《外科护理学》课程阅读资料（英文）前列腺增生 prostatic hyperplasia.pdf

n engl j med 354;6 www.nejm.org february 9, 2006 557 The new england journal of medicine established in 1812 february 9, 2006 vol. 354 no. 6 Saw Palmetto for Benign Prostatic Hyperplasia Stephen Bent, M.D., Christopher Kane, M.D., Katsuto Shinohara, M.D., John Neuhaus, Ph.D., Esther S. Hudes, Ph.D., M.P.H., Harley Goldberg, D.O., and Andrew L. Avins, M.D., M.P.H. Abstract From the Osher Center for Integrative Medicine, Department of Medicine (S.B., A.L.A.), the Division of General Internal Medicine, Department of Medicine (S.B., A.L.A.), and the Departments of Epidemiology and Biostatistics (J.N., E.S.H., A.L.A.) and Family Practice (H.G.), University of California, San Francisco, San Francisco; the General Internal Medicine Section, Department of Medicine (S.B., A.L.A.), and the Urology Section (C.K., K.S.), San Francisco Veterans Affairs Medical Center, San Francisco; and the Division of Research, Kaiser Permanente Northern California, Oakland (H.G., A.L.A.). Address reprint requests to Dr. Bent at San Francisco VAMC, 111-A1, 4150 Clement St., San Francisco, CA 94121 or at bent@itsa.ucsf.edu. N Engl J Med 2006;354:557-66. Copyright © 2006 Massachusetts Medical Society. Background Saw palmetto is used by over 2 million men in the United States for the treatment of benign prostatic hyperplasia and is commonly recommended as an alternative to drugs approved by the Food and Drug Administration. Methods In this double-blind trial, we randomly assigned 225 men over the age of 49 years who had moderate-to-severe symptoms of benign prostatic hyperplasia to one year of treatment with saw palmetto extract (160 mg twice a day) or placebo. The primary outcome measures were changes in the scores on the American Urological Association Symptom Index (AUASI) and the maximal urinary flow rate. Secondary outcome measures included changes in prostate size, residual urinary volume after voiding, quality of life, laboratory values, and the rate of reported adverse effects. Results There was no significant difference between the saw palmetto and placebo groups in the change in AUASI scores (mean difference, 0.04 point; 95 percent confidence interval, –0.93 to 1.01), maximal urinary flow rate (mean difference, 0.43 ml per minute; 95 percent confidence interval, –0.52 to 1.38), prostate size, residual volume after voiding, quality of life, or serum prostate-specific antigen levels during the one-year study. The incidence of side effects was similar in the two groups. Conclusions In this study, saw palmetto did not improve symptoms or objective measures of benign prostatic hyperplasia. (ClinicalTrials.gov number, NCT00037154.) The New England Journal of Medicine Downloaded from nejm.org on October 18, 2011. For personal use only. No other uses without permission. Copyright © 2006 Massachusetts Medical Society. All rights reserved

The NEW ENGLAND JOURNAL Of MEDICINE prostatic hyperplasia.often as an alterna- a residual yolume of more than 250 ml after void tive to pharmaceutica ing);had a history of prostate cancer,surgery for ey conduct 1 percent of th enign prosta more than 2.0mg per deciliter (177 umol per liter) The herb is widely used in Europe,where half of had a prostate-specific antigen (PSA)level of more than 4.0 ng per deciliter;were using medications extracts to rugs. ugmost prio severe co small improvements in the symptoms of benign pate if they had sto ped taking an apha-blocker prostatic hyperplasia or in urinary flow rates at least one month before randomization or discon se studies are limited by the smal 2 standar nd the ed to lack of information from participants concerning one-month,single-blind,placebo runin period and how effectively the placebo was blinded. were excluded if their rate of adherence was less widely accepted outcome m asures and a ma than 75 percent,as measured by a capsule count double-blind trial to determine the efficacy of 时the6 Eligible patients were randomly assigned to re- aw palmetto extract,160 mg twice dai aring placebo in s oft br METHODS it had been used in the vast maiority of prior clin PARTICIPANTS ical trials.An advisory committee chartered by the Natio Center fo omple fCalifor ctea a c lect the the Kaiser Foundation Research Institute,Oak be used in this trial.a proprietary cabon dioxide land,California.The stud ly took place between July 2001 and May 200 tmctgpyhdelsAinasofgelhatincapsue furni by extrac 9 ne s who had moderate-to-sever of bnign prostatic hyperplasia,as defined by a phy of samples of the extract revealed that it con- score on the Am aed 2. per nt tota al fatty acids just befo a f less thap 15 t ana vere recruited from the san francisco extract contained 90.7 percent total fatty acids Affairs Medical Cer and 0.33 percent total sterols.Placebo capsules ing com -400 itte posters,ande and a h radio advertisements.all potential participants placebo with the appearance of saw palmetto. ve phone interview Patients v advised to take the study me criteria. en who pa a sit.Pang all clinic visit:those who declined or did not ap eight visits to the study clinic over a neriod of 1d at the clinic were classified as having declined to months,including 12 months of post-random- participate.Men were ineligible if they were at ization follow-up. 558 N ENGLJ MED 354:6 WWW.NEJM.ORG FEBRUARY 9.2006 Downloaded from n without permission

The new england journal o f medicine 558 n engl j med 354;6 www.nejm.org february 9, 2006 Extracts of the saw palmetto berry are widely used for the treatment of benign prostatic hyperplasia, often as an alternative to pharmaceutical agents. In a national survey conducted in 2002, 1.1 percent of the adult population in the United States, or approximately 2.5 million adults, reported using saw palmetto.1 The herb is widely used in Europe, where half of German urologists prefer prescribing plant-based extracts to synthetic drugs.2 Although most prior randomized trials of saw palmetto have reported small improvements in the symptoms of benign prostatic hyperplasia or in urinary flow rates, these studies are limited by the small numbers of subjects enrolled, their short duration, their failure to use standard outcome measures, and the lack of information from participants concerning how effectively the placebo was blinded.3-20 Using widely accepted outcome measures and a matched placebo capsule, we conducted a randomized, double-blind trial to determine the efficacy of saw palmetto for the treatment of benign prostatic hyperplasia. Methods Participants The study protocol and all procedures were approved by the committee on human research at the University of California, San Francisco, and the Kaiser Foundation Research Institute, Oakland, California. The study took place between July 2001 and May 2004. All participants provided written informed consent. Men over the age of 49 years who had moderate-to-severe symptoms of benign prostatic hyperplasia, as defined by a score on the American Urological Association Symptom Index (AUASI) of at least 8 and a peak urinary flow rate of less than 15 ml per second, were recruited from the San Francisco Veterans Affairs Medical Center, Kaiser Permanente Northern California, and the surrounding community by direct mailings to patients, letters to primary care providers, posters, and newspaper and local radio advertisements. All potential participants were screened by means of a telephone interview to identify exclusion criteria. Men who passed the screening interview were asked to come for a clinic visit; those who declined or did not appear at the clinic were classified as having declined to participate. Men were ineligible if they were at high risk for urinary retention (defined by a peak urinary flow rate of less than 4 ml per second or a residual volume of more than 250 ml after voiding); had a history of prostate cancer, surgery for benign prostatic hyperplasia, urethral stricture, or neurogenic bladder; had a creatinine level of more than 2.0 mg per deciliter (177 μmol per liter); had a prostate-specific antigen (PSA) level of more than 4.0 ng per deciliter; were using medications known to affect urination; or had a severe concomitant disease. Patients were eligible to participate if they had stopped taking an alpha-blocker at least one month before randomization or discontinued taking saw palmetto or a 5α-reductase inhibitor six months before randomization. All potentially eligible participants were assigned to a one-month, single-blind, placebo run-in period and were excluded if their rate of adherence was less than 75 percent, as measured by a capsule count. Intervention Eligible patients were randomly assigned to receive a saw palmetto extract, 160 mg twice daily, or a similar-appearing placebo in soft brown gelatin capsules. This regimen was selected because it had been used in the vast majority of prior clinical trials.21 An advisory committee chartered by the National Center for Complementary and Alternative Medicine (NCCAM) conducted a competitive process to select the saw palmetto product to be used in this trial, a proprietary carbon dioxide extract from Indena USA in a soft gelatin capsule furnished by Rexall-Sundown. The extract was manufactured in one batch to optimize product consistency. High-performance gas chromatography of samples of the extract revealed that it contained 92.1 percent total fatty acids just before the initiation of the study; a subsequent analysis at the midpoint of the study revealed that the extract contained 90.7 percent total fatty acids and 0.33 percent total sterols. Placebo capsules contained polyethylene glycol-400, a bitter-tasting liquid with an oily appearance and no free fatty acids, and a brown coloring agent to produce a placebo with the appearance of saw palmetto. Patients were advised to take the study medication twice a day with meals and to bring all unused capsules to each study visit. Patients made eight visits to the study clinic over a period of 14 months, including 12 months of post-randomization follow-up. The New England Journal of Medicine Downloaded from nejm.org on October 18, 2011. For personal use only. No other uses without permission. Copyright © 2006 Massachusetts Medical Society. All rights reserved

SAW PALMETTO FOR BENIGN PROSTATIC HYPERPLASIA OBIECTIVES AND OUTCOMES STATISTICAL ANALYSIS The primary objectives of the study were to deter- The study was designed to have a statistical power of 90 percent to ract r s the symptoms plas score AUASand a two-sided alpha value of 0.0 rates),as compared with placebo.The AUASI is a (set below 0.05 to allow for possible interim values require symptoms ref ee Der wa from o to cent cate mild symptoms;scores of to19,moderate The primary efficacy analyses weret score severe symp- parisons of the ch nation of chan the alit cific the sa and n We as to benign prostatic hyperplasia and overall qual sessed the significance of these differences in ects mode se moc els in Study 36-ttem Short-Form General Health Sur. measures gathered from each study participant vey [SF-36]);prostate size,measured by trans- as well as terms for the fixed effects of time,study esidua volume aft group,and the interacti on between tim e and ed side eff and char We fun time within each study group using likelihood. consists of atio tests and found that for most outcomes, wh. at AUAS fit the data well.However, eral and mental health vitalit social with quadratic time effects fit the data signifi function,and physical and emotional health. cantly better,and our models for these outcomes included these nonlinear effects of time RANDOMIZATION satisfied all including com letion of the run-in period.under tional form of the effect of time.before analyz went randomization in equal proportions tothe ing the study data.For each,we presen saw pametto and placebo groups.Randomiza stra ate 8 as est d treatment fects, hich we calcu late h D)and blocked with the use of randomly cho two study groups.The linear mixed-effects mod ered block sizes of less than 10 el analyses provide these estma according to o procedure i n stata, ndard err trolled trials The randomization list g We fit theinear mixed-effect ated by personnel who were not associated with model using the XTREG procedure in Stata soft the study.The study me ation was dispensed in are (version 8.0).The overall differences in b s (pre Dy e ma the tot al response ikei出 tween the tw study participants and all study personnel who and safety monitorin board (composed of ex administered in nterventions,assessed outcomes,perts selected by the National Institutes of Health or performed data analysi d the rm who were not affiliated with the udy)elected ed se 10 een N ENGLJ MED 354:6 559 Journal of Medici Downloaded from n use only.N

saw palmetto for benign prostatic hyperplasia n engl j med 354;6 www.nejm.org february 9, 2006 559 Objectives and Outcomes The primary objectives of the study were to determine whether the daily use of saw palmetto extract reduces the symptoms of benign prostatic hyperplasia, as measured by the AUASI or objective measures of urinary obstruction (urinary flow rates), as compared with placebo. The AUASI is a validated seven-item, self-administered questionnaire that measures symptoms referable to urinary obstruction, with scores ranging from 0 to 35 according to symptom severity: scores of 0 to 7 indicate mild symptoms; scores of 8 to 19, moderate symptoms; and scores of 20 to 35, severe symptoms.22 Secondary objectives included an examination of changes in the quality of life specific to benign prostatic hyperplasia and overall quality of life (assessed by two self-administered questionnaires, the Benign Prostatic Hyperplasia [BPH] Impact Index23 and the Medical Outcomes Study 36-Item Short-Form General Health Survey [SF-3624]); prostate size, measured by transrectal ultrasonography; residual volume after voiding, measured by BladderScan (Diagnostic Ultrasound); self-reported side effects; and changes in levels of PSA, creatinine, testosterone, and other laboratory values. The SF-36 consists of 36 items, 35 of which are aggregated to evaluate eight dimensions of health: physical function, pain, general and mental health, vitality, social function, and physical and emotional health. Randomization Participants who satisfied all eligibility criteria, including completion of the run-in period, underwent randomization in equal proportions to the saw palmetto and placebo groups. Randomization was stratified according to the category of AUASI score (moderate [8 to 19] vs. severe [20 to 35])22 and blocked with the use of randomly chosen even-numbered block sizes of less than 10 according to the ralloc.ado procedure in Stata, a software module used to design randomized, controlled trials.25 The randomization list was created by personnel who were not associated with the study. The study medication was dispensed in numbered bottles (provided by the manufacturer), according to the randomization sequence. All study participants and all study personnel who administered interventions, assessed outcomes, or performed data analysis were unaware of the treatment assignment and the randomized sequence list. Statistical Analysis The study was designed to have a statistical power of 90 percent to detect a difference between groups of 3.0 in the AUASI score,26 on the basis of a published standard deviation of 6.0 in the AUASI27,28 and a two-sided alpha value of 0.04 (set below 0.05 to allow for possible interim analyses). These calculations and values required the enrollment of 178 men, and the number was increased to a target enrollment of 224 to account for a potential dropout rate of up to 20 percent. The primary efficacy analyses were the comparisons of the change over time in the AUASI scores and the peak urinary flow rate between the saw palmetto and placebo groups. We assessed the significance of these differences in changes in outcomes over time using linear mixedeffects models.29 These models included random intercepts to accommodate the repeated measures gathered from each study participant as well as terms for the fixed effects of time, study group, and the interaction between time and study group, the effects of interest in our analyses. We assessed the functional form of the effect of time within each study group using likelihoodratio tests and found that for most outcomes, linear time effects fit the data well. However, for the AUASI scores and testosterone levels, a model with quadratic time effects fit the data significantly better, and our models for these outcomes included these nonlinear effects of time. We specified the linear mixed-effects model analytic strategy, including the assessment of the functional form of the effect of time, before analyzing the study data. For each outcome, we present estimated treatment effects, which we calculated as the difference in the predicted change in the response over a period of 12 months between the two study groups. The linear mixed-effects model analyses provide these estimates along with associated standard errors, which were used to construct 95 percent confidence intervals for treatment effects. We fit the linear mixed-effects model using the XTREG procedure in Stata software (version 8.0).30 The overall differences in the total response curves between the two groups were tested with likelihood-ratio tests. The data and safety monitoring board (composed of experts selected by the National Institutes of Health who were not affiliated with the study) elected not to perform interim analyses of efficacy. Baseline variables were compared between The New England Journal of Medicine Downloaded from nejm.org on October 18, 2011. For personal use only. No other uses without permission. Copyright © 2006 Massachusetts Medical Society. All rights reserved

The new england journal o f medicine 560 n engl j med 354;6 www.nejm.org february 9, 2006 groups with the use of Student’s t-test for continuous variables and chi-square tests for categorical variables. All analyses were conducted according to the intention-to-treat principle, so that all data obtained from men who did not complete the study were included in the final analyses. All reported P values are two-sided and have not been adjusted for multiple testing.31 Three subgroup analyses were planned a priori on the basis of baseline data: an examination of changes in the primary outcome measures among men with moderate symptoms as compared with men with severe symptoms, men with a high prostate volume as compared with those with a low prostate volume (dichotomized at 40 ml),32 and men with high PSA levels as compared with men with low levels (dichotomized at 1.4 ng per deciliter).32 The funding organizations (the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Complementary and Alternative Medicine) and the supplier of saw palmetto had no role in the design or conduct of the study, the collection, management, analysis, and interpretation of the data, or the preparation, review, and approval of the manuscript. 225 Underwent randomization 775 Men were assessed for eligibility 550 Were excluded 152 Declined to participate 106 Had an AUASI score <8 101 Were taking excluded medications 94 Had maximal urinary flow rates >15 or <4 29 Were taking saw palmetto 21 Had abnormal laboratory values 12 Had undergone prostate surgery 6 Had a history of prostate cancer 27 Met other exclusion criteria 2 Had a low adherence rate during placebo run-in period Recruitment source Letter from study, 553 men Poster, 110 men Newspaper ad, 42 men Friend, 26 men Other source, 44 men 113 Assigned to and received placebo 4 Lost to follow-up 1 Moved 1 Had urinary retention 1 Opted out of study 1 Could not be contacted 5 Discontinued intervention 2 Started an alpha-blocker 1 Started saw palmetto 2 Had other illnesses (testicular pain and colon cancer) 113 Analyzed 112 Assigned to and received saw palmetto 5 Lost to follow-up 3 Moved 2 Opted out of study 5 Discontinued intervention 3 Had other illnesses (gout, rash, adrenomyeloneuropathy) 1 Started an alpha-blocker 1 Purchased and started over- the-counter saw palmetto 112 Analyzed Figure 1. Enrollment and Outcome. The New England Journal of Medicine Downloaded from nejm.org on October 18, 2011. For personal use only. No other uses without permission. Copyright © 2006 Massachusetts Medical Society. All rights reserved

saw palmetto for benign prostatic hyperplasia n engl j med 354;6 www.nejm.org february 9, 2006 561 Results Of 775 men who were screened for eligibility, 225 satisfied all eligibility criteria and underwent randomization, 112 to saw palmetto and 113 to placebo, between July 2001 and May 2003. Figure 1 shows the source of recruitment for potential participants and reasons for exclusion. Five men in the saw palmetto group and four men in the placebo group were lost to follow-up, for a completion rate of 96 percent. An additional five men in each group discontinued the study medication but completed all outcome assessments. The adherence rate was high, with 92 percent of all study medicine consumed and no significant difference in adherence between groups. The baseline characteristics of the treatment groups were similar, with the exception of the scores on the BPH Impact Index (P = 0.02) (Table 1). There was a small but significant decrease (improvement) in the AUASI score during the single-blind, placebo run-in period in both groups (mean change among all participants, −1.49; 95 percent confidence interval, −0.96 to −2.02) (Fig. 2). Both groups also had a small decrease in the AUASI score during the one-year study: the score decreased by 0.68 in the saw palmetto group (95 percent confidence interval, −1.37 to 0.01) and by Table 1. Baseline Characteristics of 225 Men with Benign Prostatic Hyperplasia.* Characteristic All Men (N = 225) Saw Palmetto (N = 112) Placebo (N = 113) Age — yr 63.0±7.7 62.9±8.0 63.0±7.4 Race or ethnic group — no. (%) White 183 (82) 94 (84) 89 (79) Black 12 (5) 4 (4) 8 (7) Asian or Pacific Islander 15 (7) 7 (6) 8 (7) Hispanic 11 (5) 6 (5) 5 (4) Other 3 (1) 1 (1) 2 (2) Education — yr 16.5±3.5 16.5±3.3 16.6±3.6 AUASI score† 15.4±5.5 15.7±5.7 15.0±5.3 BPH Impact Index score‡ 3.1±2.1 3.4±2.2 2.8±2.1 SF-36 score§ Physical subscale 49.5±8.5 49.0±8.2 50.0±8.9 Mental subscale 52.9±7.9 52.5±7.8 53.3±8.0 Sexual function (O’Leary scale)¶ 2.1±1.0 2.2±1.1 2.0±1.0 Prostate volume — ml∥ 34.2±14.5 34.7±13.9 33.9±15.2 Prostate transitional-zone volume — ml∥ 12.9±10.7 13.2±10.4 12.5±11.0 Maximal urinary flow rate — ml/sec 11.5±3.9 11.4±3.5 11.6±4.3 Residual volume after voiding — ml 82.3±58.2 80.0±51.9 84.5±63.8 PSA — ng/dl 1.7±1.4 1.8±1.4 1.6±1.4 Creatinine — mg/dl 1.0±0.17 1.0±0.16 1.0±0.18 Testosterone — ng/dl 374±135 375±128 373±142 * Plus–minus values are means ±SD. There were no significant differences in baseline characteristics between the groups except in the BPH Impact Index (P = 0.02 by Wilcoxon’s test). To convert creatinine values to micromoles per liter, multiply by 88.4. PSA denotes prostate-specific antigen. Race and ethnic group were self-reported. † Scores on the AUASI can range from 0 (no symptoms) to 35 (severe symptoms). ‡ Scores on the BPH Impact Index can range from 0 (no symptoms) to 13 (severe symptoms). § Scores on the SF-36 can range from 0 to 100; higher scores indicate a better quality of life. ¶ Overall scores on the O’Leary Scale of Sexual Function can range from 0 to 4, with higher scores indicating better function. ∥ Prostate volume was measured by transrectal ultrasonography. The New England Journal of Medicine Downloaded from nejm.org on October 18, 2011. For personal use only. No other uses without permission. Copyright © 2006 Massachusetts Medical Society. All rights reserved