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Finasteride riduce la progressione clinica della IPB in pazienti con ingrossamento della prostatsAnalisi post hoc dei risultati dello studio clinico mtops

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  • 1. Long-Term Treatment With Finasteride Improves ClinicalProgression of Benign Prostatic Hyperplasia in Men With anEnlarged Versus a Smaller Prostate: Data From the MTOPS TrialSteven A. Kaplan,* Jeannette Y. Lee, Alan G. Meehan†and John W. Kusek for the MTOPS Research Group‡From Weill Cornell Medical College, New York, New York (SAK), University of Arkansas for Medical Sciences, Little Rock,Arkansas (JYL), Merck & Co., Inc., Rahway, New Jersey (AGM), and the National Institute of Diabetes and Digestive andKidney Diseases, Bethesda, Maryland (JWK)Purpose: This post hoc analysis of the Medical Therapy of Prostatic Symptoms Abbreviations and Acronymstrial examined the effect of finasteride alone compared to placebo on the clinicalprogression of benign prostatic hyperplasia in men with a baseline prostate AUA-SI American Urologicalvolume less than 30 ml, or 30 ml or greater. Association symptom indexMaterials and Methods: Men were randomized to placebo (737), 4 to 8 mg 5AR 5 -reductasedoxazosin alone (756), 5 mg finasteride alone (768) or doxazosin plus finasteride BPH benign prostatic(786) (average followup was 4.5 years). Approximately 50% of patients had a hyperplasiabaseline prostate volume of 30 ml or greater. The present analysis was based on ITT intent to treatthe finasteride alone and placebo arms only, and included patients for whom LUTS lower urinary tractbaseline and end of study data were available. We examined the effect of treat- symptomsment on the cumulative percentage of men who did not experience clinical MTOPS Medical Therapy ofprogression of benign prostatic hyperplasia by study end. Prostatic SymptomsResults: In men with baseline prostate volume 30 ml or greater treatment with PV prostate volumefinasteride produced a significant (p 0.001) increase relative to placebo in the PVR post-void residual volumecumulative percentage of patients who did not experience clinical progression ofbenign prostatic hyperplasia (finasteride 88.1% vs placebo 77.8%). There was no Qmax maximum urinary flowsignificant (p 0.441) between-group difference in men with baseline prostate ratevolume less than 30 ml (91.4% vs 89.1%, respectively). TRUS transrectal ultrasoundConclusions: Long-term treatment with finasteride led to a significant beneficialeffect compared to placebo on the clinical progression of benign prostatic hyper- Submitted for publication June 14, 2010.plasia in patients with lower urinary tract symptoms with an enlarged prostate MTOPS was supported by the following coop- erative agreements from the National Institute of(baseline prostate volume 30 ml or greater). Finasteride had no significant effect Diabetes and Digestive and Kidney Diseases: U01compared to placebo on the clinical progression of benign prostatic hyperplasia in DK49977, U01 DK46416, U01 DK41418, U01 DK46429,patients with lower urinary tract symptoms with a smaller prostate (baseline U01 DK46431, U01 DK46437, U01 DK46437, U01 DK46468, U01 DK46472, U01 DK49880, U01 DKprostate volume less than 30 ml). 49912, U01 DK49921, U01 DK49951, U01 DK49954, U01 DK49960, U01 DK49961, U01 DK49963, U01 Key Words: prostatic hyperplasia, urinary tract, finasteride, DK49964, U01 DK49971, U01 DK49980, as well as by the National Center on Minority Health and Health organ size, prostate Disparities, National Institutes of Health. Financial sup- port and drug products for MTOPS were also provided by Merck and Pfizer.THE MTOPS trial, to our knowledge, teride (34% relative risk reduction) * Correspondence and requests for reprints: Institute of Bladder and Prostate Health, Weillis the largest and longest placebo con- and doxazosin (39% relative risk re- Cornell Medical College, Cornell University, 1300trolled study to assess the effect of duction) alone compared to placebo. York Ave., F9 West, Box 261, New York, New York 10021 (telephone: 212-746-4811; FAX: 212-medical (drug) therapy on the clinical However, the 2 drugs combined re- 746-5329; e-mail: kaplans@med.cornell.edu).progression of BPH.1,2 In that trial sulted in a superior placebo corrected † Financial interest and/or other relationshipthe risk of clinical progression of BPH risk reduction (66% relative risk re- with Merck. ‡ A list of the MTOPS study investigators haswas significantly reduced by finas- duction) compared to that for either been provided previously.10022-5347/11/1854-1369/0 Vol. 185, 1369-1373, April 2011THE JOURNAL OF UROLOGY® Printed in U.S.A. www.jurology.com 1369© 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI:10.1016/j.juro.2010.11.060
  • 2. 1370 PROSTATE SIZE AND SYMPTOM IMPROVEMENT WITH FINASTERIDEdrug alone.1 Finasteride is an inhibitor of type 2, change from baseline to study end in AUA-SI score, Qmax,5AR, which is the predominant 5AR isozyme in the PVR and PV, as well as the cumulative percentage (95% CI) ofprostate that catalyzes the reduction of testosterone to patients who did not have clinical progression of BPH by studythe more potent androgen dihydrotestosterone. Treat- end, were examined in the placebo and finasteride treatment groups in men with baseline PV less than 30 ml, and comparedment with finasteride results in a marked decrease in with those with a PV of 30 ml or greater. We also performed aintraprostatic dihydrotestosterone, leading to a reduc- per protocol analysis to assess the consistency of the results oftion in PV, improvement in urinary symptoms and a our ITT analysis for AUA-SI, Qmax, PVR and PV. The perreduction in the risk of serious BPH related outcomes protocol analysis excluded men who had been treated withincluding acute urinary retention and the need for BPH open label medical therapy for BPH or who had undergonerelated surgery.3,4 The beneficial effects of finasteride are invasive therapy for BPH before the end of study TRUS mea-generally believed to be restricted to men with an en- surement. We used a 1-way ANOVA to compare finasteridelarged prostate.4 We assessed the long-term effects of with placebo with respect to the change from baseline forfinasteride alone compared to placebo on urinary symp- AUA-SI score, Qmax and PV separately for men with baselinetoms and clinical progression of BPH in men enrolled in PV less than 30 ml and those with baseline PV 30 ml or greater.the MTOPS trial subgrouped by baseline PV. We defined For PVR the Wilcoxon rank sum test was used to compare treatment arms with respect to change from baseline. The logmen with a baseline prostate volume of less than 30 ml rank test was used to compare the treatment arms with respectas having a smaller prostate and those with a volume of to time to clinical progression of BPH.30 ml or greater as having an enlarged prostate. RESULTSMATERIALS AND METHODS Baseline and end of study PV measurements were avail-Study Design and Patient Selection able for a total of 1,140 men from the finasteride andThe design and major outcomes of the MTOPS study have placebo treatment groups (table 1). Baseline PV rangedbeen reported previously.1,2 Men at least 50 years old with from 8.8 to 181.0 ml, with 49% of men having a baselinean AUA-SI score of 8 to 30 and a Qmax of 4 to 15 ml per PV less than 30 ml. Within each PV subgroup (baselinesecond with a voided volume of at least 125 ml wereeligible for the trial. A total of 3,047 men were randomized PV less than 30, or 30 ml or greater) men randomized to1:1:1:1 to placebo, doxazosin (4 to 8 mg), finasteride (5 mg) placebo or finasteride were generally similar with respector combination therapy with doxazosin and finasteride. to baseline demographic and clinical characteristics. MenThe present analysis was based on the finasteride alone with baseline PV 30 ml or greater were slightly older,and placebo arms only, and included patients for whom and had higher mean PVR and prostate specific antigenbaseline and end of study data were available. The pri- compared to those with a baseline PV less than 30 ml.mary outcome, overall clinical progression of BPH, wasdefined as the first occurrence of an increase from baseline Change in AUA-SI Scoreof at least 4 points in the AUA-SI score (confirmed within In the ITT analysis treatment with finasteride led to a4 weeks), acute urinary retention, urinary incontinence, significant (p 0.045) mean decrease from baseline torenal insufficiency or recurrent urinary tract infection. study end in AUA-SI score relative to placebo in menSecondary outcomes included change from baseline to end with baseline PV 30 ml or greater (mean decrease ofof study in AUA-SI score, Qmax and PVR. PV was mea- 5.69 vs 4.65 in the finasteride and placebo groups,sured by TRUS in all men at baseline and at the end of respectively), whereas there was no significant be-year 5 or at the end of study followup, whichever came tween-group difference in the mean change from base-first. The average duration of followup was 4.5 years. line in AUA-SI score in men with baseline PV less thanStatistical Analysis 30 ml (mean decrease of 6.01 vs 5.06 in the finas-We first performed an ITT analysis which included all random- teride and placebo groups, respectively, table 2, part Aized men with evaluable PV data. Mean (median for PVR) of figure). The AUA-SI score results for the per proto-Table 1. Baseline and disease characteristics Baseline PV Less Than 30 ml Baseline PV 30 ml or Greater Placebo Finasteride Placebo FinasterideNo. pts 276 281 288 295Mean SD age 60.3 7.1 60.7 7.0 64.1 6.9 63.9 7.1Mean SD AUA-SI 16.2 5.7 17.2 5.8 16.8 6.0 17.1 5.8Mean SD ml/sec Qmax 10.5 2.8 10.6 2.5 10.4 2.8 10.5 2.7Median ml PVR range 38.0 (0–399) 36.0 (0–411) 52.0 (0–535) 40.0 (0–552)Mean SD ml PV 21.8 5.1 22.3 4.9 47.2 17.4 50.4 21.1PV range (ml) 8.8–29.9 9.3–29.9 30.0–181.0 30.0–170.3Mean SD ng/ml prostate specific antigen 1.3 1.1 1.3 1.2 3.1 2.3 3.3 2.3
  • 3. PROSTATE SIZE AND SYMPTOM IMPROVEMENT WITH FINASTERIDE 1371Table 2. Effect of finasteride vs placebo on change from baseline in urinary symptoms and prostate volume at study end Baseline PV Less Than 30 ml Baseline PV 30 ml or Greater Placebo Finasteride Placebo Finasteride ITT populationAUA-SI: No. pts 276 281 288 295 Mean SD 5.06 5.78 6.01 5.78 4.65 6.17 5.69 6.40 p Value 0.054 0.045Qmax (ml/sec): No. pts 273 277 282 290 Mean SD 3.06 5.96 3.67 6.97 1.78 5.83 3.31 5.74 p Value 0.268 0.002PVR (ml): No. pts 271 280 282 289 Median (range) 3.0 ( 275, 371) 1.5 ( 221, 262) 0.50 ( 458, 641) 3.0 ( 503, 411) p Value 0.992 0.192PV (ml): No. pts 276 281 288 295 Mean SD 7.19 16.80 0.28 7.98 9.38 17.00 5.79 18.35 p Value 0.001 0.001 Per protocol populationAUA-SI: No. pts 266 276 261 287 Mean SD 4.80 5.62 5.99 5.73 4.16 5.92 5.52 6.13 p Value 0.015 0.008Qmax (ml/sec): No. pts 263 272 257 284 Mean SD 2.88 5.89 3.75 6.92 1.52 5.62 3.19 5.69 p Value 0.119 0.001PVR (ml): No. pts 261 275 256 283 Median (range) 3.0 ( 275, 371) 0 ( 221, 262) 0 ( 421, 641) 3.0 ( 503, 411) p Value 0.888 0.055PV (ml): No. pts 266 276 261 287 Mean SD 7.35 16.99 0.32 8.02 11.38 15.00 5.25 17.63 p Value 0.001 0.001col analysis were generally consistent with those for Change in PVRthe ITT analysis, with significant between-group dif- In the ITT analysis treatment with finasteride and pla-ferences achieved for both PV cohorts (part B of fig- cebo led to median reductions from baseline to study endure). The largest improvement with finasteride ob- in PVR of 3.0 and 0.5 ml, respectively, in men withserved in the per protocol analysis occurred at year 2 baseline PV 30 ml or greater, and 1.5 vs 3.0 ml,in the baseline PV 30 ml or greater cohort, with a respectively, in men with baseline PV less than 30 ml,mean between-group difference of approximately 2 although the between-group differences were not statis-AUA-SI score units. This improvement was generally tically significant in either of the 2 baseline PV cohortssustained in years 3 and 4. (table 2). The PVR results for the per protocol analysisChange in Qmax were generally consistent with those for the ITT analysis.In the ITT analysis treatment with finasteride led to asignificant (p 0.002) mean increase from baseline to Change in PVstudy end in Qmax relative to placebo in men with base- In the ITT analysis treatment with finasteride led toline PV 30 ml or greater (mean increase of 3.31 and 1.78 a significantly (p 0.001) greater improvement fromml per second in the finasteride and placebo groups, baseline to study end in PV in men with baseline PVrespectively), whereas there was no significant between- 30 ml or greater (mean decrease in PV of 5.79 mlgroup difference in the mean change from baseline in with finasteride compared to a mean increase of 9.38Qmax in men with baseline PV less than 30 ml (mean ml with placebo) and in men with baseline PV lessincrease of 3.67 and 3.06 ml per second in the finasteride than 30 ml (mean increase in PV of 0.28 ml withand placebo groups, respectively, table 2). The Qmax finasteride vs a mean increase of 7.19 ml with placebo,results for the per protocol analysis were generally con- table 2). The results from the per protocol analysissistent with those for the ITT analysis. were consistent with those from the ITT analysis.
  • 4. 1372 PROSTATE SIZE AND SYMPTOM IMPROVEMENT WITH FINASTERIDEMean (SE) change from baseline in AUA-SI over time for ITT population (A) and per protocol population (B) (excluding patients whohad been crossed over to open label medical therapy or who had invasive therapy before end of study TRUS measurement) in MTOPStrial. Pbo, placebo. Fin, finasteride.Clinical Progression of BPH DISCUSSIONTreatment with finasteride led to a significant(p 0.001) increase relative to placebo in the cumu- 5AR inhibitors are generally recommended for uselative percentage of men who did not meet the cri- in patients with symptomatic BPH with an enlargedteria for the clinical progression of BPH in men with prostate.4 The wide distribution of baseline PV (8.8baseline PV 30 ml or greater (finasteride 88.1%, vs to 181.0 ml) for men enrolled in the MTOPS studyplacebo 77.8%), whereas no significant between- provided the opportunity to examine the long-term (4group difference was observed in men with baseline or more years) effects of the 5AR inhibitor finasteridePV less than 30 ml (91.4% vs 89.1%, table 3). alone compared to placebo on urinary symptoms andTable 3. Effect of finasteride vs placebo on cumulative percentage at study end of men without clinical progression of BPH Baseline PV Less Than 30 ml Baseline PV 30 ml or Greater Placebo Finasteride Placebo FinasterideNo. pts 276 280 288 295Cumulative % (95% CI) 89.1 (84.8, 92.3) 91.4 (87.5, 94.2) 77.8 (72.5, 82.1) 88.1 (83.9, 91.3) p Value 0.367 0.001
  • 5. PROSTATE SIZE AND SYMPTOM IMPROVEMENT WITH FINASTERIDE 1373the clinical progression of BPH in patients with commonly observed in the clinical setting (less than 25smaller and larger prostates. Although we did not to 40 ml or greater).1,3–7 About half of the men enrolleddefine the volume criterion for an enlarged prostate a in the MTOPS study had an enlarged prostate at base-priori, our categorization of PV 30 ml or greater as line as defined by PV 30 ml or greater. Whether aenlarged is consistent with currently accepted cut similar proportion of men with an enlarged prostate aspoints. seen in the MTOPS study present to physicians with We observed in an ITT analysis that treatment bothersome symptoms of LUTS associated with BPHwith finasteride led to a statistically significant re- is uncertain. Given the significantly lower rate of clin-duction compared to placebo in the clinical progres- ical progression of BPH observed in men with PV 30sion of BPH in patients with LUTS with an enlarged ml or greater who were treated with finasteride com-prostate (baseline PV 30 ml or greater), whereas pared to placebo, patients with symptomatic BPH withtreatment with finasteride did not demonstrate a an enlarged prostate and their treating physicianssignificant effect relative to placebo on the clinical should consider the benefits observed in this studyprogression of BPH in patients with a smaller pros- from treatment with finasteride when determiningtate (baseline PV less than 30 ml). Additionally, the treatment choice.ITT analysis showed that finasteride produced There were a number of limitations of our analy-significant improvement compared to placebo in sis. While the data analysis plan for the MTOPSAUA-SI score and Qmax in men with an enlarged study prespecified examination of the effect of PV onprostate but not in those with a smaller prostate. In outcomes, the cut points for these subgroups werethose men who had not been treated with open label not prespecified. However, the use of 30 ml ormedical therapy for BPH or those who had under- greater to define an enlarged prostate is consistentgone invasive therapy for BPH before the end of with current practice.8 In addition, we performed astudy TRUS measurement, finasteride led to an im- subgroup analysis which may be subject to bias.9provement in AUA-SI relative to placebo by year 2 in There were several strengths to our study includingthe baseline PV 30 ml or greater cohort of approxi- the large sample size, the wide distribution of base-mately 2 units, with this improvement being generally line PV and long-term followup.sustained through year 4 of the study (part B of fig-ure). The larger improvement in PV seen in patientstreated with finasteride with a baseline PV of 30 ml or CONCLUSIONSgreater (5.79 ml decrease) than in those with a base- In this post hoc analysis of MTOPS trial data, long-line PV less than 30 ml (0.28 ml increase) may have term (4 or more years) treatment with finasterideresulted in relieving symptomatic prostatic obstruc- led to a significant beneficial effect compared to pla-tion, which may have contributed to the added benefits cebo on the clinical progression of BPH in patientsof finasteride on urinary symptoms and the clinical with LUTS with an enlarged prostate (baseline PVprogression of BPH in these patients. 30 ml or greater). Finasteride had no significant Finasteride is approved for the treatment of BPH effect compared to placebo on the clinical progres-symptoms in men with an enlarged prostate based on sion of BPH in patients with LUTS with a smallerlarge long-term studies of men with a wide range of PV prostate (baseline PV less than 30 ml).REFERENCES1. McConnell JD, Roehrborn CG, Bautista OM et al: The sia (2003). Chapter 1: Diagnosis and treatment 7. McConnell JD, Bruskewitz R, Walsh P et al: The long-term effect of doxazosin, finasteride, and com- recommendations. J Urol 2003; 170: 530. effect of finasteride on the risk of acute urinary bination therapy on the clinical progression of benign retention and the need for surgical treatment 5. Kaplan SA, McConnell JD, Roehrborn CG et al: prostatic hyperplasia. New Engl J Med 2003; 349: among men with benign prostatic hyperplasia. Fi- Combination therapy with doxazosin and finas- 2387. nasteride Long-Term Efficacy and Safety Study teride for benign prostatic hyperplasia in patients Group. N Engl J Med 1998; 338: 557.2. Bautista OM, Kusek JW, Nyberg LM et al: Study with lower urinary tract symptoms and a baseline design of the Medical Therapy of Prostatic Symptoms total prostate volume of 25 ml or greater. J Urol 8. Jacobsen SJ, Jacobson DJ, Girman CJ et al: Treat- (MTOPS) trial. Control Clin Trials 2003; 24: 224. 2006; 175: 217. ment for benign prostatic hyperplasia among com- munity dwelling men: the Olmsted County study of3. Proscar® product label. Available at http://www. 6. Kaplan SA, Roehrborn CG, McConnell JD et al: urinary symptoms and health status. J Urol 1999; accessdata.fda.gov/drugsatfda_docs/label/2010/ Long-term treatment with finasteride results in a 162: 1301. 020180s033lbl.pdf. Accessed March 2010. clinically significant reduction in total prostate vol- ume compared to placebo over the full range of 9. Wang R, Lagakos SW, Ware JH et al: Statistics in4. AUA Practice Guidelines Committee: AUA guide- baseline prostate sizes in men enrolled in the medicine–reporting of subgroup analyses in clini- line on management of benign prostatic hyperpla- MTOPS trial. J Urol 2008; 180: 1030. cal trials. N Engl J Med 2007; 357: 2189.

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