Helen Bernie: Thank you so much for the invitation to talk about our paper. I'm super excited to be here today. So these are my disclosures, none are relevant to this discussion. And so a little background, platelet-rich therapies, including platelet-rich plasma and platelet-rich fibrin matrix or PRFM, they're regenerative therapies that involve the centrifugation of a patient's blood, followed by the extraction of isolated plasma containing elevated concentrations of platelets and growth factors like VEGF. And the thought is that they're hypothesized to restore erectile function by stimulating neoangiogenesis and stem cell recruitment. So these PRTs are widely marketed. You see them at men's health clinics, you see them all over as these regenerative therapies for men with ED that's refractory to PDE5 inhibitors. And they're being offered to patients with total sessions coming up, costing three to $5,000. Now, despite global clinical adoption and the promising preclinical results, the FDA classifies these treatments as unapproved and off-label.
And given the lack of robust evidence in the literature, current guidelines from all the AUA, the Sexual Medicine Society of North America, and the European Association of Urology recommend against the use of PRP outside of experimental or IRB-approved settings. So to address this gap in evidence, we actually conducted a systematic review and a meta-analysis to evaluate the efficacy and safety of platelet-rich therapies versus placebo in men with ED. Now, following PRISMA guidance, we systematically searched PubMed, Embase, Cochrane Library in April of 2023 for randomized controlled trials, comparing PRT with placebo in men that were over 18-years-old and that had organic ED. Now, the outcomes of interest were the mean change in the erectile function domain of the International Index of Erectile Function, or what you commonly hear is the IIEF score, and the rate of men achieving specifically the minimum clinically important difference or the MCID in the IIEF erectile function domain score. We looked at peak systolic velocity showing blood flow in the penis, in diastolic velocity, how well the veins clamped down, as well as visual analog scale of pain scores after injections. Now, after screening, seven randomized controlled trials were included that comprised about 480 patients, of whom almost 50% were randomized to PRTs.
Now, the median age was from 46 to 59 years and four studies used PRP injections while the other three used the PRFM. Now, PRT injections varied from anywhere from five to 10 milliliter injections and anywhere from two to eight sessions with duration lasting seven days to one month intervals between different studies. So you see a high variation here. Now, there was no significant difference when we look at the results between PRTs and placebo and the IIEF score at one month, three month, and at six months follow-up. In fact, there was no significant differences between PRTs and placebo and the rate of men achieving the minimal clinically important difference in the IIEF erectile function score at one and three months of follow-up. There was also no significant differences between platelet-rich therapies and placebo in peak systolic velocity, in diastolic velocity, and in the visual analog scale of pain scores after the injections. Sensitivity analyses excluded studies that permitted concomitant PDE5 inhibitor use, such as those and several others, and they demonstrated no significant differences between groups in the IIEF score at all follow-ups.
Additionally, when we did formulation-specific subgroup analyses where we looked comparing PRP versus PRFM, again, it demonstrated no significant difference between groups and the rate of men achieving improvement and the IIEF erectile function score at three months, either in that subgroup using PRP or if you were using PRFM. And there was no significant interaction between subgroups and the test for subgroup differences, indicating that there was no statistical difference between PRP and PRFM. Now, subgroup analyses, if we stratified by the improvement criteria used in the included studies, revealed significant differences here in the proportion of patients that actually achieved an IIEF erectile function score improvement when defined as any improvement versus the MCID criteria across all follow-up periods. And this finding really reinforces the distinction between these concepts and underscores the importance of using the minimal clinically important difference rather than just stating any improvement to evaluate changes in erectile function. Now, when we applied the GRADE tool, the overall certainty of evidence for PRT and ED treatment is considered low to moderate, and this is primarily due to the lack of standardization and the PRT preparation and administration protocols, inconsistent outcome measurements, the small pool of studies, and the resulting wide confidence intervals.
So consequently, current clinical recommendations for PRT and ED are inherently weak, highlighting the need for larger, higher-quality trials. So to conclude, while early prelim data are encouraging, our meta-analysis of almost 480 patients across seven randomized controlled trials found that platelet-rich therapies failed to demonstrate clinical superiority over placebo for improving sexual function in men with ED, and consequently, it still remains investigational and should not be offered in clinical practice outside of IRB-approved protocols. And we certainly need to acknowledge there's limitations in the current literature, right? We have the small sample sizes of existing randomized controlled trials, which could hinder the statistical power to detect differences, but furthermore, what we see widely across is that there's a lack of standardization in PRT production and the protocols with huge variations in the centrifugation, platelet concentration, dosing intervals alongside very inconsistent outcome measures that are either non-objective or they limit our ability to make comparisons and draw definitive clinical conclusions. So I think crucially, we really need to remember that a nominal increase in the IIEF erectile function score, while we see a small improvement, doesn't necessarily translate into meaningful clinical improvement.
So again, when we're doing these studies, and for anyone out there that's looking to do studies on this, which I encourage if you're using PRP, is to prioritize using the MCID to define a true therapeutic success for our patients, so that moving forward, large-scale long-term studies with standardized protocols and patient stratification are needed to really clarify the true clinical utility, if any, of PRTs in the management of ED. So thank you very much. I want to highlight our research fellow, Dr. Lucas Amorim, who will be applying for urology next year, and my old fellow, Dr. Thairo Pereira, who's now an assistant professor at the University of Rochester who also helped with this paper.
Alan Wein: Terrific and succinct summary. So these are three to $5,000, presumably out of pocket, and some of the treatment regimens are like 10 treatments.
Helen Bernie: Yeah, up to.
Alan Wein: That's a lot of out-of-pocket expense.
Helen Bernie: And for something that's not guaranteed to give you any benefit.
Alan Wein: So how was the minimal clinically important difference arrived at, let's say, for erectile dysfunction?
Helen Bernie: So it was based on data that was put together, Dr. John Mulhall, Landon Trost, and actually the SMSNA put out a really nice paper showing about the minimally clinically important difference. And for the IIEF erectile function domain score, for mild-to-moderate ED, that MCID is a two-point difference. If you have moderate ED, that's going to be five points. And if you have severe ED to actually see a significant improvement in erectile function, that MCID needs to be seven points. So when someone just says, "Oh, I had improvement," or they go up one or two points when they had severe ED at baseline that was non-responsive to PDE5 inhibitors, this is why we see this huge variation in studies. And while great, his IIEF went up from 14 to 16, is that actually making a difference in their functional outcomes clinically? So again.
Alan Wein: So are there any promising therapies between, let's say, intracavernosal injections and a prosthesis like shockwave therapy, radiofrequency? I mean, is there anything on the horizon that seems to be more positive, let's say, than this in terms of consistent clinical trials that say, "Wow, this really does work, and maybe I should go to somebody who does this?"
Helen Bernie: So these are great questions. And so I think in this scenario, it's important to kind of take a step back and think, let's frame where does maybe shockwave fit in? Because I think the best data we have is probably behind shockwave therapy. The thought is that low-intensity shockwave therapy, it's a restorative treatment, and it delivers these low-energy acoustic waves to the penile tissue. With the goal of creating basically a microtrauma, right? You want to create an injury that's going to thought to either upregulate angiogenic signaling, things like VEGF, improve penile blood flow. There's also some thought that maybe it'll recruit stem cells, which is why it's been a little caution in using it in patients that maybe had a history of prostate cancer for the post-penile rehab patient.
Alan Wein: Right.
Helen Bernie: But from a delivery standpoint, right, it's also non-invasive. It's performed in the office. You use this external probe, it goes along the shaft and the crura, and you have these series of sessions that you come in for. Now, in terms of data, this is probably where things get a little more nuanced because there are randomized and there's sham-controlled trials, and there's also some meta-analyses that suggest improvement in erectile function scores, particularly in your vasculogenic ED patients. Now, the limitations are important though. First, there's always a placebo effect. We know from the Viagra trials that there's about a 30% placebo effect. So 30% of patients off the bat are going to think they're getting better and we see that limitation, but there's a lot of heterogeneity in the devices. There are different devices. Like you mentioned, radial frequency, there's GaN light, there's different types, there's different energy settings, there's different treatment protocols.
Do you come in once a week, twice a week? Is it for 15 minutes? Is it 20 minutes? And there's also a lot of variability in patient selection and baseline severity. Are these guys with mild ED, severe ED? And then most of the time when we look at these studies, there's really short-term follow-up. So I think the longest one goes up to maybe three years, but most of these studies are not even past a year to know whether there's durability. Or if there isn't, do you need to get shockwave done again annually or is it something that you can wait a couple years? And not all trials are consistently positive. When you look closely at the sham-controlled data, you see a signal, but it's not really clean or standardized that we'd want for broad adoption. So if you think about in terms of who may benefit most, I think the data that has been out there that looks promising, that's the best controlled we have would show that it's likely men with mild-to-moderate vasculogenic ED. So these are going to be the guys that are either PDE5 inhibitor responders now, like they're responding to Cialis or Viagra and they want to be able to get an erection without having to take pills again, or it's the guys that are partial responders. "I take it, but now I don't last this long." Or "It doesn't get me as rigid."
There's less convincing evidence when you look at guys with severe ED, your post-prostatectomy patients or those with significant neurogenic or think like your 15-year diabetic patient with poorly-controlled diabetes, or smoker. But I think in the future we are going to start seeing some role for shockwave therapy, but the biggest problem is that we don't have standardization. Again, there's no standard devices, there's no standard energy protocols, there's no standard patient selection. And so I think for anyone out there that is offering this, and again, it's also not endorsed outside of a clinical trial by the AUA or the SMSNA, but I think if you are offering it, this is where we need to find the right patient phenotypes. We need to figure out what's the optimal dosing and treatment schedules, right? What's the durability? And that requires standardization. We need to have objective data. We need to be looking at the MCID. So it's not just, I got better, but is it objectively better? And is the MCID meaningful, not just by the numbers?
So I think probably my overall take is shockwave is probably the most promising that we have of the restorative therapies right now, but it's still not at that level of evidence where we can consider it routine standard of care. I don't think anything is right now outside of PDE5 inhibitors, vacuum erection device, penile injections, and then the gold standard of penile implant. But I certainly think it's going that way. We just need some better data.
Alan Wein: Is there any effort on the part of any societies like the Sexual Medicine Society of North America to conduct a large clinical trial that includes a lot of people like yourself on, let's say the plasma therapy or really any kind of therapy that people regard as, well, yeah, maybe it does, maybe it doesn't?
Helen Bernie: It's a great question. I think the biggest hindrance has been finances. I think to finance a large clinical trial like that and-
Alan Wein: Right.
Helen Bernie: You're doing it in a place where there's already approval of the ultrasound machine. People are already making a lot of money in these clinics, and I think there may be some trepidation of looking at that data or having the clinics-
Alan Wein: And just how entailed.
Helen Bernie: That are actually running it.
Alan Wein: Yeah.
Helen Bernie: Right. What if it doesn't show an improvement and then now all of a sudden they're not going to have that same income coming in towards the device and things.
Alan Wein: Terrific. Well, listen, thank you so much because that was very interesting about a topic that I don't think too many people know about, but to hear your view and the results of your study, very refreshing, very common sense, and thank you for the other comments about the other types of therapies. Look forward to running into you in the future. Thanks so much.
Helen Bernie: Thanks so much for having me.