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. 2019 Mar 14;2019(3):CD013291. doi: 10.1002/14651858.CD013291

Holmium laser enucleation of the prostate for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia

Niranjan J Sathianathen 1,✉, Eu Chang Hwang 2, Sarah Jane Brown 3, Michael Borofsky 1, Philipp Dahm 4
PMCID: PMC6417845

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects of holmium laser enucleation of the prostate for the treatment of lower urinary tract symptoms in men with benign prostate hyperplasia.

Background

Description of the condition

The human prostate gland is a walnut‐sized organ that is part of the male genitourinary system and is located below the bladder where it envelopes the urethra. Benign prostatic hyperplasia (BPH) refers to the non‐malignant growth of the prostate gland that is histologically represented by a proliferation of glandular and stromal cells predominantly within the transitional zone of the prostate (Berry 1984; McNeal 1968; McNeal 1984). The increased prostate volume and smooth muscle tone can lead to compression of the urethra, and subsequently, urinary obstruction. This commonly manifests clinically as lower urinary tract symptoms (LUTS): frequency, urgency, nocturia, weak stream, intermittency, straining and/or incomplete bladder emptying (Lepor 2005). These symptoms can be extremely bothersome and have a significant adverse impact on quality of life, especially in older men (Peters 1997). The degree of bother and effect on quality of life is generally measured through self administered questionnaires, such as the International Prostate Symptom Score (IPSS) (Barry 1992). The IPSS has been validated as a measure of symptom severity and quality of life in a range of populations (Choi 2014; O’Leary 2005). In this Cochrane Review, we will define BPH as prostatic enlargement with LUTS.

The burden of BPH in the general population is substantial and increases with age. It is reported that 72% of men over 40 years of age experience at least one LUTS at least ‘sometimes’ (Coyne 2009a). Histologically, approximately one‐half of the male population between the ages of 50 and 60 years demonstrate pathological hallmarks of BPH (Berry 1984). Left untreated, BPH can lead to serious medical consequences such as acute urinary retention, urinary tract infection, and upper tract deterioration (Speakman 2014), with a considerable impact on both an individual and population level. Men with voiding and storage symptoms have significantly lower physical and mental functioning compared to their counterparts without LUTS (Coyne 2009b). In those with voiding and storage symptoms, 20.6% and 16.2% met the self reported screening criteria of clinical anxiety and depression, respectively (Coyne 2009b). From an economic standpoint, employees with BPH have been estimated to miss 7.3 hours of work annually due to their disease (Saigal 2005). The burden of disease extends to the healthcare system with nearly 8 million physician visits in the USA during the year 2000 due to a primary or secondary diagnosis of BPH (Wei 2005). Moreover, the estimated incremental cost per person diagnosed with BPH is USD 2577 (Wei 2005). It is likely that the present‐day true cost is higher with the increased rates of intervention over time (Cornu 2010).

Diagnosis

The diagnosis of BPH is based on the following clinical features: a prostate enlargement, bothersome LUTS, and no other identified cause for the urinary problems. Clinical assessment of men with LUTS should include a detailed medical history including assessment of LUTS, a validated symptom score questionnaire, frequency volume charts, digital rectal examination, urinalysis, and prostate‐specific antigen (PSA) test (EAU 2018; Foster 2018). A digital rectal examination is important in evaluating prostate size and can aid diagnosis of prostate cancer. A PSA is only recommended if the diagnosis of prostate cancer would alter management. Urinalysis has an important role in assessing for alternative causes of the patient’s symptoms. The validated symptoms questionnaire, usually the IPSS, is crucial in assessing symptom severity and can be used to guide treatment and evaluate its efficacy. Clinicians should also consider measurement of renal function, postvoid residual urine, and urine flowmetry (EAU 2018). The last two tests can be used to discriminate between the possible causes of symptoms and to assess treatment response.

Treatment

The management of BPH is guided by the patient’s symptoms and the degree of bother. Initial treatment options include conservative management (watchful waiting and lifestyle modification) and medication (alpha‐blockers, 5‐alpha reductase inhibitors, and phosphodiesterase 5 inhibitors) (EAU 2018). Surgical options may be considered in men who have failed initial conservative and medical management, or those with complications of BPH such as acute urinary retention, recurrent urinary tract infection, bladder stones or diverticula, haematuria, or renal insufficiency. Open and endoscopic resection of prostate tissue that is impeding the flow of urine has been the linchpin of surgical management. Monopolar or bipolar transurethral resection of the prostate (TURP) has been considered the gold‐standard invasive treatment option for BPH. Although TURP continues to be a durable procedure with excellent functional outcomes (Ahyai 2010), there are still considerable associated risks: bleeding, dilutional hyponatraemia (commonly referred to as TUR syndrome), clot retention, urinary tract infection, bladder neck contracture, urethral stricture, retrograde ejaculation, and erectile dysfunction (EAU 2018). The development of bipolar electrosurgery has improved the morbidity profile of TURP (Rassweiler 2007), yet alternative surgical management options have emerged with the aim of improving both functional and safety outcomes of BPH surgery (Magistro 2017). Prostate volume and the receipt of anticoagulation medication are both important considerations in determining the optimal surgical procedure. Laser enucleation, prostatic urethral lift, transurethral microwave therapy, and transurethral needle ablation are options for patients with a prostate size between 30 and 80 mL who are not receiving anticoagulant medication, but TURP remains the standard of care (EAU 2018). The recommended first‐line treatment options in patients with a prostate greater than 80 mL are open prostatectomy, holmium laser enucleation of the prostate (HoLEP), and bipolar enucleation (EAU 2018). Laser vaporisation or enucleation are considered to be acceptable therapies for patients who continue on anticoagulants (EAU 2018). The differential cost of these procedures in each setting also impacts its uptake and accessibility.

Description of the intervention

Holmium laser enucleation of the prostate has evolved from both ablative and resectional techniques, and its technique mimics an open prostatectomy. 'Enucleation' refers to the removal of whole tissue without cutting into it, whereas the tissue is removed piece‐by‐piece in resectional procedures. Compared to other alternative BPH surgical options, HoLEP is suitable for all men that are fit for general anaesthesia, with no upper limit on prostate size (Elzayat 2005). It can be performed under a spinal anaesthetic in patients unsuitable for a general anaesthetic. It also does not require cessation of any anticoagulation medication (Tyson 2009). Furthermore, normal saline can be used for irrigation, which ameliorates the risk of dilutional hyponatraemia. The key pieces of equipment for this procedure are a high‐powered holmium end‐firing laser fiber and unit with 80‐ to 100‐watt maximum power, a 26‐ to 28‐French continuous flow resectoscope sheath, a 30‐degree cystoscope lens, and a tissue morcellator (Gilling 1996; Gilling 2007). Following induction of anaesthesia, the resectoscope is inserted into the urethra and the holmium laser is used to make a series of incisions down to the level of the surgical capsule, which permits the median and lateral lobes of the prostate to be enucleated. Each of the lobes are placed in the bladder at the time of enucleation. After enucleation is complete and haemostasis has been achieved, the tissue morcellator is placed into the bladder to remove the enucleated prostate tissue by cutting the whole prostate lobes into smaller pieces (morcellation), which are evacuated through the device. At the end of the procedure, a three‐way catheter is inserted and continuous bladder irrigation is typically started.

Adverse events of the intervention

The adverse effects of HoLEP are comparable to other BPH surgical procedures and include bleeding, acute urinary retention, reoperation, urinary tract infection, urethral stricture, transient urinary incontinence, retrograde ejaculation, and erectile dysfunction (Placer 2015). Urinary incontinence may be experienced in the early postoperative phase but tends to improve over time, with only 2.2% and 1% reporting stress and urge urinary incontinence at 12 months, respectively (Elshal 2017). It it also estimated that approximately three‐quarters of men undergoing HoLEP experience postoperative retrograde ejaculation (Kim 2014). The reported blood transfusion rate for men undergoing HoLEP is generally less than 5% (Michalak 2015). There is an additional risk of bladder injury (0.1% to 4%) with HoLEP due to the use of a morcellator that is not usually encountered with alternative BPH management options (Vincent 2015).

How the intervention might work

The fundamental principle of HoLEP is to remove the prostatic tissue that is compressing the urethra and impeding the flow of urine.

Why it is important to do this review

The current literature is unclear as to whether holmium laser enucleation of the prostate improves clinical outcomes and decreases adverse effects compared to alternative surgical treatment options. Although systematic reviews exist on the topic (Qian 2017; Tan 2007; Yin 2013), they are limited by only including a single type of surgical treatment as the comparator (e.g. transurethral resection of the prostate) and have only summarised efficacy measures such as peak urinary flow rate (Qmax), postvoid residual volume, and IPSS without focusing on patient‐important outcomes. Moreover, these reviews did not employ a rigorous methodology or assess the quality of evidence using the GRADE approach. The findings of this review will be relevant to policymakers, clinicians, and patients.

Objectives

To assess the effects of holmium laser enucleation of the prostate for the treatment of lower urinary tract symptoms in men with benign prostate hyperplasia.

Methods

Criteria for considering studies for this review

Types of studies

We will include parallel‐group randomised controlled trials (RCTs) and cluster‐RCTs. We will exclude cross‐over trials, as this study design is not relevant in this setting. If we only identify for inclusion RCTs that provide low‐quality evidence for a given outcome and comparison, we will also include non‐RCTs, such as cohort and cross‐sectional studies with concurrent comparison groups, as a source of complementary, sequential, or replacement evidence for RCTs (Schunemann 2013). We will not consider single‐armed studies for inclusion. We will include studies regardless of their publication status or language of publication.

Types of participants

We will include men over 40 years of age with a prostate volume of at least 20 mL (assessed by digital rectal examination, ultrasound, or conventional imaging) who exhibit lower urinary tract symptoms defined by an International Prostate Symptom Score (IPSS) of eight or greater, and a Qmax of less than 15 mL/s measured by non‐invasive uroflowmetry or invasive pressure flow studies, or both. We have applied an age limitation to included participants because the prevalence of lower urinary tract symptoms is low in young men and has been shown to increase with age. We will include trials in which only a subset of participants are relevant to this review (i.e. trials with > 75% relevant participants) if separate data are available for the relevant subset.

We will exclude trials of men with active urinary tract infection, bacterial prostatitis, chronic renal failure, untreated bladder calculi or large diverticula, prostate cancer, urethral stricture disease, and prior prostate, bladder neck, or urethral surgery. We will also exclude studies of patients with other conditions that affect urinary symptoms, such as neurogenic bladder due to spinal cord injury, multiple sclerosis, Parkinson's disease, or central nervous system disease.

Types of interventions

We plan to investigate the following comparisons of experimental intervention versus comparator interventions. Concomitant interventions will need to be the same in the experimental and comparator groups to establish fair comparisons.

Experimental intervention

  • Holmium laser enucleation (HoLEP)

Comparator interventions

  • Sham control (or no intervention)

  • Transurethral resection of the prostate (TURP) (monopolar or bipolar)

  • Laser ablations of the prostate (e.g. photoselective vaporisation of the prostate)

  • Laser enucleations of the prostate excluding HoLEP (e.g. thulium vapoenucleation of the prostate)

  • Other minimally invasive therapies (e.g. transurethral incision of the prostate, transurethral thermal ablation of the prostate (needle ablation, microwave therapy, and radiofrequency ablative techniques), prostate stent, and prostatic arterial embolisation)

  • Simple prostatectomy (e.g. open, laparoscopic, and robotic‐assisted prostatectomy)

Comparisons

  • HoLEP versus sham control (or no intervention)

  • HoLEP versus TURP

  • HoLEP versus laser ablations of the prostate

  • HoLEP versus alternate laser enucleations of the prostate

  • HoLEP versus other minimally invasive therapies

  • HoLEP versus simple prostatectomy

Types of outcome measures

We will not use measurement of the outcomes assessed in this review as an eligibility criterion.

Primary outcomes

  • Urological symptoms score

  • Quality of life

  • Major adverse events

Secondary outcomes

  • Retreatment

  • Erectile function

  • Ejaculatory function

  • Bleeding events

  • Acute urinary retention

  • Indwelling urinary catheter

  • Hospital stay

Method and timing and outcome measurement
Urologic symptom scores

  • Mean change measured as a validated scale, e.g. the IPSS.

  • We will consider improvement of the IPSS score of three points as a minimal clinically important difference (MCID) to assess efficacy and comparative effectiveness (Barry 1995). If possible, we will use different thresholds of MCID based on the severity of IPSS, with a threshold of three for men with mild LUTS, five for moderate LUTS, and eight for severe LUTS (Barry 1995).

Quality of life

  • Mean change measured as a validated scale (such as IPSS‐quality of life or BPH Impact Index).

  • No threshold was established for IPSS‐quality of life. We will use an MCID of 0.5 to assess efficacy and comparative effectiveness (Brasure 2016). We will consider improvement of the BPH Impact Index score of 0.5 as an MCID (Barry 1995).

Major adverse events

  • We will use the Clavien‐Dindo classification system to assess surgical complications (Dindo 2004), categorising grade III, IV, and V complications as major. If the authors of eligible studies did not use the Clavien‐Dindo system, we will judge the adverse events by severity using the information available in the studies.

Retreatment

  • We will define retreatment as requiring further BPH surgical treatment after the index procedure.

Erectile function

  • Mean change, measured as total score of International Index of Erectile Function (IIEF)‐5 questionnaire (also known as Sexual Health Inventory for Men) (Rosen 1997).

  • We will consider the MCID in the erectile function domain score of IIEF of four (Rosen 2011). If possible, we will use different thresholds of MCID based on the severity of erectile function, with a threshold of two for men with mild erectile dysfunction, five for moderate erectile dysfunction, and seven for men with severe erectile dysfunction (Rosen 2011). We will consider a difference in IIEF‐5 over five points as MCID (Spaliviero 2010).

Ejaculatory function

  • Mean change, measured as Male Sexual Health Questionnaire for Ejaculatory Dysfunction (MSHQ‐EjD) (Rosen 2007).

Bleeding events

  • We will define this as postoperative bleeding requiring a blood transfusion.

Acute urinary retention

  • Events requiring catheterisation after intervention.

Indwelling urinary catheter

  • Measured in days from intervention to urinary catheter removal.

Hospital stay

  • Measured in days from admission to discharge.

There is no reported threshold in adverse events, retreatment, ejaculatory function, acute urinary retention, indwelling urinary catheter, and hospital stay. We will consider the clinically important difference for adverse events, retreatment, acute urinary retention, and indwelling catheter as relative risk reduction of at least 25% (Guyatt 2011). We will use an MCID of 25% improvement from baseline in MSHQ‐EjD for ejaculatory function (Nickel 2015). We will use an MCID of one day to assess efficacy and comparative effectiveness for indwelling urinary catheter and hospital stay.

We will consider outcomes measured up to and including 12 months after randomisation as short term and later than 12 months as long term for urologic symptom scores, quality of life, major adverse events, erectile function, ejaculatory function, and acute urinary retention. We will assess retreatment, bleeding events, indwelling urinary catheter, and hospital stay as short term only.

Main outcomes for ‘Summary of findings’ table

We will present a ‘Summary of findings’ table reporting the following outcomes listed according to priority.

  • Urologic symptoms scores

  • Quality of life

  • Major adverse events

  • Retreatment

  • Erectile function

  • Ejaculatory function

We will consider clinically important difference for the review outcomes to rate the overall quality of the evidence in the 'Summary of findings' table (Jaeschke 1989; Johnston 2013).

Search methods for identification of studies

We will perform a comprehensive search with no restrictions on language of publication or publication status (Appendix 1). We plan to rerun searches within three months prior to the anticipated publication of the review.

Electronic searches

We will search the following sources from the inception of each database to the present.

  • MEDLINE via Ovid (from 1946)

  • Cochrane Library via Wiley

    • Cochrane Database of Systematic Reviews (CDSR)

    • Cochrane Central Register of Controlled Trials (CENTRAL)

    • Database of Abstracts of Reviews of Effects (DARE)

    • Health Technology Assessment Database (HTA)

  • Embase via Elsevier (from 1974)

  • Scopus (from 1966)

  • Web of Science (from 1900)

  • LILACS (Latin American and Caribbean Health Sciences Literature) (bvsalud.org/; from 1982)

We will also search the following.

  • ClinicalTrials.gov (www.clinicaltrials.gov/)

  • World Health Organization (WHO) International Clinical Trials Registry Platform search portal (apps.who.int/trialsearch/)

  • Grey literature repository from the current Grey Literature Report (www.greylit.org/)

If we detect additional relevant keywords during any of the electronic or other searches, we will modify the electronic search strategies to incorporate these terms and document the changes.

Searching other resources

We will attempt to identify other potentially eligible trials or ancillary publications by searching the reference lists of retrieved included trials, reviews, meta‐analyses, and health technology assessment reports. We will also contact the authors of the included trials in order to identify any further studies that we may have missed. We will contact drug/device manufacturers for ongoing or unpublished trials. We will search abstract proceedings of relevant meetings of the American Urological Association, European Association of Urology, and International Continence Society for the last four years (2015 to 2018) for unpublished studies.

Data collection and analysis

Selection of studies

We will use EndNote 2016 reference management software to identify and remove any duplicate records. Two review authors will independently scan the abstract, title, or both to determine which studies should be assessed further using Covidence 2017 software (Covidence). Two review authors will investigate all potentially relevant records as full text; map records to studies; and 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). Any discrepancies will be resolved through consensus or recourse to a third review author (PD). If resolution of a disagreement is not possible, we will designate the study as 'awaiting classification' and document the reasons for exclusion in the 'Characteristics of excluded studies' table. We will present an adapted PRISMA flow diagram showing the process of study selection (Liberati 2009).

Data extraction and management

We will develop a dedicated data abstraction form that we will pilot test ahead of time.

For studies that fulfil our inclusion criteria, two review authors will independently abstract the following information, which we will provide in the 'Characteristics of included studies' table.

  • Study design.

  • Study dates (if dates are not available, then this will be reported as such).

  • Study settings and country.

  • Participant inclusion and exclusion criteria (e.g. age, baseline IPSS, medical pretreatment).

  • Participant details, baseline demographics (e.g. age, prostate size, IPSS).

  • Number of participants by study and study arm.

  • Details of relevant experimental intervention, such as power of laser, and comparator intervention (e.g. monopolar versus bipolar energy, type of laser).

  • Definitions of relevant outcomes, and method (e.g. type of instrument, such as IPSS) and timing of outcome measurement (e.g. in months) as well as any relevant subgroups (e.g. based on age, prostate volume, severity of LUTS).

  • Study funding sources.

  • Declarations of interest by primary investigators.

We will extract outcome data relevant to this Cochrane Review as needed for calculation of summary statistics and measures of variance. For dichotomous outcomes, we will attempt to obtain numbers of events and totals for population in a 2x2 table, as well as summary statistics with corresponding measures of variance. For continuous outcomes, we will attempt to obtain means and standard deviations or data needed to calculate this information.

Any disagreements will be resolved by discussion or by consultation with a third review author (PD) if required.

We will provide information, including trial identifier, about potentially relevant ongoing studies in the 'Characteristics of ongoing studies' table.

We will contact authors of included studies to obtain key missing data as needed.

Assessment of risk of bias in included studies

Two review authors will independently assess the risk of bias of each included study. Any disagreements will be resolved by consensus or by consultation with a third review author (PD) if necessary. We will present a 'Risk of bias' summary figure to illustrate our findings. We will further summarise the risk of bias across domains for each outcome in each included study, as well as across studies and domains for each outcome in accordance with the approach for summary assessments of the risk of bias presented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a; Sterne 2016).

Assessment of risk of bias in RCTs

We will assess risk of bias using Cochrane's 'Risk of bias' assessment tool based on the following domains (Higgins 2011a).

  • Random sequence generation (selection bias)

  • Allocation concealment (selection bias)

  • Blinding of participants and personnel (performance bias)

  • Blinding of outcome assessment (detection bias)

  • Incomplete outcome data (attrition bias)

  • Selective reporting (reporting bias)

  • Other sources of bias

We will judge 'Risk of bias' domains as 'low risk', 'high risk', or 'unclear risk' according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a).

For selection bias (random sequence generation and allocation concealment), we will evaluate risk of bias at the trial level.

For performance bias (blinding of participants and personnel), we will consider all outcomes as similarly susceptible to performance bias.

For detection bias (blinding of outcome assessment), we will group outcomes as susceptible to detection bias (subjective) or not susceptible to detection bias (objective).

We will define the following endpoints as subjective outcomes.

  • Urologic symptom scores

  • Quality of life

  • Major adverse events

  • Erectile function

  • Ejaculatory function

  • Bleeding events

We will define the following endpoints as objective outcomes.

  • Retreatment

  • Acute urinary retention

  • Indwelling urinary catheter

  • Hospital stay

We will also assess attrition bias (incomplete outcome data) on an outcome‐specific basis, and present the judgement for each outcome separately when reporting our findings in the 'Risk of bias' tables.

For reporting bias (selective reporting), we will evaluate risk of bias at the trial level.

We will further summarise the risk of bias across domains for each outcome in each included study, as well as across studies and domains for each outcome, in accordance with the approach for summary assessments of risk of bias presented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a).

Assessment of risk of bias in non‐RCTs

We will assess risk of bias in non‐RCTs with ROBINS‐I: a tool for assessing risk of bias in non‐randomised studies of interventions (Sterne 2016). We will assess the following domains.

  • Bias due to confounding

  • Bias in selection of participants into the study

  • Bias in classification of interventions

  • Bias due to deviations from intended interventions

  • Bias due to missing data

  • Bias in measurement of outcomes

  • Bias in selection of the reported result

We will judge these domains as 'low risk', 'moderate risk', 'serious risk', 'critical risk', or 'no information' according to the descriptions in Sterne 2016.

Measures of treatment effect

We will express dichotomous data as risk ratios with 95% confidence intervals (CIs). We will express continuous data as mean differences (MDs) with 95% CIs, unless different studies use different measures to assess the same outcome, in which case we will express data as standardised mean differences with 95% CIs.

Unit of analysis issues

The unit of analysis will be the individual participant. Should we identify cluster‐RCTs or trials with more than two intervention groups for inclusion in the review, we will handle these in accordance with the guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).

Dealing with missing data

We will obtain missing data from study authors if feasible and perform intention‐to‐treat analyses if we have the required data, otherwise we will perform available‐case analyses. We will investigate attrition rates, that is dropouts, losses to follow‐up, and withdrawals, and will critically appraise issues of missing data. We will not impute missing data.

Assessment of heterogeneity

In the event of excessive heterogeneity that is not explained by subgroup analyses, we will not report outcome results as the pooled effect estimate in a meta‐analysis but will provide a narrative description of the results of each study.

We will evaluate heterogeneity (inconsistency) through visual inspection of the forest plots to assess the amount of overlap of CIs and the I2 statistic, which quantifies inconsistency across studies to determine the impact of heterogeneity on the meta‐analysis (Higgins 2002; Higgins 2003). We will interpret the I2 statistic as follows (Deeks 2011):

  • 0% to 40%: may not be important;

  • 30% to 60%: may indicate moderate heterogeneity;

  • 50% to 90%: may indicate substantial heterogeneity;

  • 75% to 100%: considerable heterogeneity.

When we find heterogeneity, we will attempt to explain it by examining individual study and subgroup characteristics.

Assessment of reporting biases

We will attempt to obtain study protocols to assess studies for selective outcome reporting. If we can identify no a priori protocol, we will rate the risk of bias as unclear for selective reporting.

If we include 10 or more studies investigating a particular outcome, we will use funnel plots to assess small‐study effects.

There are several possible explanations for asymmetry of a funnel plot, including true heterogeneity of effect with respect to trial size, poor methodological design (and hence bias of small trials), and publication bias. We will therefore interpret results carefully.

In the event of duplicate publications, companion documents, or multiple reports of a primary study, we will maximise yield of information by mapping all publications to unique studies and collating all available data. We will use 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.

Data synthesis

We will summarise data using a random‐effects model. We 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). We will use the Mantel‐Haenszel method for dichotomous outcomes, and the inverse variance method for continuous outcomes. We will perform analyses with Review Manager 5 software (Review Manager).

We will analyse the results for RCTs and non‐RCTs separately (Reeves 2011).

Subgroup analysis and investigation of heterogeneity

We expect the following characteristics to introduce clinical heterogeneity, and plan to carry out subgroup analyses with investigation of interactions.

  • Participant age (less than 65 years versus ≥ 65 years).

  • Prostate volume (less than or 80 mL versus ≥ 80 mL).

  • Severity of LUTS based on IPSS (score less than or equal to 19 (moderately symptomatic) versus greater than 19 (severely symptomatic)).

  • Presence of preoperative (current) urinary retention.

These subgroup analyses are based on the following observations.

  • Age is a well‐known risk factor of BPH surgery. Older patients have a higher rate of postoperative complications compared with younger patients (Bhojani 2014; Pariser 2015). The age cut‐off is based on the WHO definition of old age (WHO 2012).

  • The outcomes and complications of minimally invasive procedures such as TURP correlate with prostate volume (Reich 2008). The prostate volume cut‐off of greater than 80 mL is based on a cut‐off used by both the European Association of Urology and American Urology Association guidelines in determining which treatments are appropriate for BPH (EAU 2018).

  • The relationship between changes in IPSS scores and patient global ratings of improvement is influenced by the baseline scores (Barry 1995).

  • It is suggested that acute urinary retention is a severe complication in the natural history of BPH with a distinctive pathology, such as prostatic infarction, inflammation, and increase in sympathetic tone, and was previously an indication for surgery (Kalejaiye 2009; Spiro 1974). Additionally, BPH surgery in the setting of urinary retention has been associated with decreased success and increased morbidity compared to surgery for LUTS alone (Mebust 1989).

We plan to limit subgroup analyses to the primary outcomes.

Sensitivity analysis

We plan to perform sensitivity analyses limited to the primary outcomes in order to explore the influence of the following factor (when applicable) on effect sizes: restricting the analysis in RCTs by taking into account risk of bias, excluding studies at 'high risk' or 'unclear risk' of bias.

'Summary of findings' table

We will present the overall quality of the evidence for each outcome according to the GRADE approach (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 GRADEpro GDT (GRADEpro GDT). Any discrepancies will be resolved by consensus or by consulting a third review author (PD) if required. 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).

For RCTs, we will take account five criteria not only related to internal validity (risk of bias, inconsistency, imprecision, and publication bias), but also to external validity, such as directness of results, in downgrading the quality of evidence for a specific outcome (Schünemann 2011). For non‐RCTs, we will consider three criteria for upgrading the quality of evidence (large magnitude of effects, all plausible confounding that would reduce a demonstrated effect or suggest a spurious effect when results show no effect, and dose‐response gradient) (Schünemann 2011).

Acknowledgements

We thank the Cochrane Urology editorial team for their help and support.

Appendices

Appendix 1. Search strategy

  1. exp Prostatic Hyperplasia/

  2. (prostat* adj3 hyperplasia*).tw.

  3. (prostat* adj3 hypertroph*).tw.

  4. (prostat* adj3 adenoma*).tw.

  5. (prostat* adj3 enlarg*).tw.

  6. (BPH or BPO or BPE).tw.

  7. exp Urinary Bladder Neck Obstruction/

  8. (bladder* adj3 obstruct*).tw.

  9. BOO.tw.

  10. exp Lower Urinary Tract Symptoms/

  11. (lower urinary tract or prostatism or LUTS).tw.

  12. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11

  13. enucleation.tw.

  14. HoLEP.tw.

  15. 13 or 14

  16. 12 and 15

Contributions of authors

Sathianathen: wrote the protocol.

Hwang: wrote the protocol.

Brown: wrote the protocol, developed the search strategy.

Borofsky: wrote the protocol.

Dahm: wrote the protocol.

Sources of support

Internal sources

  • University of Minnesota, Department of Urology, USA.

    Partial salary support for Dr Niranjan J Sathianathen

External sources

  • No sources of support supplied

Declarations of interest

Sathianathen: none.

Hwang: none.

Brown: none.

Borofsky: Boston Scientific (consultant for endourology and stone management), Auris Health (consultant for robotic surgery and endourology).

Dahm: none.

Notes

Parts of the methods section of this protocol are based on a standard template developed by the Cochrane Metabolic and Endocrine Disorders Group, which has been modified and adapted for use by Cochrane Urology.

Large parts of the Background section of this review are based on that of previously published protocols on alternative treatments for lower urinary tract symptoms related to benign prostatic hyperplasia (Jung 2017a; Jung 2017b; Hwang 2018). This was done with explicit approval of both the authors of this published protocols as well as the Cochrane Urology Editorial Group.

New

References

Additional references

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