Systematic review of long-term efficacy of low-intensity shock wave in the treatment of vascular erectile dysfunction
A systematic review of the long-term efficacy of low-intensity shockwave therapy for vasculogenic erectile dysfunctionCite this article
Brunckhorst, O., Wells, L., Teeling, F. et al. A systematic review of the long-term efficacy of low-intensity shockwave therapy for vasculogenic erectile dysfunction. Int Urol Nephrol 51, 773–781 (2019). https://doi.org/10.1007/s11255-019-02127-z
Systematic review of long-term efficacy of low-intensity shock wave in the treatment of vascular erectile dysfunction
To examine the evidence basis of LISWT as a treatment for vascular erectile dysfunction, focusing on the long-term outcome of more than 6 months after treatment. From 2010 to September 2018, two independent evaluators used MEDLINE and Scopus databases to conduct systematic literature retrieval. The outcome indexes of long-term curative effect include international erectile function index score and erectile hardness score. Subgroup analysis of the effectiveness of LISWT included age, PDE5i reactivity, presence of vascular complications and smoking status. The search identified 11 studies representing 799 patients. Nine studies found that erectile function improved significantly after LISWT at 6 months follow-up (the median IIEF-EF improved to 5.3 at 6 months). However, in five studies evaluating erectile function at 12 months; Two platforms have confirmed the results, and three are deteriorating (IIEF-EF score changes from-2 to 0.1 from 6 months). However, in all these studies, erectile function did remain above the baseline results. Subgroup analysis showed that increasing age could reduce the response to LISWT treatment. Although the severity of ED, PDE5i reactivity and complications may affect the curative effect, the results are still inconsistent. LISWT may be a safe and acceptable potential treatment for ED, which has been proved to be beneficial at 6 months. In addition, there are some problems about the deterioration of curative effect, but even after 12 months of treatment, there are still obvious benefits. howeverThe quality of evidence is still very low, so it is necessary to conduct a larger multi-institutional study to standardize the confounding factors such as shock wave administration and oral drug use. Atherosclerosis and endothelial dysfunction (called vascular erectile dysfunction (ED)) are the causes of ED in 40% men over 5 years old [1]. At present, there is no known lasting or curative treatment for vascular ED [2]. At present, both AUA and EAU guidelines for the treatment of vascular ED suggest initial lifestyle changes to cope with modifiable risk factors, followed by oral phosphodiesterase 5 inhibitor (PDE5is) as the first-line drug treatment. However, only 80% of patients respond to PDE5is, because its mechanism of action requires complete nerve and basic endothelial function level [3]. PDE5is is forbidden to patients treated with nitrate, so a large number of patients with vascular ED are forced to receive second-line and third-line treatment [4]. Alternative treatment options for PDE5is include the use of simple vacuum erection devices [5], intracavernous injection and local prostaglandin E1 analogues (Alprostadil). Patients who do not respond to first-line and second-line treatment may progress to prosthetic surgery. The exact mechanism of low intensity shock wave therapy (LISWT) is not completely clear. However, it is believed that the compression caused by shock wave energy and the subsequent negative pressure, the so-called cavitation phenomenon, are an important factor [6]. These tensile forces lead to shear stress on the cell membrane,These cell membranes have been proved to have the potential to treat the root cause of vascular ED by suggesting the increase of vascular endothelial growth factor (VEGF) expression [7], the recruitment of perivascular stem cells and endothelial progenitor cells [8], thus leading to the formation of arterial neovascularization. In addition, shock wave can also improve nerve regeneration in animal research, because the hypothesis that the repair ability of damaged axons and the proliferation ability of Schwann cells increase [9], which may be useful for ED caused by neurovascular etiology. LISWT is different from any treatment scheme currently provided, because it can provide natural erection for men by treating the underlying pathophysiology rather than the symptoms. However, the evidence of its use is still in dispute, lacking the approval of the Food and Drug Administration (FDA), and it is still regarded as experimental by organizations such as the North American Society of Sexual Medicine. In addition, up to now, people mainly pay attention to the short-term efficacy of LISWT as a treatment for mobility. Therefore, this literature review aims at:
Materials and methods
The evaluation was carried out according to the guidelines defined in the statement of PRISMA for systematic evaluation and Meta-analysis [10]. The review has been pre-registered, and the registration number of PROSPERO is CRD42018112789.
Research qualification standard
The original research articles on the treatment of vascular ED with LISWT were included, and the shortest follow-up period of the cohort was 6 months. The included research types are randomized controlled trials (RCT) and prospective and retrospective single-arm experimental studies. Exclusion criteria were articles that did not use the International Index of Erectile Function-Erectile Function Domain (IIEF-EF) or Erectile Hardness Score (EHS) as the outcome parameters, and studies published before 2010 (the first trial of LISWT in angiogenic ED was conducted in 2010 [2]). In addition, animal studies, case studies, reviews, studies on the treatment of nonvascular ED with LISWT and studies not found in English were excluded from the evaluation.
Information source and search
The electronic databases MEDLINE (through PubMed) and Scopus systematically searched the research articles from January 2010 to September 2018. The combination of MeSH terms and key terms (low intensity shock wave therapy or pulsed ultrasound or low intensity ultrasound or shock wave or shock wave) and (erectile dysfunction or ED or sexual dysfunction) are used. In addition, the identified articles were thoroughly reviewed to ensure that all relevant articles were included. Search the gray literature through the abstracts on Scopus and the clinical trials being conducted by Cochrane Library and ClinicalTrials.gov, and contact the author to obtain any available preliminary data.
Research choice
The retrieval was conducted independently by two evaluators (OB and LW) to identify potential related articles. The title and abstract were screened, and then the full-text articles were screened according to the inclusion criteria to be included in the qualitative analysis. Discuss the differences between the evaluators until 100% agreement is reached.
Data collection and data items
Data extraction is carried out independently by two evaluators (OB and LW). Extract specific data from all studies, such as the type of study, the number of subjects, the demographics of subjects and the treatment plan of LISWT. The main outcome indicators of clinical efficacy include erectile function indicators more than 6 months after LESWT, such as IIEF-EF or EHS score. This includes the score improvement of the original questionnaire, the percentage improvement and the success rate defined by the score improvement study. In addition, the effectiveness of LISWT was analyzed by evaluating the population cohort (including age, PDE5i reactivity, presence of vascular complications and smoking status).
Risk of bias between individual studies and cross-studies
Cochrane bias risk tool was used to evaluate the internal validity of each individual article, and further qualitative analysis was made on randomized controlled trials and non-randomized studies [11]. Non-randomized research is conducted by the author to evaluate the method qualitatively according to the definition in online resource 1. Evaluate the bias of the research through the GRADE tool, so as to provide our summarized suggestions for each individual outcome indicator [12].
result
Research choice
A total of 521 articles were identified through literature retrieval. Repeated deletion and preliminary screening excluded 434 articles. Of the 87 full-text articles evaluated as eligible, 11 were finally included in the review (Figure 1). Fig. 1 PRISMA flow chart for article selection
Synthesis of research features and results
Of the 11 articles, 5 were randomized controlled trials and 6 were non-randomized (Table 1). Three randomized controlled trials were placebo-controlled; Others compared two different treatment groups. The total number of patients surveyed in all studies was 799. Summary of the Long-term Efficacy of Cesium Dilute Preparation in Table 1 Nine of the eleven studies [2, 13, 14, 15, 16, 17, 18, 19, 20] found that the erectile function with IIEF or EHS score increased statistically after LISWT (the IIEF-EF score improved by 5.3 from the baseline at 5.3 months after 6 months). None of these studies showed a decrease in erectile function after intervention below baseline (Figure 2). However, the results of two randomized controlled studies, Fojecki et al. and Olsen et al., did not reach the significance threshold of follow-up for more than 6 months set by the author [21, 22]. In one study, the effect of LISWT was followed up for 24 months, in four studies for 12 months and in the remaining six studies for 6 months. When evaluating studies that have been followed up for more than 6 months, there seems to be a limited improvement in IIEF scores beyond this time period (IIEF-EF scores vary between 2 and 0.1). No study showed that there was a continuous improvement at 12 months compared with 6 months, and two studies showed that the IIEF score was stable [15, 18]. Three studies show that after more than six months,The effectiveness of LISWT gradually weakened; However, in all cases, the scores remained above the baseline erectile function [13,16,21]. The largest of these studies shows that the gradual decline was conducted by Kitrey et al. The prospective single-arm trial of 156 patients showed that the initial remission rate was 63.5% at 1 month, decreased to 42.9% at 12 months, and decreased to only 34% at 2-year follow-up. Figure 2 Long-term efficacy of LISWT based on IIEF-EF score at baseline, 3 months, 6 months and 12 months.
Influence of LISWT on specific population cohort
Subgroup analysis shows that the research results are contradictory. Although most studies have no motivation to draw conclusions according to specific subgroups, the trend of results has emerged. Age, PDE5i reactivity, presence of vascular complications and smoking status are all considered to affect the therapeutic effect of LISWT.
In two of the three studies to assess age, it was found that the effectiveness of LISWT decreased with the increase of age [14, 17]. These studies found that compared with younger and healthier patients, young age is a statistically significant predictor of improving treatment responsiveness and increasing age (> 65 years old), and vascular complications shorten the duration of LISWT effect. However, in contrast, the research conducted by Bechara et al. has no statistically significant difference in age, duration of ED or complications when comparing the responders with the non-responders [18].
The severity of ED seems to have an opposite effect on the curative effect. Although the research conducted by Bechara et al. found that patients with severe ED had a better response to LISWT, and the IIEF-EF point increased the most, Kitrey and his colleagues found that the duration of the treatment effect of patients with severe ED was shortened during the 24-month follow-up [13, 18]. In addition, when considering the duration of ED symptoms, Reisman et al. found that with the increase of the duration of symptoms, the reactivity of LISWT had a negative impact, and found that the average duration of ED of LISWT non-responders was 3.5 years longer than that of responders [20]. In one study, PDE5i response was considered to be very important, in which PDE5i respondents were statistically more likely to benefit from LISWT, and the curative effect lasted longer in this cohort [14].
Two studies evaluated the effect of vascular risk factors on the effectiveness of LISWT. Reisman et al. compared patients with at least one vascular complication (cardiovascular disease, hypertension, high cholesterol) with patients without vascular complications, and found that the success rate of patients with vascular complications was low (76.2% and 93.7% respectively) [20]. A study shows that smoking status will have a negative impact on the success of LISWT, and patients with a smoking index less than 20 have a statistically significant chance of improving erectile function (91%vs 50%)[19]. In the end, the existence of ""shows mixed results. A study showed that the success rate of diabetic patients was reduced by 25%, and the duration of treatment effect was shorter [20], but Pelayo-Nieto and others found that the clinical response of diabetic patients to LISWT was improved (62%vs 47%)[19].
Article quality evaluation
The number of studies evaluating long-term follow-up after LISWT is still limited, and there are mainly non-randomized trials. The bias risk assessment of randomized trials (online resource 2) shows that the biggest concern is the selection bias introduced by the loss of research participants. Although the dropout rate is expected to be higher due to the long follow-up of the selected articles, in some studies such as Srini and Fojecki, the dropout rate is unusually high (more than 20%), and these studies are considered to have higher weight for placebo or 5-week treatment group [16,21]. This may bias the results towards those who receive treatment, thus producing false positive results. In addition, five randomized trials showed that the total number of subjects was small, all of which were single-center trials. Finally, people are worried about the false or double-blind nature of the trial. It is difficult to ensure true blindness in these cases. Many experiments have found that sham treatment is not beneficial at all, which is unexpected because some placebo effect is expected. The use of PDE5i before and during treatment is currently variable. Although most studies include a 4-week "flushing period" and PDE5i is not used, this is inconsistent in all studies, and there are additional changes around the ongoing use and restart time of PDE5i. Four studies allowed subjects to resume using PDE5i[2 one month after LISWT [2, 17, 20, 21], and one study allowed subjects to continue treatment throughout the treatment period [18]. This is very important, because it will produce impurities, which can explain the difference of long-term curative effect after LISWT. Finally,The great difference of administration schemes was determined. Individual studies vary greatly in terms of the shock wave of each treatment, the time between meetings and even the site of administration, as shown in Table 1. In view of the effect of long-term erectile function after LISWT, this limits the external effectiveness of the study.
comment
This system systematically evaluated the long-term effects of LISWT for more than 6 months on patients with angiogenic ED. Of the 11 papers identified, 9 showed a statistically significant improvement in erectile function during the 6-month follow-up. However, these studies show that erectile function has not improved continuously for more than 6 months. Three-fifths of the studies show that erectile function is gradually declining, and two of them show the platform of the results. However, it is important to note that IIEF-EF scores in all studies are still significantly higher than baseline functional scores, showing benefits even 12 months after treatment. This may be a potential vascular progression secondary to the disease, and LISWT has no effect on complications or progressive atherosclerotic diseases involving cavernous tissue [13]. The evaluation of the overall quality of the evidence of improvement of long erectile function through the GRADE scheme shows that the suggestions currently used are still very low (online resource 3). This is because there are mainly non-random evidence bases at present, and these trials present small number of patients, single institution and methodological problems about double-blind sham trials.
Sub-component analysis to evaluate the effectiveness of LISWT in individual patient cohort produced different results. Two studies show that young patients may be more likely to benefit from the long-term benefits of erectile function. It is speculated that this is secondary to structural cavernous injury and superstructure injury. The greater the activity of VEGF receptor, the greater the biological response produced by treatment [14, 17]. This leads some people to think that LISWT may play a role in early intervention and even preventive treatment of high-risk patients, thus preventing irreversible vascular changes [14, 23]. However, there is no objective evidence in this regard. Similarly, patients with severe ED are expected to see a decrease in the therapeutic effect secondary to an increase in superstructure injury. Although the previous short-term follow-up results support this point [24], our review has identified contradictory evidence in the long term, and there is no clear relationship between the severity or duration of ED and clinical efficacy.
There is limited evidence to evaluate the risk factors of cardiovascular complications and long-term treatment effect. There is comparative evidence to evaluate diabetic patients, and of course further review is needed. In addition, although smoking and other cardiovascular risk factors seem to have a negative impact on the therapeutic effect, these results are limited to a long-term study [20]. Similarly, although PDE5i responders and naive patients have been previously identified as positive predictors of treatment success in short-term studies [24], long-term studies have not been able to determine this. Only one study shows that the curative effect has improved; However, this is not statistically significant. Therefore, there is no specific evidence that any subgroup is identified as a predictor of long-term successful treatment.
As far as we know, this is the first review dedicated to evaluating the long-term efficacy of LISWT in the treatment of vascular ED. It provides important evidence that the improvement of erectile function seems to have a lasting effect at 6 months for patients who may get worse or worse 12 months after treatment. This is very important in clinic, which provides urologists with treatment evidence, but also provides evidence for frankly discussing the expectation of erectile function after 6 months of treatment. However, as mentioned above, due to different research methods, this review emphasizes further research areas for researchers to increase the evidence base around the use of LISWT.
Although there are clinical data at present, there are some problems with the established test methods, which need to be standardized in future research. Obviously, it is necessary to carry out larger-scale research in multi-institutions and multi-countries to improve the external validity of the results. In addition, the use of PDE5is before and after treatment in the literature has changed greatly. Although the irrigation period and limited use of PDE5i may improve the obtained results, it can be considered that future research should focus on more realistic applicability by maintaining the drug treatment of LISWT at the same time. In addition, future research must standardize the management of LISWT, especially in the equipment used, the treatment delivery of treatment, the course of treatment and duration, and the place of administration. The current positioning is very different in certain studies. As far as the outcome indicators are concerned, it is necessary to carry out more objective parameters through hemodynamic research and subjective indicators such as IIEF-EF and EHS score, which may be seriously affected by other factors (such as sexual partners, lifestyle, life events, psychology and complications) [13]. Finally, the evaluation determined that a longer follow-up of 12 months or more was needed to evaluate the lasting life of the treatment effect.
Like any systematic evaluation, this evaluation has its limitations. These are mainly from the existing data sets, but the number of available trials is limited, and only a few randomized studies are determined to evaluate the long-term outcome. In addition, as mentioned above, there are still some methodological problems and changes. This is especially true when considering therapeutic administration and simultaneous treatment, which means that the universality of the results must be considered, so it is impossible to make standardized suggestions. When this difference in methodology is combined with the random experiment that lacks standardized outcome indicators (such as IIEF-EF) and the huge heterogeneity of the results when trying to randomize the statistical summary of the research, it means that it is not feasible to make any meaningful statistical evaluation of the data through meta-analysis. Finally, it is always possible to miss the study, which may affect the current recommendation; However, through a comprehensive retrieval strategy and searching for gray and current literature, this risk is minimized.
conclusion
This systematic evaluation confirmed that LISWT provided a treatment to improve erectile function, and the result lasted for more than 6 months. At 12 months, the sustained benefits beyond this range seem to have some limitations, and the functional outcome either tends to be stable or even reduced. In the long-term follow-up study, the increase of age seems to reduce the response to LISWT treatment. In addition, the severity of ED, PDE5i reactivity and complications may also affect its effectiveness. However, the current results are inconsistent. Although LISWT may be a safe and acceptable long-term treatment for ED, it is obvious that further investigation is needed through larger and more standardized trials to improve its evidence base.