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Critical Review of Guidelines for BPH Diagnosis and Treatment Strategy

      Abstract

      Objectives

      To provide a critical overview of the currently available guidelines on benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS).

      Methods

      Through a nonsystematic review of MEDLINE, we identified the guidelines produced by the following institutions: American Urological Association (AUA), Australian National Health and Medical Research Council (NHMRC), British Association of Urological Surgeons (BAUS), Canadian Urological Association, European Association of Urology (EAU), and the 5th International Consultation on BPH. All the guidelines were evaluated by the international appraisal instrument provided by the Appraisal of Guidelines, Research and Evaluation (AGREE) collaboration. Moreover, the recommendations concerning diagnosis and treatment from the different guidelines were compared.

      Results

      A wide discrepancy was observed among the overall quality of the guidelines. The guidelines from the Australian NHMRC and from the AUA yielded the highest overall scores, with 86 and 72 points, respectively. According to the domains of the AGREE appraisal instrument, the scores concerning “scope and purpose” and “clarity and presentation” were quite high and quite similar among the different documents, whereas the most relevant differences were observed in domains concerning the methodology of development of the guidelines.

      Conclusion

      Although all the texts had some good aspects, we found considerable differences in the overall quality of the available guidelines, especially with regard to the methodologic issues. The guidelines from the Australian NHMRC and AUA were most adherent to the standards of quality suggested by the AGREE appraisal instrument. In cases of controversial issues, clinicians could use the summarised data to select the guidelines they trusted the most to be used in their clinical practice.

      Keywords

      1. Introduction

      Evidence-based medicine (EBM) has been defined as “the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients” [
      • Sackett D.L.
      • Rosenberg W.M.C.
      • Muir Gray J.A.
      • Haynes R.B.
      • Scott Richardson Y.
      Evidence based medicine: what it is and what it isn’t.
      ]. In the era of EBM, “high-quality healthcare implies a practice that is consistent with the best available evidence” [
      Evidence-based medicine
      A new approach to teaching the practice of medicine. Evidence-Based Medicine Working Group.
      ]. However, obtaining and critically appraising the current evidence, as well as considering that evidence in the context of an individual's circumstances, is beyond the time, skills, and resources of most clinicians. To overcome those limitations, clinical practice guidelines have been developed with the aim of providing “an evidence-based framework on which clinicians base their practice, with the purpose of reducing unwanted variations by setting agreed standards based on the best available evidence” [
      • Emberton M.
      Clinical practice guidelines for the surgeon-how should they be understood and applied?.
      ].
      Clinical practice guidelines have been defined as systematically developed statements designed to assist practitioner and patient decisions about appropriate health care for specific clinical conditions and/or circumstances [
      • Lohr K.N.
      • Field M.J.
      A provisional instrument for assessing clinical practice guidelines.
      ]. In the most relevant clinical areas several guidelines have been published and significant differences are often present among the different documents, with frequent conflicting recommendations, raising concerns about the overall quality of the process that led to the generation of the guidelines.

      1.1 What makes a good clinical guideline?

      The development of a guideline is a very long task, involving different kinds of expertise and including several relevant steps, such as planning of the objectives, search, extraction, rating and analysis of the evidence, cost analysis, draft of the recommendations, draft reviewing, guideline piloting, dissemination, and implementation, and so on. Each step may be impaired by several methodologic biases. A few papers demonstrated clearly that most of the guidelines published in the peer-reviewed medical literature did not adhere to basic methodologic standards [
      • Shaneyfelt T.M.
      • Mayo-Smith M.F.
      • Rothwangl J.
      Are guidelines following guidelines? The methodological quality of clinical practice guidelines in the peer-reviewed medical literature.
      ,
      • Grilli R.
      • Magrini N.
      • Penna A.
      • Mura G.
      • Liberati A.
      Practice guidelines developed by specialty societies: the need for a critical appraisal.
      ]. Consequently, the establishment of internationally recognised standards to improve the development and reporting of clinical guidelines has become a major medical issue, which has been addressed by both national health providers (National Institutes of Health [NIH] from the United States and National Health Service [NHS] from the United Kingdom) and independent multinational groups, such as the Appraisal of Guidelines, Research and Evaluation (AGREE) collaboration. The NHS executive group identified nine different major issues, which should identify a good-quality guideline (Table 1), including the steps of methodologic development and a plan for updating the guidelines [
      NHS, Executive
      Clinical guidelines.
      ]. Moreover, a few algorithms have been developed to analyse step by step the quality of a guideline, such as the checklist of the Health Care Evaluation Unit at St George's Hospital Medical School, London, United Kingdom [
      • Cluzeau F.A.
      • Littlejohns P.
      Appraising clinical practice guidelines in England and Wales. The development of a methodologic framework and its application to policy.
      ] and the appraisal instrument provided by the AGREE collaboration [
      The AGREE Collaboration
      Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project.
      ].
      Table 1Major characteristics of good clinical practice guidelines
      CharacteristicDescription
      ValidityLeads to the results expected of them
      ReproducibilityIf using the same evidence, other guideline groups would come to the same results
      Cost-efficacyReduce the inappropriate use of resources
      Representativity/multidisciplinarityNeeds to involve key groups and their interests
      Clinical applicabilityPatient populations affected should be unambiguously defined
      FlexibilityNeeds to identify the expectations relating to recommendations as well as patient preferences
      ClearnessUnambiguous language, which is readily understood by clinicians and patients, should be used
      ReviewabilityThe date and process of review should be stated
      Amenability to clinical auditThe guidelines should be capable of translation into explicit audit criteria
      Modified from ref.
      NHS, Executive
      Clinical guidelines.
      .
      Lower urinary tract symptoms (LUTS) are a major health problem. That terminology, initially suggested by Abrams in 1994 [
      • Abrams P.
      Ner words for old: lower urinary tract symptoms for “prostatism”.
      ], was recommended by the 5th International Consultation on BPH to replace imprecise terms such as “clinical BPH,” “symptomatic BPH,” and “prostatism” [
      ]. The same consultation recommended the use of the terms benign prostatic hyperplasia (BPH) only in case of histologic confirmation and benign prostatic enlargement (BPE) when such pathologic data were lacking. Moreover, considering the weak correlation between urinary symptoms and urodynamic observations, the term bladder outlet obstruction (BOO) was suggested to be used when a reduced urine flow rate was associated with increased detrusor pressure [
      ]. LUTS are highly prevalent. By the age of 60 yr, nearly 60% of the cohort of the Baltimore Longitudinal Study of Aging had some degree of urinary symptoms due to BPE [
      • Arrighi H.M.
      • Metter E.J.
      • Guess H.A.
      • Fozzard J.L.
      Natural history of benign prostatic hyperplasia and risk of prostatectomy, the Baltimore Longitudinal Study of Aging.
      ]. Further data from the United States showed that moderate-to-severe symptoms can occur among 13% of men aged 40–49 yr and among 28% of those older than 70 yr [
      • Chute C.G.
      • Panser L.A.
      • Girman C.J.
      • et al.
      The prevalence of prostatism: a population based survey of urinary symptoms.
      ]. Similar trends were reported in Europe as well [
      • Berges R.R.
      • Pientka L.
      Management of the BPH syndrome in Germany: who is treated and how?.
      ]. Moreover, with the changing demographic profile and the increasingly aging population in all western societies, this disorder will become even more prevalent and a major challenge for all health care systems in the future [
      • Madersbacher S.
      • Alivizatos G.
      • Nordling J.
      • Sanz C.R.
      • Emberton M.
      • de la Rosette J.J.
      EAU 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (BPH guidelines).
      ]. Those figures, as well as variations in the patterns of practice, high cost of treatment, and the increasing number of treatment options made BPH an optimal topic for guidelines development.
      To date, several guidelines are available on diagnosis, management, and follow-up of BPH/BPE and LUTS. The aim of this review is to provide a critical overview of both the quality and contents of the published guidelines.

      2. Materials and methods

      We performed a nonsystematic review of the literature. Data were identified by a search of MEDLINE using a complex search strategy including both “MeSH” (Medical Subject Heading) and “free text” protocols. Specifically, the MeSH search was conducted by the term “Prostatic Hyperplasia” retrieved from the MeSH browser provided by MEDLINE. Multiple “free text” searches were performed by applying the following terms one by one through all fields of the records: “benign prostatic hyperplasia,” “benign prostatic enlargement,” “lower urinary tract symptoms,” and “LUTS.” All the MEDLINE searches were pooled together, collecting 25,603 records. Subsequently, the following search limits were used: publication type (“Practice Guideline”) and languages (“English”). Twenty records were finally identified, whose abstracts were reviewed by three of the authors (G.N., A.G., V.F.). In addition, other significant studies cited in the reference lists of the selected papers were considered.
      After excluding the papers regarding standardisations of terminology of the International Consultation on Incontinence (3 records), LUTS in female (2 records) or paediatric (one record) patients, urinary tract infections (1 record), and prostate cancer (1 record), we identified the guidelines produced by the following institutions: American Urological Association (AUA) [
      AUA Practice Guidelines Committee
      AUA guideline on management of benign prostatic hyperplasia. Diagnosis and treatment recommendations.
      ], Australian National Health and Medical Research Council (NHMRC) [

      Clinical Practice Guidelines. The management of uncomplicated lower urinary tract symptoms in men. National Health and Medical Research Council, 2000.

      ], British Association of Urological Surgeons (BAUS) [
      • Speakman M.J.
      • Kirby R.S.
      • Joyce A.
      • Abrams P.
      • Pocock R.
      The British Association of Urological Surgeons. Guideline for the primary care management of male lower urinary tract symptoms.
      ], Canadian Urological Association [
      • Nickel J.C.
      • Herschorn S.
      • Corcos J.
      • et al.
      Canadian Urological Association Guidelines Committee. Canadian guidelines for the management of benign prostatic hyperplasia.
      ], European Association of Urology (EAU) [
      • Madersbacher S.
      • Alivizatos G.
      • Nordling J.
      • Sanz C.R.
      • Emberton M.
      • de la Rosette J.J.
      EAU 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (BPH guidelines).
      ], and World Health Organization (WHO) [
      • Cockett A.T.
      • Aso Y.
      • Denis L.
      • et al.
      World Health Organization Consensus Committee recommendations concerning the diagnosis of BPH.
      ]. When multiple editions of the guidelines were available (AUA, BAUS, EAU), we elected to analyse the most recent one. Although not indexed in MEDLINE, we included in the review the 5th International Consultation on Benign Prostatic Hyperplasia [
      ]. Since the consultation was patronized by WHO, we considered its text an update of the WHO guideline published in 1991, which, consequently, was excluded from the present study.
      The retrieved guidelines were evaluated by the AGREE appraisal instrument by three of the authors (G.N., A.G., V.F.), with any discrepancies solved by open discussion. The AGREE collaboration scale includes 23 questions grouped in six domains: scope and purpose, stakeholder involvement, rigor of development, clarity and presentation, applicability, and editorial independence. A score from 1 to 4 can be assigned for each question, 23 and 92 being the lowest and the highest possible scores [
      The AGREE Collaboration
      Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project.
      ]. The English version and several validated translations of the appraisal instrument, including instructions for the users, are available free at http://www.agreecollaboration.org.

      3. Results

      3.1 Quality of guidelines

      Table 2 summarizes our findings after application of the AGREE appraisal instrument to the analysed guidelines.
      Table 2AGREE appraisal instrument for clinical practice guidelines: summary of six domains and overall scores for the analysed guidelines
      DomainsAustralian NHMRC5th IC on BPHAUABAUSEAUCanadian Urological Association
      Year of publication200020012003200420042005
      Scope and purpose121011121111
      Stakeholder involvement146121288
      Rigor of development24923151212
      Clarity and presentation161416161514
      Applicability1255554
      Editorial independence855855
      Overall score864972685654
      Guidelines are listed according to the year of publication; 23 and 92 were the lowest and highest possible scores, respectively.
      NHMRC = National Health and Medical Research Council; IC = International Consultation; BPH = benign prostatic hyperplasia; AUA, American Urological Association; BAUS = British Association of Urological Surgeons; EAU, European Association of Urology.
      A wide discrepancy was observed among the overall quality of the guidelines. The guidelines from the Australian NHMRC and from the AUA yielded the highest overall scores, being definitely the most “evidence-based.” The worst scores were obtained by EAU, the Canadian guidelines, and the 5th International Consultation on BPH.
      According to the domains of the AGREE appraisal instrument, the scores concerning “scope and purpose” and “clarity and presentation” were quite high and quite similar among the different documents, meaning that the aims of the guideline, specific clinical questions, target patient population as well as format and languages of the guidelines were addressed adequately in all cases. The most relevant differences were actually observed in the domains concerning the methodology followed during the guideline development.
      First of all, with regard to the “stakeholder involvement” domain, the steering groups of the best-ranked guidelines were multidisciplinary, including urologists, general practitioners, experts in general medicine and family medicine [
      AUA Practice Guidelines Committee
      AUA guideline on management of benign prostatic hyperplasia. Diagnosis and treatment recommendations.
      ], health economists [

      Clinical Practice Guidelines. The management of uncomplicated lower urinary tract symptoms in men. National Health and Medical Research Council, 2000.

      ], nurses [
      • Speakman M.J.
      • Kirby R.S.
      • Joyce A.
      • Abrams P.
      • Pocock R.
      The British Association of Urological Surgeons. Guideline for the primary care management of male lower urinary tract symptoms.
      ], and patients [

      Clinical Practice Guidelines. The management of uncomplicated lower urinary tract symptoms in men. National Health and Medical Research Council, 2000.

      ,
      • Speakman M.J.
      • Kirby R.S.
      • Joyce A.
      • Abrams P.
      • Pocock R.
      The British Association of Urological Surgeons. Guideline for the primary care management of male lower urinary tract symptoms.
      ].
      As far as the “rigor of development” domain was concerned, AUA and NHMRC had extremely high scores (23 and 24, respectively, of a maximum possible score of 28). The AUA text depicted step by step the 3-yr work done to carry out an excellent meta-analysis of the available evidence, which was closely related to the guideline recommendations. The Australian NHMRC was the text that better rated the level of the gathered evidence, applying a system similar to the most widely accepted scale from the Oxford Centre for Evidence-Based Medicine [

      Phillips B, Ball C, Sackett D, et al. Levels of evidence and grades of recommendation. Oxford Centre for Evidence-Based Medicine, http://www.cebm.net/levels_of_evidence.asp#levels.

      ]. Moreover, the panel of the Australian guidelines provided a straightforward cost analysis and was the only one to include a plan for updating the guidelines in the final document. Those were two of the best qualities of that excellent text [

      Clinical Practice Guidelines. The management of uncomplicated lower urinary tract symptoms in men. National Health and Medical Research Council, 2000.

      ].
      Regarding the “applicability” domain, the Australian NHMRC guideline was the only one to propose a series of indicators for guideline dissemination (e.g., 80% of general practitioners being aware of the LUTS guidelines and 40% of men aged ≥50 yr with bothersome urinary symptoms aware of the consumer guidelines within a year of publication) and implementation (e.g., reduction of prostate-specific antigen [PSA] test ordering; reduction of referral to urologists for investigation and management of men not bothered by urinary symptoms; increase of watchful waiting programs; decrease in transurethral resections of the prostate [TURPs] performed on men ‘not at all’ or only ‘mildly’ bothered by uncomplicated urinary symptoms) [

      Clinical Practice Guidelines. The management of uncomplicated lower urinary tract symptoms in men. National Health and Medical Research Council, 2000.

      ]. These latest issues justified the maximum score in the “applicability” domain. In contrast, most of those issues were ignored in the other guidelines.
      The differences in the overall quality of the guidelines as assessed by the AGREE appraisal instrument were paralleled by the suggested diagnostic recommendation, with the best scoring guidelines being those that recommend the lowest numbers of tests (Table 3).
      Table 3Diagnostic tests recommended by the analysed guidelines in the evaluation of male lower urinary tract symptoms
      Australian NHMRC5th IC on BPHAUABAUSEAUCanadian Urological Association
      History, physical exam and DRERRRRRM
      Symptom scoreRRRRRR
      Voiding diaryOROOOO
      Urine analysisRRRRRM
      UroflowmetryNROOORO
      PVR measurementNROOORO
      Serum creatinineNRNDNRORO
      Serum PSANRROORR
      Upper urinary tract imagingNRONRNRONR
      Prostate ultrasound scansNROONRONR
      Pressure-flow studyNROOOONR
      Cysto-uretroscopyNROONRONR
      Total recommended or mandatory procedures353374
      Guidelines are listed according to the year of publication.
      R = recommended; M = mandatory; O = optional; NR = not recommended; ND = not discussed; DRE = digital rectal examination; PVR = postvoiding residual urine; PSA = prostate-specific antigen. Other abbreviations are defined in Table 2.

      3.2 Diagnostic recommendations

      Table 3 summarises the recommended procedures in the routine assessment of patients with LUTS due to BPE.
      All the guidelines agreed in recommending medical history, physical examination, symptom assessment by a validated score, and urinalysis. Medical history should be focused on the urinary tract and, in addiction, address general health issues that might cause bladder dysfunction or polyuria, as well as disease that might impair general health conditions for eventual surgical procedures. Family history of prostatic disease as well as personal history of previous surgical procedures should be taken into account. The Australian NHMRC provided a clear list of conditions that should be assessed, such as bowel habit, comorbidity (neurologic or psychiatric conditions, diabetes, cardiac disease, or poor mobility), drug intakes (diuretics, antidepressants, and antihypertensives), social/employment and psychological issues relevant to the management of LUTS, and mental state with specific attention to dementia, anxiety, and depression [

      Clinical Practice Guidelines. The management of uncomplicated lower urinary tract symptoms in men. National Health and Medical Research Council, 2000.

      ].
      Similarly, all the documents suggested a careful physical examination, including a digital rectal examination (DRE). Moreover, AUA guidelines highlighted the need for a focused neurologic examination to assess general mental status, ambulatory status, lower extremity neuromuscular function, and anal sphincter tone [
      AUA Practice Guidelines Committee
      AUA guideline on management of benign prostatic hyperplasia. Diagnosis and treatment recommendations.
      ]. The DRE was aimed at detecting gross distortion of the anatomy suggestive of a diagnosis of locally advanced prostate cancer, at estimating prostate volume, and excluding other anorectal pathologies. Although the DRE tends to underestimate the real prostate size, it is usually recognised that prostates that feel enlarged at rectal examination are usually confirmed to be large through imaging techniques [
      • Bosch J.L.H.R.
      • Bohnen A.M.
      • Groeneveld F.P.M.J.
      Validity of digital rectal examination and serum prostate specific antigen in the estimation of prostate volume in community-based men aged 50 to 78 years: the Krimpen study.
      ]. Moreover, even if the correlation between prostate size and symptoms is not so strict, the Olmsted study showed that the odds of having moderate to severe LUTS were 1.5 and 3.5 times higher for patients with prostates larger than 30 ml and 50 ml, respectively [
      • Girman C.J.
      • Jacobsen S.J.
      • Rhodes T.
      • et al.
      Prostate size related to urinary symptoms and health related quality of life in randomly selected men.
      ].
      Further agreement among the guidelines was found in the use of a symptom score, the International Prostate Symptom Score (IPSS) being the most commonly applied. The index has a high internal consistency and test-retest reliability [

      Clinical Practice Guidelines. The management of uncomplicated lower urinary tract symptoms in men. National Health and Medical Research Council, 2000.

      ], and it has been translated and validated in several languages. Although that score does not appropriately address urinary continence and bother due to LUTS as well as their interference with daily activities, it is considered a fundamental tool for planning therapeutic strategy and assessing response to therapy or disease progression during the follow-up. In the AUA guidelines further attention was given to other questionnaires (such as the International Continence Society male questionnaire, Danish Prostatic Symptom Score, BPH Impact Index), which, however, were all considered optional.
      Urinalysis was similarly recommended by all the guidelines, with the aim of detecting microhematuria or pyuria, which might be clues to bladder carcinoma, urinary tract infections, urethral strictures, bladder stones, and other conditions that might be causes of LUTS.
      Those listed above were the only procedures recommended by the guidelines of AUA, Australian NHMRC, and BAUS in the initial assessment of patients with LUTS. However, the EAU, Canadian, and 5th International Consultation on BPH guidelines suggested the use of further tests.
      Guidelines from Canadian Urological Association, EAU, and the 5th Consultation on BPH recommended having a PSA sample in patients with LUTS. Wisely, AUA guidelines, which considered PSA an optional test, highlighted the need to offer a PSA test to those patients with “at least a 10-year life expectancy and for whom knowledge of the presence of prostate cancer would change management” or “for whom the PSA measurement may change the management of their voiding symptoms” [
      AUA Practice Guidelines Committee
      AUA guideline on management of benign prostatic hyperplasia. Diagnosis and treatment recommendations.
      ]. Similar caveats were also included in the EAU guidelines and in the International Consultation on BPH. In contrast, Australian NHMRC guidelines underscored that early prostate cancer was a silent disease and that “men with uncomplicated LUTS should be advised that current data suggest that they have little or no increased risk of prostate cancer” [

      Clinical Practice Guidelines. The management of uncomplicated lower urinary tract symptoms in men. National Health and Medical Research Council, 2000.

      ]. Hence, the Australian document discouraged the use of PSA testing and advised informing patients that “there is no scientific evidence of a relationship between LUTS and presence of early prostate cancer” [

      Clinical Practice Guidelines. The management of uncomplicated lower urinary tract symptoms in men. National Health and Medical Research Council, 2000.

      ]. Moreover, the AUA and Australian guidelines recommended extensively informing patients of the consequence of PSA testing.
      Determination of serum creatinine levels was also advocated by EAU guideline documents, with the aim of diagnosing renal insufficiency. However, analysing >10,000 patients enrolled in randomised clinical trials, the panel of AUA guidelines reported a rate of silent renal insufficiency <2%, mostly unrelated to BPH, discouraging the routine testing of creatinine [

      Clinical Practice Guidelines. The management of uncomplicated lower urinary tract symptoms in men. National Health and Medical Research Council, 2000.

      ]. Wisely, BAUS guidelines suggested having creatinine tested in cases where chronic urinary retention was suspected. EAU guidelines recommended, besides, uroflowmetry and postvoiding residual (PVR) urine measurement. The panel of the 5th International Consultation on BPH highlighted the value of uroflowmetry as a screening test, even though the test is unable to distinguish lower urinary tract obstruction from poor bladder contraction. Even with a peak flow rate (Qmax) >15 ml/s, 30% of the patients had urodynamically proven BOO, where those figures were as low as 10% for Qmax <10 ml/s [
      • Poulsen A.L.
      • Schou J.
      • Puggaard L.
      • Torpedersen S.
      • Nordling J.
      Prostatic enlargement, symptomatology, and pressure/flow evaluation:interrelations in patients with symptomatic BPH.
      ]. Moreover, flow rates have to be considered inaccurate for voided volumes <125–150 ml and a learning effect has been shown, which suggests the value of at least two separate flow rates [

      Clinical Practice Guidelines. The management of uncomplicated lower urinary tract symptoms in men. National Health and Medical Research Council, 2000.

      ]. Indeed, the diagnostic role of uroflowmetry is far from being optimal. Although several papers showed that the lower the Qmax, the higher the chances of symptom improvement after surgery, Jensen reported that 71% of the patients who underwent TURP with Qmax >15 ml/s had symptom relief, compared to 92% for those with Qmax <10 mL/s [
      • Jensen K.M.
      • Jorgensen J.B.
      • Mogensen P.
      Urodynamics in prostatism. I. Prognostic value of uroflowmetry.
      ].
      Similarly, several limitations impaired the use of PVR urine measurement. Several studies highlighted that the reproducibility of the test was poor, as suggested by considerable intraindividual variations in residual urine values. Moreover, the magnitude of PVR volume was not or was only weakly correlated with the severity of urinary symptoms and with urodynamic parameters such as voiding pressures and peak urine flow rate. Most importantly, however, pretreatment PVR volume is at best only weakly associated with treatment outcome and residual urine is not a contraindication to watchful waiting or medical therapy. Although large PVR volumes may indicate bladder dysfunction and predict a slightly less favourable response to treatment, major disagreement was evident among the guidelines, with each document suggesting different cut-points (200 ml for EAU, 300 ml for BAUS, and 350 ml for AUA guidelines). Interestingly, BAUS guidelines suggested performing upper urinary tract imaging and pressure-flow study in all the patients with persistently large PVR values.
      Higher level of agreement was seen among the different guidelines concerning further diagnostic tests. Pressure-flow studies were considered optional by all the guidelines, with the exception of the Australian NHMRC, which did not recommend their use. According to the EAU text, they might be indicated before surgery in patients with Qmax >15 ml/s, in the elderly (e.g., >80 yr), in younger men (e.g., <50 yr), in the presence of large PVR (>300 ml), in patients with suspicion of neurogenic bladder dysfunction (e.g., neurologic disease such as Parkinson disease), or after radical pelvic surgery or unsuccessful invasive BPH treatment [
      • Madersbacher S.
      • Alivizatos G.
      • Nordling J.
      • Sanz C.R.
      • Emberton M.
      • de la Rosette J.J.
      EAU 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (BPH guidelines).
      ]. The aim of the invasive urodynamic test is to identify patients without a clear BOO, who have the lowest chance to benefit from surgery.
      Similarly, almost all the guidelines considered the use of frequency-volume charts or voiding diaries optional, to be indicated in case of predominant storage symptoms (especially nocturia).
      Most of the guidelines did not recommend the use of imaging techniques of the upper urinary tract because in patients with apparently uncomplicated LUTS, the prevalence of upper tract dilatation has been estimated to range from 0.8% to 2.5%. Indication for such imaging may, however, include haematuria, urinary tract infections, renal insufficiency, history of urolithiasis, and history of urinary tract surgery. Similarly, all the guidelines did not recommended the routine use of prostate imaging (e.g., transrectal ultrasound scan), which might be indicated only in the case of minimally invasive surgery (where prostate volume might be a limiting factor) or for selecting the most appropriate conventional surgical therapy (transurethral incision of the prostate [TUIP], TURP, or open prostatectomy). In that context, anatomic features of the prostate, such the presence of an intravesical middle lobe, may affect the choice of therapy. Although few papers showed an interesting diagnostic role of the bladder wall thickness as a marker of BOO [
      • Manieri C.
      • Carter S.S.
      • Romano G.
      • Trucchi A.
      • Valenti M.
      • Tubaro A.
      The diagnosis of bladder outlet obstruction in men by ultrasound measurement of bladder wall thickness.
      ], measurement of bladder wall thickness is currently not part of the recommended diagnostic work-up of patients with LUTS.
      Finally, urethrocystoscopy was not recommended in the initial assessment of patients with LUTS prior to watchful waiting or medical therapy, but it has to be considered in patients with a history of microscopic or gross haematuria, urethral strictures (or risk factors, such as history of urethritis or urethral trauma), bladder cancer, previous lower urinary tract surgery, or before surgery.

      3.3 Treatment recommendations

      The major outcomes of BPE/BPH treatment are relief of patients’ symptoms and improvement of quality of life, and, more recently added, altering the disease progression [
      • Nordling J.
      Altering disease progression: the key to successful patient management.
      ]. Most of the treatment recommendations provided by the guidelines were focused on the first two objectives, although those more recently developed provided further insights on disease progression.
      In most of the clinical cases, the cornerstone of treatment planning was established on symptom severity and the degree of bother. Patients with mild (IPSS ≤ 7), not bothersome, or slightly bothersome symptoms are considered candidates for a watchful waiting program.
      Watchful waiting is a management strategy in which the patient is monitored by his physician without receiving any active intervention for LUTS. Various conservative measures may be used to reduce the degree of bother, such as minor lifestyle modifications and bladder training. Lifestyle modifications consist of the reduction of fluid intake, toilet scheduling, reviewing patient's medication and changing the time of administration or substituting drugs for others that have fewer urinary effects, treatment of constipation, and reversal, where possible, of polyuria [
      • Madersbacher S.
      • Alivizatos G.
      • Nordling J.
      • Sanz C.R.
      • Emberton M.
      • de la Rosette J.J.
      EAU 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (BPH guidelines).
      ,

      Clinical Practice Guidelines. The management of uncomplicated lower urinary tract symptoms in men. National Health and Medical Research Council, 2000.

      ].
      In patients with moderate to severe (IPSS ≥ 8) or bothersome symptoms, almost all the guidelines indicated the central role of the patient in selecting the kind of treatment he accepted the most, once clearly informed about efficacy and side-effect profiles. The currently available options include medical therapy, minimally invasive surgical therapy, and conventional surgical therapies.
      The mainstays of drug therapy are currently α-blockers and 5-α-reductase inhibitors. α-Blocker therapy is based on the hypothesis that LUTS are partly caused by α1-adrenergic–mediated contraction of prostatic smooth muscle and bladder neck, resulting in BOO [
      • Roehrborn C.G.
      • Prajsner A.
      • Kirby R.
      • Andersen M.
      • Quinn S.
      • Mallen S.
      A double-blind placebo-controlled study evaluating the onset of action of doxazosin gastrointestinal therapeutic system in the treatment of benign prostatic hyperplasia.
      ]. α-Adrenergic receptor antagonists, such as doxazosin, tamsulosin, alfuzosin, and terazosin, reduce this process, relieving BOO. The use of those drugs has been widely studied. Meta-analytical data from AUA guidelines suggest that alfuzosin, doxazosin, tamsulosin, and terazosin are similarly effective in partially relieving symptoms, producing a 4-to-6 point improvement in the AUA Symptom Index. The most relevant adverse events reported with α-blocker therapy are orthostatic hypotension, dizziness, tiredness, asthenia, ejaculatory problems, and nasal congestion. The adverse event profile appears slightly different between the four α-blocking agents, with tamsulosin having a lower probability of orthostatic hypotension but a higher probability of ejaculatory dysfunction than the other α-blockers [
      • Rosen R.C.
      • Giuliano F.
      • Carson C.C.
      Sexual dysfunction and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).
      ,
      • Zlotta A.R.
      • Teillac P.
      • Raynaud J.P.
      • Schulman C.C.
      Evaluation of male sexual function in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) treated with a phytotherapeutic agent (Permixon), tamsulosin or finasteride.
      ,
      • McVary K.T.
      Erectile dysfunction and lower urinary tract symptoms secondary to BPH.
      ].
      Finasteride and dutasteride are the currently available 5-α-reductase inhibitors. Both of them impair the intraprostatic conversion of testosterone in dihydrotestosterone, reducing the size of the prostate, increasing the peak urinary flow rate, and relieving LUTS within 6–9 mo of therapy. The reported adverse events are primarily sexually related and include decreased libido, ejaculatory dysfunction, and erectile dysfunction. However, those adverse events are reversible and uncommon after the first year of therapy. Relevant analyses of both the Proscar Long-term Efficacy and Safety Study (PLESS) [
      • McConnell J.D.
      • Bruskewitz R.
      • Walsh P.
      • et al.
      The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia.
      ] and Medical Therapy of Prostatic Symptoms (MTOPS) [
      • McConnell J.D.
      • Roehrborn C.G.
      • Bautista O.M.
      • et al.
      The long-term effect of doxazosin, finasteride, and combination therapy on the progression of benign prostatic hyperplasia.
      ] randomised controlled trials, moreover, allowed further insights on finasteride efficacy. MTOPS trial randomised 3047 men to placebo, doxazosin, finasteride, or the combination therapy of doxazosin and finasteride. The trial showed a significant reduction in both the incidence of acute urinary retention and need of surgery for LUTS in patients treated with finasteride, whereas doxazosin was only able to delay these events for about 2–2.5 yr, without preventing them in the end [
      • McConnell J.D.
      • Roehrborn C.G.
      • Bautista O.M.
      • et al.
      The long-term effect of doxazosin, finasteride, and combination therapy on the progression of benign prostatic hyperplasia.
      ]. Similar data were reported in the studies on dutasteride as well [
      • Roehrborn C.G.
      • Boyle P.
      • Nickel J.C.
      • Hoefner K.
      • Andriole G.
      ARIA3001 ARIA3002 and ARIA3003 Study Investigators
      Efficacy and safety of dual inhibitor of 5-alpha reductase type 1 and 2 (dutasteride) in men with benign prostatic hyperplasia.
      ,
      • Debruyne F.
      • Barkin J.
      • van Erps J.
      • Reis M.
      • Tammela T.L.J.
      • Roehrborn C.
      on behalf of the ARIA3001, ARIA3002, ARIB3003 Study Investigators
      Efficacy and safety of long-term treatment with the dual 5a-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia.
      ,
      • Marberger M.
      • Harkaway R.
      • de la Rosette J.
      Optimising the medical management of benign prostatic hyperplasia.
      ]. Those data clarified the key role of 5-α-reductase inhibitors in preventing disease progression. All the guidelines published after the MTOPS trial discussed the option to offer 5-α-reductase inhibitors or combination therapy of 5-α-reductase inhibitors and α-blockers as appropriate treatment for patients with LUTS with demonstrated prostatic enlargement. AUA guidelines reported, moreover, that “patients with symptomatic prostatic enlargement but without signs of bother may be offered 5-α-reductase inhibitor to prevent disease progression” after a clear presentation of advantages and disadvantages of that kind of therapy [
      AUA Practice Guidelines Committee
      AUA guideline on management of benign prostatic hyperplasia. Diagnosis and treatment recommendations.
      ]. In addiction, BAUS guidelines highlighted the possible use of 5-α-reductase inhibitors in patients at high risk of disease progression (PSA >1.4 ng/ml, prostate volume >30 cc), regardless of the presence of bothersome symptoms [
      • Speakman M.J.
      • Kirby R.S.
      • Joyce A.
      • Abrams P.
      • Pocock R.
      The British Association of Urological Surgeons. Guideline for the primary care management of male lower urinary tract symptoms.
      ].
      All the guidelines agreed in not recommending phytotherapeutic agents (Pygeum africanum, Serenoa repens). Although several randomised clinical trials and a few meta-analyses demonstrated clearly the efficacy of Serenoa repens in improving both IPSS score and maximum flow rate [
      • Wilt T.J.
      • Ishani A.
      • Rutks I.
      • MacDonald R.
      Phytotherapy for benign prostatic hyperplasia.
      ,
      • Boyle P.
      • Robertson C.
      • Lowe F.
      • Roehrborn C.
      Updated meta-analysis of clinical trials of Serenoa repens extract in the treatment of symptomatic benign prostatic hyperplasia.
      ], all the guidelines did not recommended the routinely use of plants extracts because of the lack of long-term studies. However, long-term randomised controlled studies are ongoing. Table 4 summarises the recommendations for the pharmacologic therapeutic options.
      Table 4Pharmacologic therapies recommended by the analysed guidelines for male lower urinary tract symptoms
      Australian NHMRC5th IC on BPHAUABAUSEAUCanadian Urological Association
      α-blockers
       AlfuzosinNDRRRRR
       DoxazosinRRRRRR
       PhenoxybenzamineNDNDNRNDNDND
       PrazosinNRNDNRNDNDNR
       TamsulosinRRRRRR
       TerazosinRRRRRR
      5-α reductase inhibitors
       DutasterideNDNRRRRR
       FinasterideRRRRRR
       Combination therapyNDNDRRRR
       Phytotherapeutic drugsNRNRNRNRNRNR
       Anticholinergic drugsRNDNDNDNDND
      Guidelines were listed according to the year of publication. Abbreviations are defined in Table 2, Table 3.
      All the guidelines agreed in recommending surgical treatment for patients with complicated LUTS, such as those with refractory urinary retention who had failed at least one trial of catheter removal, renal insufficiency, recurrent urinary tract infections, persistent gross hematuria, or bladder stones due to BOO and refractory to other therapies. Other candidates for surgery are the patients who refuse medical therapy or achieve unsatisfactory benefit or have unacceptable side-effects following drug therapies. All guidelines agreed in considering TURP as the gold standard of treatment, excluding cases with small prostate, suitable for TUIP, or very large glands, suitable for open prostatectomy.
      Moreover, several minimally invasive therapies have been developed for LUTS/BPE management, which are considered as alternatives to either surgical or medical treatments. Most of those treatment modalities use the thermal effects of different sources of energy on the prostate tissue, with the aim of producing irreversible tissue damage [
      • Zlotta A.R.
      • Djavan B.
      Minimally invasive therapies for benign prostatic hyperplasia in the new millennium: long-term data.
      ]. Transurethral microwave thermotherapy (TUMT) and transurethral needle ablation (TUNA) are those that have been more extensively tested and are currently recommended by several guidelines. On the other hand, interstitial laser coagulation (ILC), water-induced thermal therapy (WIT), and high-intensity focused ultrasound (HIFU) are still considered investigational. Table 5 summarises the recommendations for the nonpharmacologic therapeutic options.
      Table 5Nonpharmacologic therapies recommended by the analysed guidelines for male lower urinary tract symptoms
      Australian NHMRC5th IC on BPHAUAEAUCanadian Urological Association
      Minimally invasive therapies
       TUMTR with caveatRR with caveatRR
       TUNANRRRRR
       Prostatic stentR with caveatR with caveatR with caveatR with caveatR with caveat
       Balloon dilatationNRNRNRNRNR
       ILCNDRNRRNR
       WITNDNRNRNRNR
       HIFUNRNDNRNRNR
      Surgical therapies
       TUIPRRRRR
       TURPRRRRR
       Open prostatectomyRRRRR
       TUVPNRRRRR
       HoLEPR with caveatRRRR
       VLAPRRRRND
      BAUS guidelines were not included in the table because of the lack of specific considerations on nonpharmacological therapeutic options.
      TUMT = transurethral microwave thermotherapy; TUNA = transurethral needle ablation; ILC = interstitial laser coagulation; WIT = water-induced thermal therapy; HIFU = high-intensity focused ultrasound; TUIP = transurethral incision of the prostate; TURP = transurethral resection of the prostate; TUVP = transurethral (electro)vaporization of the prostate; HoLEP = transurethral holmium laser enucleation of the prostate; VLAP = visual laser ablation of the prostate. Other abbreviations are defined in Table 2, Table 3.
      Extensive insights on minimally invasive therapy and surgery are beyond the purpose of the present review.

      4. Discussion

      The present study provided a quality ranking of the most commonly used clinical practice guidelines on male LUTS by the application of a validated appraisal instrument. Although all the texts presented some good aspects, we found considerable differences in the overall quality of the available guidelines, especially with regard to the methodologic issues. The texts from the Australian NHMRC and AUA were those that adhered most to the standards of quality suggested by the AGREE appraisal instrument.
      The assessment of guideline quality is an increasing health problem, given that hundreds of guidelines are currently available in the medical literature. A few papers addressed the quality of the published guidelines, mostly in the fields of general medicine, with urology only marginally involved. In 2003 Irani et al. performed a study similar to the present one, assessing quality of the BPH guidelines through the checklist of the St George's Hospital Health Care Evaluation Unit [
      • Irani J.
      • Brown C.T.
      • Van der Meulen J.
      • Emberton M.
      A review of guidelines on benign prostatic hyperplasia and lower urinary tract symptoms: are all guidelines the same?.
      ]. However, because of the rapid development of new guidelines and updating of older editions, only the text from the Australian NHMRC was analysed in both Irani's and our papers, which was rated as the best guideline. However, different appraisal instruments were used in the two papers. We used the instrument provided by the AGREE collaboration because its rigorous development process, involving more than 250 appraisers from 11 nations, led to a powerful tool, recognised worldwide and adopted by several health agencies (WHO, National Institute for Clinical Excellence in the United Kingdom, National Federation of Cancer Centers in France, the Agency for Quality in Medicine in Germany) [
      The AGREE Collaboration
      Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project.
      ].
      Slight differences were evident within the titles of the guidelines. Only the guidelines of Australian NHMRC [

      Clinical Practice Guidelines. The management of uncomplicated lower urinary tract symptoms in men. National Health and Medical Research Council, 2000.

      ], BAUS [
      • Speakman M.J.
      • Kirby R.S.
      • Joyce A.
      • Abrams P.
      • Pocock R.
      The British Association of Urological Surgeons. Guideline for the primary care management of male lower urinary tract symptoms.
      ], and EAU [
      • Madersbacher S.
      • Alivizatos G.
      • Nordling J.
      • Sanz C.R.
      • Emberton M.
      • de la Rosette J.J.
      EAU 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (BPH guidelines).
      ] were appropriately focused on male LUTS, whereas the other one was aimed at BPH management.
      With regard to the content of the guidelines, as stated, the most relevant differences were found in the diagnostic recommendations, with the low-ranked guidelines advising more procedures (Table 3). Although all the appraisal instruments assessing the quality of a guideline relied heavily on how well documented the guideline development process was, it did not guarantee excellent recommendations because unsystematically (“opinion-based”) developed guidelines might provide wise recommendations and, vice versa, a well-reported one may include imperfect advice. Notwithstanding, to date, those criteria are largely accepted among methodologists and experts on guideline development and implementation. Moreover, Irani et al. reported a linear relationship among the number of recommended diagnostic tests and the overall guideline score, with the high-score guidelines recommending the lowest number of tests [
      • Irani J.
      • Brown C.T.
      • Van der Meulen J.
      • Emberton M.
      A review of guidelines on benign prostatic hyperplasia and lower urinary tract symptoms: are all guidelines the same?.
      ].
      The choice to offer a PSA test is the most critical issue in the initial assessment of patients with LUTS due to BPE. Beyond prostate cancer diagnosis, recent studies are suggesting a new role for PSA in patients with BPH. Analysis of the placebo arm of PLESS, a double-blind, randomised, placebo-controlled trial, in which 3040 men with LUTS and enlarged prostate glands were randomised to finasteride 5 mg or placebo [
      • McConnell J.D.
      • Bruskewitz R.
      • Walsh P.
      • et al.
      The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia.
      ], highlighted the possible role of PSA as a marker of disease progression. Specifically, the baseline PSA level was a powerful predictor of long-term changes in the IPSS score and Qmax, as well as of the risk of acute urinary retention and the need for surgery. The studies suggested that the patients above the lowest tertile of PSA distribution (≥ 1.4 ng/ml) were those with the worst long-term outcome [
      • Roehrborn C.G.
      • McConnell J.D.
      • Lieber M.
      • et al.
      Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. PLESS Study Group.
      ,
      • Roehrborn C.G.
      • Boyle P.
      • Bergner D.
      • et al.
      Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a 4-year, randomized trial comparing finasteride versus placebo. PLESS Study Group.
      ,
      • Roehrborn C.G.
      • McConnell J.
      • Bonilla J.
      • et al.
      Serum prostate specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia. PROSCAR long-term efficacy and safety study.
      ,
      • Roehrborn C.G.
      The potential of serum prostate-specific antigen as a predictor of clinical response in patients with lower urinary tract symptoms and benign prostatic hyperplasia.
      ]. Similar data were reconfirmed in the MTOPS study [
      • McConnell J.D.
      • Roehrborn C.G.
      • Bautista O.M.
      • et al.
      The long-term effect of doxazosin, finasteride, and combination therapy on the progression of benign prostatic hyperplasia.
      ] and the dutasteride phase 3 study, highlighting the new dimension of PSA as a biomarker for disease progression [
      • Bartsch G.
      • Fitzpatrick J.M.
      • Schalken J.A.
      • Isaacs J.
      • Nordling J.
      • Roehrborn C.G.
      Consensus statement: the role of prostate-specific antigen in managing the patient with benign prostatic hyperplasia.
      ,
      • Tubaro A.
      • La Vecchia C.
      Uroscreening Study Group
      The relation of lower urinary tract symptoms with life-style factors and objective measures of benign prostatic enlargement and obstruction: an Italian survey.
      ]. Those issues were included in the most recently published guidelines (AUA, BAUS, and EAU) and can have a major role in therapy planning.
      Other, less relevant, differences were observed in the treatment recommendations. The most recently published guidelines addressed more deeply the possible role of 5-α-reductase inhibitors in preventing BPH progression. That was mostly related to the publication of MTOPS data in 2003 [
      • McConnell J.D.
      • Roehrborn C.G.
      • Bautista O.M.
      • et al.
      The long-term effect of doxazosin, finasteride, and combination therapy on the progression of benign prostatic hyperplasia.
      ]. Two of the latest texts, the guideline from the AUA and BAUS recommended the use of 5-α-reductase inhibitors in patients at high risk of disease progression, regardless of symptoms [
      • Speakman M.J.
      • Kirby R.S.
      • Joyce A.
      • Abrams P.
      • Pocock R.
      The British Association of Urological Surgeons. Guideline for the primary care management of male lower urinary tract symptoms.
      ]. The possible advantages in terms of BPH progression, however, have to be weighed against both oncologic and economic issues. Data from the Prostate Cancer Prevention Trial showed clearly that long-term treatment with finasteride reduced the overall incidence of prostate cancer but, meanwhile, seemed to increase the risk of high-grade tumours [
      • Thompson I.M.
      • Goodman P.J.
      • Tangen C.M.
      • et al.
      The influence of finasteride on the development of prostate cancer.
      ]. Although those data might be seen as biased by the effects of finasteride on prostate volume and Gleason score system reliability, those concerns have not been unequivocally dispelled. Moreover, according to the MTOPS data, 29 patients (confidence interval, 19–59) had to be treated with combination therapy and 31 (confidence interval, 20–74) with finasteride alone to prevent a single patient from undergoing surgery. Although the cut-points of PSA and prostate volume suggested by the BAUS guideline identified high-risk patients, where the benefit might be higher and the number needed to treat lower, further studies would be desirable to address those health economic issues.
      Excluding the guidelines from the Australian NHMRC, all the other guidelines did not take into consideration antimuscarinic drugs. Although less prevalent, “storage” LUTS are, indeed, highly bothersome and few papers suggested the concomitant use of anticholinergic drugs with α-blockers [
      • Lee J.Y.
      • Kim H.W.
      • Kohn J.S.
      • Suh H.J.
      • Chancellor M.B.
      Comparison of doxazosin with or without tolterodine in men with symptomatic bladder outlet obstruction and an overactive bladder.
      ,
      • Athanasopoulos A.
      • Gyftopoulos K.
      • Giannitsas K.
      • Fisfis J.
      • Perimenis P.
      • Barbalias G.
      Combination treatment with an alpha-blocker plus an anticholinergic for bladder outlet obstruction: a prospective, randomized, controlled study.
      ]. Moreover, recent experimental data suggested a possible action for acetylcholine on the afferent nerves within the detrusor and the sub-urothelium, which could help to explain the role of antimuscarinic drugs in patients with LUTS [
      • Andersson K.E.
      Antimuscarinics for treatment of overactive bladder.
      ].
      The present review might be useful in several ways. Clinicians could use the summarised data to select the guidelines they trust the most to be used in their clinical practice. On the other hand, the limitations highlighted for the low-score guidelines might be useful to support their update. In that scenario, the use of an appraisal instrument such as the one provided by the AGREE collaboration might be fundamental for improving the overall quality of the upcoming guidelines.

      5. Conclusion

      Our study provided a quality ranking of the most commonly used clinical practice guidelines on male LUTS by the AGREE appraisal instrument. Although all the texts had some good aspects, we found that considerable differences were evident in the overall quality of the available guidelines, especially with regard to the methodologic issues. The text from the Australian NHMRC and AUA were those most adherent to the standards of quality suggested by the AGREE appraisal instrument. In cases where controversial recommendations were evident among the different guidelines, clinicians could use the summarised data to select the guidelines they trust the most to be used in their clinical practice. Methodologic considerations suggested the need to consider the quality of a guideline as a significant parameter to be assessed.

      Acknowledgement

      The authors would like to thank Prof. J. C. Nickel, who kindly provided the guidelines of the Canadian Urological Association.

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