1、Therapeutic Advances in UrologyMeta-analysisMeta-analysis of randomized controlled trials that assess the efficacy of low- intensity shockwave therapy for the treatment of erectile dysfunctionJeffrey D. Campbell, Bruce J. Trock, Adam R. Oppenheim, Ifeanyichukwu Anusionwu, Ronak A. Gor and Arthur L.

2、BurnettAbstractBackground: The aim of this study was to perform a meta-analysis of randomized controlled trials (RCTs) that evaluate the efficacy of low-intensity extracorporeal shock wave therapy (LiESWT) for the treatment of erectile dysfunction (ED).Materials and methods: A comprehensive search o

3、f PubMed, Medline, and Cochrane databases was performed from November 2005 to July 2018. RCTs evaluating efficacy of LiESWT in thetreatmentof EDwereselected. Theprimary outcomeswerethemean difference between treatment and sham patients in the International Index of Erectile Function-Erectile Functio

4、n (IIEF-EF) domain score 1 month after treatment, and themean change in IIEF-EF from baseline to 1 month post-treatment. The secondary analysis considered the percentage of men whose erectile hardness score (EHS) changed from3 aftertreatment. Allanalysesusedarandomeffectsmethod to pool study-specifi

5、c results.Results: Atotal of seven RCTs provided data for 607 patients. The mean IIEF-EF 1month post-treatment ranged from 12.8 to 22.0 in thetreatment group versus 8.1716.43 in the sham group. The mean difference between the treatment and sham groups at the 1month follow up was a statistically sign

6、ificant increase in IIEF-EF of 4.23 (p = 0.012). Overall, fiveoftheseventrialsprovided dataontheproportion ofpatientswithbaseline EHS3 at 1month post-treatment. Theproportions ranged from 3.5 to 90% in thetreatment group versus 09% in thesham group and thepooled relative risk of EHSimprovementforthe

7、treated versus shamgroup was6.63 (p=0.0095). No significant adverse events were reported.Conclusions: This is the first meta-analysis that evaluates RCTs exploring LiESWT as a treatment modality strictly for ED. This therapeutic strategy appears to be well tolerated with short-term benefits. However

8、 further studies exploring specific treatment regimens and long- term outcomes are needed.Keywords: erectiledysfunction, low-intensityextracorporeal shockwavetherapy, randomized trials, IIEFReceived: 5 September 2018; revised manuscript accepted: 23 February 2019.Ther Adv Urol2019, Vol. 11: 113DOI:

9、10.1177/ 1756287219838364 The Author(s), 2019. Article reuse guidelines: /journals- permissionsCorrespondence to: Jeffrey D. Campbell The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins Medical Institutions, 600N. Wolfe Street, Marburg 405, Baltimore, MD

10、 21287, USAWestern University, Department of Surgery, Division of Urology, London, ON, Canada JBruce J. Trock Ronak A. Gor Arthur L. BurnettThe James BuchananBrady Urological Institute and Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD, USAAdam R

11、. Oppenheim Department of Urology, Einstein HealthcareIntroductionErectile dysfunction (ED) is the consistent or recur- rent inability to attain or maintain a penile erection that is sufficient for sexual satisfaction, including satisfactory sexual performance.1 The prevalence ofED in the general po

12、pulation ranges from 30 to 65% in men aged 4080 years.2 Current medical treatments, including phosphodiesterase type 5 (PDE5) inhibitors have variable efficacies and there remains an ongoing need for well-tolerated andNetwork, Philadelphia, PA, USAIfeanyichukwu Anusionwu Department of Urology, Hahne

13、mann University Hospital, Philadelphia, PA, USA/home/tau1Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (/licenses/by-nc/4.0/) which permits non-comme

14、rcialuse, reproduction and distribution oftheworkwithout further permission provided the original work is attributed as specified on the SAGE and Open Access pages (/en-us/nam/open-access-at-sage).Therapeutic Advances in Urology 112/home/tauclinically durable

15、 therapeutic options for treatment- refractory men.Emerging evidence has suggested that low- intensity extracorporeal shockwave therapy (LiESWT) may offer benefit for patients with ED.36 Shockwave therapy (SWT) relies on external energy sources depositing pulses of energy into a fluid environment, t

16、hen propagat- ingtheharnessed energyuntilitmeets thetarget tissue where the energy is deployed.7 Though SWT has played animportant role in the treat- ment of urolithiasis for decades, recent advance- ments have allowed for broader applications. In a low-intensity state, SWT appears to induce angioge

17、nesis and improve perfusion in target tis- sues.8 Cardiologists have employed SWT for patients with refractory angina, while orthopedic surgeons and physical therapists have explored its role in tendinitis and nonhealing bone frac- tures.911 The precise mechanism of neoangio- genesis is not complete

18、ly understood; however, it appears that there is a release of vascular endothelial growth factor (VEGF) and fibroblast growth factor in response to cell membrane microtrauma and mechanical stress.12 VEGF is an important mediator of neoangiogenesis and collateral blood flowformation, andanincreased c

19、oncentration of this cytokine has been demon- strated in multiple basic science studies.13,14 Clinically, increased penile angiogenesis should demonstrate an increase in penile blood flow and erectile function.15 SWT has also been shown to increase brain-derived neurotrophic factor expression throug

20、h activation of PERK/ ATF4 signaling pathway,16 which offers a puta- tive mechanism for a neuronal regenerative effect and may implicate this treatment in cav- ernous nerve injury models of ED.Though several studies have examined the use of LiESWT in ED, mostlackaplacebocontrol, and have a heterogen

21、eous design and data analysis, which render rigorous interpretation difficult. A handfulof meta-analyseshaveexamined LiESWT for ED. However, their validity is limited by heter- ogenous data that included extracorporeal shock wave therapy for conditions such as pelvic pain, nonrandomized prospective

22、studies without con- trols, and inconsistent outcome measures.36 The purpose of this meta-analysis is to systematically clarifytheroleof LiESWTasitspecificallypertains to the treatmentof ED basedonthecurrent evi- dence from randomized controlled trials (RCTs).Material and methodsSearch strategy and

23、inclusion criteriaA systematic search of PubMed and Cochrane databases from November 2005 to May 2018 was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines17 using the search term erectile dysfunction. The search returned 12,294 articles

24、. Animal studies were excluded. Figure 1 highlights our article evaluation process. A total of 16 articles met the criteria for further analysis. Exclusion criteria included: (1) non-English language articles, (2) articles on patients with Peyronies disease, and(3) nonrandomized studies. A total of

25、seven RCTs were available for analysis. Overall, two investigators performed the searches and reviewed the studies (JDC, ARO or RAG). Discrepancies among the investigators were resolved by discussion.Data extractionData were extracted from the seven available RCTs1824 by two investigators (JDC and B

26、JT). The accuracy of extracted data was cross checked and clarified with the manuscript authors as necessary. Extracted data from each study included age, treatment year, number of patients in each treatment arm, mean International Index of Erectile Function- Erectile Function (IIEF-EF) domain score

27、 at baseline and post-treatment and their respec- tive standard deviation (SD), change in IIEF-EF post-treatment, and the proportion of patients increasing from erectile hardness score (EHS) 2 at baseline to EHS 3 at 1 month post-treatment. Table 1 describes data from each study used in the meta-ana

28、lysis.Risk of bias assessmentA risk of bias assessment was performed using the tool for RCTs developed by the Cochrane Collaboration. This tool evaluates the potential risk of bias as low, unclear, or high in each of seven domains: random sequence generation, allocation concealment, blinding of part

29、icipants and personnel, blinding of outcome assess- ment, incomplete outcome data, selective reporting, and other bias, that is, sources of potential bias not addressed by the other six categories.25 JD Campbell, BJ Trock et al.Figure 1. Preferred PRISMA flowchart depicting the search strategy and a

30、rticle selection process.ED, erectile disfunction; LiESWT, low-intensity extracorporeal shock wave therapy; PRISMA, Reporting Items for Systematic Reviews and Meta-Analysis; RCT, randomized controlled /home/tau3Statistical analysisAnalysis was performed on outcomes availabl

31、e from at least five trials. The primary analysis focused on the IIEF-EF, pooling estimates of the mean scores at the 1 month post-treatment meas- urement, and alsopooling thechange frombase- line to 1 month post-treatment. The secondary analysis considered the percentage of men whose EHS changed fr

32、om 2 at baseline to 3 at the post-treatment measure, and the percentage of men with at least a 5 point improvement on the IIEF-EF. Several of the studies lacked a number ofdetails of thedata so a number of assumptions were required. These are indicated by footnotes to Table 1, and include the follow

33、ing:(a) Not providing standard error of the mean (SEM) for follow-up IIEF-EF scores.21 For that study we assumed that the SEM values at follow up were the same as those at baseline, based on similar length of error bars in Figure 4 from thepublication.(b) Standard deviations (SDs) for baseline, fol-

34、 low up, and change in IIEF-EF were not described.18 For that study SD values were estimated using the relationship of IIEF-EF score per measured unit length (mm) on they-axistoscalethelengthofthe SDbars in Figure 2(a and b) from the publication.(c) Means and SDs for baseline, follow up, and change

35、in IIEF-EF in Kitrey andTherapeutic Advances in Urology 114Table 1. Characteristics and outcomes of seven randomized trials of LiESWT for treatment of erectile dysfunction.Study (country)Srini16 (India)Olsen17 (Denmark)Yee18 (China)Vardi19 (Israel)Kitrey20 (Israel)Kalyvianakis21 (Greece)Fojecki22 (D

36、enmark)Year(s) treated20092011201220132011201220092010NDND2014Age median range; mean SDshamND60 (3779)63.3 6.457 (3577)64 (2981)55.1 (3872)63.3 9.5treatmentND59 (4180)58.9 7.658 (2772)60 (2878)53.0 (3172)65.4 7.9Treatment regimen12 total tx with5 weeks sham12 total tx12 total tx with12 total tx with

37、12 total tx with10 total tx withLiESWT or sham;or LiESWT;LiESWT orLiESWT oreither LiESWT orLiESWT orsham or LiESWT;1, 3, 6, 9, 125, 12, 24-sham; 1-monthsham; 1 andsham; 1, 6, 12, 18,sham; 1,3,6,9, 121 monthmonths post-txwk post-txpost-tx3-month post-24-month post-txmonths post-txpost-tx measuremeasu

38、resmeasuresmeasurestx measuresmeasuresmeasures# randomizedsham40543421181663treatment95513646403063# completed trialsham17542820181660treatment60513040373058sham9.2 (SD 3.6*)ND10.2 SD 3.811.5 0.868.0 (SD 3.215) 14.6 SD 3.411.5 SD 6.6treatment9.5 (SD 3.6*)ND10.2 SD 3.812.6 0.757.67 (SD 3.072) 13.8 SD

39、 3.610.9 SD 7.1sham10.6 (SD 4.3*)ND15.8 SD 6.114.5 0.868.17 (SD 3.215) 16.43 SD 3.513.0 SD 7.9/home/tauFollow-up IIEF-EFJD Campbell,BJTrocketal.5Study (country)Srini16 (India)Olsen17 (Denmark)Yee18 (China)Vardi19 (Israel)Kitrey20 (Israel)Kalyvianakis21 (Greece)Fojecki22 (Denmark)

40、/home/tauTable 1. (Continued)treatment22.0 (SD 4.3*)ND17.8 SD 4.819.3 0.7513.33 (SD 6.933) 18.46 SD 3.612.8 SD 7.8#Change in IIEF-EFtreatment12.5 (SD 4.3*)ND5.3 SD 5.56.7 0.94.83 (SD 7.32) 4.66 SD 3.62.2 SD 7.5sham1.4 (SD 3.7*)ND3.8 SD 3.63.0 1.40.08 (SD 1.81) 1.83 SD 3.451.5 SD

41、7.3% IIEF-EF 5-point improvementshamND37.1ND20012.5#38.3% increasing EHS from 2 to 3treatmentND43.2ND6540.556.7#37.9CI, confidence interval; EHS, erection hardness scale; IIEF-EF, International Index of Erectile Function-Erectile Function domain; IQR, interquartile range; LiESWT, low-intensity extra

42、corporeal shockwave therapy; ND, not described; SD, standard deviation; SEM, standard error of the mean; tx, treatment.*SD estimated using the relationship of IIEF-EF score permeasuredunitlength (mm) on the y-axis to scale thelength of the SD bars in Figure 2(b) (baseline andfollow-up IIEF-EF), or F

43、igure 2(a) (change in IIEF-EF).SEM not described, assume values are the same as for baseline based on similar error bars in Figure 4.mean and SD estimated from median and IQR using the method of Wan and colleagues6SD of differencecalculated withmeans and SDs from baseline and followupforeach treatme

44、nt group #Percentageachieving minimal clinicallyimportantdifference withthesizeof differencenotspecified #Incorrect IIEF-EF score and 95% CI in published paper. First author provided corrected score and SD in email.#Results concerning the change in EHS were only available on a subset (n = 83), but t

45、he number within each group was not provided. We assumed that the ratio of sample sizes of sham:treatment for this endpoint would be the same as the corresponding ratio in all patients who completed the trial, (60:58=1.034). We estimated the number in the treatment group (nT) and sham group (np) by

46、solving the following system of equations:np+nt = 83np/nt = 60/58This gave an estimate of nT = 41, so np was estimated as 83 41 = 42.3.5#ND54.168.0 (n = 28)ND5790treatmentsham09ND0 (n = 12)0ND6.7#Therapeutic Advances in Urology 116/home/tauFigure 2. Difference in International In

47、dex of Erectile Function-Erectile Function domain score at 1month post-treatment follow up between treated versus placebo patients.colleagues22 were estimated from median and interquartile range, respectively using the method described by Wan and colleagues.26(d) The SD of the difference between bas

48、e- lineandfollow-upmeasures was notpro- vided,23,24 so it was calculated based on themeansand SDsatbaseline andfollow up using established formulae for the SD of a difference.27(e) Results concerning the change in EHS in Fojecki and colleagues24 were only availa- ble on asubset(n = 83), butthenumber

49、 within each treatment group was not pro- vided. We assumed that the ratio of sam- ple sizes of sham:treatment for this endpoint would be the same as the corre- sponding ratio in all patients who com- pleted this trial, (60:58 = 1.034). We estimated the number in the treatment group (nT) and sham gr

50、oup (np) by solving the following simple system of equations:np + nT = 83np / nT = 60 / 58In addition, some ofthemeans and SDsforone study were incorrect,24 and corrected numbers were obtained bycontacting thefirst author.These assumptions were evaluated in sensitivity analyses. Analyses of pooled d

51、ifferences in means were performed using the method of Sutton28 as implemented in NCSS 2007 (NCSS Software, Kaysville, UT, USA), and pooled relative risks were performed using Mantel-Haenszel meth- ods29,30 as implemented in StatsDirect version2.8.0 (StatsDirect, Cheshire, UK); all pooled esti- mate

52、s were derived using a random effects model.31ResultsThe seven RCTs in this analysis are summarized in Table 1.1824 The studies encompassed patients from five different countries, including Israel, India, China, Denmark, and Greece. Mean ages ranged from 5765 years across the seven trials. There was

53、 a total of 607 patients randomized, 519 (86%) of whom completed the trial. Treatment time periods were similar across studies, ranging from 2009 to 2014. All trials enrolled men with history of organic ED for at least 6 months and excluded men with ED associated with prostate surgery, pelvic radiat

54、ion, penile abnormalities, and hormonal or neurological conditions.A total of five trials limited eligibility to men who had previously responded to phosphodiesterase type-5 inhibitors (PDE5is).18,19,2123 Only two tri- als stated that all men had baseline EHS 2.19,22 A total of five studies required

55、 a PDE5i washout period of 4 weeks,18,19,21,23,24 onestudyrequired 2 weeks,20 and one study used a 4 week run-in period with PDE5i therapy and kept patients on this medication to evaluate whether there was an improvement in response.22In five studies, LiESWT was delivered by a focused electrohydraul

56、ic unit (Omnispec ED1000, Medispec, Germantown, MD, USA) to either three23 or five18,2022 locations on the penis (distal, mid, proximal, left and right crura) for a total of 1500 shocks per session (energy density 0.09 mJ/ mm2, frequency 120/min). One study delivered LiESWT using an electromagnetic unit (Duolith SD1, Storz, Tagerwilen, Switzerland) to six loca- tions on the penis (distal, center, and proximal part of each corpus cavernosum); settings were 0.15 mJ/ mm2, 25 Hz, 3000 total impulses and total energy of 12.8 J per treatment.19 The final study used a piezoelectr