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1.  The Prostate Cancer Intervention Versus Observation Trial:VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): Design and Baseline Results of a Randomized Controlled Trial Comparing Radical Prostatectomy With Watchful Waiting for Men With Clinically Localized Prostate Cancer 
Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death in men. In the United States, 90% of men with prostate cancer are more than age 60 years, diagnosed by early detection with the prostate-specific antigen (PSA) blood test, and have disease believed confined to the prostate gland (clinically localized). Common treatments for clinically localized prostate cancer include watchful waiting (WW), surgery to remove the prostate gland (radical prostatectomy), external-beam radiation therapy and interstitial radiation therapy (brachytherapy), and androgen deprivation. Little is known about the relative effectiveness and harms of treatments because of the paucity of randomized controlled trials. The Department of Veterans Affairs/National Cancer Institute/Agency for Healthcare Research and Quality Cooperative Studies Program Study #407:Prostate Cancer Intervention Versus Observation Trial (PIVOT), initiated in 1994, is a multicenter randomized controlled trial comparing radical prostatectomy with WW in men with clinically localized prostate cancer. We describe the study rationale, design, recruitment methods, and baseline characteristics of PIVOT enrollees. We provide comparisons with eligible men declining enrollment and men participating in another recently reported randomized trial of radical prostatectomy vs WW conducted in Scandinavia. We screened 13 022 men with prostate cancer at 52 US medical centers for potential enrollment. From these, 5023 met initial age, comorbidity, and disease eligibility criteria, and a total of 731 men agreed to participate and were randomized. The mean age of enrollees was 67 years. Nearly one-third were African American. Approximately 85% reported that they were fully active. The median PSA was 7.8ng/mL (mean 10.2ng/mL). In three-fourths of men, the primary reason for biopsy leading to a diagnosis of prostate cancer was a PSA elevation or rise. Using previously developed tumor risk categorizations incorporating PSA levels, Gleason histologic grade, and tumor stage, it was found that approximately 40% had low-risk, 34% had medium-risk, and 21% had high-risk prostate cancer based on local histopathology. Comparison to our national sample of eligible men declining PIVOT participation as well as to men enrolled in the Scandinavian trial indicated that PIVOT enrollees are representative of men being diagnosed and treated in the United States and quite different from men in the Scandinavian trial. PIVOT enrolled an ethnically diverse population representative of men diagnosed with prostate cancer in the United States. Results will yield important information regarding the relative effectiveness and harms of surgery compared with WW for men with predominately PSA-detected clinically localized prostate cancer.
doi:10.1093/jncimonographs/lgs041
PMCID: PMC3540866  PMID: 23271771
2.  Serenoa repens monotherapy for benign prostatic hyperplasia (BPH): an updated Cochrane systematic review 
BJU international  2012;109(12):1756-1761.
Objective
To estimate the effectiveness and harms of Serenoa repens monotherapy in the treatment of lower urinary tract symptoms (LUTS) consistent with benign prostatic hyperplasia (BPH).
Materials and methods
We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and other sources through to January 2012 to identify randomised trials.
Trials were eligible if they randomised men with symptomatic BPH to receive Serenoa repens extract monotherapy for at least 4 weeks in comparison with placebo, and assessed clinical outcomes and urodynamic measurements.
Our primary outcome was improvement in LUTS, based on change in urological symptom-scale scores.
Results
In all, 17 randomised controlled trials (N = 2008) assessing Serenoa repens monotherapy (typically 320 mg/day) vs placebo met inclusion criteria, although only five reported American Urological Association Symptom Index (AUASI) or International Prostate Symptom Scores (IPSS). Trial lengths ranged from 4 to 72 weeks. The mean age of all enrolees was 64.3 years and most participants were of White race. The mean baseline total score was 14 points, indicating moderately severe symptoms. In all, 16 trials were double blinded and adequate treatment allocation concealment was reported in six trials.
In a meta-analysis of three high quality long-to-moderate term trials (n = 661), Serenoa repens therapy was no better than placebo in reducing LUTS based on the AUASI/IPSS (weighted mean difference [WMD] −0.16 points, 95% confidence interval [CI] −1.45 to 1.14) or maximum urinary flow rate (Qmax; WMD 0.40 mL/s, 95% CI −0.30 to 1.09). Based on mostly short-term studies, Qmax measured at study endpoint were also not significantly different between treatment groups (WMD 1.15 mL/s, 95% CI −0.23 to 2.53) with evidence of substantial heterogeneity (I2 58%).
One long-term dose escalation trial (72 weeks) found double and triple doses of Serenoa repens extract did not improve AUASI compared with placebo and the proportions of clinical responders (≥ 3 point decrease in the AUASI) were nearly identical (43% vs 44% for Serenoa repens and placebo, respectively) with a corresponding risk ratio of 0.96 (95% CI 0.76–1.22).
Long-term, Serenoa repens therapy was no better than placebo in improving nocturia in one high-quality study (P = 0.19). Pooled analysis of nine short-term Permixon® trials showed a reduction in the frequency of nocturia (WMD −0.79 times/night, 95% CI−1.28 to −0.29), although there was evidence of heterogeneity (I2 76%)
Adverse events of Serenoa repens extracts were few and mild, and incidences were not statistically significantly different vs placebo. Study withdrawals occurred in ≈10% and did not differ between Serenoa repens and placebo.
Conclusions
Serenoa repens therapy does not improve LUTS or Qmax compared with placebo in men with BPH, even at double and triple the usual dose.
Adverse events were generally mild and comparable to placebo.
doi:10.1111/j.1464-410X.2012.11172.x
PMCID: PMC3513282  PMID: 22551330
Serenoa repens; benign prostatic hyperplasia; phytotherapy; systematic review
3.  Excessive Antibiotic Utilization in Men with Prostatitis 
The American journal of medicine  2008;121(5):444-449.
Background
Prostatitis accounts for two million outpatient visits annually. The vast majority of prostatitis cases fit the definition of chronic pelvic pain syndrome for which routine antibiotic use is not indicated.
Methods
Inpatient, Outpatient, and Pharmacy Datasets from the Veterans Health Administration were used to quantify the magnitude of antibiotic use attributable to chronic pelvic pain syndrome. Specifically, men with a diagnosis of infectious/acute prostatitis, and/or a urinary tract infection were excluded, and the remaining men with a diagnosis of prostatitis were defined as having chronic pelvic pain syndrome.
Results
Annual prevalence of chronic pelvic pain syndrome was 0.5%. Prescriptions for fluoroquinolone antibiotics were filled in 49% of men with a diagnosis of chronic pelvic pain syndrome compared to five percent in men without chronic pelvic pain syndrome. Men with chronic pelvic pain syndrome were greater than seven times more likely to receive a fluoroquinolone prescription independent of age, race/ethnicity and comorbid conditions. Increased use of other antibiotics was also observed. High utilization was similar in men with either infectious/acute prostatitis or chronic pelvic pain syndrome.
Conclusions
Despite evidence that antibiotics are not effective in the large majority of men with chronic pelvic pain syndrome, they were prescribed in 69% of men with this diagnosis. Some increased use is probably due to uncontrolled confounding by comorbid conditions or inaccurate diagnostic coding. However, a seven-fold higher rate of fluoroquinolone usage suggests strategies to reduce unnecessary antibiotic use in men with prostatitis are warranted.
doi:10.1016/j.amjmed.2008.01.043
PMCID: PMC2409146  PMID: 18456041
4.  Statin use and risk of prostate cancer in the prospective Osteoporotic Fractures in Men (MrOS) Study 
Background
Statins are a common medication for cholesterol control that may also have effects on cancer-related pathways. The evidence of an association between statins and prostate cancer risk remains ambiguous.
Methods
We examined statin use in a prospective cohort of 5069 elderly US men and the risk of incident total, low/high stage, and low/high grade prostate cancer diagnosed between 2000-2008. We used multivariate logistic regression models to estimate relative risks and 95% confidence intervals, adjusting for demographic and lifestyle characteristics.
Results
There was no evidence of an association between statin use and any of the prostate cancer endpoints (total, low/high stage, low/high grade prostate cancer), adjusting for age, study site, race, body mass index, marital status, family history of prostate cancer, number of comorbidities, physical activity, and smoking history.
Conclusions and Impact
In this study of elderly US men, we observed a null association between statin use and risk of prostate cancer.
doi:10.1158/1055-9965.EPI-12-0816
PMCID: PMC3489270  PMID: 22879205
5.  Evaluative Care Guideline Compliance is Associated with Provision of BPH Surgery 
Urology  2012;80(1):84-89.
Objectives
To determine the impact of evaluative care guideline compliance on surgical intervention for BPH.
Methods
From Medicare claims data, we developed a cohort of men new to a urologist with a diagnosis of BPH. We determined urologists’ compliance with guideline recommended care (3 months) and their time- and geography-standardized average monthly Medicare expenditures (1 year). At the level of the urologist, we assessed the impact of these measures on the use of surgical therapy within 1 year of the new patient visit.
Results
Of 10,248 patients in the cohort, 675 received surgical intervention (6.7%). Guideline compliance (2% received surgery in highest quintile; 11% lowest quintile) was associated with surgical intervention. The results were robust to adjustment for patient and surgeon factors (Guideline Compliance - OR 0.09; 95% CI 0.06 to 0.15 highest to lowest adherence).
Conclusions
Urologists who tend to follow the AUA best practice guidelines for BPH evaluation perform surgical interventions on their BPH patients less frequently than urologists who do not follow these guidelines.
doi:10.1016/j.urology.2012.03.011
PMCID: PMC3392961  PMID: 22608799
6.  Doxazosin in the treatment of benign prostatic hypertrophy: an update 
Clinical Interventions in Aging  2006;1(4):389-401.
We evaluated the efficacy and safety of a1 - blocker doxazosin for treatment of lower urinary tract symptoms (LUTS) compatible with benign prostatic hypertrophy (BPH). Fourteen randomized controlled trials enrolled 6261 men, average age 64 years, who had moderately severe LUTS and flow impairment. Compared with baseline measures and placebo effect, doxazosin resulted in a statistically significant improvement in both LUTS and flow. However, when compared with placebo, the average magnitude of symptom improvement (International Prostate Symptom Score [IPSS] improvement <3 points) typically did not achieve a level detectable by patients. Combined doxazosin and finasteride therapy improved LUTS and reduced the risk of overall clinical progression of BPH compared to each drug separately in men followed over 4 years. Reported mean changes from baseline in the IPSS were −7.4, −6.6, −5.6, and −4.9 points for combination therapy, doxazosin, finasteride, and placebo, respectively. Combination therapy reduced the need for invasive treatment for BPH and the risk of long-term urinary retention. The absolute reductions compared with placebo were less than 4% and primarily seen in men with prostate gland volume >40 mL or PSA levels >4 ng/mL. Efficacy was comparable with other a1–blockers. Withdrawals from treatment for any cause were comparable to placebo. Dizziness and fatigue occurred more frequently with doxazosin compared to placebo.
PMCID: PMC2699642  PMID: 18046916
benign prostatic hypertrophy (BPH); doxazosin; a1-adrenoceptor antagonists; lower urinary tract symptoms; systematic review
7.  Changes in Initial Expenditures for Benign Prostatic Hyperplasia Evaluation in the Medicare Population: A Comparison to Overall Medicare Inflation 
The Journal of urology  2012;187(5):1739-1746.
Introduction
Benign prostatic hyperplasia (BPH) creates significant expenses for the Medicare program. We sought to determine trends in expenditures for BPH evaluative testing after urologist consultation, and place these trends in the context of overall Medicare expenditures.
Methods
Using a 5% national sample of Medicare beneficiaries from 2000 to 2007, we developed a cohort of men with claims for new visits to urologists for diagnoses consistent with symptomatic BPH (n=40,253). We assessed trends in initial expenditures (within 12 months of diagnosis; inflation and geography adjusted) by categories of evaluative tests derived from the 2003 AUA Guideline on the Management of BPH. Using governmental reports on Medicare expenditures, trends in BPH expenditures were compared to overall and imaging-specific Medicare expenditures. Comparisons were assessed by Z-tests and regression analysis for linear trends as appropriate.
Results
Between 2000 and 2007 inflation adjusted total Medicare expenditure per patient for the initial evaluation of BPH patients seen by urologists increased from $255.44 to $343.98 (p<0.0001). Increases in BPH related imaging (55%), were significantly less than increases in overall Medicare expenditures on imaging (104%; p<0.001). The 35% increase in per patient expenditures for BPH was significantly lower than the increase in overall Medicare expenditure per enrollee (45%; p=0.0.0015).
Conclusion
From 2000 to 2007, inflation adjusted expenditures on BPH related evaluations increased. This growth was slower than overall growth in Medicare expenditures, and increases in imaging expenditures related to BPH were restrained compared to the Medicare program as a whole.
doi:10.1016/j.juro.2011.12.079
PMCID: PMC3539409  PMID: 22425128
Prostatic Hyperplasia; Medicare; Health Expenditures
8.  Bringing an Organizational Perspective to the Optimal Number of Colorectal Cancer Screening Options Debate 
Improving colorectal cancer (CRC) screening rates represents a challenge for primary care providers. Some have argued that offering a choice of CRC screening modes to patients will improve the currently low adherence rates. Others have raised concerns that offering numerous CRC screening options in practice could overwhelm patients and thus dampen enthusiasm for screening. In this article we assemble evidence to critically evaluate the relative merit of these opposing views. We find little evidence to support the hypothesis that the number of options offered will affect adherence (either positively or negatively), or that expanding the modalities offered beyond FOBT and colonoscopy will improve patient satisfaction. Therefore, we assert future decisions about the number of CRC screening modes to offer would more productively be focused on considerations such as what benefit the health-care organization would derive from offering additional modes, and how this change would affect other critical components of a successful screening program such as timely diagnosis. In light of these organizational level considerations, we agree with the assertion made by others that a screening program limited to FOBT and colonoscopy is likely to be ideal in most settings.
doi:10.1007/s11606-011-1870-y
PMCID: PMC3286551  PMID: 21915765
colorectal neoplasms; mass screening; choice behavior; decision making; organizational decision making
9.  Implications of the prostate intervention versus observation trial (PIVOT) 
Asian Journal of Andrology  2012;14(6):815.
doi:10.1038/aja.2012.103
PMCID: PMC3720112  PMID: 22983306
10.  Radical Prostatectomy versus Observation for Localized Prostate Cancer 
The New England journal of medicine  2012;367(3):203-213.
BACKGROUND
The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known.
METHODS
From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality.
RESULTS
During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P = 0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P = 0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P = 0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P = 0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death.
CONCLUSIONS
Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.)
doi:10.1056/NEJMoa1113162
PMCID: PMC3429335  PMID: 22808955
11.  Urologist Compliance with AUA Best Practice Guidelines for Benign Prostatic Hyperplasia in the Medicare Population 
Urology  2011;78(1):3-9.
Objectives
To improve BPH care, the American Urological Association created best practice guidelines for BPH management. We evaluate trends in use of BPH related evaluative tests and the extent to which urologists comply with the guidelines for evaluative tests.
Methods
From a 5% random sample of Medicare claims from 1999 to 2007, we created a cohort of 10,248 patients with new visits for BPH to 748 urologists. Trends in use of BPH related testing were determined. After classifying urologists by compliance with best practice guidelines, models were fit to determine the differences in use of BPH related testing among urologists. Further models defined the extent to which individual BPH related tests influenced guideline compliance.
Results
Use of most BPH testing increased over time (p < 0.001) except PSA (declined; p < 0.001) and ultrasound (p=0.416). Northeastern and Midwestern urologists were more likely to be in the lowest compliance group compared to Southern and Western urologists (29%, 27%, 13% and 19% respectively; p = 0.01). Testing associated with high guideline compliance included urinalysis and PSA (p < 0.01 for both), while prostate ultrasound (p = 0.03), cystoscopy (p < 0.01), uroflow (p < 0.01), and post void residual (p = 0.02) were associated low guideline compliance. Urodynamics, PVR, cytology, serum creatinine, and upper tract imaging were not strongly associated with guideline compliance.
Conclusion
Despite the AUA guidelines for BPH care, wide variations in evaluation and treatment are seen. Improving guideline adherence and reducing variation could improve BPH care quality.
doi:10.1016/j.urology.2010.12.087
PMCID: PMC3126893  PMID: 21601254
Prostatic Hyperplasia; Practice Guideline; Physician’s Practice Patterns
12.  Impact of Diastolic and Systolic Blood Pressure on Mortality: Implications for the Definition of “Normal” 
ABSTRACT
BACKGROUND
The National Heart, Lung and Blood Institute currently defines a blood pressure under 120/80 as “normal.”
OBJECTIVE
To examine the independent effects of diastolic (DBP) and systolic blood pressure (SBP) on mortality and to estimate the number of Americans affected by accounting for these effects in the definition of “normal.”
DESIGN, PARTICIPANTS AND MEASURES
Data on adults (age 25–75) collected in the early 1970s in the first National Health and Nutrition Examination Survey were linked to vital status data through 1992 (N = 13,792) to model the relationship between blood pressure and mortality rate adjusting for age, sex, race, smoking status, BMI, cholesterol, education and income. To estimate the number of Americans in each blood pressure category, nationally representative data collected in the early 1960s (as a proxy for the underlying distribution of untreated blood pressure) were combined with 2008 population estimates from the US Census.
RESULTS
The mortality rate for individuals over age 50 began to increase in a stepwise fashion with increasing DBP levels of over 90. However, adjusting for SBP made the relationship disappear. For individuals over 50, the mortality rate began to significantly increase at a SBP ≥140 independent of DBP. In individuals ≤50 years of age, the situation was reversed; DBP was the more important predictor of mortality. Using these data to redefine a normal blood pressure as one that does not confer an increased mortality risk would reduce the number of American adults currently labeled as abnormal by about 100 million.
CONCLUSIONS
DBP provides relatively little independent mortality risk information in adults over 50, but is an important predictor of mortality in younger adults. Conversely, SBP is more important in older adults than in younger adults. Accounting for these relationships in the definition of normal would avoid unnecessarily labeling millions of Americans as abnormal.
doi:10.1007/s11606-011-1660-6
PMCID: PMC3138604  PMID: 21404131
blood pressure; hypertension; guidelines; mortality
13.  Chapter 12: Systematic Review of Prognostic Tests 
Journal of General Internal Medicine  2012;27(Suppl 1):94-101.
A number of new biological markers are being studied as predictors of disease or adverse medical events among those who already have a disease. Systematic reviews of this growing literature can help determine whether the available evidence supports use of a new biomarker as a prognostic test that can more accurately place patients into different prognostic groups to improve treatment decisions and the accuracy of outcome predictions. Exemplary reviews of prognostic tests are not widely available, and the methods used to review diagnostic tests do not necessarily address the most important questions about prognostic tests that are used to predict the time-dependent likelihood of future patient outcomes. We provide suggestions for those interested in conducting systematic reviews of a prognostic test. The proposed use of the prognostic test should serve as the framework for a systematic review and to help define the key questions. The outcome probabilities or level of risk and other characteristics of prognostic groups are the most salient statistics for review and perhaps meta-analysis. Reclassification tables can help determine how a prognostic test affects the classification of patients into different prognostic groups, hence their treatment. Review of studies of the association between a potential prognostic test and patient outcomes would have little impact other than to determine whether further development as a prognostic test might be warranted.
doi:10.1007/s11606-011-1899-y
PMCID: PMC3364355  PMID: 22648680
prognosis; predictive accuracy; reclassification; review
14.  Chapter 11: Challenges in and Principles for Conducting Systematic Reviews of Genetic Tests used as Predictive Indicators 
Journal of General Internal Medicine  2012;27(Suppl 1):83-93.
In this paper, we discuss common challenges in and principles for conducting systematic reviews of genetic tests. The types of genetic tests discussed are those used to 1). determine risk or susceptibility in asymptomatic individuals; 2). reveal prognostic information to guide clinical management in those with a condition; or 3). predict response to treatments or environmental factors. This paper is not intended to provide comprehensive guidance on evaluating all genetic tests. Rather, it focuses on issues that have been of particular concern to analysts and stakeholders and on areas that are of particular relevance for the evaluation of studies of genetic tests. The key points include:The general principles that apply in evaluating genetic tests are similar to those for other prognostic or predictive tests, but there are differences in how the principles need to be applied or the degree to which certain issues are relevant.A clear definition of the clinical scenario and an analytic framework is important when evaluating any test, including genetic tests.Organizing frameworks and analytic frameworks are useful constructs for approaching the evaluation of genetic tests.In constructing an analytic framework for evaluating a genetic test, analysts should consider preanalytic, analytic, and postanalytic factors; such factors are useful when assessing analytic validity.Predictive genetic tests are generally characterized by a delayed time between testing and clinically important events.Finding published information on the analytic validity of some genetic tests may be difficult. Web sites (FDA or diagnostic companies) and gray literature may be important sources.In situations where clinical factors associated with risk are well characterized, comparative effectiveness reviews should assess the added value of using genetic testing along with known factors compared with using the known factors alone.For genome-wide association studies, reviewers should determine whether the association has been validated in multiple studies to minimize both potential confounding and publication bias. In addition, reviewers should note whether appropriate adjustments for multiple comparisons were used.
doi:10.1007/s11606-011-1898-z
PMCID: PMC3364361  PMID: 22648679
genetic test; systematic review methods; predictive tests; prognostic tests; risk
15.  Systematic Review of the Literature on Comparative Effectiveness of Antiviral Treatments for Chronic Hepatitis B Infection 
OBJECTIVES
To evaluate the comparative effectiveness of antiviral drugs in adults with chronic hepatitis B monoinfection for evidence-based decision-making.
METHODS
A systematic review of randomized controlled clinical trials (RCTs) published in English. Results after interferon and nucleos(t)ides analog therapies were synthesized with random-effects meta-analyses and number needed to treat (NNT).
RESULTS
Despite sustained improvements in selected biomarkers, no one drug regimen improved all intermediate outcomes. In 16 underpowered RCTs, drug treatments did not reduce mortality, liver cancer, or cirrhosis. Sustained HBV DNA clearance was achieved in one patient when two were treated with adefovir (NNT from 1 RCT = 2 95%CI 1;2) or interferon alfa-2b (NNT from 2 RCTs = 2 95%CI 2;4), 13 with lamivudine (NNT from 1 RCT = 13 95%CI 7;1000), and 11 with peginterferon alfa-2a vs. lamivudine (NNT from 1 RCT = 11 95%CI 7;25). Sustained HBeAg seroconversion was achieved in one patient when eight were treated with interferon alfa-2b (NNT from 2 RCTs = 8 95%CI 5;33) or 10—with peginterferon alfa-2b vs. interferon alfa-2b (NNT from 1 RCT = 10 95%CI 5;1000). Greater benefits and safety after entecavir vs. lamivudine or pegylated interferon alfa-2b vs. interferon alfa-2b require future investigation of clinical outcomes. Adverse events were common and more frequent after interferon. Treatment utilization for adverse effects is unknown.
CONCLUSIONS
Individual clinical decisions should rely on comparative effectiveness and absolute rates of intermediate outcomes and adverse events. Future research should clarify the relationship of intermediate and clinical outcomes and cost-effectiveness of drugs for evidence-based policy and clinical decisions.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-010-1569-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s11606-010-1569-5
PMCID: PMC3043173  PMID: 21203860
antiviral agents/adverse effects; antiviral agents/therapeutic use; hepatitis B/therapy; treatment outcome; cost-benefit analysis; decision trees
16.  Urologist Practice Styles in the Initial Evaluation of Elderly Men with BPH 
Urology  2011;77(3):535-540.
Objectives
As the medical and surgical specialists for men with LUTS, urologists provide testing to evaluate symptoms and determine therapy. We sought to investigate the degree to which expenditures on these evaluations vary among urologists and the factors associated with such variation.
Methods
We developed a cohort of men with an initial urologist visit for BPH from a 5% sample of Medicare patients (1999–2007) and established a physician level factor, practice style, as a function of average per patient expenditures. We then determined which AUA BPH guideline elements explained variation in quantity and expenditures for BPH testing, and also examined the impact of patient and physician factors on practice style.
Results
A nearly 15 fold variation in urologist’s average per patient expenditures existed ($35 to $527 per month; Median $92). Practice styles were associated with physician (p < 0.01 all examined variables) and patient (p < 0.01 for comorbidity, race and socioeconomic status) factors. Guideline recommended care was provided at lower rates by the lowest expenditure urologists compared to middle to highest intensity urologists (p < 0.01). Practice style variations were attributable mainly to differences in tests characterized by the guidelines as optional and not-recommended (p < 0.01).
Conclusions
Expenditures for BPH evaluations vary substantially by geography, practice setting, and experience and are accounted for largely by differences in the use of optional and not-routinely recommended tests. Greater standardization could enhance patient care and reduce health care costs.
doi:10.1016/j.urology.2010.07.485
PMCID: PMC3074578  PMID: 21256570
Prostatic Hyperplasia; Practice Guideline; Physician’s Practice Patterns
17.  Projecting the Clinical Benefits of Adjuvant Radiotherapy versus Observation and Selective Salvage Radiotherapy after Radical Prostatectomy: A Decision Analysis 
Our purpose was to project and compare clinical and quality-adjusted life year (QALY) outcomes of adjuvant radiotherapy (ART) vs. salvage radiotherapy (SRT) after radical prostatectomy for men with locally advanced prostate cancer.
We constructed a Markov model to simulate the randomized studies of observation vs. ART, assuming 75% of observation patients would receive SRT at prostate specific antigen (PSA) recurrence. Transition probabilities and utility inputs were drawn from randomized trials of ART and cohort studies of SRT. We projected 10-year PSA recurrence-free survival, metastasis-free survival and overall survival.
We found that observation with selective SRT yielded slightly worse outcomes than ART for post-RT PSA recurrence-free survival (47% and 52%), metastasis-free survival (69% and 70%) and overall survival (72% and 73%). Findings were robust to sensitivity analyses. After adjusting for the disutility of RT, observation plus SRT yielded better QALYs at 10 years than ART (6.80 and 6.13 QALYs).
Thus, observation plus SRT may be optimal for men likely to comply with surveillance who wish to minimize treatment side effects. These findings reflect outcomes for the average patient given the current level of evidence and are meant to help inform current decision-making as we await future clinical studies of comparative effectiveness.
doi:10.1038/pcan.2011.27
PMCID: PMC3156938  PMID: 21691281
prostate cancer; radiotherapy; decision analysis
18.  Reduction in Physician Reimbursement and Use of Hormone Therapy in Prostate Cancer 
Background
Use of androgen suppression therapy (AST) in prostate cancer increased more than threefold from 1991 to 1999. The 2003 Medicare Modernization Act reduced reimbursements for AST by 64% between 2004 and 2005, but the effect of this large reduction on use of AST is unknown.
Methods
A cohort of 72 818 men diagnosed with prostate cancer in 1992–2005 was identified from the Surveillance, Epidemiology, and End Results database. From Medicare claims data, indicated AST was defined as 3 months or more of AST in the first year in men with metastatic disease (n = 8030). Non-indicated AST was defined as AST given without other therapies such as radical prostatectomy or radiation in men with low-risk disease (n = 64 788). The unadjusted annual proportion of men receiving AST was plotted against the median Medicare AST reimbursement. A multivariable model was used to estimate the odds of AST use in men with low-risk and metastatic disease, with the predictor of interest being the calendar year of the payment change. Covariates in the model included age in 5-year categories, clinical tumor stage (T1–T4), World Health Organization grade (1–3, unknown), Charlson comorbidity (0, 1, 2, ≥3), race, education, income, and tumor registry site, all as categorical variables. The models included variations in the definition of AST use (≥1, ≥3, and ≥6 months of AST). All statistical tests were two-sided.
Results
AST use in the low-risk group peaked at 10.2% in 2003, then declined to 7.1% in 2004 and 6.1% in 2005. After adjusting for tumor and demographic covariates, the odds of receiving non-indicated primary AST decreased statistically significantly in 2004 (odds ratio [OR] = 0.70, 95% confidence interval = 0.61 to 0.80) and 2005 (OR = 0.61, 95% confidence interval = 0.53 to 0.71) compared with 2003. AST use in the metastatic disease group was stable at 60% during the payment change, and the adjusted odds ratio of receiving AST in this group was unchanged in 2004–2005.
Conclusions
In this example of hormone therapy for prostate cancer, decreased physician reimbursement was associated with a reduction in overtreatment without a reduction in needed services.
doi:10.1093/jnci/djq417
PMCID: PMC3001964  PMID: 21131577
19.  Serenoa repens for benign prostatic hyperplasia 
Background
Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, can lead to obstructive and irritative lower urinary tract symptoms (LUTS). The pharmacologic use of plants and herbs (phytotherapy) for the treatment of LUTS associated with BPH is common. The extract of the berry of the American saw palmetto, or dwarf palm plant, Serenoa repens (also known by its botanical name of Sabal serrulatum), is one of several phytotherapeutic agents available for the treatment of BPH.
Objectives
This systematic review aimed to assess the effects of Serenoa repens in the treatment of LUTS consistent with BPH.
Search strategy
Trials were searched in computerized general and specialized databases (MEDLINE, EMBASE, and The Cochrane Library), by checking bibliographies, and by handsearching the relevant literature.
Selection criteria
Trials were eligible if they (1) randomized men with symptomatic BPH to receive preparations of Serenoa repens (alone or in combination) for at least four weeks in comparison with placebo or other interventions, and (2) included clinical outcomes such as urologic symptom scales, symptoms, and urodynamic measurements. Eligibility was assessed by at least two independent observers.
Data collection and analysis
Information on patients, interventions, and outcomes was extracted by at least two independent reviewers using a standard form. The main outcome measure for comparing the effectiveness of Serenoa repens with placebo or other interventions was the change in urologic symptom-scale scores. Secondary outcomes included changes in nocturia and urodynamic measures. The main outcome measure for side effects or adverse events was the number of men reporting side effects.
Main results
In this update 9 new trials involving 2053 additional men (a 64.8% increase) have been included. For the main comparison - Serenoa repens versus placebo - 3 trials were added with 419 subjects and 3 endpoints (IPSS, peak urine flow, prostate size). Overall, 5222 subjects from 30 randomized trials lasting from 4 to 60 weeks were assessed. Twenty-six trials were double blinded and treatment allocation concealment was adequate in eighteen studies.
Serenoa repens was not superior to placebo in improving IPSS urinary symptom scores, (WMD (weighted mean difference) −0.77 points, 95% CI −2.88 to 1.34, P > 0.05; 2 trials), finasteride (MD (mean difference) 0.40 points, 95% CI −0.57 to 1.37, P > 0.05; 1 trial), or tamsulosin (WMD −0.52 points, 95% CI −1.91 to 0.88, P > 0.05; 2 trials).
For nocturia, Serenoa repens was significantly better than placebo (WMD −0.78 nocturnal visits, 95% CI −1.34 to −0.22, P < 0.05; 9 trials), but with the caveat of significant heterogeneity (I2 = 66%). A sensitivity analysis, utilizing higher quality, larger trials (≥ 40 subjects), demonstrated no significant difference (WMD −0.31 nocturnal visits, 95% CI −0.70 to 0.08, P > 0.05; 5 trials) (I2 = 11%). Serenoa repens was not superior to finasteride (MD −0.05 nocturnal visits, 95% CI −0.49 to 0.39, P > 0.05; 1 trial), or to tamsulosin (per cent improvement) (RR) (risk ratio) 0.91, 95% CI 0.66 to 1.27, P > 0.05; 1 trial).
Comparing peak urine flow, Serenoa repens was not superior to placebo at trial endpoint (WMD 1.02 mL/s, 95% CI −0.14 to 2.19, P > 0.05; 10 trials), or by comparing mean change (WMD 0.31 mL/s, 95% CI −0.56 to 1.17, P > 0.05; 2 trials).
Comparing prostate size at endpoint, there was no significant difference between Serenoa repens and placebo (MD −1.05 cc, 95% CI −8.84 to 6.75, P > 0.05; 2 trials), or by comparing mean change (MD −1.22 cc, 95% CI −3.91 to 1.47, P > 0.05; 1 trial).
Authors’ conclusions
Serenoa repens was not more effective than placebo for treatment of urinary symptoms consistent with BPH.
doi:10.1002/14651858.CD001423.pub2
PMCID: PMC3090655  PMID: 19370565
*Phytotherapy; *Serenoa; Androgen Antagonists [*therapeutic use]; Plant Extracts [*therapeutic use]; Prostatic Hyperplasia [*drug therapy]; Randomized Controlled Trials as Topic; Urination [drug effects]
20.  Progression of Lower Urinary Tract Symptoms Among Older Men: A Community Based Study 
The Journal of urology  2010;183(5):1915-1920.
Purpose
Progression of lower urinary tract symptoms (LUTS) among community dwelling older men is not well described.
Materials and Methods
We evaluated 5,697 participants in MrOS, a prospective cohort study of community dwelling men aged 65 years and older. We characterized LUTS utilizing the American Urological Symptom Index (AUA-SI) at two time points: study entry and 2-year follow-up. Progression was examined in the overall cohort and within strata of baseline symptoms (AUA-SI ≤ 7 points and ≥8 points) using descriptive statistics.
Results
At baseline, the mean (SD) age was 73.5 (5.8) years and mean (SD) AUA-SI score was 8.3 (6.3). Mean (SD) and median total AUA-SI increased during follow-up by 1.1 (5.0) and 1.0 points, respectively. Of the 3092 men with AUA-SI ≤ 7 at baseline, 883 (29%) reported LUTS progression (AUA-SI ≥8 points) at follow-up. The frequency of LUTS progression increased with advancing baseline age. Of the 2605 men with AUA-SI ≥ 8 at baseline, 622 (24%) reported progression of at least 4 AUA-SI points at follow-up. Among the 2200 men with baseline AUA-SI ≤7 and no prior history of BPH or LUTS treatments, 94% remained untreated, 2% reported BPH surgery, and 4% reported medication use at follow-up.
Conclusions
Up to 29% of community dwelling older men with no or mild LUTS will develop clinically significant LUTS within 2 years. These data help elucidate the natural history of LUTS in the community and provide useful data for designing clinical trials of LUTS prevention.
doi:10.1016/j.juro.2010.01.026
PMCID: PMC2896268  PMID: 20303101
benign prostatic hyperplasia; lower urinary tract symptoms; risk factor; epidemiology; progression
21.  Commentary: controversies in NICE guidance on prostate cancer 
BMJ : British Medical Journal  2008;336(7644):612-614.
doi:10.1136/bmj.39501.621690.AD
PMCID: PMC2267986  PMID: 18340077
22.  Urinary Symptoms and Risk of Falls in Older Men 
BJU international  2009;104(1):63-68.
OBJECTIVE
To evaluate the association of urinary symptoms with risk of falls in community-dwelling elderly men.
PATIENTS AND METHODS
We evaluated 5872 participants in MrOS, a prospective cohort study of risk factors for falls and osteoporotic fractures among community-dwelling men aged 65 years and older. We used Poisson regression models with a robust variance estimator to evaluate the association of urinary symptoms at study entry with falls occurring during 1 year of follow-up. We considered age, history of falls, history of dizziness, multiple physical performance measures, body size, and medication use as potential confounders.
RESULTS
At baseline, 3188 (54%) reported mild, 2301 (39%) moderate, and 383 (7%) severe symptoms. Compared to men with mild symptoms, the adjusted 1-year cumulative incidence of falls was significantly higher among men with moderate or severe symptoms. Risk of at least 1 fall was increased by 11% among those with moderate (relative risk [RR] 1.11, 95% confidence interval [95% CI] = 1.01 - 1.22; P = 0.02) and by 33% among those with severe symptoms (RR 1.33, 95% CI = 1.15 - 1.53; P < 0.001). Further, those with moderate had a 21% (RR 1.21, 95% CI = 1.05 - 1.40; P = 0.01) and those with severe symptoms a 63% (RR 1.63, 95% CI = 1.31 - 2.02; P < 0.001) increased risk of at least 2 falls. Symptoms most strongly associated with falls were urinary urgency, difficulty initiating urination, and nocturia.
CONCLUSION
Moderate and severe urinary symptoms independently increase the 1-year risk of falls—particularly recurrent falls—in community-dwelling older men.
doi:10.1111/j.1464-410X.2008.08317.x
PMCID: PMC3031126  PMID: 19154508
falls; benign prostatic hyperplasia; lower urinary tract symptoms; risk factor; overactive bladder; elderly; American Urological Association Symptom
23.  Benign prostatic hyperplasia. Part 2—Management 
BMJ : British Medical Journal  2008;336(7637):206-210.
doi:10.1136/bmj.39433.670718.AD
PMCID: PMC2213816  PMID: 18219042
24.  Benign prostatic hyperplasia. Part 1—Diagnosis  
BMJ : British Medical Journal  2008;336(7636):146-149.
doi:10.1136/bmj.39421.685023.AE
PMCID: PMC2206313  PMID: 18202067
25.  Diet, Fluid, or Supplements for Secondary Prevention of Nephrolithiasis: A Systematic Review and Meta-Analysis of Randomized Trials 
European urology  2009;56(1):72-80.
Context
Although numerous trials have evaluated efficacy of diet, fluid, or supplement interventions for secondary prevention of nephrolithiasis, few are included in previous systematic reviews or referenced in recent nephrolithiasis management guidelines.
Objective
To determine efficacy and safety of diet, fluid, or supplement interventions for secondary prevention of nephrolithiasis.
Evidence acquisition
Systematic review and meta-analysis of trials published January 1950 to March 2008. Sources included Medline and bibliographies of retrieved articles. Eligible trials included adults with a history of nephrolithiasis; compared diet, fluids, or supplements with control; compared relevant outcomes between randomized groups (eg, stone recurrence); had ≥3 mo follow-up; and were published in the English language. Data were extracted on participant and trial characteristics, including study methodologic quality.
Evidence synthesis
Eight trials were eligible (n = 1855 participants). Study quality was mixed. In two trials, water intake >2 l/d or fluids to achieve urine output >2.5 l/d reduced stone recurrence (relative risk: 0.39; 95% confidence interval: 0.19–0.80). In one trial, fewer high soft drink consumers assigned to reduced intake had renal colic than controls (34% vs 41%, p = 0.023). Content and results of multicomponent dietary interventions were heterogeneous; in one trial, fewer participants assigned increased dietary calcium, low animal protein, and low sodium had stone recurrence versus controls (20% vs 38%, p = 0.03), while in another trial, more participants assigned diets that included low animal protein, high fruit and fiber, and low purine had recurrent stones than controls (30% vs 4%, p = 0.004). No trials examined the independent effect of altering dietary calcium, sodium, animal protein, fruit and fiber, purine, oxalate, or potassium. Two trials showed no benefit of supplements over control treatment. Adverse event reporting was poor.
Conclusions
High fluid intake decreased risk of recurrent nephrolithiasis. Reduced soft drink intake lowered risk in patients with high baseline consumption. Data for other dietary interventions were inconclusive, although limited data suggest possible benefit from dietary calcium.
doi:10.1016/j.eururo.2009.03.031
PMCID: PMC2925677  PMID: 19321253

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