dr. boyke subali, spu rsu. a. wahab sjahranie - samarinda
TRANSCRIPT
Current Strategic on BPH Management – Combination
Therapy
Dr. Boyke Subali, SpURSU. A. Wahab Sjahranie - Samarinda
PrevalenceSub Tittle
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When should BPH be considered as a disease?
Current Treatment of BPH
Prevalence of Histologic BPH Increases with Age
Roehrborn CG, et al.International Journal of Impotence Research.2008; 20: S11–S18
BPH influenced Daily activities
Garraway WM, et al. Br J Gen Pract. 1993;43(373):318-321.
Prostatic parcYes!
When should BPH be considered as a disease?
Bothersome symptoms?
When should BPH be considered as a disease?
Benign Prostate Hyperplasia (BPH)Benign prostatic hyperplasia (BPH) is a pathologic process that contributes to, but is not the sole cause of, lower urinary tract symptoms (LUTS) in aging menBenign prostatic hyperplasia is defined histologically as a disease process characterized by stromal and epithelial cell hyperplasia.Originates from transition zone
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AUA Guideline. J Urol.2003;170:530-547Roehrborn CG. International Journal of Impotence Research.2008;20:S11–S18
Lee KL et al. J Urol 2004;172:1784–1791
BPH is characterised by non-malignant
enlargement of the prostate
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Hypertrophieddetrusormuscle
Obstructedurinary flow
Prostate
Bladder
Urethra
Normal BPH
Enlargementof the prostate
Adapted from Kirby RS et al. Benign Prostatic Hyperplasia. Health Press, Oxford, 1999 available at: http://www.glaxosmithkline.rs/vasezdravlje-bph.html
BPH is caused by an imbalance of cell proliferation (growth) and apoptotic (death) signals – leads to increase in
number of prostate cells and prostate size
DHT-androgen receptor complex
Growth factors
Unbalanced
DHT T
5α-reductasetypes 1 and 2
Serum DHT Serum testosterone (T)
Prostatecell
Increasedcell growth
Cell death
8Adapted from Kirby RS, McConnell. Benign Prostatic Hyperplasia. Health Press Ltd, 1999
BPH, LUTS, BPE and BOOClinical, anatomical, and pathophysiological changes
BPH = Benign Prostatic Hyperplasia Histological: stromoglandular
hyperplasia May be associated with
Clinical: presence of bothersome LUTS2
Anatomical: enlargement of the gland (BPE = Benign Prostatic Enlargement)2
Pathophysiological: compression of urethra and compromise of urinary flow (BOO = Bladder Outlet Obstruction)2
Nordling J et al. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK: Health Publication Ltd; 2001:107-166.
Histological BPH
All Men>40 y
`BOOObstruction
BPEEnlargement
LUTS/Bother
BPH can cause lower urinary tract symptoms (LUTS)
Voiding symptoms, caused by an enlarged prostate Weak urinary stream Prolonged voiding Abdominal straining Hesitancy Intermittency Incomplete bladder emptying Terminal and post-void
dribbling
BPH symptoms may include:
Storage symptoms, which can result from enlarged prostate or overactive bladder (OAB) Frequency Nocturia Urgency Incontinence
LUTS are not specific to BPH – not all men with LUTS have BPH and not all men with BPH have LUTS
Associated symptoms of BPH include: Dysuria Haematuria Haematospermia
Diagnostic tests recommended by the EAU BPH guidelines
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Medical history Symptom score Physical examination (incl. DRE) PSA Creatinine measurement* Urinalysis Flow rate** Post-void residual volume**
EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547
*Not recommended by the AUA guidelines** Considered optional in the AUA guidelines
Symptoms scoreEvaluating symptom severity is an important part of the initial assessment
Symptom severity is probably best assessed through the use of a validated symptom score
The internationale standard instrument is the International Prostate Symptom Score (IPSS)
The IPSS comprises of 8 questions: 7 questions about the severity of symptoms
These are identical to the 7 questions of the AUA Symptom Index*
1 question on global quality of life
12EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547
*The AUA guidelines recommend use of the AUA-SI (7 questions)
IPSS questionnaire
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Over the past month, how often have you… Not at all Less than 1 time in 5
Less than half the time
About half the
time
More than half the time
Almost always
YOUR SCORE
1. …had a sensation of not emptying your bladder completely after you finish urinating?
0 1 2 3 4 5
2. …had to urinate again less than two hours after you finished urinating?
0 1 2 3 4 5
3. …stopped and started again several times when you urinated?
0 1 2 3 4 5
4. …found it difficult to postpone urination? 0 1 2 3 4 5
5. …had a weak urinary stream? 0 1 2 3 4 5
6. …had to push or strain to begin urination? 0 1 2 3 4 5
7. Over the past month, how many times did you most typically get up to urinate from the time you went to bed at night until the time you got up in the morning?
None Once Twice 3 times 4 times 5 times or more
TOTAL
8. QUALITY OF LIFE DUE TO URINARY SYMPTOMSIf you were to spend the rest of your life with your urinary condition the way it is now, how would you feel about that?
Delighted Pleased Mostly satisfied
Mixed – about equally satisfied & dissatisfied
Mostly dissatisfied
Unhappy Terrible
0 1 2 3 4 5 6
Total IPSS indicates symptom severity
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Total IPSS Symptom severity
0–7 Mild
8–19 Moderate
20 Severe
EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554
Physical examinationPhysical examination during the initial assessment of a man with LUTS suggestive of BPH should include:
Focused neurological examination Digital rectal examination (DRE)
To help evaluate prostate size To help exclude the presence of prostate cancer,
as well as prostatitis and other pelvic pathologies
15EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554
The clinical utility of PSA in assessing men with LUTS
suggestive of BPH
Strong relationship between serum PSA and prostate volume enables clinicians to estimate prostate size in BPH patients
Serum PSA thresholds can be used to predict the presence of a prostate >30ml or >40ml with sensitivity between 60-70% and specificity 70%.
Along with current prostate size, serum PSA provides prognostic information about:
Prostate growth Symptoms and bother deterioration Sexual dysfunction Flow rate worsening Risk for AUR and surgery
In general higher levels of serum PSA indicate faster and greater risk for progression 16
Roehrborn CG. Int J Impot Res 2008; 20: s19–26
UrinalysisAlthough benign prostatic obstruction is the most frequent cause of LUTS in men, LUTS can also be caused by urinary tract infection or bladder cancer
The absence of haematuria or pyruria on urinalysis helps to rule out these conditions
Guidelines recommend urinalysis to aid differential diagnosis
17EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547
Flow rate determined by uroflowmetry
Uroflowmetry is a simple non-invasive test that can reveal abnormal voiding.Serial flows (two or more) with a voided volume exceeding 150 ml are recommended to obtain a representative flow test.
LUTS in the presence of a normal peak flow rate (Qmax= 15ml/s) are more likely to have a non-BPH-related cause, and men with Qmax <10 ml/sec are more likely to have urodynamic obstruction
Uroflowmetry is recommended by the EAU as part of the initial assessment of a man with LUTS, as well as being required prior to prostatectomy
Uroflowmetry is considered by the AUA to be an option following the initial patient evaluation
18EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547
Measurement of post-void residual (PVR) volume
Measurement of PVR urine is recommended by the EAU guidelines and considered optional by the AUA
PVR volume is calculated by measurement of bladder height, width and length obtained by
transabdominal ultrasonography This is a simple, accurate and non-invasive method
Large PVR volumes (>200 mL) may indicate bladder dysfunction and predict a less favourable response to BPH treatment
EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–55419
Current Treatment of BPH
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Aims of treatment: EAU and AUA guidelines
The aim of therapy is to improve lower urinary tract symptoms (LUTS) and quality of life, and to prevent BPE/BPO-related complications such as urinary retention or upper urinary tract dilatation (EAU)
The patient's perception of the severity of the condition, as well as the degree to which it interferes with his lifestyle or causes embarrassment, should be the primary consideration in choosing therapy (AUA)
EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547
BPE = Benign prostatic enlargementBPO = Benign prostatic obstruction
Treatment – initial management
Initial management of men with LUTS suggestive of BPH can be categorized into:
Watchful waiting Medical therapy Surgical management Non-surgical intervention / Minimally invasive therapy
EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547
ManagementThe following are important components of WW:
Education
Reassurance
Periodic monitoring
Lifestyle modifications
Brown C et al. Curr Opin Urol 2004; 14: 7–12
Medical therapy The following medical treatments are
recommended for BPH treatment :
Alpha blockers (as monotherapy)
5 alpha-reductase inhibitors - 5ARIs (as monotherapy)
Combination therapy
EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547
Need for a new approach
Dependence on alpha-blocker monotherapy is failing a proportion of men with BPHNeed to move away from ‘one-size-fits-all’ medicine to a more personalised approachNeed for tailored solutions consistent with treatment guidelinesAppropriate treatment needed for men with moderate symptoms onwards, prostate volume ≥30 ml and PSA ≥1.5 ng/mlEmberton M et al. BJU Int 2011 Jan 25. doi: 10.1111/j.1464-410X.2010.10041.x
What is the optimal treatment for men with moderate symptoms
onwards, prostate volume ≥30 ml and PSA ≥1.5 ng/ml?
CombAT study provides insights into treatment of men with moderate symptoms onwards, prostate volume ≥30 ml and PSA ≥1.5 ng/mlEntry criteria for CombAT:
Male aged ≥50 years Diagnosis of BPH by history and DRE IPSS ≥12 (moderate-to-severe symptoms) Prostate volume ≥30 cc by TRUS Serum PSA 1.5–10.0 ng/ml Two voids at screening with Qmax >5 and
≤15 ml/sec (moderate-to-severe impairment) and minimum voided volume of ≥125 mlSiami P et al. Contemp Clin Trials 2007;28:770–
779
What can we learn from the CombAT data?
What benefit does combination therapy with dutasteride and tamsulosin have on:
Symptoms? Quality of life? Risk of long-term complications such as AUR and
BPH-related surgery?
Baseline
Study month
Ad
jus
ted
me
an c
han
ge
fro
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asel
ine
in I
PS
S
Superior symptom relief with combination therapy with
dutasteride and tamsulosin versus either monotherapy
Roehrborn CG et al. Eur Urol 2010;57:123–131; Barry MJ et al. J Urol 1995;154:1770–74
Tamsulosin (n = 1582)Dutasteride (n = 1592)Combination (n = 1575)
p <0.001 combination versus tamsulosin
p <0.001 combination versus dutasteride
2421181512963 27 30 33 36 39 42 45 48
0.0
-1.0
-2.0
-3.0
-4.0
-5.0
-6.0
-7.0
-8.0
-6.3-6.3-6.3-6.3-6.2-6.2-6.2-6.0-6.0
-6.4 -6.5
-5.6-5.4
-4.8-4.8
-5.4 -5.3-5.3 -5.2-5.2-5.2-5.3-5.1-5.0 -4.9-4.9-4.8
-4.5
-4.7-4.4
-4.5 -4.4 -4.4-4.3-4.1 -4.2
-4.0 -4.0-3.8 -3.8 -3.8
-4.5-4.8
-4.2-4.0
-3.4
-2.8
-6.4
Symptom improvement of at least 3 units is generally considered to be perceptible for the patient and
accepted as the minimum threshold of clinical relevance
Symptom improvement with combination therapy starts as
rapidly as tamsulosin monotherapy
Patients with LUTS consider storage symptoms to be most bothersome symptoms
All symptoms
Dysuria
Postmicturition dribble
Incomplete emptying
Straining
Hesitancy
Weak stream
Stress incontinence
Urge incontinence
Overflow or other incontinence
Urgency
Nocturia
Daytime frequency
0.00.51.01.52.02.53.03.54.0
Storagesymptoms
Häkkinen JT et al. Eur Urol 2007;51:473–478
n=1803 to 2046, depending on the symptomBother index
Combination therapy with dutasteride and tamsulosin superior to both monotherapies at 4 years:
Storage symptoms
Combination Tamsulosin Dutasteride
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
-2.3
-1.4
-1.9
Adjusted mean change from baseline in IPSS storage score
*p<0.001 versus combination
*
*
Montorsi F et al. BJU Int 2011 Feb 23; DOI: 10.1111/j.1464-410X.2011.10129.x
Many men with moderate-to-severe symptoms (IPSS ≥8) have both storage and voiding symptoms:
findings from a population-based survey
Glasser DB et al. Int J Clin Pract 2007;61:1294–1300
Age (years)
Prevalence of LUTS subtypes (%)
40–49_x000d_(
n=130)
50–59_x000d_(
n=125)
60–69_x000d_(
n=115)
≥70_x000d_(n=111)
Total_x000d_(n=481)
0%
20%
40%
60%
80%
100%
32% 33% 32%20%
29%
37% 33% 35%46%
38%
19% 27% 20% 26% 23%
Voiding Mixed Storage
Storage symptoms: sum of scores on IPSS items 2, 4 and 7 was ≥4 and score on item 4 (i.e. urgency) was ≥1Voiding symptoms: sum of scores on IPSS items 1, 3, 5 and 6 was ≥5Mixed symptoms: criteria met for both storage and voiding symptoms
Combination therapy with dutasteride and tamsulosin superior to both monotherapies at
4 years:Voiding symptoms
Combination Tamsulosin Dutasteride
-4.5
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
-4.0
-2.4
-3.5
Adjusted mean change from baseline in IPSS voiding score
*p<0.001 versus combination
*
*
Montorsi F et al. BJU Int 2011 Feb 23; DOI: 10.1111/j.1464-410X.2011.10129.x
Symptoms: What can we conclude?
Over 4 years, combination therapy with dutasteride and tamsulosin provided significantly superior symptom improvement compared with either monotherapy for:
Total symptoms Storage symptoms Voiding symptoms
Symptom improvement starts as rapidly as tamsulosin monotherapy
The BIIA disease-specific 4-item instrument that measures the impact of LUTS on
Physical discomfort Worry about health Degree of bother Limitations of daily activities
Total scores range from 0 (no impact) to 13 (highest negative impact)
Montorsi F et al. Int J Clin Pract 2010;64:1042–1051
BII: combination therapy with dutasteride and tamsulosin superior to both
monotherapies at 4 years
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48-2.5
-2.0
-1.5
-1.0
-0.5
0.0Adjusted mean change from baseline in BII
p≤0.008 combination versus tamsulosin
Month
p≤0.003 combination versus dutasteride
Montorsi F et al. Int J Clin Pract 2010;64:1042–1051
TamsulosinDutasterideCombination
-1.2
-1.8
-2.2
Mean baseline BII = 5.3
The PPSM questionnaire was developedby GSK to assess patient satisfactionwith treatment in the CombAT study
12 questions covering six areas Control of urinary symptoms Strength of urinary stream Two aspects of pain of urination Effect on usual activities Overall satisfaction Whether the respondent would ask their doctor for
this medicationPPSM total score ranges from 7 (best) to 49 (worst) Question 12: possible responses are yes, no and not
sure
Montorsi F et al. Int J Clin Pract 2010;64:1042–1051; Black L et al. Health Qual Life Outcomes 2009;7:55
PPSM total score: combination therapy with dutasteride and tamsulosin superior to both
monotherapies at 4 years
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48-8.0
-7.0
-6.0
-5.0
-4.0
-3.0
-2.0
-1.0
0.0Adjusted mean change from baseline in PPSM total score
Month
p<0.001 combination versus dutasteride
Montorsi F et al. Int J Clin Pract 2010;64:1042–1051
p<0.001 combination versus tamsulosin
TamsulosinDutasterideCombination
-4.1
-5.5
-7.0
Mean baseline PPSM total score = 25
Satisfaction with treatment (PPSM Q11): combination therapy with dutasteride and
tamsulosin superior to both monotherapies at 4 years
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 4830%
40%
50%
60%
70%
80%
90%Percentage of patients satisfied with treatment
p<0.001 combination versus tamsulosin
Month
p≤0.002 combination versus dutasteride
Montorsi F et al. Int J Clin Pract 2010;64:1042–1051
0%
TamsulosinDutasterideCombination
80%
74%
69%
PPSM Q12: Would you ask your doctor for the medication you received in the
study?
Combination Tamsulosin Dutasteride0%
20%
40%
60%
80%
100%
64%
55%58%
Montorsi F et al. Int J Clin Pract 2010;64:1042–1051
Percentage of patients responding ‘Yes’
*p<0.01 versus combination
* *
QoL: What can we conclude?
Combination therapy with dutasteride and tamsulosin provides significantly superior improvements in patient-reported QoL and treatment satisfaction than either monotherapy
Improved overall QoL (IPSS Q8) Reduced impact of BPH (BII) Improved treatment satisfaction (PPSM)
Superiority of combination therapy versus both monotherapies was sustained out to 4 years
16141210
86420
0 12 24 36 48Time (months)
Per
cen
t o
f p
atie
nts
CombinationDutasterideTamsulosin
291610
271623
401611
431457
491484
1021464
581347
651365
1461307
671274
841277
1911176
CombinationCumulative no. of eventsNo. at riskDutasterideCumulative no. of eventsNo. at riskTamsulosinCumulative no. of eventsNo. at risk
CombAT 4-year primary endpoint:
Time to first AUR or BPH-related surgery
Roehrborn CG et al. Eur Urol 2010;57:123–131
8 months
ConclusionsIn men with moderate symptoms onwards with prostate volume ≥30 ml and PSA ≥1.5 ng/ml, CombAT shows that over 4 years, combination therapy with dutasteride and tamsulosin
Significantly improves symptoms and QoL versus either monotherapy
Significantly reduces the risk of AUR or BPH-related surgery versus tamsulosin monotherapy
431Madersbacher S et al. Eur Urol 2004;46:547–554; 2Roehrborn CG et al. Eur Urol 2010;57:123–131; 3Montorsi F et al. Int J Clin Pract 2010; 4Emberton M et al. Int J Clin Pract 2008; 62: 18–26
Implications of CombAT study: What do these results mean
for patients?Men with BPH/LUTS may experience a substantial reduction in their quality of life
In many men, the progressive course of BPH raises the prospect of worsening symptoms, AUR and the need for surgery4
Major goals of BPH treatment include improvement of symptom scores, lowering risk of disease progression, improving patient-reported quality of life and treatment satisfaction1
In the CombAT study, combination therapy was associated with: Improvement of symptoms2 Reduced risk of BPH clinical progression2 Reduced risk of AUR or BPH-related surgery2
Improved patient-reported health outcomes3
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