Low‐intensity shockwave therapy for erectile dysfunction

Objectives

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

To assess the effects of low‐intensity shockwave therapy (LiSWT) for men with erectile dysfunction.

Background

Description of the condition

Erectile dysfunction is defined as the consistent or recurrent inability to attain and/or maintain penile erection sufficient for sexual satisfaction, satisfactory performance, or both (Burnett 2018). Erectile dysfunction has a prevalence estimated at approximately 40% in men between 40 and 49 years old and up to as high as 90% in men aged 70 years and older (Allen 2019). Studies suggest that erectile dysfunction is becoming more prominent in men younger than 40 years, with reported prevalence rates of between 10% and 16% (McCabe 2016; Nguyen 2017).

Risk factors include medical comorbidities such as diabetes mellitus, cardiovascular disease, hypertension, obesity, hyperlipidemia metabolic syndrome, abdominal‐pelvic interventions, benign prostatic hyperplasia, and psychiatric disorders (Yafi 2016). Medications used to treat these conditions may also contribute to erectile dysfunction. Socioeconomic status may play a role, in that men from low socioeconomic environments are at increased risk of erectile dysfunction and tend to seek less counsel (Rasmussen 2020). Smoking, medications, and hormonal factors are other well‐defined risk factors (Cao 2013; Lewis 2004).

The European Association of Urology Guidelines on Sexual and Reproductive Health define three categories for erectile dysfunction: organic, psychogenic, and mixed (Salonia 2021). Most cases of erectile dysfunction are classified as mixed type, given they usually involve both organic and psychological factors.

Diagnosis

Evaluation for erectile dysfunction starts with the patient history and a physical examination. Evaluation of a patient's partner in the same way can also be helpful. The history should include past medical, psychological, and sexual issues. The International Index of Erectile Function (IIEF) is widely used to assess the severity of erectile dysfunction (Rosen 1997). It is a patient‐targeted questionnaire consisting of five domains: erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. Depending on the response, individuals can be classified as having severe (5 to 7 points), moderate (8 to 11 points), mild to moderate (12 to 16 points), mild (17 to 21 points), or no erectile dysfunction (22 to 25 points). A complementary method to assess erectile rigidity is called Erection Hardness Score (EHS), developed by Goldstein and colleagues in 1998 during a sildenafil dose‐response trial (Goldstein 1998).

Additional laboratory tests that may aid in erectile dysfunction diagnosis and its etiology include a total blood count, serum chemistry, fasting glucose, hemoglobulin A1C, lipid profile, and morning levels of total testosterone to evaluate for synchronous hypogonadism. Additional tests – such as serum‐free testosterone and serum luteinizing hormone – can be pursued should the testosterone level found to be low. Meanwhile, another common etiology of erectile dysfunction is local treatment for prostate cancer in the form of radical prostatectomy and radiation therapy (external beam or brachytherapy), with or without adjuvant systematic androgen deprivation therapy.

The psychological aspect of erectile dysfunction can be challenging to diagnose, and a multi‐specialty approach can be initiated, involving sexual therapists, psychologists, and urologists (Burnett 2018).

Treatment

Treatment of erectile dysfunction should focus on patient‐important outcomes and treatment success should not be based solely on recovering penile rigidity. Lifestyle modifications, such as weight loss programs and regular exercise, have resulted in erectile dysfunction improvement, and thus should be the first recommendation to men presenting with erectile dysfunction (Ostfeld 2021). Interventions directed toward cardiovascular health are also thought to be beneficial (Hackett 2016). If there are suitable alternatives, beta blockers, thiazide diuretics, and other medications known for their erectile dysfunction‐exacerbating features should be discontinued (Shamloul 2013). Psychosexual therapy, including anxiety reduction, interpersonal therapy, behavioral therapy, couples' communication, and sexual skills training, have helped in ameliorating psychosexual barriers and alleviating erectile dysfunction (Melnik 2007).

After conservative methods have failed, or often concurrently with these methods, pharmacological therapies are offered. Phosphodiesterase‐5 inhibitors (PDE5 inhibitors) are often the first‐line treatment (Yuan 2013), notably sildenafil, tadalafil, and vardenafil. These oral agents are easy to use and mostly effective, but studies show limitations (Hellstrom 2003). These include interaction with a variety of other medications (antidepressant, antifungal, antiretroviral, and antihypertensive medications) and risk of hypotension with concomitant use with nitrates (Irwin 2019). Other commonly used modalities for erectile dysfunction are vacuum constriction devices (VCDs), intraurethral prostaglandin suppositories, intracavernosal injection therapy, and surgical placement of a penile prosthesis (Mobley 2017). Several of these agents have also been used in post‐prostatectomy rehabilitation for erectile dysfunction, although with limited success rates (Philippou 2018). Other treatments, such as ginseng, which are not regulated by the US Food and Drug Administration, do not appear to be effective (Lee 2021).

An established technology for the treatment of kidney stones, shockwave therapy (SWT) has recently been used for erectile dysfunction, with what are described as promising results (Lu 2017; Vardi 2010). Although multiple studies have yielded conflicting results about whether the intervention actually works, direct‐to‐consumer marketing of this treatment has resulted in relatively widespread use (Canguven 2021).

Description of the intervention

Since the 1980s, SWT has been widely used for the treatment of renal stones. It has also been adapted for different diseases, such as musculoskeletal disorders, myocardial infarction, nonhealing wounds, plantar fasciitis, Peyronie's disease, and erectile dysfunction (Bakr 2021; Campbell 2022; Clavijo 2017; Lohrer 2010). A shockwave is defined as a wave that propagates through a medium causing a characteristic rapid rise time and high positive peak pressure. This pressure is thought to cause neovascularization and tissue regeneration.

Shockwaves can be categorized as electrohydraulic shockwaves, electromagnetic shockwaves, piezoelectric shockwaves, and radial shockwaves (Katz 2020). These forms of shockwaves are produced with several commercially available generators. These generators have a probe (i.e. a wand‐like device) that is usually applied systematically to all sections of the left and right corpora cavernosa (which contain the expandable erectile tissue responsible for erections), namely, the two crura (which represent the tips of the corpora), the root (where the two corpora come together), the middle part, and the tip of the penile shaft during a typical treatment session (Sighinolfi 2022). The sessions usually take 15 to 20 minutes. The number and frequency of sessions varies between protocols – from once every week for four weeks to once every week for 12 weeks and possibly even more – depending on the manufacturer's recommendations, physician preference, and patient availability (Kurosawa 2022).

Shockwave therapy for erectile dysfunction generally is referred to as low‐intensity shockwave therapy (LiSWT), focused shockwave therapy (FSWT), or extracorporeal shockwave therapy (ESWT). For the different types of shockwaves, the commercially available generators include the following:

• electrohydraulic shockwaves: ED1000, Medispec, Gaithersburg, MD, USA; UroGold 100, MTS Medical UG, Konstanz, Germany;

• electromagnetic shockwaves: Duolith SD1, Storz Medical, Tagerwilen, Switzerland; MoreNova & Renova, Direx Group, Wiesbaden, Germany; Aries 2, Dornier MedTech, Wessling, Germany; and

• piezoelectric shockwaves: PiezoWave 2, Richard Wolf, Knittlingen, Germany (Katz 2020).

Our study will focus on LiSWT as an erectile dysfunction therapy that includes the application of shockwaves to the penile shaft using an electrohydraulic, an electromagnetic, or a piezoelectric generator, with any treatment protocol (frequency and duration of treatment, energy densities, pulses per minute, etc.). The use of radial shockwaves in erectile dysfunction is a relatively newer field with limited availability compared to LiSWT (Sandoval‐Salinas 2021); this treatment is beyond the scope of our study.

Two reviews of LiSWT for erectile dysfunction have highlighted that clinical trials in this field have different protocols, devices, settings, types of shockwaves, and even different nomenclature for the procedures used (Clavijo 2017; Katz 2020). An example of the non‐standardized nomenclature is the term "linear" shockwave therapy. Some studies use this term to describe the linear alignment of the corpora of the penis and the correspondingly linear application of LiSWT. Other studies use the term "linear" therapy to refer to the extent of tissues targeted with one pulse from the probe, and contrast it to "focused" therapy which targets a smaller area (Patel 2020; Reisman 2015). The terminological diversity in this research area detracts from the power of the evidence.

Adverse effects of the intervention

LiSWT for erectile dysfunction has mostly been reported to be safe with few and relatively minor adverse effects (Gruenwald 2013). The most commonly encountered adverse effects seem to be bruising and hematoma and usually require no intervention (Yuan 2021). Hematuria, infection of penile skin, painful erection, and difficulty having intercourse secondary to infection or pain might be other potential adverse effects.

How the intervention might work

Shockwaves are thought to be able to induce neovascularization through a cascade of reactions due to focused energy. Shockwaves are believed to exert physical forces on tissue in two ways. First, there is mechanical stress from exposure to the high peak pressure shockwave. Second, in liquids, shockwaves form cavitation bubbles, which are focal areas of vaporization of the liquid. These cavities then collapse when subjected to high pressures, resulting in local trauma and neovascularization (Young Academic Urologists 2017). Nurzynska 2008 also found that shockwaves increase vascular endothelial growth factor (VEGF) secretion and VEGF receptor sensitivity in myocardial cells, which could also induce neovascularization. The mechanism of action of this modality is suggested not only to involve vascular regeneration but also nerve repair. Peng 2020 indicated that application of LiSWT after nerve surgery promoted nerve regeneration and improved the functional outcomes. Underlying mechanisms include an increase of neurotrophic factors, Schwann cell activation, and cellular signaling activation for cell activation and mitosis induced by LiSWT. These results, together with other studies (Usta 2019), suggest that this treatment may also be useful in men after prostatectomy with erectile dysfunction due to injury to the neurovascular bundles.

Why it is important to do this review

Although LiSWT may be a potentially new and valuable treatment option for erectile dysfunction which may reverse some of the underlying causes (Vardi 2010), it remains unclear how effective it really is. While existing systematic reviews compare LiSWT to placebo or other therapies used to treat erectile dysfunction (Clavijo 2017; Zou 2017), none so far has used the same rigorous methodology expected of Cochrane Reviews, including the application of GRADE. Given the high prevalence of erectile dysfunction, and the impact on men's health, the benefits and harms of LiSWT should be carefully assessed. Assessing and quantifying the existing evidence using Cochrane Review methodology will help to guide patients and practitioners, as well as policymakers, and help determine the role of LiSWT in treating erectile dysfunction.

Objectives

To assess the effects of low‐intensity shockwave therapy (LiSWT) for men with erectile dysfunction.

Methods

Criteria for considering studies for this review

Types of studies

We will include only randomized controlled trials (RCTs) as this is the study design most likely to provide high‐certainty evidence in this subject. In a scoping review, we found no well‐designed observational studies that are likely to contribute anything more than low‐certainty evidence. We will exclude pseudo‐randomized trials (i.e. those using alternating allocation). We will also exclude cross‐over trials and cluster‐randomized trials as they are not relevant to the clinical question of interest. We will include studies regardless of their publication status or the language of publication.

Types of participants

We will include men with organic or mixed erectile dysfunction who are 18 years of age or older. Should we identify studies in which only a subset of participants is relevant to this review, we will include such studies if data are available separately for the relevant subset.

Diagnostic criteria for erectile dysfunction

Men with primary organic and mixed erectile dysfunction, as identified by their clinical history, who are interested in seeking treatment.

Variety in diagnostic criteria, disease severity, or both may produce significant variability in the clinical characteristics of the participants included, and in the results obtained (which we will investigate through subgroup analysis). Trials involving participants with comorbid disorders will be eligible for inclusion, as long as the primary focus of the intervention is erectile dysfunction.

Exclusion criteria

We plan to exclude trials with participants with: iatrogenic causes of erectile dysfunction (pelvic surgery, radiation, antiandrogen therapy); neurologic/primary psychogenic causes of erectile dysfunction; erectile dysfunction secondary to anatomic anomalies or hypogonadism. We will exclude studies that target men who develop erectile dysfunction after a kidney transplant or radical prostatectomy.

Types of interventions

We plan to assess trials which compare low‐intensity shockwave therapy (LiSWT) on the penis to either sham treatment or no treatment.

Our review will include the application of shockwaves to the penile shaft under any treatment protocol (frequency and duration of treatment, energy densities, pulses per minute, etc.) utilizing:

• electrohydraulic generators;

• electromagnetic generators; and

• piezoelectric generators.

We will exclude trials utilizing "radial" shockwave therapy for erectile dysfunction as the energy dispersion and tissue penetration with this method falls outside the scope of our review (Wu 2020).

Concomitant interventions will have to be the same in the experimental and comparator groups to establish fair comparisons. If a trial includes multiple arms, we will include any arm that meets the review's inclusion criteria.

Minimum duration of intervention and follow‐up

Given the lack of consensus about minimum treatment standards (in terms of number of applications, frequency and duration of LiSWT treatment, and energy density), we will include all treatment protocols. We will also include studies with any length of follow‐up.

Types of outcome measures

We will not exclude studies because one or several of our primary or secondary outcome measures were not reported in the publication. If included studies report none of our primary or secondary outcomes, we will contact the authors to obtain this information. If we are unable to obtain these outcomes, we will nevertheless include the study and provide the available information.

Primary outcomes

• Erectile function

• Discontinuation of treatment

• Adverse events

Secondary outcomes

• Patient/partner satisfaction

• Penile rigidity

• Quality of sexual life

Method and timing of outcome measurement

Erectile function

• We will evaluate this outcome with validated questionnaires, such as the erection domain of IIEF (IIEF‐EF; Rosen 1997), IIEF‐5 (Rhoden 2002), or the IIEF question 15 (Rosen 1997).

• We will use a minimal clinically important difference (MCID) IIEF of 4 points as suggested in the literature (Rosen 2011); for other validated instruments we will also use the MCID reported in the medical literature.

Discontinuation of treatment

• We will take into account any cause of treatment discontinuation at any time after participants are randomized to intervention/comparator groups.

• We will consider a 5% absolute difference in discontinuation rates from treatment as the MCID.

Adverse events

• We will focus on adverse events reported in trials that can be assumed to be secondary to the intervention; namely, penile bruising, hematoma, hematuria, infection of penile skin, painful erections, and urinary retention.

• We will consider a 5% absolute difference in adverse event rates as the MCID.

Patient/partner satisfaction

• We will use data obtained by validated questionnaires; for example, the Watts Sexual Function Questionnaire (Watts 1982).

• We will use MCIDs as reported in the literature for these questionnaires. In the absence of published thresholds, we will derive a relevant threshold using a distribution‐based methodological approach (Watt 2021).

Penile rigidity

• We will assess this outcome with validated questionnaires, such as the Erectile Hardness Score (EHS) (Goldstein 1998).

• We will use an MCID of 1 point change on the EHS (Alappattu 2017).

Quality of sexual life

• We will use data obtained by validated questionnaires, such as the Sexual Quality of Life Questionnaire Male (SQoL‐M) (Abraham 2008).

• We will use MCIDs as reported in the literature for these questionnaires. In the absence of published thresholds, we will derive a relevant threshold using a distribution‐based methodological approach (Watt 2021).

We will review all outcomes at short term (≤ three months) and long term (> three months).

Main outcomes for the summary of findings tables

We will present summary of findings tables for both short‐term and long‐term outcomes, reporting all the outcomes in the following order of importance:

• erectile function;

• discontinuation of treatment;

• adverse events;

• patient/partner satisfaction;

• penile rigidity;

• quality of sexual life.

Search methods for identification of studies

We will perform a comprehensive search with no restriction on the language of publication or publication status.

Electronic searches

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

• Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (via Wiley from 1991)

• MEDLINE (via Ovid from 1946)

• Embase (Elsevier from 1947)

• Web of Science Core Collection (Clarivate from 1900)

• Scopus (Elsevier from 1966)

• Latin American and Caribbean Health Sciences Literature (LILACS, from 1982; https://lilacs.bvsalud.org/en/)

We will also search the following sources.

• ClinicalTrials.gov (www.ClinicalTrials.gov)

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

• 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 try to identify potentially eligible trials or ancillary publications based on the referenced studies in our included trials, systematic reviews, meta‐analyses and health technology assessment reports. We will contact the study authors of included trials, and device manufacturers, or both, for ongoing or unpublished trials to identify any unpublished or ongoing studies that we may have missed in our search results.

Data collection and analysis

Selection of studies

We will use reference management software to identify and remove duplicate records (EndNote 2022). Two review authors (OE, KK) will independently scan the abstract, title, or both, of remaining records retrieved, to determine which studies should be assessed further. Working independently, two review authors (OE, KK) will then investigate all potentially relevant records in 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 2022). We will resolve any discrepancies 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 we will contact study authors for clarification. We will document reasons for exclusion of studies that may have reasonably been expected to be included in the review in a 'Characteristics of excluded studies' table. We will present a Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow diagram showing the process of study selection (Page 2020).

Data extraction and management

We will develop a dedicated data abstraction form that we will pilot test on at least one study.

For studies that fulfill inclusion criteria, two review authors (OE, KK) 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 (for example: severity of erectile dysfunction at baseline, prior treatments for erectile dysfunction, medical comorbidities);

• participant details, baseline demographics (for example: age, body mass index, severity of erectile dysfunction at baseline)

• number of participants by study and by study arm;

• details of relevant experimental and comparator interventions (for example: energy density (mJ/mm²), duration and frequency of treatment, targeted spots on the penis, pulses per week, generator type used);

• definitions of relevant outcomes, method and timing of outcome measurement, as well as any relevant subgroups;

• study funding sources;

• primary investigators' declarations of interest.

We will extract outcomes data relevant to this Cochrane Review to calculate summary statistics and measures of variance. For dichotomous outcomes, we will attempt to obtain numbers of events and totals to populate a 2 x 2 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 necessary to calculate this information.

We will resolve any disagreements by discussion, or, if required, by consultation with a third review author (PD).

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

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

Dealing with duplicate and companion publications

In the event of duplicate publications, companion documents, or multiple reports of a primary study, we will maximize information yield 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.

Assessment of risk of bias in included studies

Working independently, two review authors (OE, KK) will assess the risk of bias in each included study. We will resolve disagreements by consensus, or by consultation with a third review author (PD).

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

• 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' and will evaluate individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). We will present a risk of bias summary figure to illustrate these findings.

For performance bias (blinding of participants and personnel) and detection bias (blinding of outcome assessment), we will evaluate the risk of bias separately for each outcome, and we will group outcomes according to whether they are measured subjectively or objectively when reporting our findings in the risk of bias tables.

We will consider all outcomes as being similarly susceptible to performance bias.

We define all outcomes except 'discontinuation of treatment' as susceptible to detection bias, thereby making blinding important.

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

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

Measures of treatment effect

We will try to express dichotomous data as a risk ratio (RR) with 95% confidence interval (CI). For continuous outcomes measured on the same scale (e.g. IIEF), we will estimate the intervention effect using the mean difference (MD) with 95% CI. For continuous outcomes measuring the same underlying concept (e.g. SQoL‐M) but using different measurement scales, we will calculate the standardized mean difference (SMD). For rare events, such as event rates below 1%, we will use the odds ratio (OR). We will use a minimal clinically important difference (MCID) to identify the proportion of participants that experience a clinically meaningful change.

Unit of analysis issues

The unit of analysis will be the individual participant. We will handle trials with more than two intervention groups in accordance with guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions for inclusion in the review (Higgins 2023).

Dealing with missing data

We will obtain missing data from study authors, if feasible, and will perform intention‐to‐treat (ITT) analyses if data are available. Otherwise, we will perform available‐case analyses. We will investigate attrition rates (e.g. dropouts, losses to follow‐up and withdrawals), and will critically appraise issues of missing data. We will not impute missing data.

Assessment of heterogeneity

We will only perform meta‐analysis where this is meaningful; that is, when the treatments, participants, and outcomes are sufficiently similar. In the event of excessive heterogeneity unexplained 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 identify 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 assess the impact of heterogeneity on the meta‐analysis (Higgins 2002; Higgins 2003). We will interpret the I² statistic as follows (Deeks 2022):

• 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 determine possible reasons for it by examining individual study and subgroup characteristics.

Assessment of reporting biases

We will attempt to obtain study protocols to assess for selective outcome reporting.

If we include 10 or more studies investigating a particular outcome, we will use funnel plots to assess small‐study effects, which we will interpret in a manner consistent with guidance in the Cochrane Handbook (Higgins 2022).

Data synthesis

Unless there is good evidence for homogeneous effects across studies, we will summarize data using a random‐effects model. In addition, we will perform statistical analyses according to the statistical guidelines contained in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022). For dichotomous outcomes, we will use the Mantel‐Haenszel method; for continuous outcomes, we will use the inverse variance method. We will use RevMan Web 2020 software to perform analyses.

Subgroup analysis and investigation of heterogeneity

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

• Response to PDE5 inhibitors (responders versus non‐responders): the decision to perform this subgroup analysis is based on studies suggesting greater effectiveness of LiSWT in PDE5 responders (Zou 2017).

• Baseline severity (mild versus mild‐to‐moderate versus moderate or severe erectile dysfunction): the decision to perform this subgroup analysis is based on studies suggesting that baseline erectile dysfunction severity might be a determinant of treatment response to LiSWT (Tzou 2021).

We will use the test for subgroup differences in RevMan Web 2020 to compare subgroup analyses if there are sufficient studies.

Sensitivity analysis

We plan to perform sensitivity analyses in order to explore the influence of risk of bias (when applicable) on effect sizes, restricting the analysis by excluding studies at high or unclear risk of bias.

Summary of findings and assessment of the certainty of the evidence

We will present the overall certainty of the evidence for each outcome according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, which takes into account five criteria: four related to internal validity (risk of bias, inconsistency, imprecision, publication bias), and one related to external validity, the directness of results (Guyatt 2008). For each comparison, two review authors (OE, KK) will independently rate the certainty of evidence for each outcome as 'high', 'moderate', 'low', or 'very low' using GRADE's software, GRADEpro GDT (GRADEpro GDT 2022). We will resolve any discrepancies by consensus, or, if needed, through arbitration by a third review author (EH or PD). For each comparison, we will present a summary of the evidence for the main outcomes in a summary of findings table, which will provide 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 2023). If meta‐analysis is not possible, we will present the results in a narrative summary of findings table. We will interpret results using a minimally contextualized approach (Zeng 2022), and use GRADE narrative language to characterize the certainty of evidence and magnitude of effect (Santesso 2020).

The summary of findings table(s) will present all six outcomes described in this protocol.

What's new

Date	Event	Description
20 September 2023	New citation required and major changes	Entirely new protocol by new author team.

History

Protocol first published: Issue 11, 2018

Notes

We have based parts of the Methods and Appendix 1 sections of this Cochrane protocol on a standard template established by Cochrane Metabolic and Endocrine Disorders.

Appendices

Appendix 1. Search strategies

1.1. MEDLINE via Medline
#1	exp Extracorporeal Shockwave Therapy/
#2	exp Ultrasonic Therapy/
#3	(shock wave* or shockwave*).tw.
#4	(Ultraso* adj2 therap*).tw.
#5	ESWT.tw.
#6	ECSW.tw.
#7	#1 or #2 or #3 or #4 or #5 or #6
#8	exp Erectile Dysfunction/
#9	Erectile dysfunction*.tw.
#10	Erectile function*.tw.
#11	Erectile failure*.tw.
#12	Erection failure*.tw.
#13	ED.tw.
#14	Penile erect*.tw.
#15	Impoten*.tw.
#16	(sexual adj (function* or dysfunction* or problem* or symptom* or arous*)).tw.
#17	(sex adj (function* or dysfunction* or problem* or symptom* or arous*)).tw.
#18	exp Impotence, Vasculogenic/
#19	#9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18
#20	#7 and #19
#21	randomized controlled trial.pt.
#22	controlled clinical trial.pt.
#23	randomized.ab.
#24	placebo.ab.
#25	drug therapy.fs.
#26	randomly.ab.
#27	trial.ab.
#28	groups.ab.
#29	#21 or #22 or #23 or #24 or #25 or #26 or #27 or #28
#30	exp animals/ not humans.sh.
#31	#29 not #30
#32	#20 and #31
1.2. Embase
#1	'shock wave therapy'/exp
#2	'ultrasound therapy'/exp
#3	'shock wave*':ti,ab OR shockwave*:ti,ab
#4	(ultraso* NEAR/2 therap*):ti,ab
#5	eswt:ti,ab
#6	ecsw:ti,ab
#7	#1 OR #2 OR #3 OR #4 OR #5 OR #6
#8	'erectile dysfunction'/exp
#9	'erectile dysfunction*':ti,ab
#10	'erectile function*':ti,ab
#11	'erectile failure*':ti,ab
#12	'erection failure*':ti,ab
#13	ed:ti,ab
#14	'penile erect*':ti,ab
#15	impoten*:ti,ab
#16	(sexual NEXT/1 (function* OR dysfunction* OR problem* OR symptom* OR arous*)):ti,ab
#17	(sex NEXT/1 (function* OR dysfunction* OR problem* OR symptom* OR arous*)):ti,ab
#18	'organic impotence'/exp
#19	#8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18
#20	#7 AND #19
#21	(random*:ti,ab,tt OR 'randomization'/de OR 'intermethod comparison'/de OR placebo:ti,ab,tt OR compare:ti,tt OR compared:ti,tt OR comparison:ti,tt OR ((evaluated:ab OR evaluate:ab OR evaluating:ab OR assessed:ab OR assess:ab) AND (compare:ab OR compared:ab OR comparing:ab OR comparison:ab)) OR ((open NEXT/1 label):ti,ab,tt) OR (((double OR single OR doubly OR singly) NEXT/1 (blind OR blinded OR blindly)):ti,ab,tt) OR 'double blind procedure'/de OR ((parallel NEXT/1 group*):ti,ab,tt) OR crossover:ti,ab,tt OR 'cross over':ti,ab,tt OR (((assign* OR match OR matched OR allocation) NEAR/6 (alternate OR group OR groups OR intervention OR interventions OR patient OR patients OR subject OR subjects OR participant OR participants)):ti,ab,tt) OR assigned:ti,ab,tt OR allocated:ti,ab,tt OR ((controlled NEAR/8 (study OR design OR trial)):ti,ab,tt) OR volunteer:ti,ab,tt OR volunteers:ti,ab,tt OR 'human experiment'/de OR trial:ti,tt) NOT ('randomized controlled trial'/de OR 'controlled clinical trial'/de) NOT (((random* NEXT/1 sampl* NEAR/8 ('cross section*' OR questionnaire* OR survey OR surveys OR database OR databases)):ti,ab,tt) NOT ('comparative study'/de OR 'controlled study'/de OR 'randomised controlled':ti,ab,tt OR 'randomized controlled':ti,ab,tt OR 'randomly assigned':ti,ab,tt) OR ('cross‐sectional study'/de NOT ('randomized controlled trial'/de OR 'controlled clinical study'/de OR 'controlled study'/de OR 'randomised controlled':ti,ab,tt OR 'randomized controlled':ti,ab,tt OR 'control group':ti,ab,tt OR 'control groups':ti,ab,tt)) OR ('case control*':ti,ab,tt AND random*:ti,ab,tt NOT ('randomised controlled':ti,ab,tt OR 'randomized controlled':ti,ab,tt)) OR ('systematic review':ti,tt NOT (trial:ti,tt OR study:ti,tt)) OR (nonrandom*:ti,ab,tt NOT random*:ti,ab,tt) OR 'random field*':ti,ab,tt OR (('random cluster' NEAR/4 sampl*):ti,ab,tt) OR (review:ab AND review:it NOT trial:ti,tt) OR ('we searched':ab AND (review:ti,tt OR review:it)) OR 'update review':ab OR ((databases NEAR/5 searched):ab) OR ((rat:ti,tt OR rats:ti,tt OR mouse:ti,tt OR mice:ti,tt OR swine:ti,tt OR porcine:ti,tt OR murine:ti,tt OR sheep:ti,tt OR lambs:ti,tt OR pigs:ti,tt OR piglets:ti,tt OR rabbit:ti,tt OR rabbits:ti,tt OR cat:ti,tt OR cats:ti,tt OR dog:ti,tt OR dogs:ti,tt OR cattle:ti,tt OR bovine:ti,tt OR monkey:ti,tt OR monkeys:ti,tt OR trout:ti,tt OR marmoset*:ti,tt) AND 'animal experiment'/de) OR ('animal experiment'/de NOT ('human experiment'/de OR 'human'/de)))
#22	#20 AND #21
1.3. Cochrane Library
#1	[mh "Extracorporeal Shockwave Therapy"]
#2	[mh "Ultrasonic Therapy"]
#3	("shock wave*" or shockwave*):ti,ab,kw
#4	(ultraso* near/2 therap*):ti,ab,kw
#5	eswt:ti,ab,kw
#6	ecsw:ti,ab,kw
#7	#1 OR #2 OR #3 OR #4 OR #5 OR #6
#8	[mh "Erectile Dysfunction"]
#9	((Erectile or erection) near/1 (dysfunction* or function* or failure*)):ti,ab,kw
#10	ED:ti,ab,kw
#11	("Penile erect*"):ti,ab,kw
#12	Impoten*:ti,ab,kw
#13	(sexual next/1 (function* OR dysfunction* OR problem* OR symptom* OR arous*)):ti,ab,kw
#14	(sex next/1 (function* OR dysfunction* OR problem* OR symptom* OR arous*)):ti,ab,kw
#15	[mh "Impotence, Vasculogenic"]
#16	#8 or #9 or #10 or #11 or #12 or #13 or #15
#17	#7 and #16
1.4. Scopus
#1	TITLE‐ABS("shock wave*" OR shockwave* OR (Ultraso* W/2 therap*) OR ESWT OR ECSW) AND TITLE‐ABS(((Erectile or erection) Pre/1 (dysfunction* or function* or failure*)) OR (Penile Pre/1 erect*) OR Impoten* OR (sex* Pre/1 (function* OR dysfunction* OR problem* OR symptom* OR arous*))) AND ( INDEXTERMS ( "clinical trials" OR "clinical trials as a topic" OR "randomized controlled trial" OR "Randomized Controlled Trials as Topic" OR "controlled clinical trial" OR "Controlled Clinical Trials" OR "random allocation" OR "Double‐Blind Method" OR "Single‐Blind Method" OR "Cross‐Over Studies" OR "Placebos" OR "multicenter study" OR "double blind procedure" OR "single blind procedure" OR "crossover procedure" OR "clinical trial" OR "controlled study" OR "randomization" OR "placebo" ) ) OR ( TITLE‐ABS‐KEY ( ( "clinical trials" OR "clinical trials as a topic" OR "randomized controlled trial" OR "Randomized Controlled Trials as Topic" OR "controlled clinical trial" OR "Controlled Clinical Trials as Topic" OR "random allocation" OR "randomly allocated" OR "allocated randomly" OR "Double‐Blind Method" OR "Single‐Blind Method" OR "Cross‐Over Studies" OR "Placebos" OR "cross‐over trial" OR "single blind" OR "double blind" OR "factorial design" OR "factorial trial" ) ) ) OR ( TITLE‐ABS ( clinical trial* OR trial* OR rct* OR random* OR blind* ) )
1.5. Web of Science
#1	TS=("shock wave*" OR shockwave* OR (Ultraso* NEAR/2 Therap*) OR ESWT OR ECSW) AND TS=(((Erectile or erection) NEAR/1 (dysfunction* or function* or failure*)) OR (Penile NEAR/1 erect*) OR Impoten* OR (sex* NEAR/1 (function* OR dysfunction* OR problem* OR symptom* OR arous*))) AND (TS=(randomised OR randomized OR randomisation OR randomisation OR placebo* OR (random* AND (allocat* OR assign*)) OR (blind* AND (single OR double OR treble OR triple))))
1.6	Latin American and Caribbean Health Sciences Literature
	(mh:("Erectile Dysfunction" OR "Impotence, Vasculogenic") OR tw:(((erectile OR erection) AND (dysfunction* or function* or failure*)) OR impoten$ OR "penile erection" OR ((sex OR sexual) AND (function* OR dysfunction* OR problem* OR symptom* OR arous*)))) AND ((mh:("Extracorporeal Shockwave Therapy" OR "Ultrasonic Therapy")) OR (tw:("shock wave*" OR shockwave* OR ultraso* OR eswt OR ecsw))) AND ((PT:"randomized controlled trial" OR PT:"controlled clinical trial" OR PT:"multicenter study" OR MH:"randomized controlled trials as topic" OR MH:"controlled clinical trials as topic" OR MH:"multicenter studies as topic" OR MH:"random allocation" OR MH:"double‐blind method" OR MH:"single‐blind method") OR ((ensaio$ OR ensayo$ OR trial$) AND (azar OR acaso OR placebo OR control$ OR aleat$ OR random$ OR enmascarado$ OR simpleciego OR ((simple$ OR single OR duplo$ OR doble$ OR double$) AND (cego OR ciego OR blind OR mask))) AND clinic$)) AND NOT (MH:animals OR MH:rabbits OR MH:rats OR MH:primates OR MH:dogs OR MH:cats OR MH:swine OR PT:"in vitro")
1.7. ClinicalTrials.gov
#2	Condition or disease = (erectile OR impotence OR impotent OR "penile erection" OR "sexual dysfunction" OR "sexual function" OR "sexual problem" OR "sexual symptom" OR "sexual arousal")
#2	Other terms = ("shock wave" OR shockwave OR ESWT OR ECSW)
#3	1 AND 2
1.8. World Health Organization International Clinical Trials Registry Platform search portal
#1	Basic search = (erectile OR impotence OR impotent OR erection) AND (shock wave OR shockwave OR ESWT OR ECSW)
1.9. Grey Literature Report
#1	(erectile OR erection OR impotence OR impotent) AND (shockwave OR shock wave)

Contributions of authors

OE: wrote the protocol.

KK: revised and edited the protocol.

MHK: developed the search methods.

ECH: revised the protocol and provided methodological input.

YB: revised the protocol and provided clinical input.

AG: revised the protocol and provided clinical input.

SP: provided clinical input.

PD: developed the review idea, revised the protocol, and administrated the project.

Sources of support

Internal sources

• Minneapolis VA Health Care System, USA

  Salary support for Philipp Dahm for Cochrane‐related work

External sources

• None, Other

  None

Declarations of interest

OE is a Fellow for Cochrane Urology; however, he was not involved in the editorial process of this review.

KK declares no conflicts of interest.

MHK declares no conflicts of interest.

ECH is a Contact Editor for Cochrane Urology; however, he was not involved in the editorial process of this protocol.

YB declares no conflicts of interest.

AG declares no conflicts of interest.

SP declares no conflicts of interest.

PD is the Co‐ordinating Editor of Cochrane Urology; however, he was not involved in the editorial process of this protocol.

Amended to reflect a change in scope (see 'What's new')