La terapia medica dell’IPB - · PDF fileDjavan et al. Urology2004
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Transcript of La terapia medica dell’IPB - · PDF fileDjavan et al. Urology2004
![Page 1: La terapia medica dell’IPB - · PDF fileDjavan et al. Urology2004](https://reader033.fdocument.pub/reader033/viewer/2022051406/5aba254a7f8b9a684c8eaa74/html5/thumbnails/1.jpg)
La terapia medica dell’IPB
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IPB IPB èè una malattiauna malattiache progredisce nel tempoche progredisce nel tempo
Olmsted County study: IPSS + 0,34/annoPLESS : 7% AUR in 4 anniMTOPS: 18 % Progressione
Componente prostatica effetto massa
Componente vescicale deterioramento funzionale
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Progressione dell’ IPB
Incidenza di ritenzione urinaria acuta
Incidenza di chirurgia IPB-correlata
Fattori di rischio di progressione
Età: >62 anni *PSA: > 1,6 ng/mL *TRUS: > 31 mL *Qmax: <10,6 mL/secAUASS: >17PVR: >39 mL* p< 0,05 MTOPS
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Alterazioni morfologiche del detrusorein pazienti ostruiti
BPH
“Ipertrofia cellulare”“Spazi intercellulari più ampi”“Incrementato deposito di collagene”
Detrusore normale
Pattern mioipertrofico
Elbadawi et al.J Urol 150: 1681, 1993
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Terapia medica EBMAUA/EAU guidelines
α1-liticiAlfu-tera-doxa-tamsulo
Inibitori 5α-reduttasiFinasteride-Dutasteride
Terapia di combinazione
α1-litici + I5AR
MTOPS
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Medical Therapy
Two-Drug Therapy Activates Two Distinct and Complementary Mechanisms of Action
Alpha blockers 5-Alpha reductase inhibitors
Improve symptoms and increase urinary flow rate by relaxingprostatic and bladder-neck smooth musclethrough sympathetic activity blockade
Improve symptoms, increase urinary flow rate, and prevent BPH outcomes by reducing prostate enlargementthrough hormonal mechanisms
Adapted from Roehrborn CG Curr Opin Urol 2001;11:17-25; National Cancer Institute. NIH Publication No. 99-4303, 1999.
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Alfa-litici
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Alfa-litici
Distribuzione dei recettori α1nelle basse vie urinarie
TRIALS
Roehborn et al Urology 1996- TERAZOSIN VS PLACEBO
McNeil et al. BJU Int 1999- ALFUZOSIN VS PLACEBO
Chapple et al. Curr Opin Urol 2001 - ALFUZOSIN VS PLACEBO
Djavan et al. Urology 2004
Roehborn et al BJU Int 2006 ALTESS- ALFUZOSIN VS PLACEBO
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Studio ALTESS
Reclutamento e randomizzazione
Screenatin=2.746
Screenatin=2.746
Randomizzati (Giorno 0)n=1.522
Randomizzati (Giorno 0)n=1.522
Placebon=763
Placebon=763
Alfuzosina 10 mg ODn=759
Alfuzosina 10 mg ODn=759
Follow up: 2 anni
Roehrborn CG et al. BJU Int 2006;97:734-741
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Studio ALTESSMiglioramento dell’IPSS su 2 anni
-7 -6 -5 -4 -3 -2 -1 0
4,7
5,9Alfuzosina
Placebo
*p=0,0017
Miglioramento medio dell’IPSS dal basale
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Studio ALTESSMiglioramento della QoL su 2 anni
-1,5 -1,2 -0,9 -0,6 -0,3 0
0,9
1,3Alfuzosina
Placebo
Miglioramento medio del bother dal basale
*p=0,0001
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Studio ALTESSMiglioramento del Qmax (Mese 12)
0 0,5 1 1,5 2
1,3
2,0Alfuzosina
Placebo
Miglioramento medio del Qmax dal basale
*p=0,001
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Studio ALTESSIncidenza cumulativa di RUA
0
0,005
0,01
0,015
0,02
0,025
0,03
0 90 180 270 360 450 540 630 720
% c
on e
vent
i
Placebo
Alfuzosina
Log rank test p=0,82
Giorni
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Studio ALTESSIncidenza cumulativa di chirurgia
0
0,01
0,02
0,03
0,04
0,05
0,06
0,07
0 90 180 270 360 450 540 630 720
-22%
% c
on e
vent
i
Giorni
Placebo
Alfuzosina
Log rank test p=0,28
Roehrborn CG et al. BJU Int 2006; 97:734-741
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% c
on e
vent
i
Anni dalla randomizzazione
Studio MTOPSIncidenza cumulativa di chirurgia
p<0,0001 ; df=3
00
22
44
66
88
1100
00..00 00..55 11..00 11..55 22..00 22..55 33..00 33..55 44..00 44..55 55..00 55..55
PlaceboPlacebo DoxazosinaDoxazosina FinasterideFinasteride AssociazioneAssociazione
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Quale alpha-litico ?
EAU Guidelines 2007
There is no difference between differentalpha-blockers (tamsulosin, doxazosin, terazosin, alfuzosin) in terms of efficacy
Altough the side-effect profiles for some drugs are reported to be more favourable, supportive data are weak
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Inibitori 5 alpha-reduttasi
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Ruolo dei 5ARI
La 5α-reduttasi (5AR) esiste in 2 isoenzimi: tipo 1 (5AR1) e tipo 2 (5AR2)
DHTTestosterone
5AR2
5AR1
Ingrossamento della prostata
Russell et al. Annu Rev Biochem 1994;63:25–61
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Meccanismo d’azione della finasteride
DHT-androgen receptor complex
DHT
TestosteroneCellulaprostatica
5AR1 5AR2
Finasteride
Morte cellulareMaggior crescita
cellulare
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Meccanismo d’azione della dutasteride
TestosteroneCellulaprostatica
Maggior crescitacellulare Morte cellulare
5AR1 5AR2Dutasteride Dutasteride
DHT
DHT-androgen receptor complex
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5ARI trials
Andersen et al. Urology 1995Lepor et al. N Engl J Med 1996Nickel et al. CMAJ 1996 PROSPECTMcConnell et al N Engl J Med 1998 PLESSLowe et al. Urology 2003
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“The effect of FINASTERIDE on the risk of acute urinary retention and the need for surgical treatment
among men with benign prostatic hyperplasia”PLESS study
McConnell et al N Engl J Med 1998
Symptom score
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PLESS study
Maximal Urinary Flow Rate
N Engl J Med 1998
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PLESS study
Probability of Surgery
N Engl J Med 1998
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PLESS studyProbability of Acute Urinary Retention
N Engl J Med 1998
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PCPT: PCPT: RiduzioneRiduzione delldell’’incidenzaincidenza del del Carcinoma Carcinoma ProstaticoProstatico ((PCaPCa) con i 5ARI) con i 5ARI
Nel Prostate Cancer Prevention Trial (PCPT), 18.882 uominisono stati randomizzati a ricevere il 5 ARI selettivo per iltipo-2, finasteride, 5 mg/giorno o il placebo per 7 anni.
Nel gruppo con finasteride, l’incidenza di PCa è stata ridottadel 24.8% (p<0.001) in confronto al gruppo placebo.
L’incidenza di tumori di grado elevato (Gleason grade 7–10), tuttavia, è più alta nel gruppo con finasteriderispetto al placebo (6.4% vs. 5.1%, p=0.005).
Thompson et al. N Engl J Med 2003;349(3):215–24
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“Efficacy and safety of long-term treatment with the dual 5 alpha-reductase inhibitor DUTASTERIDE in men with
symptomatic benign prostatic hyperplasia”Debruyne et al Eur Urol 2004
3 large-scale, randomised, placebo-controlledPhase III studies
BPH related surgery
Urinary symptoms
TPV
Risk of AUR
Flow rate
Aria 3001Aria 3002Arib 3003
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Maggiore soppressione dei livelli di DHT osservaticon dutasteride in confronto con finasteride
Soppressione media (± SD) di DHT dopo 24 settimane di terapia
Dutasteride 0.5 mg/day Finasteride 5.0 mg/day
-94.7%± 3.3%
-70.8%± 18.3%p<0.001
Clark et al. J Clin Endocrinol Metab 2004; 89: 2179–84
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Dutasteride Dutasteride versus versus FinasterideFinasterideIPSSIPSS
23.3%
43.3%
0
10
20
30
40
50
Finasteride (n=120)
Dutasteride (n=120)
Pazienti (%)p=0.0016
Ogni decremento nel punteggio AUA-SI a 3 mesi
Hagerty, Ginsberg and Harkaway. EAU 2004
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Miglioramento dell’ AUA-SI Score a 4 anni con Dutasteride vs.
Finasteride0
-1
-2
-3
-4
-5
-6
-7
Dutasteride
Finasteride
Variazione dell’ AUA-SI score a 4 anni-6.5
-3.3
Debruyne et al. Eur Urol 2004:46;488–95McConnell et al. N Engl J Med 1998;338:557–63 Confronto indiretto di dutasteride dati a 4 anni vs. PLESS
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Riduzione del Riduzione del VOLUME PROSTATICOVOLUME PROSTATICOa 4 a 4 annianni con con DutasterideDutasteride vs.vs.
FinasterideFinasteride
-30%
-25%
-20%
-15%
-10%
-5%
0%
Dutasteride
Finasteride-27.3%
-18%
% riduzione del PV a 4 anni
Debruyne et al. Eur Urol 2004:46;488–95 McConnell et al. N Engl J Med 1998;338:557–63 Confronto indiretto di dutasteride dati a 4 anni vs. PLESS
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Miglioramento del Miglioramento del QQmaxmax a 4 a 4 annianni con con DutasterideDutasteride vs.vs. FinasterideFinasteride
0.0
0.5
1.0
1.5
2.0
2.5
3.0Dutasteride
Finasteride
Aumento del Qmax a 4 anni (mL/sec)
+2.7+1.9
Debruyne et al. Eur Urol 2004:46;488–95McConnell et al. N Engl J Med 1998;338:557–63 Confronto indiretto di dutasteride dati a 4 anni vs. PLESS
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Rischio di AUR e di CHIRURGIA con Dutasteride vs. Finasteride
1.9%2.2%
2.8%
4.6%
0%
1%
2%
3%
4%
5%Incidenza di AUR e chirurgia
Dutasteride
Finasteride
AUR Chirurgia
Roehrborn et al. Urology 2002:60;434–41McConnell et al. N Engl J Med 1998;338:557–63 Confronto indiretto di dutasteride dati a 4 anni vs. PLESS
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Terapia combinataalfa-litici + 5ARI
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Terapia combinata: il meglio di due mondi?
5ARIs α-bloccanti
Riduzione del VP
Mantenimento della riduzione del VP
Miglioramento dei sintomi e del flusso
Sollievo dai sintomi in 1-2 settimane
Conservato miglioramento dei sintomie del flusso
Prevenzione della progressione sintomatica
Riduzione a lungo termine del rischio di RUAe di intervento chirurgico
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MTOPS (Medical Therapy Of Prostatic Symptoms)
Study Design: OverviewDouble-blind, placebo-controlled, multicenter, randomized Average follow-up: 4.5 years
RandomizedN=3047
Entry Criteria• Men ≥50 years of age• AUA symptom score 8–30• Qmax 4–15 ml/sec• Voided volume ≥125 ml
Doxazosin(n=756)
PROSCAR™
(n=768)
PROSCAR +doxazosin
(n=786)
Placebo(n=737)
AUA=American Urological Association; Qmax=maximum urinary flowAdapted from Bautista OM et al Control Clin Trials 2003;24:224-243.
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Studio MTOPSvariazione dell’IPSS a 4 anni
Valore mediano basale dell’AUA SI = 17,0
Associazione
Placebo
Doxazosina
Finasteride
4,0
6,0
5,0
7,0
(p<0,001)
(p<0,047)
(p<0,001)
2 4 6 8 10Riduzione mediana dal basale
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Studio MTOPS
Variazione del Qmax a 4 anni
Placebo 1,4
2,5
2,2
3,7
(p<0,001)
(p<0,047)
(p<0,001)Associazione
Doxazosina
Finasteride
1 2 3 4
Valore mediano basale del Qmax = 10,6
Riduzione mediana dal basale5
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Studio MTOPSincidenza cumulativa di RUA
4
3,5
3
2,5
Inci
denz
a
2
1,5
p=0,009
p<0,001
1
0,5
0
0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5 4,0 4,5 5,0 5,5
Anni dalla randomizzazione
Placebo FinasterideDoxazosina Associazione
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% c
on e
vent
i
Anni dalla randomizzazione
Studio MTOPSIncidenza cumulativa di chirurgia
p<0,0001 ; df=3
00
22
44
66
88
1100
00..00 00..55 11..00 11..55 22..00 22..55 33..00 33..55 44..00 44..55 55..00 55..55
PlaceboPlacebo DoxazosinaDoxazosina FinasterideFinasteride AssociazioneAssociazione
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MTOPS (Medical Therapy Of Prostatic Symptoms)
ConclusionsCombination therapy is the most effective form of medical
therapy for BPH66% reduction in risk of BPH progression (p<0.001*)64% reduction in worsening symptoms (p<0.001*)81% reduction in risk of AUR (p<0.001*)67% reduction in need for invasive BPH therapy (p<0.001*)
Long-term monotherapy and combination therapy were well tolerated and effective
*vs. placebo at 4 years Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396.
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Tutti i pazienti con IPB dovrebberoessere trattati con un’associazione?
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Aumento dell’AUA Symptom Score (≥4)Rapporto con il volume prostatico
0
5
10
15
20
25
Inci
denz
a cu
mul
ativ
a (%
<20 20-40 >40
Volume prostatico mediante TRUS (cc)
Placebo Dox Fin Comb
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Aumento dell’AUA Symptom Score (≥4)Rapporto con i valori di PSA
02468
1012141618
Cum
ulat
ive
Inci
denc
e (%
)
<1,4 1,4-3,9 >=4,0
Baseline Serum PSA (ng/ml)
Placebo Dox Fin Comb
PSA basale (ng/mL)
Inci
denz
a cu
mul
ativ
a (%
)
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Ritenzione Urinaria AcutaRapporto con il volume prostatico
0
0,5
1
1,5
2
2,5
3
3,5
Cum
ulat
ive
Inci
denc
e (%
)
<20 20-40 >40
Prostate Volume by TRUS (cc)
Placebo Dox Fin Comb
Volume prostatico mediante TRUS (cc)
Inci
denz
a cu
mul
ativ
a (%
)
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Ritenzione Urinaria AcutaRapporto con i livelli di PSA
0
1
2
3
4
5
6
Cum
ulat
ive
Inci
denc
e (%
)
<1,4 1,4-3,9 >=4,0
Baseline Serum PSA (ng/ml)
Placebo Dox Fin Comb
PSA basale (ng/mL)
Inci
denz
a cu
mul
ativ
a (%
)
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Terapia chirurgica dell’IPBRapporto con il volume prostatico
0123456789
10
Cum
ulat
ive
Inci
denc
e (%
)
<20 20-40 >40
Prostate Volume by TRUS (cc)
Placebo Dox Fin Comb
Volume prostatico mediante TRUS (cc)
Inci
denz
a cu
mul
ativ
a (%
)
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Terapia chirurgica dell’IPBRapporto con i livelli di PSA
0
2
4
6
8
10
12
Cum
ulat
ive
Inci
denc
e (%
)
<1.4 1.4-3.9 >=4.0
Baseline Serum PSA (ng/ml)
Placebo Dox Fin Comb
PSA basale (ng/mL)
Inci
denz
a cu
mul
ativ
a (%
)
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Studio MTOPS: incidenza cumulativa di progressione
0
5
0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5 4,0 4,5 5,0 5,5
10
15
20
Raddoppiano i costiAumenta il rischio di effetti collaterali
Per <10% riduzione delrischio di progressione
Anni dalla randomizzazione
Paz
ient
icon
eve
nti(
%)
Placebo FinasterideDoxazosina Associazione
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Studio MTOPS: effetti collaterali più frequenti
Incidenza su 100 pz/anno AssociazioneFinasterideDoxazosinaPlacebo
0,7*
0,9*
1,3*
1,4*
3,4*
2,8*
4,6*
4,6*
5,9*
5,6*
0,50,50,3Sincope
0,40,9*0,4Sonnolenza
0,61,00,6Dispnea
0,81,00,7Edema periferico
1,9*1,20,9Disturbi eiaculazione
2,5*1,71,5Riduzione libido
1,74,5*2,2Astenia
2,74,4*2,5Ipotensione ortostatica
2,54,8*2,5Vertigini
4,9*3,93,6Disfunzione erettile
*p<0,05 vs placebo
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Impatto sulla pratica quotidiana?
Età >62PSA >1,6TRUS >31
La maggiorparte dei casi
CUT-OFF di progressione
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LoLo studio studio CombATCombAT
Tamsulosin (0.4 mg od)
Dutasteride (0.5 mg od)
Combination
Placebo run-in
Safety follow-up
phaseScre
enin
g
Single-blind Double-blind Washout
ARTICLE IN PRESS
16 wks4 wks Treatment period = 4 years
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SSymptomymptom MManagement anagement AAfter fter RReducing educing TTherapy:herapy: SMARTSMART––11
Combinazione
DT36
Placebo run-in
4 wSingle-
blind (SB)
Combinazione0.5 mg dutasteride
+ 0.4 mg tamsulosinaod
24 w
SB
Dutasteride placebo
12 w
Doppio cieco
DT24 + D12
Placebo
1 w
SBBarkin et al (2002)
Endpoint primario a 30 settimane
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SMARTSMART--1: 1: RisultatiRisultati chiavechiaveMaggiori benefici nella continuazione della terapia di combinazione nei
pazienti con sintomi più severi
Barkin et al. Eur Urol 2003;44:461–66Pazienti (%)
93%84% 86%
57.5%
7%16% 14%
42.5%
0
20
40
60
80
100Severi (baseline IPPS ≥ 20)Moderati (baseline IPPS < 20)
Dutasteride +Tamsulosina
per 30 settimane(n=111)
Dutasteride +Tamsulosina
per 24 settimaneDutasteride +
placebo per 12settimane
(n=109)
Dutasteride +Tamsulosina
per 30 settimane(n=42)
Dutasteride +Tamsulosina
per 24 settimaneDutasteride +
placebo per 12 settimane
(n=40)
Pazienti che si sentono meglioPazienti che si sentono peggio
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Plant extracts
Further studies meeting the criteriaproposed by WHO-BPH conference
(12-month duration, randomised, placebo-controlled)are required before plant extracts can berecommended for the treatment of LUTS
EAU Guielines 2007
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Conclusioni
Fitofarmaci
Alfa-litici
Terapia di combinazione
?
SEMPRE
RISCHIO DI PROGRESSIONE
Età >62PSA >1,6TRUS >31
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…Looking to the future…
New is not always better