5-alpha-reductase inhibitors for lower urinary tract symptoms secondary to benign prostatic obstruction(protocol)

Transcription

1 Cochrane Database of Systematic Reviews 5-alpha-reductase inhibitors for lower urinary tract symptoms secondary to benign prostatic obstruction(protocol) García-Perdomo HA, Lopez HE, Tacklind J García-Perdomo HA, Lopez HE, Tacklind J. 5-alpha-reductase inhibitors for lower urinary tract symptoms secondary to benign prostatic obstruction. Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD DOI: / CD alpha-reductase inhibitors for lower urinary tract symptoms secondary to benign prostatic obstruction(protocol) Copyright 2015 The Cochrane Collaboration. Published by John Wiley& Sons, Ltd.

2 T A B L E O F C O N T E N T S HEADER ABSTRACT BACKGROUND OBJECTIVES METHODS ACKNOWLEDGEMENTS REFERENCES APPENDICES CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT NOTES i

3 [Intervention Protocol] 5-alpha-reductase inhibitors for lower urinary tract symptoms secondary to benign prostatic obstruction Herney A García-Perdomo 1, Hugo E Lopez 2, James Tacklind 3 1 Urology, University of Valle, Cali, Colombia. 2 Urology, University of Rosario, Bogotá, Colombia. 3 Independent contractor, Minneapolis, Minnesota, USA Contact address: Herney A García-Perdomo, Urology, University of Valle, Calle 4B No 36-00, Cali, Valle, 164, Colombia. herney.garcia@correounivalle.edu.co. Editorial group: Cochrane Urology Group. Publication status and date: New, published in Issue 11, Citation: García-Perdomo HA, Lopez HE, Tacklind J. 5-alpha-reductase inhibitors for lower urinary tract symptoms secondary to benign prostatic obstruction. Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD DOI: / CD A B S T R A C T This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of 5-alpha-reductase inhibitors (5ARIs) for treating lower urinary tract symptoms (LUTS) secondary to benign prostatic obstruction (BPO). B A C K G R O U N D Description of the condition Benign prostatic hyperplasia (BPH) is characterized histopathologically by an increased number of epithelial and stromal cells in the periurethral area of the prostate (Barry 2001). It is a very common condition with a histologic prevalence estimated to be over 50% in men 50 to 69 years and over 90% in men 81 to 90 years (Roehrborn 2007), and this condition is the fourth most commonly diagnosed in men over the age of 50 (Issa 2006). Enlargement of the prostate may cause progressive occlusion of the urethra, which can result in voiding and storage urinary tract symptoms. As the prostate increases the number of its cells, there is a progressive enlargement of the prostate (benign prostatic enlargement, BPE) which may cause a progressive obstruction of the urethra (benign prostatic obstruction, BPO) which may cause lower urinary tract symptoms (LUTS). So-called obstructive or voiding symptoms include a weak urinary stream, hesitancy, intermittency, incomplete bladder emptying, terminal urine dribbling and abdominal straining (Barry 2001; Jacobsen 1996). So-called storage symptoms include urinary frequency, urgency and nocturia (Barry 1997; Jacobsen 1996). Both kinds of symptoms are called LUTS, which reflects a variety of conditions in the urinary tract. Moreover, BPH and LUTS can adversely impact on the lower urinary tract function and result in complications such as refractory urinary retention, recurrent urinary tract infection, hematuria, bladder stones, renal insufficiency, or large bladder diverticula, among others (Jacobsen 1997). LUTS can adversely impact on the quality of life of men, affecting their physical and mental health, causing a restriction in their daily activities, sleep and sexual function (Garraway 1993; Rosen 2003). 1

4 Description of the intervention The treatment goal in men with symptomatic BPH is to relieve the bothersome LUTS secondary to BPO. The choice of therapy depends on the short-term and long-term clinical response rates, the associated effects and potential complications, and costs. Available treatments include lifestyle modifications, pharmacological treatment and surgical interventions. According to the literature, transurethral prostate surgery is the gold standard for treating BPO in men who have experienced complications of BPO due to BPH, such as recurrent (systemic) urinary tract infections, acute urinary retention, cystolithiasis (bladder stone formation), hematuria and renal failure. Other surgical options are open and (robotic-assisted) laparoscopic prostate surgery, as well as laser enucleation or fulguration, which may offer similar efficacy in experienced hands (McVary 2010). The main pharmacological agents to treat LUTS secondary to BPO are alpha-blockers (tamsulosin, alfuzosin, doxazosin, terazosin, among others), 5-alpha-reductase inhibitors (5ARIs), and their combination. According to the guidelines of the American Urological Association (McVary 2010), 5ARIs are appropriate and effective treatment alternatives for men with LUTS secondary to BPH. Combination therapy of alpha-blockers and 5ARIs appears best suited for men with moderate to severe LUTS symptoms, high risk progression and/or prostate larger than 40 cc in size (Roehrborn 2010). Another treatment option is phytotherapy with different types of agents; some of these are botanicals (Serenoa repens (S. repens), Pygeum africanum (P. africanum), Urtica dioica (U. dioica) and Cucurbita pepo (C. pepo)) or nutraceuticals (isoflavones, lycopene, selenium and β-sitosterol). They are used for relieving LUTS, however assessments of their effectiveness have shown mixed results (Pagano 2014; Wilt 2002). Although clinical guidelines recommend against using phytotherapies to treat LUTS secondary to BPH (McVary 2010), urologists and men around the world continue to use them. 5ARIs will be the experimental intervention of interest in this Cochrane review. and the need for surgical treatment. 5ARIs also reduce the risk of prostate cancer (Andriole 2010; Roehrborn 2010). Meanwhile, the magnitude, consistency, and relative effectiveness of 5ARIs, as well as their adverse effects, are not well known. Tacklind 2010 found that finasteride improved long-term (> 1 year) LUTS versus placebo and that long-term combination therapy with alpha-blockers (doxazosin, terazosin) significantly improved LUTS compared to finasteride monotherapy. Combined finasteride and doxazosin improved symptoms and decreased the absolute risk of progression equally to doxazosin alone (Tacklind 2010). Why it is important to do this review BPH is the main cause of LUTS secondary to BPO in ageing men. These LUTS represent a significant burden as they interfere with activities of daily living, generate various degrees of bother and worry, and impact on psychological well-being and general health (Girman 1994). Epidemiological studies and placebo arms of randomized controlled studies have shown that BPH is a progressive condition, defined as a worsening of symptoms, increasing prostate volume and decreasing urine flow, having as final outcomes: episodes of acute urinary retention or the need for surgery. This review will serve to update the Cochrane review Tacklind 2010, which assessed the effects of the 5ARI finasteride, now with an expanded scope to include all 5ARIs. Given that pharmacotherapy for LUTS secondary to BPH is an active field for clinical research, the existing Cochrane review does not include some of the more recent studies, and appears outdated. The proposed Cochrane review update will use rigorous Cochrane methods to provide a comprehensive review of the totality of evidence on the benefits and harms associated with the class of 5ARIs, and will assess the available evidence using the GRADE approach (Guyatt 2008). For clinicians, patients and health policymakers, a better understanding of the benefits and harms of 5ARIs will provide useful healthcare information. How the intervention might work Androgens and specifically dihydrotestosterone (DHT) serve the development and growth of the prostate. Generally, the 5-alphareductase enzyme transforms testosterone into DHT within the prostate cell. Therefore, 5ARIs diminish the level of DHT and have been reported to result in a reduction of the prostate size. They also reduce the static component of the bladder outlet obstruction (NICE 2010). Studies have reported that therapy with 5ARIs (dutasteride and finasteride) reduces the risk of clinical progression (lowers prostate size, relieves urethral obstruction and lowers detrusor dysfunction) and improves LUTS by decreasing episodes of frequent urination O B J E C T I V E S To assess the effects of 5-alpha-reductase inhibitors (5ARIs) for treating lower urinary tract symptoms (LUTS) secondary to benign prostatic obstruction (BPO). M E T H O D S Criteria for considering studies for this review 2

5 Types of studies Randomized controlled trials (RCTs) with at least six months duration of follow-up. We will exclude cluster-randomized and crossover trials. We will not consider publication status or language of publication in determining eligibility. Types of participants Men with LUTS secondary to BPO. Eligible participants should not have received prior treatment with 5ARIs, and men with any comorbidities will be eligible. We will include studies in which only a subset of participants are relevant to this review, if data are available separately for the relevant subset. Types of interventions Experimental interventions 5ARIs (such as dutasteride and finasteride) Comparator interventions Placebo Phytotherapies Surgery Active pharmacologic controls (alpha-blockers and combined therapy (5ARI plus alpha-blockers)) Comparisons 5ARIs versus placebo 5ARIs versus phytotherapies 5ARIs versus surgery 5ARIs versus alpha-blockers 5ARIs versus combined therapy Types of outcome measures We will not use measurement of outcomes assessed in this review to determine study eligibility. We will calculate the minimally important difference for each primary outcome to aid our interpretation of results. We will assess the primary and secondary outcomes at six, 12 and 24 months, if this is possible. Primary outcomes Mean change in urologic symptom scores, assessed with a validated scale (such as the International Prostate Symptom Score (IPSS); clinically meaningful improvement is generally considered to be four-point decrease in the IPSS). Mean change in quality of life, assessed with a validated scale (such as the SF-12 or SF-36). Number of participants who experience a major adverse effect (graded as the Common Terminology Criteria for Adverse Events (CTCAE): Grade 3 = severe; Grade 4 = life-threatening or disabling; Grade 5 = death-related; we will also consider the definition used in each clinical trial). Secondary outcomes Number of participants requiring surgical intervention. Number of participants with episodes of acute urinary retention. Change in nocturia, measured as the number of episodes per night. Number of participants that experience the following adverse effects (graded as the CTCAE: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening or disabling; Grade 5 = death-related; we will also take into account the way the study investigators describe them in each clinical trial): erectile dysfunction breast enlargement and pain ejaculatory dysfunction decreased libido orthostatic hypotension. Main outcomes for Summary of findings table Mean change in urologic symptom scores. Quality of life. Major adverse effects. Number of participants requiring surgical intervention. Number of participants with episodes of acute urinary retention. Search methods for identification of studies We will perform a comprehensive search for studies, with no restrictions for language or publication status. Electronic searches We will search the following electronic bibliographic databases. Cochrane Central Register of Controlled Trials (CENTRAL) via OVID (latest issue; Appendix 1). MEDLINE via OVID (1990 to present; Appendix 2). SCOPUS (includes EMBASE) (1990 to present; Appendix 3). DARE (Database of Abstracts of Reviews of Effects) (1990 to present; Appendix 4). Google Scholar (1990 to present; Appendix 5). 3

6 LILACS (Latin American and Caribbean Center on Health Sciences Information) (1990 to present). HTA (Health Technology Assessments) (1990 to present). We will also search the following trial registers for ongoing trials. World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) ( network/en/). ClinicalTrials.gov (clinicaltrials.gov/). Searching other resources We will search conference databases (European Association of Urology Congress 1990 to present and American Urological Association Annual Meeting 1990 to present). We will also handsearch reference lists of all pertinent reviews and studies found. We will attempt to contact authors of identified trials to find out if they are aware of other published or unpublished trials. Data collection and analysis We will perform the review following the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). Selection of studies Two review authors (HAG, HEL) will independently screen the titles and abstracts of all records identified by the searches to determine which studies should be assessed further. One review author will remove duplicates. Two review authors (HAG, HEL) will obtain the full text of the remaining potentially relevant records, will link together multiple reports of the same study and will independently use a standardized eligibility form to classify studies as included studies, excluded studies, studies awaiting classification, or ongoing studies, in accordance with the criteria for each provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). If some of the information needed to classify the study is missing, we will attempt to contact the study authors for clarification. If any disagreement arises, then it will be discussed; if disagreement persists, then it will be arbitrated by a third review author (JT). We will document reasons for exclusion of studies that may have reasonably been expected to be included in the review in a Characteristics of excluded studies table. We will present an adapted Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram showing the process of study selection (Liberati 2009). Data extraction and management Two review authors (HAG, HEL) will independently extract the following data, which we will provide in the Characteristics of included studies table, using a standard data abstraction form that we will pilot test ahead of time. Study details: dates when the study was conducted, location and setting, study design, population size and attrition rate. Participant details: inclusion and exclusion criteria, study population, demographics. Intervention details: sample size for each intervention/ comparator group, type of intervention, time period for the intervention, and details of the intervention such as dose, route, frequency, duration, as applicable. Outcome details: outcomes reported from among primary and secondary outcomes; method of outcome measurement; timing of outcome measurement. Other details: funding sources and declarations of interest. We will extract outcome data relevant to this review as needed for calculation of summary statistics and measures of variance. For the dichotomous variables, we will extract data on the total number of participants randomized, the number that experienced the outcomes, the number analyzed, as well as summary statistics with corresponding measures of variance. For continuous outcomes, we will extract data on the total number of participants analyzed, means and standard deviations (SDs) or data necessary to calculate this information, and the number of participants randomized. Disagreement between the two review authors abstracting data will be resolved by discussion and, if disagreement persists, then a third review author will assess the study. We will translate any studies reported in non-english language journals before assessment. We will provide information, including trial identifier, about potentially relevant ongoing studies in the table Characteristics of ongoing studies. We will request, by mail, any further information required from the original study authors, and include relevant information obtained. Dealing with duplicate and companion publications In the event of duplicate publications, companion documents or multiple reports of a primary study, we will maximize yield of information by mapping all publications to unique studies, collating all available data and using the most complete data-set aggregated across all known publications. In case of doubt, we will give priority to the publication reporting the longest follow-up associated with our primary or secondary outcomes. We will highlight any discrepancy between published versions. Assessment of risk of bias in included studies Two review authors (HAG, HEL) will independently assess the methodological quality of each included trial using a standard quality assessment form (Higgins 2011a). We will resolve disagreements by consensus, or by consultation with a third review author. We will assess risk of bias using the Cochrane tool for assessment of risk of bias (Higgins 2011b). We will assess the following domains. 4

7 1. Random sequence generation (selection bias). 2. Allocation concealment (selection bias). 3. Blinding of participants and personnel (performance bias). 4. Blinding of outcome assessment (detection bias). 5. Incomplete outcome data (attrition bias). 6. Selective reporting (publication bias). 7. Other potential bias. We will judge each domain as low, high, or unclear risk of bias and will evaluate individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We will present a Risk of bias summary figure to illustrate these findings. For performance bias (blinding of participants and personnel) and detection bias (blinding of outcome assessment), we will evaluate the risk of bias separately for each outcome, and we will group outcomes according to whether measured subjectively or objectively when reporting our findings in the Risk of bias tables. We will also assess attrition bias (incomplete outcome data) on an outcome-specific basis, and will group outcomes with like judgments when reporting our findings in the Risk of bias tables. We will further summarize the risk of bias across domains for each outcome in each included study, as well as across studies and domains for each outcome. We define the following endpoints as objective outcomes. Number of participants with episodes of acute urinary retention. Number of participants requiring surgical intervention. We define the following endpoints as subjective outcomes. Mean change in urologic symptom scores. Mean change in quality of life. Major adverse effects. Change in nocturia, measured as the number of episodes per night. Adverse effects: Erectile dysfunction Breast enlargement and pain Ejaculatory dysfunction Decreased libido Orthostatic hypotension. Should we identify trials with more than two intervention groups for inclusion in the review, we will handle these in accordance with guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c), and would attempt to accomplish this by combining all relevant experimental intervention groups of the study into a single group and combining all relevant control intervention groups into a single control group, if appropriate. Dealing with missing data We will obtain missing data from study authors, if feasible, and will perform intention-to-treat (ITT) analyses if data are available; we will otherwise perform available case analyses. We will investigate attrition rates, e.g. drop-outs, losses to follow-up and withdrawals, and will critically appraise issues of missing data. We will not impute missing data. Assessment of heterogeneity We will only consider conducting a meta-analysis if the included studies are similar in terms of participants, interventions, and outcomes (clinical homogeneity). We will assess statistical heterogeneity between trial results visually by inspecting the amount of overlap of CIs in the forest plots. We will analyze heterogeneity using a χ 2 test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance, and with the I 2 test (Higgins 2011a). We will interpret I 2 as follows (Deeks 2011). 0% to 40%: might not be important. 30% to 60%: may represent moderate heterogeneity. 50% to 90%: may represent substantial heterogeneity. 75% to 100%: considerable heterogeneity. When we find heterogeneity, we will attempt to determine possible reasons for it by examining individual study and subgroup characteristics. Measures of treatment effect We will express and compare dichotomous data using risk ratios (RRs), the absolute risk reduction and number needed to treat (NNT) if appropriate. We will express continuous data as mean differences (MDs) unless different studies use different measures to assess the same outcome, in which case we will express data as standardized mean differences (SMDs). We will present all effect estimates with 95% confidence intervals (CIs). Unit of analysis issues Assessment of reporting biases We will attempt to obtain study protocols to assess for selective outcome reporting. If we identify sufficient RCTs (more than 10 studies), we will attempt to examine for reporting bias using a funnel plot (Higgins 2011a). Data synthesis Unless there is good evidence for homogeneous effects across studies, we will summarize data using a random-effects model. We 5

8 will interpret random-effects meta-analyses with due consideration of the whole distribution of effects. In addition, we will perform statistical analyses according to the statistical guidelines contained in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). For dichotomous outcomes, we will use the Mantel-Haenszel method; for continuous outcomes, we will use the inverse variance method. We will analyze the data using Review Manager 5 (RevMan 2014); we will additionally use Stata if necessary. Subgroup analysis and investigation of heterogeneity We will attempt to conduct the following subgroup analyses. 1. Prostate size ( 40 cc versus < 40 cc (measured by transrectal ultrasound)). 2. Age ( 65 years versus < 65 years). 3. Treatment duration (6 to 12 months versus > 12 months). 4. Baseline prostate symptom severity: mild (0 to 7) versus moderate (8 to 19) versus severe (20 to 35) (based on IPSS). Based on literature in this field (Roehrborn 2010), the important characteristics to analyze in LUTS secondary to BPH are the enlarged prostate, treatment duration and the IPSS. Roehrborn et al suggests that for prostates less than 40 cc, an alpha-blocker would be more appropriate, and for prostates more than 40 cc, combination therapy or 5ARI would be more effective (Roehrborn 2010). Regarding the duration of the treatment, people with this condition would have to take this medication for at least six months, and according to this, in the Combination of Avodart and Tamsulosin (CombAT) study Roehrborn et al suggests treatment duration greater than 12 months (Roehrborn 2010). Regarding the IPSS, Roehrborn 2010 suggests combination therapy is more effective for enlarged prostates that produce moderate and severe symptoms. On the other hand, regarding adverse effects, medications might produce erectile dysfunction so it would be a great concern for people less than 65 years. We will use the test for subgroup differences in Review Manager 5 to compare subgroup analyses if there are sufficient studies ( RevMan 2014). Sensitivity analysis We will perform a sensitivity analysis based on the risk of bias assessment, excluding trials at high or unclear risk of bias. Summary of findings table We will present the overall quality of the evidence for each outcome according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, which takes into account five criteria not only related to internal validity (risk of bias, inconsistency, imprecision, publication bias) but also to external validity such as directness of results (Guyatt 2008). For each comparison, two review authors will independently rate the quality of evidence for each outcome as high, moderate, low, or very low using GRADEproGDT 2015; discrepancies will be resolved by consensus, or, if needed, by arbitration by a third review author. For each comparison, we will present a summary of the evidence for the main outcomes in a Summary of findings table, which provides key information about the best estimate of the magnitude of the effect, in relative terms and absolute differences for each relevant comparison of alternative management strategies; numbers of participants and studies addressing each important outcome; and the rating of the overall confidence in effect estimates for each outcome (Guyatt 2011; Schünemann 2011). If meta-analysis is not possible, we will present results in a narrative Summary of findings table. A C K N O W L E D G E M E N T S None. R E F E R E N C E S Additional references Andriole 2010 Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, et al. Effect of dutasteride on the risk of prostate cancer. New England Journal of Medicine 2010;362(13): Barry 1997 Barry MJ, Fowler FJ Jr, Bin L, Pits JC 3rd, Harris CJ, Mulley AG Jr. The natural history of patients with benign prostatic hyperplasia as diagnosed by North American urologists. Journal of Urology 1997;157(1):10 4. Barry 2001 Barry MJ, Roehrborn CG. Benign prostatic hyperplasia. British Medical Journal (Clinical Research Ed.) 2001;323 (7320): Erratum in: British Medical Journal (Clinical Research Ed.) 2002;324(7340):775. Deeks 2011 Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 9: Analysing data and undertaking meta-analyses. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version [updated March 2011]. The Cochrane Collaboration, Available from 6

9 Garraway 1993 Garraway WM, Russell EB, Lee RJ, Collins GN, McKelvie GB, Hehir M, et al. Impact of previously unrecognized benign prostatic hyperplasia on the daily activities of middle-aged and elderly men. British Journal of General Practice 1993;43(373): Girman 1994 Girman CJ, Epstein RS, Jacobsen SJ, Guess HA, Panser LA, Oesterling JE, et al. Natural history of prostatism: impact of urinary symptoms on quality of life in 2115 randomly selected community men. Urology 1994;44(6): GRADEproGDT 2015 [Computer program] McMaster University (developed by Evidence Prime, Inc.). GRADEproGDT: GRADEpro Guideline Development Tool [ Hamilton: McMaster University (developed by Evidence Prime, Inc.), Guyatt 2008 Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Schünemann HJ, et al. GRADE: what is quality of evidence and why is it important to clinicians?. BMJ (Clinical Research Ed.) 2008;336(7651): [DOI: /bmj BE] Guyatt 2011 Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology 2011;64(4): [DOI: / j.jclinepi ] Higgins 2011a Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version [updated March 2011]. The Cochrane Collaboration, Available from Higgins 2011b Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version [updated March 2011]. The Cochrane Collaboration, Available from Higgins 2011c Higgins JPT, Deeks JJ, Altman DG (editors). Chapter 16: Special topics in statistics. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version [updated March 2011]. The Cochrane Collaboration, Available from Issa 2006 Issa MM, Fenter TC, Black L, Grogg AL, Kruep EJ. An assessment of the diagnosed prevalence of diseases in men 50 years of age or older. American Journal of Managed Care 2006;12(4 Suppl):S83-9. Jacobsen 1996 Jacobsen SJ, Girman CJ, Guess HA, Rhodes T, Oesterling JE, Lieber MM. Natural history of prostatism: longitudinal changes in voiding symptoms in community dwelling men. Journal of Urology 1996;155(2): Jacobsen 1997 Jacobsen SJ, Jacobson DJ, Girman CJ, Roberts RO, Rhodes T, Guess HA, et al. Natural history of prostatism: risk factors for acute urinary retention. Journal of Urology 1997; 158(2): Liberati 2009 Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Medicine 2009;6(7):e [DOI: /journal.pmed ] McVary 2010 McVary KT, Roehrborn CG, Avins AL, Barry MJ, Bruskewitz RC, Donell RF, et al. American Urological Association guideline: management of benign prostatic hyperplasia (BPH). benign-prostatic-hyperplasia.cfm (accessed 1 April 2015). NICE 2010 National Institute for Health and Care Excellence. Lower urinary tract symptoms in men: management. NICE guidelines [CG97]. (accessed 27 October 2015). Pagano 2014 Pagano E, Laudato M, Griffo M, Capasso R. Phytotherapy of benign prostatic hyperplasia. A minireview. Phytotherapy Research : PTR 2014;28(7): RevMan 2014 [Computer program] The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, Roehrborn 2007 Roehrborn CG, Nuckolls JG, Wei JT, Steers W, BPH Registry and Patient Survey Steering Committee. The Benign Prostatic Hyperplasia Registry and Patient Survey: study design, methods and patient baseline characteristics. BJU International 2007;100(4): Roehrborn 2010 Roehrborn CG, Siami P, Barkin J, Damião R, Major-Walker K, Nandy I, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. European Urology 2010;57 (1): Rosen 2003 Rosen R, Altwein J, Boyle P, Kirby RS, Luckas B, Meuleman E, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). European Urolology 2003;44(6):

10 Schünemann 2011 Schünemann HJ, Oxman AD, Higgins JPT, Vist GE, Glasziou P, Guyatt GH. Chapter 11: Presenting results and Summary of findings tables. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version [updated March 2011]. The Cochrane Collaboration, Available from Stata [Computer program] StataCorp. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP, Wilt 2002 Wilt T, Ishani A, Mac Donald R, Rutks I, Stark G. Pygeum africanum for benign prostatic hyperplasia. Cochrane Database of Systematic Reviews 2002, Issue 1. [DOI: / CD001044] References to other published versions of this review Tacklind 2010 Tacklind J, Fink HA, MacDonald R, Rutks I, Wilt TJ. Finasteride for benign prostatic hyperplasia. Cochrane Database of Systematic Reviews 2010, Issue 10. [DOI: / CD pub3] Indicates the major publication for the study A P P E N D I C E S Appendix 1. CENTRAL search strategy 1. exp prostatic hyperplasia 2. benign prostatic hyperplasia.mp 3. benign prostatic hypertrophy.mp 4. benign prostatic obstruction.mp 5. 1 or 2 or 3 or 4 6. exp finasteride 7. finasteride.mp 8. dutasteride.mp. 9. (Proscar or Avodart).mp. 10. exp 5-alpha reductase inhibitors or 7 or 8 or 9 or and randomized controlled trial.pt 14. controlled clinical trial.pt 15. randomized.ab 16. placebo.ab 17. drug therapy.fs 18. randomly.ab 19. trial.ab 20. groups.ab or 14 or 15 or 16 or 17 or 18 or 19 or exp animals/not humans.sh not and 23 8

11 Appendix 2. MEDLINE (Ovid) search strategy 1. exp prostatic hyperplasia 2. benign prostatic hyperplasia.mp 3. benign prostatic hypertrophy.mp 4. benign prostatic obstruction.mp 5. 1 or 2 or 3 or 4 6. exp finasteride 7. finasteride.mp 8. dutasteride.mp. 9. (Proscar or Avodart).mp. 10. exp 5-alpha reductase inhibitors or 7 or 8 or 9 or and randomized controlled trial.pt 14. controlled clinical trial.pt 15. randomized.ab 16. placebo.ab 17. drug therapy.fs 18. randomly.ab 19. trial.ab 20. groups.ab or 14 or 15 or 16 or 17 or 18 or 19 or exp animals/not humans.sh not and 23 Appendix 3. SCOPUS search strategy (includes EMBASE) (((TITLE-ABS-KEY( prostatic hyperplasia OR bph OR lower urinary tract symptom* OR luts)) OR (KEY( prostate hypertrophy )) OR (KEY( benign prostatic obstruction ))) AND ((TITLE-ABS-KEY(finasteride OR proscar OR dutasteride OR avodart)) OR (TITLE-ABS-KEY( 5 ari OR five alpha reductase inhibitor* OR 5alpha reductase inhibitors OR steroid 5alpha reductase inhibitors OR 5 alpha reductase inhibitor* )))) AND ( randomized controlled trial* OR rct* OR controlled clinical trial* ) Appendix 4. DARE search strategy 1. (dutasteride or finasteride).mp [mp=title,full text, keywords] 2. (proscar or avodart).mp [mp=title,full text, keywords] 3. 1 or 2 4. benign prostatic hyperplasia.mp [mp=title,full text, keywords] 5. benign prostatic obstruction.mp [mp=title,full text, keywords] 6. benign prostatic hypertrophy.mp [mp=title,full text, keywords] 7. 4 or 5 or and 7 9

12 Appendix 5. Google Scholar search strategy Strategy With all of the words: finasteride With the exact phrase: NA With at least one of the words: randomized randomised controlled trial RCT Without the words: hirsutism, hirsute, alopecia, hair loss, prostate cancer Where my words occur: in the title of the article Return articles dated between Strategy with all of the words: NA with the exact phrase: randomized with at least one of the words: 5-ARI, 5α-reductase, inhibitors, 5-alpha reductase without the words: hirsutism, hirsute, alopecia, hair loss, prostate cancer, male-pattern baldness where my words occur: in the title of the article return articles dated between Strategy with all of the words: dutasteride with the exact phrase: NA with at least one of the words: randomized randomised controlled trial RCT without the words: hirsutism, hirsute, alopecia, hair loss, prostate cancer where my words occur: in the title of the article Return articles dated between C O N T R I B U T I O N S O F A U T H O R S HA García-Perdomo: conceiving the review, designing the review, coordinating the review, data collection for the review, designing search strategies, undertaking searches, screening search results, screening retrieved papers against inclusion criteria, appraising quality of papers, extracting data from papers, writing to authors of papers for additional information, data management, entering data into Review Manager, analysis of data, interpretation of data, drafting the protocol, drafting the review, critical revision of the protocol/ review for important intellectual content, and providing general advice on the review. HE Lopez: conceiving the review, designing the review, data collection for the review, screening search results, screening retrieved papers against inclusion criteria, appraising quality of papers, extracting data from papers, writing to authors of papers for additional information, analysis of data, interpretation of data, drafting the protocol, drafting the review, critical revision of the protocol/review for important intellectual content, and providing general advice on the review. J Tacklind: conceiving the review, designing the review, data collection for the review, designing search strategies, undertaking searches, screening search results, screening retrieved papers against inclusion criteria, appraising quality of papers, extracting data from papers, writing to authors of papers for additional information, analysis of data, interpretation of data, drafting the protocol, drafting the review, critical revision of the protocol/review for important intellectual content, and providing general advice on the review. 10

13 D E C L A R A T I O N S O F I N T E R E S T HA García-Perdomo: none known. HE Lopez declares the following relevant financial activity: received payment from GlaxoSmithKline for serving as a speaker. J Tacklind: none known. S O U R C E S O F S U P P O R T Internal sources None, Other. External sources None, Other. N O T E S Parts of the Methods section of this protocol are based on a standard template developed by the Cochrane Metabolic and Endocrine Disorders Group that has been modified and adapted for use by the Cochrane Urology Group. 11