Archivio Italiano di Urologia e Andrologia 2018; 90, 4276 ORIGINAL PAPER Low-intensity shock wave therapy for erectile dysfunction and the influence of disease duration Pedro Simoes de Oliveira, Tiago Ribeiro de Oliveira, Álvaro Nunes, Francisco Martins, Tomé Lopes SCI-Centro de Urologia, Lisbon, Portugal. Objective: Low-intensity shock-wave treat- ment (LiSWT) is a therapy for erectile dys- function (ED) with good results reported in the literature. The aim of this study was to evaluate the results of LiSWT on patients treated for ED and the influence of ED duration in treatment outcomes. Material and methods: We performed an open-label single-arm prospective study of patients treated with LiSWT for ED. Patients were assessed with the IIEF-5 at baseline and at six weeks and three months after LiSWT, and with penile dynamic Doppler ultrasound before treatment and six weeks after. Patients were divided into two groups accordingly to ED evolu- tion time: ≤ 24 months and > 24 months. Results: Twenty-five patients were enrolled, 13 had ED ≤ 24 months and 12 > 24 months. Median baseline IIEF-5 was 14, at 6 weeks post LiSWT was 16 (p < 0.001) and at 3 months post LiSWT was 18 (p < 0.001). Mean baseline peak systolic veloci- ty (PSV) was 29.3 ± 13.0 cm/s, after LiSWT was 35.9 ± 15.2 cm/s (p 0.001). Mean baseline end-diastolic velocity (EDV) was 2.6 ± 4.8 cm/s and after LiSWT was 1.3 ± 4.3 cm/s (p 0.015). No statistical significative difference was identified between the two groups. Conclusions: LiSWT is a safe, harmless and repeatable treat- ment tool for ED with good outcomes reported. Our results sug- gest that length of disease duration doesn´t negatively influ- ences treatment results. KEY WORDS: Erectile dysfunction; Penis; Shock wave therapy; Time-to-treatment; Treatment outcome. Submitted 4 October 2018; Accepted 15 November 2018 Summary No conflict of interest declared. and, therefore improvement in erectile function (3). Published studies have different samples, different proto- cols and different inclusion criteria. There is still no evi- dence of which patient is the best candidate for LiSWT. The aim of our study was to evaluate the results of LiSWT on patients treated for ED and looking for cofounding factors that could influence treatment out- comes, specially duration of ED. MATERIALS AND METHODS We performed an open-label single-arm prospective study of all patients who underwent LiSWT for ED, at a single center from June 2016 to March 2018. Patients were assessed with the simplified International Index of Erectile Function (IIEF-5) before starting the treatment and at six weeks and three months after. Assessment included also penile dynamic Doppler ultrasound (PDDU) before treatment and six weeks after. Inclusion criteria included, age over 18 years-old, a total IIFE-5 score < 22, no psychiatric disturbance and no active skin lesion at the treatment site. Treatment was performed using the PiezoWave2 (Richard Wolf GmbH, Knittlingen, Germany) device with a linear probe. Treatment protocol included a weekly session for six weeks. Each session delivered 2000 shocks on the perineum plus 2000 shocks on dorsum penis with an energy flux density (EFD) of 0.160 mJ/mm2. During treatment every patient had tadalafil 5 mg daily. Patients were divided into two groups accordingly to ED evolution time, defined by time-to-treatment since the beginning of symptoms: ≤ 24 months (group 1) and > 24 months (group 2). Other analyzed variables included, age, type of ED (arte- riogenic, arteriogenic + venous leak, post radical prosta- tectomy and, venous leak), ED risk factors and PDE5i treatment necessity and response. An increase in the IIEF-5 after LiSWT was considered “improvement”. Regarding PDDU, an increase in peak sys- tolic velocity (PSV) and/or decrease in end-diastolic veloci- ty (EDV) after LiSWT was considered “improvement”. Regarding PDE5i treatment, “improvement” was defined when a patient previously on PDE5i, was able to leave medication. “Improvement” in PDEi5 response was con- sidered whenever a patient subjectively improved the response to medication after LiSWT considering three categories: “good”, “moderate” and “bad”. DOI: 10.4081/aiua.2018.4.276 INTRODUCTION Erectile dysfunction (ED) is a common condition affecting more than 50% of men aged 40-70 years (1). Available treatments include phosphodiesterase type 5 inhibitors (PDE5i), vacuum devices, topical, intraurethral or intra- cavernosal, administration of vasoactive agents or, in the most severe cases, penile prosthesis. Although many patients are satisfied with these treatments, others are not, due to poor response or impossibility of using them. Low-intensity shock wave therapy (LiSWT) is another available first line therapy for ED. Since Vardi et al. (2) first described its use on ED, several reports have been published with encouraging results. Although the mech- anism of action is poorly understood, it is suggested that LiSWT can induce neovascularization, anti-inflamma- tion and tissue regeneration leading to structural changes de Oliveira_Stesura Seveso 10/01/19 16:09 Pagina 276 277Archivio Italiano di Urologia e Andrologia 2018; 90, 4 Low-intensity shock wave therapy The primary endpoint was any observed change in IIEF-5 and PDDU associated with LiSWT and comparing results between groups 1 and 2 regarding the influence of disease duration in treatment response. The secondary endpoint was to evaluate the response to treatment with PDE5i associated with LiSWT and comparing results between groups 1 and 2. Also, LiSWT results were evalu- ated accordingly with ED type and risk factors. Adverse events, patient satisfaction and recom- mendation were also assessed. Clinical data was analyzed using IBM SPSS Statistics, version 24.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were reported as fre- quencies for categorical variables and, mean, median (first quartile - third quartile) and stan- dard deviation for continuous variables. Comparison between pre-treatment and post- treatment and between groups 1 and 2 results was performed using the Wilcoxon Signed-Rank test. χ2-test (two-sided Pearson χ2-test with two degrees of freedom) was used between IIEF-5, PDDU, PDE5i, ED type and ED risk factors. Fisher's exact test was used when the expected frequency was of five or less. Statistical signifi- cance was considered for p values < 0.05. RESULTS Twenty-five patients were enrolled, 13 had ED ≤ 24 months (group 1) and 12 > 24 months (group 2). Fifteen patients had arteriogenic ED, four arteriogenic and venous leak ED, three post-radical prosta- tectomy ED and, three venous leak. Median age was 61 years-old (range: 27-73). Patient demographics are described in Table 1. Table 2 shows the results of the total study sample. Median base- line IIEF-5 was 14, at 6 weeks post LiSWT was 16 (p < 0.001) and at 3 months post LiSWT was 18 (p < 0.001), with an improvement of 68% and 72% respectively. Mean baseline PSV was 29.3 ± 13.0 cm/s, after LiSWT was 35.9 ± 15.2 cm/s (p 0.001) representing an 84% improvement. Mean baseline EDV was 2.6 ± 4.8 cm/s, after LiSWT was 1.3 ± 4.3 cm/s (p 0.015) repre- senting an 68% improvement. There was no significative result in PDE5i treatment, nevertheless, PDE5i response had an improve- ment of 36% (p 0.004). Tables 2a and 2b show the specif- ic results of group 1 and group 2 respectively and separately. Table 1. Patient demographics. Total number 25 patients total 13 patients ED ≤ 24 months 12 patients ED > 24 months Age at LiSWT (years) Median (range) Total 61 (27-73) ED ≤ 24 months 56 (42-73) ED > 24 months 62.5 (27-73) ED type n (%) n (%) n (%) Total ED ≤ 24 months ED > 24 months Arteriogenic 15 (60) 9 (69) 6 (50) Arteriogenic + venous leak 4 (16) 1 (8) 3 (25) Post-radical prostatectomy 3 (12) 2 (15) 1 (8) Venous leak 3 (12) 1 (8) 2 (17) ED risk factors n (%) n (%) n (%) Total ED ≤ 24 months ED > 24 months Hypertension 16 (64) 8 (62) 8 (67) Dyslipidemia 15 (60) 8 (62) 7 (58) Diabetes 7 (28) 5 (39) 2 (17) Tobacco 5 (20) 4 (31) 1 (8) Obesity 8 (32) 5 (39) 3 (25) ED evolution time Median (months) Range (months) Total 24 5 - 192 ED ≤ 24 months 18 5 - 24 ED > 24 months 66 30 -192 LiSWT: Low-intensity shock wave therapy; ED: Erectile dysfunction. Table 2. Results. IIEF-5 Summary statistics Pre-LiSWT 6 weeks Post-LiSWT p value 3 months Post-LiSWT p value Min-max 5-21 5-24 5-25 Median (IQR) 14 (10.0-16.5) 16 (11.0-20.5) *< 0.001 18 (11.5-22) *< 0.001 Mean ± SD 13.3 ± 4.9 15.6 ± 5.9 16.6 ± 6.3 Improvement % (n) 68.0 (17) 72.0 (18) Penile dynamic duplex ultrasound Summary statistics PSV PSV p value EDV EDV p value Pre-LiSWT Post-LiSWT Pre-LiSWT Post-LiSWT Min-max 4,7-59.2 8.0-70.0 -6.0-13.8 -7.3-8.0 Median (IQR) 27.4 31.6 *0.001 2.1 2.6 *0.015 (21.0-32.4) (27.2-42.1) (-0.9 -6.3) (-2.2 -4.9) Mean ± SD 29.3 ± 13.0 35.9 ± 15.2 2.6 ±4.8 1.3 ± 4.3 Improvement % (n) 84.0 (21) 68.0 (17) PDE5i treatment Pre-LiSWT % (n) Post-LiSWT % (n) p value Yes 72.0 (18) 52.0 (13) 0.063 No 28.0 (7) 48.0 (12) Improvement % (n) 20.0 (5) PDE5i response Pre-LiSWT % (n) Post-LiSWT % (n) p value Good 16.0 (4) 20.0 (5) Moderate 32.0 (8) 20.0 (5) *0.004 Bad 24.0 (6) 12.0 (3) Improvement % (n) 36.0 (9) IIEF-5: international index of erectile function (5 questions); LiSWT: Low-intensity shock wave therapy; IQR: Interquartile range; SD: Standard deviation; PSV: Peak systolic velocity; EDV: End-diastolic velocity; PDE5i: Phosphodiesterase type 5 inhibitors. * Statistical significance with p < 0.05 de Oliveira_Stesura Seveso 10/01/19 16:09 Pagina 277 Archivio Italiano di Urologia e Andrologia 2018; 90, 4 P. Simoes de Oliveira,T. Ribeiro de Oliveira, Á. Nunes, F. Martins, T. Lopes 278 Table 3 shows the results of the total study sample accordingly with type of ED. Statistical signifi- cance was seen only in the IIEF-5 at 6 weeks after LiSWT, presenting the best response patients with arteriogenic and/or venous leak ED (p 0.021). Table 4 shows the results of the total study sample accordingly with ED risk factors. Statistical sig- nificance was seen in the PDE5i response improvement, where dia- betic patients presented the worse response (p 0.027). Table 5 compares the results and treatment improvement between the two groups. No statistical signi- ficative difference was identified beside a better PDE5i response in patients with ED > 24 months. At the end of the study, overall patient satisfaction with LiSWT was 76% and, 80% of patients would recommend it (Table 6). No adverse effect was reported. DISCUSSION ED is a common medical condition and epidemiological data have shown a high incidence and preva- lence worldwide (1). This greatly disseminated and progressive condi- tion has great impact in patient´s quality of life and it´s no wonder efforts have been made in order to find a successful treatment. Although the true mechanism of action is not well understood, according to basic science evidences it can be hypothesized that LiSWT may act by several pathways leading to cell proliferation, angiogenesis, nerve regeneration and anti-inflam- mation (3). It is theorized that ener- gy carried by LiSWT compresses the tissue and the following negative pressure originates tensile forces leading to shear stress on cell mem- branes. This phenomenon is called “cavitation” and triggers a chain of events that cause the release of angiogenic factors such as endothe- lial NO synthase, vascular endothe- lial growth factor and proliferating cell nuclear antigen (3). Following this rationale, Vardi et al pioneered the first study using LiSWT for ED. Twenty men with vasculogenic ED were included in their study: at one-month post- Table 2a. Results ED ≤ 24 months. Table 2b. Results ED > 24 months. IIEF-5 Summary statistics Pre-LiSWT 6 weeks Post-LiSWT p value 3 months Post-LiSWT p value Min-max 5-21 5-24 5-25 Median (IQR) 15.0 (10.5-16.5) 17 (11.5-22) *0.008 17 (11.5-22.5) *0.012 Mean ± SD 13.8 ± 4.6 16.4 ± 5.9 16.9 ± 6.2 Improvement % (n) 69.2 (9) 61.5 (8) Penile dynamic duplex ultrasound Summary statistics PSV PSV p value EDV EDV p value Pre-LiSWT Post-LiSWT Pre-LiSWT Post-LiSWT Min-Max 4,7 - 59.2 8.0-70.0 -6.0 – 10.1 -7.3-8.0 Median (IQR) 27.0 30.1 *0.017 1.5 2.6 *0.630 (21.0-36.9) (25.2-40.6) (-2.2 -4.2) (-0.1 -4.2) Mean ± SD 29.6 ± 14.5 34.6 ± 15.5 1.6 ±4.0 2.2 ± 4.0 Improvement % (n) 84.6 (11) 61.5 (8) PDE5i treatment Pre-LiSWT % (n) Post-LiSWT % (n) p value Yes 46.2 (6) 38.5 (5) 1.000 No 53.8 (7) 61.5 (8) Improvement % (n) 7.7 (1)) PDE5i response Pre-LiSWT % (n) Post-LiSWT % (n) p value Good 15.4 (2) 7.7 (1) Moderate 7.7 (1) 15.4 (2) 0.500 Bad 23.1 (3) 15.4 (2) Improvement % (n) 15.4 (2) IIEF-5: international index of erectile function (5 questions); LiSWT: Low-intensity shock wave therapy; IQR: Interquartile range; SD: Standard deviation; PSV: Peak systolic velocity; EDV: End-diastolic velocity; PDE5i: Phosphodiesterase type 5 inhibitors. * Statistical significance with p < 0.05 IIEF-5 Summary statistics Pre-LiSWT 6 weeks Post-LiSWT p value 3 months Post-LiSWT p value Min-max 5-21 5-22 5-24 Median (IQR) 12.5 (9.3-17.3) 15 (10.3-20.8) *0.008 18 (10.5-22.0) *0.018 Mean ± SD 12.8 ± 5.4 14.8 ± 6.1 16.2 ± 6.6 Improvement % (n) 66.7 (8) 83.3 (10) Penile dynamic duplex ultrasound Summary statistics PSV PSV p value EDV EDV p value Pre-LiSWT Post-LiSWT Pre-LiSWT Post-LiSWT Min-max 13.2-58.8 14.7-68.2 -5.1-13.8 -7.3-6.9 Median (IQR) 28.5 32.7 *0.016 5.6 1.7 *0.005 (20.5-29.6) (28.5-47.5) (-1.3 -7.2) (-5.1 -5.5) Mean ± SD 29.0 ± 11.7 37.3 ± 15.5 3.8 ± 5.4 0.3 ± 5.4 Improvement % (n) 83.3 (10) 75.0 (9) PDE5i treatment Pre-LiSWT % (n) Post-LiSWT % (n) p value Yes 100 (12) 66.7 (8) 0.125 No 0.0 (0) 33.3 (4) Improvement % (n) 33.3 (4) PDE5i response Pre-LiSWT % (n) Post-LiSWT % (n) p value Good 16.7 (2) 33.3 (4) Moderate 58.3 (7) 25.0 (3) *0.016 Bad 58.3 (7) 25.0 (3) Improvement % (n) 58.3 (7) IIEF-5: international index of erectile function (5 questions); LiSWT: Low-intensity shock wave therapy; IQR: Interquartile range; SD: Standard deviation; PSV: Peak systolic velocity; EDV: End-diastolic velocity; PDE5i: Phosphodiesterase type 5 inhibitors. * Statistical significance with p < 0.05 de Oliveira_Stesura Seveso 10/01/19 16:09 Pagina 278 279Archivio Italiano di Urologia e Andrologia 2018; 90, 4 Low-intensity shock wave therapy treatment, mean IIEF-ED (erectile function domain) significantly improved from 13.5 ± 4.1 to 20.9 ± 5.8 (p < 0.001) (2). Later, this group conducted a randomized, double-blind, sham controlled study with 67 men. At one-month post-treatment, the mean IIEF-ED increased by 6.7 points in the treat- ed group while in the sham group increased by 3.0 points (p 0.0322) (4). Another randomized, double- blind, placebo-controlled study by Yee et al, with 58 men, concluded that LiSWT presented significant improvement at 4 weeks post-treat- ment only in patients with severe ED (IIEF-ED improvement in LiSWT group was 10.1 ± 4.1, in placebo group was 3.2 ± 3.3 (p 0.003)) (5). Ruffo et al reported a study with 31 patients with mild to moderate ED.that achieved signifi- cant improvement in IIEF-ED: baseline mean IIEF-ED was 16.54 ± 6.35, at one-month post-treat- ment was 21.13 ± 6.31 (p 0.0075) and, at three-month was 21.03 ± 6.38 (p 0.0096) (6). A meta-analy- sis conducted by Lu et al., compris- ing 14 studies including 833 patients revealed that LiSWT could significantly improve IIEF (mean difference 2.00; p < 0.0001) (7). Another meta-analysis conducted by Clavijo et al., comprising seven randomized controlled trials involving 602 patients, also report- ed a statistically significant improvement in pooled change in IIEF-ED score from baseline to fol- low-up in men treated with LiSWT compared with those receiving sham therapy (6.40 points; 95% CI 1.78-11.02; p < 0.001 vs 1.65 points; 95 CI 0.92-2.39; p < 0.0001; between-group difference p 0.047) (8). Our results are in line with previous reported studies. Overall baseline median IIEF-5 was 14, at six weeks post-treat- ment was 16 (p < 0.001) and, at 3 months 18 (p < 0.001), correspon- ding to an improvement of 68% and 72% respectively. At 3 months, median IIEF-5 actually changed category from mild-to-moderate to mild. Lu et al. (7) in his meta- analysis also reported a good ther- apeutic effect by 3 months, sug- gesting that changes induced by LiSWT may not be immediate but Table 3. Results by ED type. IIEF-5 improvement 6 weeks Post-LiSWT p value 3 months Post-LiSWT p value Arteriogenic 80.0 (12) 73.3 (11) Arteriogenic + venous leak 50.0 (2) *0.021 75.0 (3) 0.459 Post-RP 0.0 (0) 33.3 (1) Venous leak 100 (3) 100 (3) Penile dynamic duplex ultrasound improvement PSV Post-LiSWT % (n) p value EDV Post-LiSWT % (n) p value Arteriogenic 86.7 (13) 60.0 (9) Arteriogenic + venous leak 75.0 (3) 0.532 100 (4) 0.133 Post-RP 66.7 (2) 33.3 (1) Venous leak 100 (3) 100 (3) PDE5i treatment improvement % n p value Arteriogenic 20.0 3 Arteriogenic + venous leak 25.0 1 1.000 Post-RP 0 0 Venous leak 33.3 1 PDE5i response improvement % n p value Arteriogenic 20.0 3 Arteriogenic + venous leak 75.0 3 0.119 Post-RP 33.3 1 Venous leak 66.7 2 ED: Erectile dysfunction; IIEF-5: international index of erectile function (5 questions); LiSWT: Low-intensity shock wave therapy; Post-RP: Post radical prostatectomy; PSV: Peak systolic velocity; EDV: End-diastolic velocity; PDE5i: Phosphodiesterase type 5 inhibitors. * Statistical significance with p < 0.05 Table 4. Results by ED risk factor. IIEF-5 improvement 6 weeks Post-LiSWT p value 3 months Post-LiSWT p value HTA 58.8 (10) 0.661 55.6 (10) 0.208 Diabetes 29.4 (5) 1.000 22.2 (4) 0.355 Tobacco 17.6 (3) 1.000 16.7 (3) 0.597 Dyslipidemia 58.8 (10) 1.000 55.6 (10) 0.659 Obesity 35.3 (6) 0.680 38.9 (7) 0.362 Penile dynamic duplex ultrasound improvement PSV Post-LiSWT % (n) p value EDV Post-LiSWT % (n) p value HTA 57.1 (12) 0.260 64.7 (11) 1.000 Diabetes 23.8 (5) 0.548 23.5 (4) 0.640 Tobacco 23.8 (5) 0.549 29.4 (5) 0.140 Dyslipidemia 61.9 (13) 1.000 70.6 (12) 0.194 Obesity 38.1 (8) 0.269 35.3 (6) 0.680 PDE5i treatment improvement % n p value HTA 40.0 2 0.312 Diabetes 0.0 0 0.274 Tobacco 20.0 1 1.000 Dyslipidemia 60.0 3 1.000 Obesity 20.0 1 0.642 PDE5i response improvement % n p value HTA 44.4 4 0.200 Diabetes 0.0 0 *0.027 Tobacco 22.2 2 1.000 Dyslipidemia 55.6 5 1.000 Obesity 22.2 2 0.661 ED: Erectile dysfunction; IIEF-5: international index of erectile function (5 questions); LiSWT: Low-intensity shock wave therapy; Post-RP: Post radical prostatectomy; PSV: Peak systolic velocity; EDV: End-diastolic velocity; PDE5i: Phosphodiesterase type 5 inhibitors. * Statistical significance with p < 0.05 de Oliveira_Stesura Seveso 10/01/19 16:09 Pagina 279 Archivio Italiano di Urologia e Andrologia 2018; 90, 4 P. Simoes de Oliveira,T. Ribeiro de Oliveira, Á. Nunes, F. Martins, T. Lopes 280 rather delayed in time. Our subgroups analysis by length of disease duration showed no significant difference improvement in IIEF-5 between groups at 6 weeks or at 3 months follow-up post-treatment (p 1.00 and p 0.378 respectively), suggesting that time of ED do not alter treatment outcomes. Pelayo-Nieto et al, in a study with 15 patients reported an overall improvement in IIEF-ED of 80% (14.23 vs 19.69; p < 0.0013) and no influence of ED duration was found using a cut-off of 3 years (p < 0.20) (9). In a multicenter open-label prospective study with 58 patients, Reisman et al. reported an overall improvement of 81.03% in IIEF-ED (IIEF-ED average increase 7.5 ± 4.7; p < 0.001). Furthermore, a only mod- erate negative Pearson correlation coefficient of -0.62 was found between the duration of ED and success of treatment, showing satisfactory success rates in cases of ED up to 10 years of duration (10). Also, Bechara et al, in a study with 50 patients, concluded that time of ED did not influenced the results (11). Our study evaluation relied not only in subjective patient questionnaire like IIEF-5, but also assessed penile hemodynamics with a tangible tool like penile Doppler ultrasound. Our overall results showed a significant improvement both in mean PSV (29.3 cm/s vs 35.9 cm/s; p 0.001) and mean EDV (2.6 cm/s vs 1.3 cm/s; p 0.015) with both post-treatment values within normal ranges. Also, subgroups analysis by length of disease duration showed no significant differ- ence between the two groups (PSV improvement in group 1 was 84.6% vs 83.3% in group 2; p 1.000 and EDV improvement in group 1 was 61.5% vs 75.0% in group 2; p 0.673).The majority of published studies addressed treat- ment outcomes with sexual func- tion and quality of live question- naires but not many have assessed penile hemodynamics in patients treated with LiSWT for ED. Kalyvianakis et al., in a double- blinded, randomized, sham con- trolled trial with 46 patients, like in our study, used PDDU to evalu- ate patients at 3 months post-treat- ment and reported a mean change in PSV of 4.5 cm/s and 0.6 cm/s for the treatment and sham-control groups, respectively (p < 0.001) (12). Other studies, namely Vardi et al (4) and Kitrey et al. (13) also assessed penile hemodynamics with another technique using the flow mediated dilation. Both groups reported significant improvement (p < 0.0001). These results show that LiSWT indeed produces changes in penile vasculariza- tion associated with improved hemodynamics. Another endpoint of our study was to evaluate the influence of LiSWT in PDE5i response and if patients were able to leave this medication after treatment. Significant results were seen in patients who still needed PDE5i after treat- ment, because their response to medication improved (overall improvement of 36.0%; p 0.004). Significant dif- ference was present between groups (p 0.041), being group 2 the major responsible for this improvement, showing that patients with longer ED responded better to PDE5i after LiSWT. It is a fact that these patients were all on PDE5i previously, thus, more used to it and more aware, and this might have influenced the results. At the end of the study 5 patients (20%) were able to leave per- manently PDEi5 and achieve spontaneous erections, nevertheless this was not statistically significative (p 0.063). Others have evaluated the effect of LiSWT on PDE5i response. Grueenwald et al., in a study with 29 men with severe ED and poor response to PDEi5, showed that one month post-treatment, 34% of patients returned to sexual activity without the necessity for pharmacotherapy (14). Our protocol included having tadalafil 5 mg daily. Although it could induce a bias in the results, following the concept of angiogenesis and neovascularization asso- ciated with LiSWT, concomitant PDE5i produces a con- tinuous local stimulus that might contribute to a syner- gic effect with LiSWT and potentiate global response in the best interest for the patient. Kitrey et al., in a prospec- tive randomized, double-blind sham-controlled study with 55 patients, also used PDEi5 during LiSWT and showed that 54% of these patients achieved erections hard enough for penetration, in comparison of 0% of the sham group (PDE5i only) (13). The meta-analysis per- Table 5. Results comparison. IIEF-5 improvement 6 weeks 6 weeks p value 3 months 3 months p value Post-LiSWT % (n) Post-LiSWT % (n) Post-LiSWT % (n) Post-LiSWT % (n) ED > 24 months ED ≤ 24 months ED > 24 months ED > 24 months 69.2 (9) 66.7 (8) 1.000 61.5 (8) 83.3 (10) 0.378 Penile dynamic duplex ultrasound improvement PSV PSV p value EDV EDV p value Post-LiSWT % (n) Post-LiSWT % (n) Post-LiSWT % (n) Post-LiSWT % (n) ED > 24 months ED ≤ 24 months ED > 24 months ED > 24 months 84.6 (11) 83.3 (10) 1.000 61.5 (8) 75.0 (9) 0.673 PDE5i treatment improvement Post-LiSWT % (n) Post-LiSWT % (n) p value ED ≤ 24 months ED > 24 months 7.7 (1) 33.3 (4) 0.160 PDE5i response improvement Post-LiSWT % (n) Post-LiSWT % (n) p value ED ≤ 24 months ED > 24 months 15.4 (2) 58.3 (7) *0.041 IIEF-5: international index of erectile function (5 questions); LiSWT: Low-intensity shock wave therapy; IQR: Interquartile range; SD: Standard deviation; PSV: Peak systolic velocity; EDV: End-diastolic velocity; PDE5i: Phosphodiesterase type 5 inhibitors. * Statistical significance with p < 0.05 Table 6. Patient questionnaire. Satisfaction Recommendation Adverse effects % (n) % (n) % (n) Total 76.0 (19) 80.0 (20) 0.0 (0) ED ≤ 24 months 76.9 (10) 84.6 (11) 0.0 (0) ED > 24 months 75.0 (9) 75.0 (9) 0.0 (0) de Oliveira_Stesura Seveso 10/01/19 16:09 Pagina 280 281Archivio Italiano di Urologia e Andrologia 2018; 90, 4 Low-intensity shock wave therapy formed by Lu et al. showed that the IIEF increased more significantly in the group with LiSWT combined with PDE5i use (mean difference: 4.20; 95% CI, 0.16-8.24; p 0.04), supporting the use of combination therapy (7). When stratified by type of ED, our results showed that patients with vasculogenic ED, whether arteriogenic and/or venous leak, presented the best results, regarding IIEF-5 at 6 weeks post-treatment and, patients with ED post radical prostatectomy, the worse results (p 0.021). There is a consensus in the literature that the major sug- gested mechanism of action of LiSWT is by angiogenesis and neovascularization, and that explains why patients with vasculogenic ED are expected to be the best candi- dates to this treatment. Nevertheless, assuming mecha- nisms of action like nerve regeneration, other patients may be candidates. Frey et al., in a study with 16 patients who underwent nerve-sparring robotic radical prostatec- tomy, reported significant changes in IIEF-5 post-LiSWT, with a median increase of +3.5 at one-month (p 0.0049) and, +1 at one-year post-treatment (p 0.046), neverthe- less, the majority of patients achieved only marginal improvements in ED category (15). ED postprostatecto- my is usually a severe and complex side-effect, caused by direct trauma, stretching, heating, ischemia and local inflammation of the cavernous nerves (16). Nerve dam- age results in impaired erections and inadequate penile oxygenation, leading to smooth muscle apoptosis and fibrosis (17). In this setting, it may be too ambitious expecting evident results with LiSWT, but it may have a role as adjunctive therapy in penile rehabilitation. When looking for the influence of ED risk factors on LiSWT outcomes, our study showed that diabetic patients presented the worse results. In fact, statistical significance was found in PDEi5 response, where diabet- ic patients didn´t show any improvement (p 0.027). Reisman et al., comparing diabetic and non-diabetic patients, had a success rate 25% higher in the latter group (70.83% vs 88.24% respectively) (10). Hisasue et al, in subgroup analysis by comorbidities, found worse results in diabetic patients with only 3/10 achieving a score of 3 in Erection Hardness Score (18). These results all together suggest a negative impact of diabetes on the efficacy of LiSWT. Contemporary LiSWT machines can be divided into 3 main types based on the mechanism of shock waves namely electrohydraulic, electromagnetic and piezoelec- tric. The majority of studies have used the first two types. The piezoelectric device differs from the others in that it offers full organ coverage and higher treatment parame- ters. Motil et al., like in our study, used a piezoelectric machine and reported an average IIEF-5 score improve- ment from 14.4 baseline to18.6 at 1-month post-treat- ment. A total of 75 patients were treated and they had PDE5i during treatment (19). Fojecki et al., in a random- ized, double-blinded, sham-controlled study with 126 patients, also used a piezoelectric device, and reported success rates based on the IIEF-EF score of 38.3% in the sham group and 37.9% in the active group (OR = 95, 95% CI = 0.45-2.02, p 0.902), showing no clinical rele- vant effect of LiSWT (20). Although using the same device, Fojecki et al., delivered less energy to the penis, using an EFD of 0.09 mJ/mm2, in contrast Motil et al., like in our study an EFD of 0.160 mJ/mm2 was used. Also, in the Fojecki study, patients had a 4-weeks wash-out period of PDEi5 and medication was not allowed during treat- ment. This protocol differences may be responsible for different outcomes between these studies, reinforcing the benefit of using adjuvant PDEi5 with LiSWT. Limitations of our study are the absence of a sham-con- trol arm, a small number of patients and the short fol- low-up period. Also, the concomitant use of PDE5i could induce a bias. Nevertheless, the strengths include being prospective, having evaluated penile hemodynamics in all patients with a tangible and reliable tool as PDDU, no limitation in inclusion criteria regarding type of ED and looking for cofounding factors that could influence treat- ment outcomes, specially duration of ED. LiSWT is a safe, harmless, repeatable treatment modality for ED with good functional outcomes reported. Our results suggest that length of disease duration doesn´t negatively influences treatment results. Also, concomi- tant use of PDE5i should be considered. REFERENCES 1. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994; 151:154. 2. Vardi Y, Appel B, Jacob G, et al. Can low intensity extracorpore- al shockwave therapy improve erectile function? A 6-month follow- up pilot study in patients with organic erectile dysfunction. Eur Urol. 2010; 58:243-248. 3. Wang HJ, Cheng JH, Chuang YC. Potential applications of low- energy shock waves in functional urology. Int J Urol. 2017; 24:573- 581. 4. Vardi Y, Appel B, Kilchevsky A, Gruenwald I. Does low intensity extracorporeal shockwave therapy have a physiological effect on erectile function? Short-term results of a randomized, double-blind, sham controlled study. J Urol. 2012; 187:1769-1775. 5. Yee CH, Chan ES, Hou SS, Ng CF. Extracorporeal shockwave therapy in the treatment of erectile dysfunction: a prospective, ran- domized, double-blinded, placebo controlled study. Int J Urol. 2014; 21:1041-1045. 6. Ruffo A, Capece M, Prezioso D, et al. Safety and efficacy of low intensity shockwave (LISW) treatment in patients with erectile dys- function. Int Braz J Urol. 2015; 41:967-974. 7. Lu Z, Lin G, Reed-Maldonado A, et al. Low-intensity extracorpo- real shock wave treatment improves erectile function: a systematic review and meta-analysis. Eur Urol. 2017; 71:223-233. 8. Clavijo RI, Kohn TP, Kohn JR, Ramasamy R. Effects of low-inten- sity extra- corporeal shockwave therapy on erectile dysfunction: a systematic review and meta-Analysis. J Sex Med. 2017; 14:27-35. 9. Pelayo-Nieto M, Linden-Castro E, Alias-Melgar A, et al. Linear shock wave therapy in the treatment of erectile dysfunction. Actas Urol Esp. 2015; 39:456-459. 10. Reisman Y, Hind A, Varaneckas A, Motil I. Initial experience with linear focused shockwave treatment for erectile dysfunction: a 6-month follow-up pilot study. Int J Impot Res. 2015; 27:108-112. 11. Bechara A, Casabé A, De Bonis W, Gomez Ciciclia P. Twelve- month efficacy and safety of low-intensity shockwave therapy for erectile dysfunction in patients who do not respond to phosphodi- esterase type 5 inhibitors. Sex Med. 2016; 4:e225-e232. de Oliveira_Stesura Seveso 10/01/19 16:09 Pagina 281 Archivio Italiano di Urologia e Andrologia 2018; 90, 4 P. Simoes de Oliveira,T. Ribeiro de Oliveira, Á. Nunes, F. Martins, T. Lopes 282 12. Kalyvianakis D, Hatzichristou D. Low-intensity shockwave therapy improves hemodynamic parameters in patients with vascu- logenic erectile dysfunction: a triplex ultrasonography-based sham- controlled trial. J Sex Med. 2017; 14:891-897. 13. Kitrey ND, Gruenwald I, Appel B, et al. Penile low intensity shock wave treatment is able to shift PDE5i nonresponders to responders: a double-blind, sham controlled study. J Urol. 2016; 195:1550-1555. 14. Gruenwald I, Appel B, Vardi Y. Low-intensity extracorporeal shock wave therapy–a novel effective treatment for erectile dysfunc- tion in severe ED patients who respond poorly to PDE5 inhibitor therapy. J Sex Med. 2012; 9:259-264. 15. Frey A, Sonksen J, Fode M. Low-intensity extracorporeal shock- wave therapy in the treatment of postprostatectomy erectile dys- function: a pilot study. Scand J Urol 2016; 50:123-127. 16. Burnett AL. Rationale for cavernous nerve restorative therapy to preserve erectile function after radical prostatectomy. Urology 2003; 6:491-497. 17. Iacono F, Gianella R, Somma P, et al. Histological alterations in cavernous tissue after radical prostatectomy. J Urol. 2005; 173:1673-1676. 18. Hisasue S, China T, Horiuchi A, et al. Impact of aging and comorbidity on the efficacy of low- intensity shock wave therapy for erectile dysfunction. Int J Urol. 2016; 23:80-84. 19. Motil I, Kubis I, Sramkova, T. Treatment of vasculogenic erectile dysfunction with Piezowave2 device. Application of low intensity shockwaves using novel linear shockwave tissue coverage (LSTC- ED®) technique. A prospective, multicentric, placebo-controlled study. Adv Sex Med. 2016; 6:15-18. 20. Fojecki GL, Tiessen S, Osther PJS. Effect of low-energy linear shockwave therapy on erectile dysfunction – a double-blinded, sham- controlled, randomized clinical trial. J Sex Med 2017; 14:106-1. Correspondence Pedro Simoes de Oliveira, MD (Corresponding Author) pedrosimoesdeoliveira@gmail.com Tiago Ribeiro de Oliveira,MD tiagoribeirooliveira@sapo.pt Álvaro Nunes, MD alvaronunes@portugalmail.pt Francisco Martins, MD faemartins@gmail.com Tomé Lopes, MD tomematoslopes@gmail.com SCI-Centro de Urologia Av. Defensores de Chaves, 83, 1º, 1000-115, Lisbon, Portugal de Oliveira_Stesura Seveso 10/01/19 16:09 Pagina 282