) that was significantly
greater with silodosin than with placebo,
with no differences between silodosin and 0.4 mg tamsulosin.
NAFTOPIDIL: _______
Overall conclusion: ______
the only compound developed with a distinct selectivity for the α1d-AR subtype; preclinical studies showed a threefold higher selectivity for α1d-AR compared with α1a-AR
good safety profile, with dizziness and hypotension being the most commonly reported AEs
small number of studies and the lack of placebo-controlled trials, a strong conclusion on the efficacy of naftopidil could not be drawn.
TAMSULOSIN vs. ALFUZOSIN
Buzelin et al.
RESULTS:
No differences were observed in terms of both efficacy and tolerability between the drugs, but patients treated with tamsulosin reported a higher rate of retrograde ejaculation.
Both tamsulosin and alfuzosin are uroselective compounds that do not require dose titration and are currently recommended for use at a daily dose of 0.4 mg and 10 mg, respectively
Treatment-emergent AEs associated with α1-blockers are caused by _____.
______ are the most commonly reported AEs according to RCTs.
the effect of every drug on the vascular tissue, CNS, and urogenital system
Overall, dizziness, asthenia, hypotension, and anejaculation
Alpha-blockers: greater incidence of vascular AEs for the _____
nonuroselective compounds terazosin and doxazosin compared with alfuzosin, tamsulosin, and silodosin.
Related to the higher affinity of nonuroselective compounds for the α1b-AR subtype, which is widely present at the level of vascular tissues.
The inhibition of this receptor can lead to a decrease in either systolic or diastolic blood pressure, and to a number of associated events, such as dizziness, asthenia, headache, palpitations, and syncope.
Overall, α1-blockers should be carefully administered in patients taking _____
The concomitant use of α1-blockers with ______ is not recommended.
Physicians should warn patients regarding a risk for ______.
AEs such as dizziness and orthostatic hypotension may lead to ______ in older patients.
antihypertensive medications.
other α-blocker compounds
first-dose hypotension with α1-blockers
AEs such as dizziness and orthostatic hypotension may lead to falls, fractures, and institutionalization in older patients.
Positive effects of α1-blockers on erectile function have been variably observed and ascribed to the beneficial effect of these drugs in terms of _____ and ______
LUTS relief and QoL improvement
*** there is evidence showing that α-AR inhibition within cavernosal tissue may lead to smooth
muscle relaxation and to a consequent enhancement of the erection
Ejaculation disorders associated with α1-blocker therapy, due to: _____(2)
smooth muscle inhibition at the level of the bladder neck was originally considered the main reason for retrograde ejaculation;
furthermore, a direct effect of α1-blockers on seminal vesicles leading to anejaculation has also been proposed
the nonselective compounds _____ and ______ did not show a detrimental effect on ejaculation in RCTs.
doxazosin and terazosin
Tamsulosin vs silodosin in terms of ejaculation disorders
meta-analysis including data from 10 randomized trials, showing that the odds of reporting ejaculation disorders was significantly HIGHER for SILODOSIN than for tamsulosin.
What is IFIS?
Intraoperative floppy iris syndrome (IFIS) was firstly reported after
the intake of tamsulosin
the syndrome occurs during cataract surgery, and is characterized by a
(1) floppy iris that flutters and billows in response to normal intraoperative
fluid movement,
(2) prolapse of iris tissue toward surgical incisions,
(3) progressive intraoperative miosis despite standard preoperative
pupil dilation.
Discontinuation of the use of drug before cataract surgery does NOT significantly reduce the risk for IFIS. Cataract surgeons should ask about either current or previous use of α1-blockers.
North American Finasteride Trial
evaluated the effect of either 1 mg or 5 mg finasteride given once daily for 12
months in 895 patients with BPH
RESULTS: _____
AEs: _____
Data showed significant symptomatic relief in men treated with 5 mg finasteride as compared with placebo, with a maximal decrease of 2.7 points on the Boyarsky scale after 12 months
progressive decrease in PV in both finasteride groups; after 12 months of treatment, the mean reduction in PV from the baseline was 19% in men treated with 5 mg finasteride.
the most frequently observed AEs in the 5-mg group were decreased libido (4.7%) and ejaculatory disorders (4.4%)
Finasteride is a _____.
selective inhibitor of the type 2, 5α-reductase isozyme and is responsible for decreasing
intraprostatic DHT levels without reaching a castration level because of the remaining activity of the type 1 5α-reductase isozyme converting serum testosterone to DHT at the level of the skin and liver
FINASTERIDE
Andersen et al., 1995 2-year multicenter RCT
707 patients with LUTS associated with prostate enlargement on
DRE (mean volume at the baseline, 40 mL) were randomized to
receive 5 mg finasteride or placebo
RESULTS: _____
AEs: ______
Fewer patients in the finasteride group as compared with the placebo group developed urinary retention or needed prostate surgery.
overall rate of AEs was similar between the groups, although a higher rate of sexual dysfunctions was observed in the finasteride group than in the placebo group (19% vs. 10%)
Proscar Long-Term Efficacy and Safety Study (PLESS)
longest-duration multicenter RCT ever reported in terms of BPH medical therapy
The study enrolled 3040 men with a mean PV of 55 mL and moderate to severe symptoms treated with finasteride or placebo and followed up for 4 years
RESULTS: ____
finasteride showed a 51% reduction in the risk for either AUR or surgery compared with patients given placebo
AUR: after 4 years was 7% in the finasteride group and 3% in the placebo group (57% risk reduction).
The PCPT showed that finasteride ____
The PCPT showed that finasteride reduced the incidence of diagnosed PCa (vs. placebo), although an increased incidence of high-grade disease was observed, possibly because of a volume change effect.
*** Finasteride has been demonstrated to significantly decrease serum
PSA levels by approximately 50%
Dutasteride is a _____.
Roehrborn 2002 RCT Results: _____
AEs: _____
DOSE: _____
Dual inhibitor of 5α-reductase types 1 and 2.
the mean reduction in the symptom score from the baseline was
4.5 after dutasteride treatment and 2.3 with placebo
the most frequent AEs were erectile dysfunction and decreased libido, observed in 6% and
3.7% of patients, respectively, after 1 year of treatment; however, these rates significantly DROPPED after 2 years of treatment.
Daily dose of 0.5 mg with or without a meal; a long-term treatment (at least 6 months) is usually needed to observe a clinical benefit
Dutasteride vs. finasteride
SAME in terms of PV and symptom relief and PFR increase
After 1 year of treatment, there was no difference in terms of symptom relief and PFR increase
between patients treated with dutasteride and patients treated
with finasteride;
similarly, the reduction of PV was comparable
between the groups.
REDUCE trial
Andriole 2010
Dutasteride vs. placebo in preventing PCa
RESULTS: _____
There was a 23% relative reduction in the risk for PCa within 4
years of treatment with dutasteride. However, a small increase in
the number of cancers with a Gleason score of 8 or more was
observed in the treatment arm.
*** FDA Oncologic Drugs Advisory Committee voted AGAINST the use of
dutasteride for reducing the risk for PCa, and the manufacturer has
withdrawn the application
Zanoterone is a _____.
a steroidal competitive androgen receptor antagonist
*** observed minimal efficacy and the greater than expected frequency
of AEs led to early trial discontinuation
Flutamide is a _____
a nonsteroidal antiandrogen that inhibits the binding of testosterone and DHT to the androgen receptor.
*** The between-group comparisons of mean changes from the baseline in the investigated outcomes were not statistically significant at any time point.
No significant difference between placebo and flutamide was observed in terms
of any other efficacy outcome.
Cetrorelix is ______
a GnRH antagonist allowing a submaximal, noncastrating
blockade of testosterone and DHT.
Atamestane is ______
Multicenter RCT results:
a highly selective aromatase inhibitor that lowers both serum and intraprostatic levels of estradiol and estrone
no relief of symptoms or improvement of urinary flow parameters. Moreover, a dose-dependent increase in peripheral androgen concentration was observed, and this may be the reason for the lack of efficacy of the drug.
Therapy with finasteride has been associated with a roughly ____
of PV along with modest relief of urinary symptoms and modest improvement of urinary flow parameters as compared with placebo.
Long-term data have shown a ______
20% reduction
51% reduction in the risk for either AUR or surgery for patients treated with finasteride.
*** Both finasteride and dutasteride have a higher efficacy in patients with larger PV;
long-term (≥6 months) treatment is required to observe a significant reduction of PV and a benefit in terms of symptom relief.
In the REDUCE trial and PCPT, a reduction in ____ was observed after therapy with 5ARIs.
However, caused by a concomitant small increase in _____
neither finasteride nor dutasteride are indicated for PCa prevention.
PCa incidence
the detection of high-grade tumors,
International clinical guidelines suggest therapy with 5ARIs for patients with _____
an enlarged prostate (>40 mL) and moderate to severe symptoms.
Muscarinic receptor antagonists are mainly used for the treatment
of patients with OAB syndrome; however, both the European
and the American international clinical guidelines support the
use of these compounds to treat patients with ______.
BOO mainly presenting with storage LUTS
Treatment with tolterodine was compared with placebo was _____
associated with a significant reduction of BOOI compared with
placebo;
significant differences in terms of the volume to the first detrusor contraction (+59 mL; 95% CI, 19 to 100 mL)
maximum cystometric capacity (+67 mL; 95% CI, 35 to 103 mL)
favoring tolterodine over placebo (P < 0.003) were also observed.
*** patients treated with tolterodine as a monotherapy did
not report any significant improvement in terms of measures of
urgency or significant reduction of IPSS compared with patients
who received placebo.
*** Overall, the efficacy of antimuscarinics alone in patients with BOO/
BPH is controversial, although storage symptom relief has been
demonstrated
the use of antimuscarinic drugs may lead to treatment-related side
effects, including_________
dry mouth (≤16%), constipation (≤4%), nasopharyngitis (≤3%), dizziness (≤5%), and CNS side effects (cognitive dysfunction or delirium)
International clinical guidelines suggest the use of antimuscarinic therapy in patients with ____
moderate to severe LUTS who mainly complain of bladder storage symptoms and present with
a baseline PVR volume lower than 200 mL
***antimuscarinics can be safely administered in patients with low PVR volume and no history of AUR.
_____ is the predominant form of β-ARs in the bladder
Its stimulation is responsible for an ______
The β3 subtype
increase in bladder capacity without a significant change in micturition pressure, PVR volume, and voiding contraction
Mirabegron acts as a ______
β3-AR agonist at the level of the bladder, inducing detrusor smooth muscle relaxation and contributing to urine storage
However, because of previous evidence showing a significant increase of ____ among healthy volunteers (Malik et al., 2012), mirabegron is not recommended
for______
systolic blood pressure
patients with uncontrolled hypertension.
International clinical guidelines suggest the use of mirabegron as an option for the treatment of patients with ______
The recommended starting dose is ______
moderate to severe LUTS and prevalent storage symptoms
25 mg daily with or without food, which may be further increased to 50 mg.
Theories supporting PDE5Is in treatment of male LUTS: _______(5)
The inhibition of PDE5 at the level of the endothelial and
smooth muscle cells of blood vessels can lead to increased
oxygenation of both the bladder and the prostate
PDE5Is can relax the prostate and bladder neck smooth muscle
Vardenafil: antiproliferative effect mediated by the cyclic GMP/protein kinase
In rat models, PDE5Is decreased the activity of afferent nerves
in the lower urinary tract, with a hypothesized consequent
decrease in terms of perception of bladder filling and urgency
Tadalafil: reduce prostate inflammation, suggesting that PDE5Is may attenuate
the negative effect of metabolic alterations on prostatic tissue.
TADALAFIL outcomes: ______
Men in the tadalafil group were more likely
to show a 3-point or greater decrease in the IPSS by 12 weeks
than those in the placebo group (60.9% vs. 42.7%).
Urodynamic studies, and meta-analyses of RCTs did NOT report
a significant impact of tadalafil in terms of urodynamic and uroflowmetry
parameters
International clinical guidelines currently suggest PDE5Is as an alternative therapy for men with ______
The only officially licensed PDE5I for the treatment of male LUTS: _____
moderate to severe LUTS, with or without associated erectile dysfunction
Tadalafil
Medical Therapy of Prostatic Symptoms Trial (MTOPS):
Multicenter RCT aimed at assessing the outcomes of both monotherapy with doxazosin or finasteride and combination therapy over a period of NO LESS THAN 4 years
RESULTS: _____
Both doxazosin and finasteride were significantly more effective than placebo in reducing the risk for clinical progression; moreover, combination therapy was even more effective than monotherapy
the risk for AUR was significantly LOWER than with placebo ONLY for the combination therapy and finasteride groups
Compared with placebo, both finasteride and combination therapy reduced the risk for receiving invasive therapy by 64% and 67%, respectively
a reduction of the AUASI score was observed over time in all active treatment groups compared with placebo, with a greater reduction found in the combination therapy group compared with the doxazosin group and the finasteride group
Similarly, PFR increased in all groups.
Medical Therapy of Prostatic Symptoms Trial (MTOPS):
Multicenter RCT aimed at assessing the outcomes of both monotherapy with doxazosin or finasteride and combination therapy over a period of NO LESS THAN 4 years
AEs:
the overall rate of AEs was significantly higher in the combination therapy group as compared with both the placebo group and the monotherapy groups.
However, the rates of each individual side effect were similar to those observed in the monotherapy groups.
Combination of Avodart and Tamsulosin (CombAT) Trial
Investigated whether the combination of dutasteride and tamsulosin was more effective than monotherapy in reducing the risk for AUR and BPH-related surgery
Only men with a PV of 30 mL or greater and a serum PSA level of 1.5 ng/mL or greater were included
Randomized to receive either 0.5 mg dutasteride once daily plus placebo, or 0.4 mg tamsulosin
once daily plus placebo or tamsulosin plus dutasteride for 4 years
RESULTS: _____
Greater risk reduction for AUR and BPH related–surgery both for men treated with the combination therapy and for men treated with dutasteride monotherapy compared with men treated with tamsulosin monotherapy
Treatment with both drugs reduced the risk for AUR by 65.8% as compared with treatment
with tamsulosin alone
Combination Therapy:
Both the MTOPS trial and the CombAT trial support the therapeutic advantage of the combination of 5ARIs and α1-blockers to treat patients with _______
moderate to severe LUTS at high risk for BPH clinical progression (PV ≥ 30 to 40 mL and PSA level ≥1.5 ng/mL) as now suggested by international guidelines
According to the results of the Symptoms Management After Reducing Therapy (SMART) trial, use of α1-blockers may be discontinued after ____ of successful combination therapy without symptom deterioration being expected
6 months
Phytotherapy: Two agents have been mainly investigated in preclinical studies:
africanum)
MOA: _____
the extract of the BERRY of the American dwarf palm (saw palmetto, Serenoa repens) and the extract from the BARK of the African plum tree (Pygeum africanum)
MOA: The anti-inflammatory effect of plant extracts is caused by the inhibition of cyclooxygenases and lipoxygenases in the eicosanoid cascade.
The antiandrogenic action of Serenoa repens has been associated
with the following: ______
• Inhibition of 5α-reductase isoenzymes I and II
• Inhibition of DHT binding to the cytosolic androgen receptor
• Inhibition of nuclear estrogen receptors in prostatic tissue
• Modulation of prolactin-induced prostatic growth by receptor
signal transduction
Overall, these results suggest that Serenoa repens therapy ______
does NOT relieve LUTS or increase PFR compared with placebo in men with BPH, even at double or triple the usual dose.
The initial management of AUR consists of______
Immediate bladder decompression by catheterization.
After catheterization, patients could undergo either immediate surgery or a TWOC.
A high rate of patients with a successful TWOC will experience a subsequent
AUR episode, with ____ of them failing to void within _____
80% of them failing to void within 6 months
** At this point, pressure-flow studies and surgery are indicated.
Factors associated with a HIGH risk of TWOC failure (3):
Advanced age, severe LUTS, and large volume drained at catheterization
(≥1 L) are all factors associated with a higher risk for TWOC
failure;
Longitudinal population-based studies provided data showing
that BPH is a _____
Olmsted Study: 2115 men 40 to 79 years of age followed up for 12
years; RESULTS: ______
Progressive disease
Olmsted results:
Average IPSS increase of 0.18 points per year,
A decrease in PFR of 2% per year,
And a prostate growth rate of 1.9% per year
BPH may lead to serious events other than symptom deterioration, including AUR, hypoactive detrusor activity, and eventually hydronephrosis.
