Trinity Bivalacqua, MD, PhD, discusses the available evidence for the use of restorative therapies for erectile dysfunction.
Trinity Bivalacqua, MD, PhD
Restorative therapies are an exciting area of potential treatments for patients with erectile dysfunction (ED); however, there is a paucity of clinical data regarding their efficacy and safety, according to Trinity Bivalacqua, MD, PhD.1
The goal of restorative therapies in ED is to reestablish whole-organ function and reverse penile dysfunction using regenerative medicine technology, Bivalacqua explained in a presentation during the 2020 AUA Virtual Experience. The restorative therapies for ED include platelet rich plasma (PRP), stromal vascular fraction (SVF), amniotic fluid (AF), and stem cells (mesenchymal cells, adipose derived stem cells, amniotic stem cells, and cord blood stem cells).
Restorative therapies are “particularly relevant for patients who have had radical prostatectomies and have post-prostectomy ED, as well as for patients with severe ED as it relates to peripheral vascular disease and diabetes,” said Bivalacqua, director of Urologic Oncology at Johns Hopkins Univsersity.
Although the potential of restorative therapy to treat ED itself, and not just its symptoms, has created a lot of buzz in the urology community, Bivalacqua said the lack of data in the literature backing the efficacy and safety of the technology means it should currently be reserved for clinical trials. Accordingly, this is the current position of the Sexual Medicine Society of North America (SMSNA), which sponsored Bivalacqua’s discussion:
“Given the lack of regulatory agency approval for any restorative (regenerative) therapies for the treatment of ED and until such time as approval is granted, SMSNA believes that the use of shock waves or stem cells or platelet rich plasma is experimental and should be conducted under research protocols (clinical trials) in compliance with Institutional Review Board approval.”
In his discussion during the AUA online platform, Bivalacqua discussed the limited available evidence in the literature for each ED-focused restorative therapy and the next steps for this technology.
PRP is the most common restorative therapy used for ED. This treatment can be applied through intracavernous injection. Although he did not make a recommendation for its use outside of clinical trials, Bivalacqua said PRP “Falls under the HCT/P 361 exemption proposed by the FDA. This means in clinical practice you can use…PRP…without gaining FDA approval. As long as the tissue/biospecimen is not manipulated once it’s removed from the patient, it is then exempt from FDA approval and clinical trials.”
With PRP, a clinician can use a normal centrifuge to isolate the PRP, which can then be injected. It does not have a specific CPT billing code, but can be categorized under a nonspecific code for blood transfusion and reinfection. For the most part, it is not covered by insurance or Medicare, with the post common payment form being cash, said Bivalacqua. Regarding clinical evidence, there have been no randomized clinical trials of PRP.
Bivalacqua said there is 1 peer-reviewed trial2 of PRP in the literature, but it only had safety results. The study assessed PRP in 17 patients with various urological diseases, including 4 patients with ED. The results showed that PRP injections were safe overall, with some mild bruising, but no serious adverse events.
Autologous SVF involves the removal of adipose tissues, often through liposuction. The removed tissues are then separated into individual components, with the key components, such as adipose-derived stem cells (ADSCs) and endothelial precursor cells (EPCs), being reinjected into the patient. ADSCs and EPCs “release beneficial cytokines and growth hormones, which promote tissue survival, angiogenesis, and further stem cell recruitment,” said Bivalacqua.
Since SVF involves the patient specimens being manipulated, unlike with PRP, this procedure does not fall under the FDA HCT/P 361 exemption and no SVF devices are currently FDA approved. There is also no clinical trial data in the literature supporting the efficacy of SVF.
Some trials have been published showing promise for low-intensity shockwave therapy as a treatment for patients with ED. One study3 looked at the long-term efficacy of low-intensity shockwave therapy using an electrohydraulic device in 156 patients who initially had a successful outcome according to the minimal clinically important difference on the International Index of Erectile Function-Erectile Function (IIEF-EF). Patients were assessed per the IIEF-EF at 6, 12, 18, and 24 months.
Although the treatment was successful in 63.5% (n = 99) of patients at 1 month after treatment, efficacy gradually decreased over time. Among the 99 patients who initially responded, only 53 (53.5%) were still experiencing a beneficial treatment effect at 2 years’ follow-up.
“They found that there was very little durability of the shock-wave therapy in patients with severe ED. Whatever effect was seen was then mitigated at 24 months,” said Bivalacqua. “Those patients with non-severe ED—those who would typically respond to PDE-5 inhibitors—had a more efficacious response.”
Another study4 of low-intensity shockwave therapy used an electromagnetic device to treat patients with ED. There were 87 evaluable patients who were randomized to receive 1 of 2 shockwave regimens: Group A (n= 45) received 3600 shocks (720/day) over 5 days and Group B (n = 42) received 3600 shocks over 2 weeks (600 over 3 days each week). The was a statistically significant improvement in IIEF-EF score for both groups, with a mean increase of 2.7 in both group A and group B (P <.05). There was also a statistically significant improvement in Erectile Hardness Scale score in both arms at 0.6 points in group A and 0.5 points in group B.
Although the improvements were statistically significant, the benefits were minor, leaving Bivalacqua to ask, “The question is, ‘Is this clinically significant?’ My perspective on this is that this did not include a sham group and the improvement was in patients who were typically PDE-5–inhibitorresponders. But I do think we have to acknowledge that using the electromagnetic probe, which causes a lower peak energy, may be safer for patients.”
While it is an exciting field, Bivalacqua noted that there is an “ugly side” to restorative therapies for ED”
“The global use of PRP, especially in North America, is very high, despite the lack of any clinical evidence that it is effective or safe,” said Bivalacqua, adding, “Some practitioners are ‘cashing in’ on the hype of shockwave therapy even though the treatments are not FDA approved.”
To combat these issues, Bivalacqua said several questions need to be answered in the literature. The next steps with restorative therapies are “determining optimal dosing regimens; assessing the total power and number of shocks with shockwave devices; determining the optimal device choice—electromagnetic versus electrohydraulic; and evaluating the duration of studies and role of maintenance therapy. But more importantly, we need to have a sham in randomized controlled trials.”
Bivalacqua also provided several suggestions on how the efficacy of the available restorative therapies could be improved.
“The future is combination therapy, where we include low-intensity shockwave therapy with the injection of either SVF or stem cells. And we have to include a maintenance phase. Other protein- and gene-based therapies, such as SDF-1, which hone stem cells, are obviously an important next step. And neurotrophic factors placed at the time of radical prostatectomy are the only way that we are going to be able to regenerate nerves post prostatectomy.”
1. Bivalacqua T. State-of-the-Art Lecture: Update on Clinical Trials on Restorative Therapies for Erectile Dysfunction. Presented during 2020 AUA Virtual Experience. June 27-28, 2020.
2. Matz EL, Pearlman AM, Terlecki RP, et al. Safety and feasibility of platelet rich fibrin matrix injections for treatment of common urologic conditions. Investig Clin Urol. 2018;59(1):61-65. doi: 10.4111/icu.2018.59.1.61
3. Kitrey ND, Vardi Y, Appel B, et al. Low intensity shock wave treatment for erectile dysfunction-how long does the effect last? J Urol 2018;200(1):167-170. doi: 10.1016/j.juro.2018.02.070
4. Patel P, Katz J, Lokeshwar SD, et al. Phase II randomized, clinical trial evaluating 2 schedules of low-intensity shockwave therapy for the treatment of erectile dysfunction. Sex Med. 2020 Jun; 8(2): 214–222. doi: 10.1016/j.esxm.2020.01.010