The neW ENGLAND JOURNAL of MEDICINE BLISHED IN 1813 FEBRUARY 9,200G VOL.354 NO. 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 BACKGROUND From the Osher Center LA )and th METHODS omly assigne d 225 mer ovethe age of 49 year ty of Ca of treatm ent with saw palmetto extract 60 me twice a day or placebo.Thep and the mary outcome measures were changes in the scores on the American Urological s) Association Symptom Index (AUASI)and the maximal urinary flow rate.Second and th ent San RESULTS 山N配 minute:95 percent confidence interval,-0.52 to 1.38),prostate size,residual vol- ume after voidi tigen levels during the one-year study.The incide CONCLUSIONS In this study,saw palmetto did enign prostatic hyperplasia.(Clin N ENGLJ MED 354:6 WWW.NEJM.ORG FEBRUARY 9.2006 557 d Journal of Medici ciety
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 Of MEDICINE 553m 225 Underwent randomization tto fo ad other illnesses (go 113 Analyzed 112 Analyzed Figure 1.Enrollment and Outcome. groups with the use of Student's ttest for con prostate volume as compared with those with a low prostate volume (dichotomized at 40 ml), ical va aldata obtained from men who did not com plete the study were included in the final analy- The funding organizations (the National Insti- ses.All reported I values are two-sided and have tute of Diab and Digestive and Kidney Dis not been adjuste esand the nter for Co on the basis of baseline data:an examination of palmetto had no role in the design or conduct changes in the primary outcome measures among of the study,the collection,management,analysis. men wit tion,review,and approval manuscrip 560 N ENGLJ MED 354:6 WWW.NEJM.ORG FEBRUARY 9.200 Downloaded from neim. s without permission
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 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 acteristics of 225 Men with Benign Prostatic Hyperplasia.* All Men (N=225) Saw Palmetto (N-112) Age-yr 63.047.7 62.9±8.0 63.0±7.4 Race or ethnic group-no.(% White 18382) 94(34 89(79 Black 12(5) 4(4④ 8 Asian or Pacific lslande 15 7间 :0 Hispanic 115) 6( Other 3(1) 1(0) 22) Education-yr 16.5±3.5 16.5±3.3 16.6±3.6 AUASI scoret 154+55 15.7±5.7 150+53 BPH Impact Index score 3.1421 3422 2.821 SF-36score Physical subscale 49.5±8.5 49.0±8.2 50.0±8. Mental subscale 529±7.9 52.5±7.8 53.3+8.0 Sexual function (O'Leary scale) 21+10 22411 20+10 Prostate volume 34.24145 34713.9 339+15 12.9410. 1324104 1251.0 Maximal urinary flow rate-ml/sec 115+39 114+35 116+43 fter voiding- 823+58 80.0=51.9 845638 SA-ng/dl 181 161 Creatinine-mg/dl 1.00.1 1.0±016 1.0±0.18 Testosterone一ng/dl 374±135 375±128 373±142 ethnic grou ca act Ind to 13 fs ores on the Sh on can r cores indicating better function. RESULTS study medicine consumed and no significant dif erence in adherence between groups.The base 775me ned for eligibility, line randomization.112 to saw palmetto and 113 to BPH Impact Index (P=0.02)(Table 1). placebo,between July 2001and May 2003.Figure There was a small but significant decrease shows the source of recruitment for potential (impro men )in the AUASI score during the d reasons for n period in un for a com- ercent confidence interval -096 to -2 02)(Fig 2).Both groups also had a small decrease in the n each group dis AUASI score dur ng t e on-yer study:the s out comp 1.37 to 0.o1)and by N ENGLJ MED 354:6 WWW.NEJM.ORG FEBRUARY 9.2006 561 Downloaded fromn use only.N
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
The NEW ENGLAND JOURNAL Of MEDICINE in however,no significant difference between groups in the mean change in AUASI scores over time (differen in mean ch ange.0.0 5 per shows that the fitted curves for the sw palmetto and placebo groups nearly coincide,indicating 2 Similarly.there was no significant difference Mo3 Mo5 Mo9 between groups in the change in the peak uri- nary flow rate du ng the one-year he pee 5 -0.25 1.10)in the saw palmetto group and by-0.01m per minute (95 percent confidence interval,-0.68 in the placebo group (me Values at screer prerandom alues.The ful val.-0.52 to 138).Figure 3 shows that the fitted curves for the saw palmetto and placebo groups nearly coincide,indicating similar changes in the Table 2.Changes in Primary and Secondary Outcome Measures. Measure 幽 meon仕S目change Primary outcomes AUASI scoret -0.68±0.35 0.72±035 0.041-0.93to1011 Peak urinary flow rate(ml/sec) 0.4240.34 -0.01±0.34 043(-0.52to1.38) Secondary outcomes Prostate volume (ml) 3.76=0.98 4.98±096 -1221-3.90to1.47刀 Prostate transitional-zone volume (ml) 32641.03 2.01±1.01 125（-1.57to4.07 Residual volume after voiding (ml) 14.10:724 18.62±7.14 -451-24.44to15.42） BPH Impact Index scoret -0.33±013 -0.09±0.13 -024(-0.60to0.13) SF-36 scoref Mental subscale -0.72±077 0.47±0.71 -1.18(-3.16to0.79 Physical subscale 0.10±0.6 0.51±0.66 0.61（-1.24to2.45) Sexual function (O'Leary scale) -0.06±010 0.07±0.10 -013（-0.40to0.14) Laboratory values Creatinine(mg/dl 0.002±0.0 -0.004±0.01 0.006（-0.02to0.03 Testosterone (ng/dl =16,82±874 -1.42±864 -15.40(-39.49to8.69 PSA (ng/dl) -0.005±0.07 0.15±0.07 -0.16（-0.36to0.04) SE.Toconver values to micromoles per iter,multiply by4.Cldenotes confidence interval. 35 ct li 0(no s ms)to 13(s to 1 res on the O L ating better functio 562 N ENGLJ MED 354:6 WWW.NEJM.ORG FEBRUARY 9.2006 Downloaded from neim
The new england journal o f medicine 562 n engl j med 354;6 www.nejm.org february 9, 2006 0.72 in the placebo group (95 percent confidence interval, −1.40 to −0.04) (Table 2). There was, however, no significant difference between groups in the mean change in AUASI scores over time (difference in mean change, 0.04 point; 95 percent confidence interval, −0.93 to 1.01). Figure 2 shows that the fitted curves for the saw palmetto and placebo groups nearly coincide, indicating similar changes in AUASI scores over time in the two groups (likelihood-ratio chi-square test, 0.62 with 2 degrees of freedom; P = 0.73). Similarly, there was no significant difference between groups in the change in the peak urinary flow rate during the one-year study period. The peak urinary flow rate changed by 0.42 ml per minute (95 percent confidence interval, −0.25 to 1.10) in the saw palmetto group and by −0.01 ml per minute (95 percent confidence interval, −0.68 to 0.66) in the placebo group (mean difference, 0.43 ml per minute; 95 percent confidence interval, −0.52 to 1.38). Figure 3 shows that the fitted curves for the saw palmetto and placebo groups nearly coincide, indicating similar changes in the 18 AUASI Score 16 17 15 14 12 13 0 Screening Randomization Mo 3 Mo 9 Mo 12 No. Analyzed Saw palmetto Placebo 107 109 108 109 108 112 Mo 6 108 111 112 113 112 113 Saw palmetto Placebo Figure 2. Mean (±SE) Change in American Urological Association Symptom Index (AUASI) Scores in the Saw Palmetto and Placebo Groups. Values at screening represent prerandomization screening values. The full range of the scale is from 0 to 35, with higher numbers indicating more severe symptoms. Table 2. Changes in Primary and Secondary Outcome Measures.* Measure Saw Palmetto (N = 112) Placebo (N = 113) Difference between Groups (95% CI) mean (±SE) change Primary outcomes AUASI score† −0.68±0.35 −0.72±0.35 0.04 (−0.93 to 1.01) Peak urinary flow rate (ml/sec) 0.42±0.34 −0.01±0.34 0.43 (−0.52 to 1.38) Secondary outcomes Prostate volume (ml) 3.76±0.98 4.98±0.96 −1.22 (−3.90 to 1.47) Prostate transitional-zone volume (ml) 3.26±1.03 2.01±1.01 1.25 (−1.57 to 4.07) Residual volume after voiding (ml) 14.10±7.24 18.62±7.14 −4.51 (−24.44 to 15.42) BPH Impact Index score‡ −0.33±0.13 −0.09±0.13 −0.24 (−0.60 to 0.13) SF-36 score§ Mental subscale −0.72±0.72 0.47±0.71 −1.18 (−3.16 to 0.79) Physical subscale 0.10±0.67 −0.51±0.66 0.61 (−1.24 to 2.45) Sexual function (O’Leary scale)¶ −0.06±0.10 0.07±0.10 −0.13 (−0.40 to 0.14) Laboratory values Creatinine (mg/dl) 0.002±0.01 −0.004±0.01 0.006 (−0.02 to 0.03) Testosterone (ng/dl) −16.82±8.74 −1.42±8.64 −15.40 (−39.49 to 8.69) PSA (ng/dl) −0.005±0.07 0.15±0.07 −0.16 (−0.36 to 0.04) * Plus–minus values are means ±SE. To convert creatinine values to micromoles per liter, multiply by 88.4. CI denotes confidence interval, and PSA prostate-specific antigen. † 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. 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 eak urinary flow rate over time in the ty dikelihood-ratio chi-square rest.0.87 with 2de 14 grees of freedom;P=0.65). Examination of the 13 12- sF-36,1n creat did .The pre subgroup analyses also sho ed no b enefit for e were to the baseline AUASI score (P=0.32),P tate size Screening Randomi-Mo 3 Mo6 Mo9 Mo 1 for UAS 1106101o prostate size(P=0.63),or PSA level (P= 0871 A total of 26 serious adverse even occurred Change in Peak Urinary Flow Rates in- in 17 participant during the s udy:8 in men as Values at screening represent prerandomization screening values rse event did not differ 6 able3.Serious Adverse Events. tween the two groups (P=0.31 by Fisher's exact Ihere wer nt in the ups (0.51 vs.0.4 P=0.7 by Student's ttest) Events Cardiovascular event 2 The adequacy of blinding was assessed by ask Bladder cance ing participants whether they believed they were al ing saw palmetto or placeb At 1 per om eebonmpaiewih6peentofmeminthe Mela placebo group (P=0.38). Prostate cance Shortness of breat DISCUSSION 0 Total In this year-long randomized trial,we found that Patients with≥1 event 6 1 saw palmetto was not superior to placebo for im proving rinary symptoms and ecuve mea were narrow,excluding clinically important ef that a clinically meaningful change in symptoms of b enign prostatic rplasia requires a enc -0.9339 101)is in the (includi ENGLJ MED 354:6 WWW.NEJM.ORG FEBRUARY 9.2006 563 Downloaded from r se only.N other use mhoupemison
saw palmetto for benign prostatic hyperplasia n engl j med 354;6 www.nejm.org february 9, 2006 563 peak urinary flow rate over time in the two groups (likelihood-ratio chi-square test, 0.87 with 2 degrees of freedom; P = 0.65). Examination of the secondary outcome measures also revealed no significant difference between treatment groups (Table 2). Changes in prostate size, residual volume after voiding, the BPH Impact Index, the overall quality of life as measured by the SF-36, and serum PSA, creatinine, and testosterone levels did not differ significantly between the two groups. The preplanned subgroup analyses also showed no benefit for any of the subgroups: for the AUASI outcome, there were no significant differences in response between the groups when stratified according to the baseline AUASI score (P = 0.32), prostate size (P = 0.23), or PSA level (P = 0.86). Similarly, for the peak urinary flow rate, there were no interactions with the baseline AUASI score (P = 0.13), prostate size (P = 0.63), or PSA level (P = 0.87). A total of 26 serious adverse events occurred in 17 participants during the study: 8 in men assigned to saw palmetto and 18 in men assigned to placebo (Table 3). The risk of at least one serious adverse event did not differ significantly between the two groups (P = 0.31 by Fisher’s exact test). There were also no significant differences in the mean number of nonserious adverse events per participant in the saw palmetto and placebo groups (0.51 vs. 0.47, P = 0.72 by Student’s t-test) (Table 4) or in the change in laboratory values, including testosterone, PSA, and creatinine levels (Table 2). The adequacy of blinding was assessed by asking participants whether they believed they were taking saw palmetto or placebo capsules. At 12 months, 40 percent of men in the saw palmetto group believed they were taking the herbal extract, as compared with 46 percent of men in the placebo group (P = 0.38). Discussion In this year-long randomized trial, we found that saw palmetto was not superior to placebo for improving urinary symptoms and objective measures of benign prostatic hyperplasia. The confidence intervals around the finding of no effect were narrow, excluding clinically important effects. For example, the 95 percent confidence interval for the difference in the change in the AUASI score between groups (−0.93 to 1.01) is consistent with only a 1-point improvement in the AUASI score. Previous research has suggested that a clinically meaningful change in symptoms of benign prostatic hyperplasia requires a change in the AUASI score of at least 3 points.26 Also, all symptomatic measures (including the AUASI and 14 Peak Urinary Flow Rate (ml/min) 9 10 11 12 13 0 Screening Randomization Mo 3 Mo 9 Mo 12 No. Analyzed Saw palmetto Placebo 101 105 100 103 101 102 Mo 6 101 106 106 107 112 113 Saw palmetto Placebo Figure 3. Mean (±SE) Change in Peak Urinary Flow Rates in the Saw Palmetto and Placebo Groups. Values at screening represent prerandomization screening values. Table 3. Serious Adverse Events. Variable Saw Palmetto (N = 112) Placebo (N = 113) number Events Cardiovascular event 2 7 Elective orthopedic surgery 3 3 Gastrointestinal bleeding 2 1 Bladder cancer 0 1 Colon cancer 0 1 Elective hernia repair 0 1 Hematoma 0 1 Melanoma 1 0 Prostate cancer 0 1 Shortness of breath 0 1 Rhabdomyolysis 0 1 Total 8 18 Patients with ≥1 event 6 11 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 Table 4.The 10 Most Commonly Repor don Several facto het vatiable N3 prior evidence.We measured the adequacy of blinding,and we found that blinding was effe 10 Most common events tive. with as ar percentage of m pper respiratory tract infection 0 pain other studies did not assess the adequacy of blind- ing.and since saw palmetto has such a strong. Diarrhe pungen or,ma esopha x diseas bd ominl pai who are given placebo (who may be aware they cebo),artificial nt pain or swelling are taking pla increasing the sible tha pa oug study had attributes that made them less likely nts with any adverse even to have a response to saw palmetto.However the cha sof participants the bpH Impact index)and all obiective measure and peak urinary flow rate wer (including urinary flow rates.residual volume af similar to those of men in previous trials of herbs ter voiding,and prostate size tent in or pharmaceutical agents for benign prostatic The among patients with either more or less seve oroduce a mea symptoms or among patients with either small surable effect. or large prostate glands this pe the ctive identi domized.p rolled trial tudie that the metto,of which 18 were double-blind and 13 ingredient is contained within the fatty-acid to alone with placebo.C frac Although there are no widely accepte saw ntom Scalel it found tha ntain either 80 to 95 saw palmetto improved symptom scores by 2.2 fatty acids and percen placebo (95 ne of the tatty nd greater than at the o 0.2 perc odu cebo.the summary estimate showed that saw 0.2 to 0.5 percent sterols The extract we used palmetto increased the peak urinary flow rate b (which,on sep rate measurements,had 90.7 ml per second m atty a Is and 0.33 nt ste t advi including a mean du sory committee chartered by the NCCAM a failure to use validate The saw palmet also had othe in 10 of the 31 Nonetheless the weight of the nrior evidene y that nrovides weh-hased informa suggested that saw palmetto may induce mild- tion tested the majority of saw palmetto products vailable in the ow measures had atty acid 山 eve 564 N ENGLJ MED 354:6 WWW.NEJM.ORG FEBRUARY 9.200 Downloaded from r without permission
The new england journal o f medicine 564 n engl j med 354;6 www.nejm.org february 9, 2006 the BPH Impact Index) and all objective measures (including urinary flow rates, residual volume after voiding, and prostate size) were consistent in showing no evidence of an effect. The subgroup analyses indicated that there was no benefit among patients with either more or less severe symptoms or among patients with either small or large prostate glands. In 2001, a systematic review identified 21 randomized, placebo-controlled trials of saw palmetto, of which 18 were double-blind and 13 compared saw palmetto alone with placebo. Only one of the studies of saw palmetto alone used a symptom scale equivalent to the AUASI (the International Prostate Symptom Scale); it found that saw palmetto improved symptom scores by 2.2 points, as compared with placebo (95 percent confidence interval, 0.3 to 4.4).13 In nine of the studies that compared saw palmetto with placebo, the summary estimate showed that saw palmetto increased the peak urinary flow rate by 1.86 ml per second more than placebo (95 percent confidence interval, 0.60 to 3.12).21 The studies included in this review had a number of methodologic limitations, including a mean duration of 13 weeks, a failure to use validated symptom scores, and inadequate concealment of treatment assignment in 10 of the 21 studies.21 Nonetheless, the weight of the prior evidence suggested that saw palmetto may induce mildto-moderate improvements in urinary symptoms and flow measures. Several factors can explain the discrepancy between our negative study and the summary of prior evidence. We measured the adequacy of blinding, and we found that blinding was effective, with a similar percentage of men in the saw palmetto and placebo groups reporting that they believed they were taking the active extract. Since other studies did not assess the adequacy of blinding, and since saw palmetto has such a strong, pungent odor, many prior studies may not have achieved adequate blinding. Inadequate blinding has the potential to reduce the response in men who are given placebo (who may be aware they are taking placebo), artificially increasing the comparative efficacy of saw palmetto. It is also possible that the participants in this study had attributes that made them less likely to have a response to saw palmetto. However, the baseline characteristics of participants in our trial with regard to age, symptom scores, prostate volume, and peak urinary flow rate were similar to those of men in previous trials of herbs or pharmaceutical agents for benign prostatic hyperplasia.21,28,32-34 The level of active ingredient in the extract may not have been sufficient to produce a measurable effect. We cannot completely address this possibility, because the active ingredient in saw palmetto, if one exists, is not known. However, prior in vitro studies suggest that the active ingredient is contained within the fatty-acid fraction.35 Although there are no widely accepted guidelines on the contents of saw palmetto extract, authorities have recommended that the extract contain either 80 to 95 percent combined fatty acids and sterols36-38 or 85 to 95 percent fatty acids and greater than 0.2 percent sterols.39 The U.S. Pharmacopeia states that the product should contain 70 to 95 percent fatty acids and 0.2 to 0.5 percent sterols.40 The extract we used (which, on separate measurements, had 90.7 to 92.1 percent fatty acids and 0.33 percent sterols) meets all the criteria proposed by the various authorities and was selected by an expert advisory committee chartered by the NCCAM. The saw palmetto extract we used also had characteristics similar to those of other commonly used products in the United States. A reference laboratory that provides Web-based information tested the majority of saw palmetto products available in the United States and found that 17 of 22 tested products had fatty acid levels of 85 Table 4. The 10 Most Commonly Reported Nonserious Adverse Events. Variable Saw Palmetto (N = 112) Placebo (N = 113) number 10 Most common events Upper respiratory tract infection 12 10 Back pain 4 4 Rash 1 3 Diarrhea 2 2 Gout 2 2 Gastroesophageal reflux disease 0 3 Abdominal pain 2 1 Joint pain or swelling 2 1 Trauma 2 1 Cough 1 2 Patients with any adverse event 39 34 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 to 95 percent and sterol levels of more than 0.2 percent.The saw palmetto extract in our study ed by(D.e)from the Dr.K having re had the same range of values for these ingredi Me d In d ha ents and is the ore similar to the majority o daily for one year does not improve lower urinary nd Evel and Arle tract symptoms caused by benign prostatic hy- mm REEERINGES ta (Per- g ac di s osi prostatica.Uro 57.68 Medical Cer 99 d trial of an extr of th rstein JD. 25.5y with l s MS,Cha As 20039226757 26.Lepor n AW.p aL smith H.Memo atic b atic N EnglI Med 19%6335533-9 020 27. ruske 25 M.e The effe 40 6.Carbin BE.Larsson B.Lindahl O. nt am 17. BanerHwasaosuCCosdMn ized con ollege Departm ikam 200 62 02.346-5列 dmiedmeicd L De vl lege Sta Serenoa rep ex.:Stat 20L0 Gould AL,Roehrborn CG. ische ing im ent of benign of ra Dru3laet1995 I RL. a in fficacy of the e n guide sdi on the 1.Emili E,Lo Cig M.Petrone U.R. OM,e ati clinici su un n dinical progre of be N ENGLJ MED 354:6 WWW.NEJM.ORG 565 Journal of Medici Downloaded from nejm 18201F
saw palmetto for benign prostatic hyperplasia n engl j med 354;6 www.nejm.org february 9, 2006 565 to 95 percent and sterol levels of more than 0.2 percent.39 The saw palmetto extract in our study had the same range of values for these ingredients and is therefore similar to the majority of currently available products. In summary, we found that 160 mg of saw palmetto given twice daily for one year does not improve lower urinary tract symptoms caused by benign prostatic hyperplasia. Supported by a grant (1 RO1 DK56199-01, to Dr. Avins) from the National Institute of Diabetes and Digestive and Kidney Diseases and by a grant (1 K08 ATO1338-01, to Dr. Bent) from the National Center for Complementary and Alternative Med icine. Dr. Kane reports having received consulting fees from both American Medical Systems and Intuitive Surgical, and having received lecture fees from Merck and TAP. Dr. Shinohara reports having received lecture fees from GlaxoSmithKline and Pfizer. Dr. Avins reports receiving grant support from Merck. No other potential conflict of interest relevant to this article was reported. We are indebted to the study team — Drs. Suzanne Staccone and Evelyn Badua, Amy Padula, Bertina Lee, and Arleen Sakamoto — as well as to Drs. Henry Leung (research pharmacy) and Howard Leong (laboratory sciences) for providing outstanding clinical care; and to Dr. Joseph Presti for his help in the initial planning of the study. References Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementary and alternative medicine use among adults: United States, 2002. Adv Data 2004;343:1-19. Lowe FC, Ku JC. Phytotherapy in treatment of benign prostatic hyperplasia: a critical review. Urology 1996;48:12-20. Champault G, Patel JC, Bonnard AM. A double-blind trial of an extract of the plant Serenoa repens in benign prostatic hyperplasia. Br J Clin Pharmacol 1984;18: 461-2. Tasca A, Barulli M, Cavazzana A, Zattoni F, Artibani W, Pagano F. Treatment of obstructive symptomatology caused by prostatic adenoma with an extract of Serenoa repens: double-blind study vs. placebo. Minerva Urol Nefrol 1985;37:87- 91. (In Italian.) Reece Smith H, Memon A, Smart CJ, Dewbury K. The value of permixon in benign prostatic hypertrophy. Br J Urol 1986; 58:36-40. Carbin BE, Larsson B, Lindahl O. Treatment of benign prostatic hyperplasia with phytosterols. Br J Urol 1990;66:639- 41. Bauer HW, Casarosa C, Cosci M, Fratta M, Blessmann G. Saw palmetto fruit extract for treatment of benign prostatic hyperplasia: results of a placebo-controlled double-blind study. MMW Fortschr Med 1999;141:62. (In German.) Metzker H, Kieser M, Holscher U. Wirksamkeit eines Sabal-Urtica-kombinationspraparates bei der behandlung der benignen prostatahyperplasie (BPH). Urologe [B] 1996;36:292-300. Descotes JL, Rambeaud JJ, Deschaseaux P, Faure G. Placebo-controlled evaluation of the efficacy and tolerability of Permixon in benign prostatic hyperplasia after the exclusion of placebo responders. Clin Drug Invest 1995;9:291-7. Mandressi A, Tarallo U, Maggioni A, Tombolini P, Rocco F, Quadraccia S. Medical treatment of benign prostatic hyperplasia: efficacy of the extract of Serenoa repens (Permixon) compared to that of the extract of Pygeum africanum and a placebo. Urologia 1983;50:752-8. Emili E, Lo Cigno M, Petrone U. Risultati clinici su un nuovo farmaco nella 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. terapia dell’ipertofia della prostata (Permixon). Urologia 1983;50:1042-8. Boccafoschi C, Annoscia S. Confronto fra estratto di serenoa repens e placebo mediante prova clinica controllata in pazienti con adenomatosi prostatica. Urologia 1983;50:1257-68. Gerber GS, Kuznetsov D, Johnson BC, Burstein JD. Randomized, double-blind, placebo-controlled trial of saw palmetto in men with lower urinary tract symptoms. Urology 2001;58:960-4. 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SAW PALMETTO FOR BENIGN PROSTATIC HYPERPLASIA 392387 KS.Testos a.The minute he CE.a hia:Lipp n. USP28-NF23 saw palmetto.(Ac. 566 N ENGLJ MED 354:6 WWW.NEJM.ORG FEBRUARY 9.2006
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