Scott MacDiarmid, MD, FRCPSC

When we think about the OAB [overactive bladder] pathway, I often will say that the barrier to third-line therapies is getting people to move beyond medication, whether it’s apathy, their interest, etc. But the more third-line therapies you have, the more benign and fun and noninvasive, you’re going to attract more people to move beyond medication more often. For instance, 2 of my partners would say when it comes to a couple of the third lines, “Why don’t you just do it?” They can’t wait to be trained. The more we have these kinds of therapies, we have to get more people, other than just folks like you and I who love incontinence, to treat them. It’s 1 step forward. One of my talks is called “Neuromodulation for the Masses,” and this will help get us closer. It’s an imperfect treatment. They all are, but I’m hoping it increases the utilization of all of them and that all the boats will rise at the same time, because we need to help these folks because the drugs aren’t doing it.

 Seventy-five percent [of OAB cases] aren’t managed. We also need to adapt to the heightened level of customer service that is expected, where it’s not just about the efficacy for patients. They want low risk, high return, and they want it to be easy on them, so we need more therapies like that.

Scott, there are more therapies coming out. Do you have any updates about other changes to the overactive bladder menu coming down the pipes?

We need more. There are a lot of tibial nerve stimulators in development, and that’s wonderful, because whether they come out with rechargeable batteries or leads that work well, we need more tools. I have my bias in terms of safety and things in terms of being above the fascia. Long battery lives are important. That’s a general statement that probably most would agree with. In terms of some other treatments I’m involved with, I’ve published on the saphenous nerve, which I hope that we can show with a study that’s going to start soon. I won’t dive into any details. It’s stimulation of the saphenous nerve for overactive bladder, transcutaneously or superficially. If that works out, it’s going to help a lot of patients with home therapy and hopefully drive a lot of the third lines that we’ve talked about today.

 That’s exciting, considering we have patients driving hours to come see us. Or there are some patients who aren’t going to want any incision or implant. Transcutaneous treatments like that would be a tremendous addition, and high up in that pathway.

To our viewing audience, we hope you found this 

 discussion to be comprehensive for your needs, and more importantly, helpful for your patients with OAB. Lastly, I want to dedicate this piece to Andrew Shapiro, [MD,] a fellow eCoin investigator taken from us too soon, but we charge ahead for needed change in your memory.

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Drs MacDiarmid and Rogers discuss barriers to OAB treatments and therapies on the horizon.

Future of Overactive Bladder Treatment

Let me comment on the redos [reimplantations], because that was one of the things you wanted to ask me. With Judy, my research nurse who is doing all of these with me, it was almost the same. You prep the patient the same, you do the same markings, you put in the same local anesthetic, and you open up the same incision. There’s a bit of a scar between the incision, and the eCoin is purposely below it. Because if you’ve ever had a wound infection, which I did once, it’s still 1 cm-plus away from the top of the eCoin, so you can clear up the wound infection and not get the eCoin. I had that exact patient with a positive culture of staph.

But with that little area, there’s an easy technique to spread that and open that up, and the pseudocapsule is very easy to find. You make a little scalpel blade, you open it up, use your scissors to open up a pseudocapsule like you’re used to, for instance with sacral nerve stimulation, and you slip it out, put in a new one, and say, “We’re closing it again.” There are a few tricks, but overall, the replacement is easy and equally safe. It’s a little more challenging, but it’s easy to do and safe. We’ve got 1-year data. We did the feasibility study. We finished that, it was 1-year follow up, then we [removed the devices from those patients]. We had a large cohort of 23 patients who had one reimplanted and were followed again for a year, and the data basically look the same. In fact, it looked a little better, but it might have been on patient selection on responders. But they did very well when you replace it.

 And all of those were done in the office, which speaks to the fact that it’s achievable to do these exchanges.

 You’re not changing the stimulation amount of scar or impedance that’s occurring because you’re not messing with that bottom stimulation area. And certainly, people who are going to choose to have another eCoin responded the first go-round because the responder rate is 82% at 6 months, and a 36% dry rate.

My last question on reimplants is, when we did the pivotal study, we were very mindful of lateral shifting before encapsulation off the nerve. I’m excited that with the reimplants, you shouldn’t have to worry about lateral shifting off the nerve because you’re putting it into that existing pocket.

Yes, that won’t be going anywhere. You’re right, it’s in the capsule. It’s like a little glove.

OAB experts share their experience with reimplantation of a tibial nerve stimulation device (eCoin).

Reimplantation of Tibial Nerve Stimulation Device (eCoin)

 Scott, we can both agree that it was meaningful to be part of the eCoin trial. Could you review some of those pivotal results?

As you know, eCoin had a feasibility study—we’ll come back to that in a few moments—and it had very favorable results. There’s a pivotal trial that has been wrapped up, and the product is now hoping to get FDA approval soon. It was a study that evaluated the efficacy and safety of the eCoin device for the treatment of refractory overactive bladder. The primary end point was at 48 weeks of stimulation, or 52 weeks after implantation. It was 132 patients who were finally evaluated. Just by chance, about 98% were women. They had refractory overactive bladder and had to fail at least 1 medication. They could have failed either botulinum toxin or PTNS [percutaneous tibial nerve stimulation] as well.

We decided when we helped with the study design that if they had failed the sacral neurostimulator, they weren’t in the study. The average age was 64. There were mainly women, but some men with refractory overactive bladder. They were leaking 4.3 times a day at baseline. That’s moderately severe; that’s a fairly leaky group. It was an office-based procedure, we can go through that in a bit. We used a template. You had a choice, but I think everybody did it under local [anesthesia] in their office. Basically, the device, it takes about 20 minutes to put in. It doesn’t take much longer than that. We were overfastidious and overcareful in terms of wound care because this was a new treatment. We were using a shower bag and dressings, etc, early on. It was kept dry for 2 weeks. There were good wound checks at 1 to 2 weeks. They used a compression sock for a month, and had limited biking and heavy activity for 2 months.

We looked at the efficacy at 1 month, 2 months, and 3 months, right up to the usual 6, 7, or 8 times over the total of 48 weeks post-stimulation. We used typical things, like bladder diaries and quality of life. The primary end point—this is important—was the percentage of patients at 48 weeks who had a reduction in urge incontinence greater than or equal to 50%. The FDA likes that as a primary end point. I like it. It’s a responder analysis, because we know that the patient population is happy when they’ve achieved that degree of continence control or improvement in their incontinence. Then we use OAB-q [Overactive Bladder Questionnaire], we use the Patient Global Impression of Improvement, and a Likert scale in how satisfied you were. Then there were some general questions comparing this to other treatments you’ve had.

It was a well-designed study. There were 15 centers, and it was open-label. We looked at trying to do a sham. It’s very difficult to do a sham. One of the reasons why a 1-year end point was agreed upon by the FDA is because that can help eliminate some placebo effect if you follow someone for a full year. It also gives you great safety information.

 Those are all good points. I want to make it clear that there’s no screening that excluded implant of a patient. That’s important to note. We also did a 48-week survey asking patients, responders and nonresponders, their experience with the therapy. I found this very encouraging, because a lot of times in medicine, it’s subjective feedback that ends up counting more than the objective. That’s obviously very important, but sometimes subjective feedback is what pushes therapies that you deliver to patients, and 89% would recommend it to friends and family members. Ninety-seven percent felt the procedure was well explained, which is incredible, because we’re used to talk tracks with sacral [stimulation], and we didn’t know what we were doing—or at least I didn’t. I just said, “We’re going to take this nickel thing, we’re going to put in your leg, and we’re going to turn it on.”

The feasibility data look good, and patients signed up for that with pretty limited counseling overall. When patients were asked, “Would you prefer another therapy over eCoin?” only 4% or less would choose one of the legacy therapies or medications, or one of our existing third-line therapies. That shows that subjectively, patients did way better than the objective data, and I always find that encouraging because patient experience is becoming more of a hot topic in medicine.

You mentioned the feasibility study data. It did mirror the results as far as the efficacy and safety data with the pivotal study. Sixty-eight percent of patients at 48 weeks had a reduction greater than or equal to 50%. I like the following numbers: 43% of patients were 75% improved or greater. The dry rate, which means you’re dry in a 3-day diary, was 21%. If you think about, it’s almost 70% of patients who were 50% improved or greater, it was approximately 40% of patients who were 75% improved, and approximately 20% of patients were dry. If you’re leaking 4.3 times a day at baseline, those are good data.

If you look at the curves, the first time that efficacy was evaluated was after 4 weeks of stimulation, and they had a lot of the benefit by then. But by 8 weeks, you saw that’s where the plateau started, and then the efficacy data persisted. I forgot to mention that the tibial nerve was being stimulated for 30 minutes every 3 days for 18 weeks, and then it was every 4 days to the end of the study. There were very good urge incontinence data in terms of responders. The median reduction was approximately 70%. They went down to about 2.6 leaks a day after starting at 4.3. The quality-of-life scores had dramatic improvements that were very durable as well for the OAB-q and the other ones I’ve mentioned.

As far as tolerability and safety—that’s what we were concerned about—it was very well tolerated. There were a lot of mild and moderate adverse effects, like some swelling in the ankle, some discomfort, and maybe a little redness, and those settled down. As far as infections, there were 4 explantations [removals of the device]. Three were due to infection—a wound infection or an infection of the implant—and one was felt to be an atopic dermatitis. There was such a skin reaction, and even though things settled down and the device wasn’t infected, the device was removed. That was the call by the physician at the time. The infection rate was around 2.3%, which is what was expected. That’s what Valencia [Technologies] was hoping for. When you put an implant in, based upon other parts of the body and other implants, that was very acceptable.

 It’s definitely within the range of 2% to 6% explant rate for neuromodulation devices per the FDA. They’re in the ballpark for what the bar is.

Tell us a little about the feasibility trial that some of us were involved with, my friends from New Zealand, etc. What were their results?

 It was 46 patients, and it showed similar safety and efficacy results, where at 12 months there was a 65% responder rate and a 26% dry rate, which was very compelling. Seventy percent were better, or above, subjectively. The stimulation paradigm shifted slightly from the feasibility to the pivotal study, where in the feasibility, stimulation for the first 12 weeks was every other day for 30 minutes, and then it shifted to every 15 days for 30 minutes thereafter. The pivotal optimized the stim [stimulation] paradigm more; there’s still a lot of room there to grow and explore. The battery longevity was slightly lower. It wasn’t an average of 3 years, it was more like 1 to 2 years. So once again, an improvement going into the pivotal study.

But what really matters is these are New Zealand surgeons and 3 United States surgeons, and no one was high volume in sacral neuromodulation [SNM] going into it necessarily, and 100% were completely naive to what the procedure was. Only 3 were repeats going into the pivotal study. Scott, you presented the feasibility results at SUFU [Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction meeting] in 2018. I saw those data, and I’ve been wanting…implant for a very long time. People talked about it and kicked it around, and being someone who’s high volume in SNM and PTNS, I felt like that was such a sweet spot to meld those 2, pros and cons with each of them. That’s why I got involved, because what you presented was real. It was very compelling for something in its infancy.

How do you think eCoin addresses some of the perceived weaknesses of other third-line therapies?

These are all imperfectly good treatments, and if you look at the perceived or real weakness of each of the other 3, eCoin would address the retreatment rate and the need to come to the office by the patient with PTNS. There are some long-term third-party payer issues with PTNS. There’s a perception by physicians, perhaps an economic one, that you need nurses and infrastructure. If you think through those, it likely will address most, if not all, of those.

Botulinum toxin is another great treatment, but there’s a retreatment rate that some patients don’t like. There’s a fear of retention, even though it’s low. It’s something that they hear. I also hear people think it’s a toxin. Some people are concerned about botulinum toxin. After you speak to them, you can put any concerns on that to rest, but it does address those. With sacral nerve stimulation, whether it’s perceived by the patient, it’s more invasive. I like the fact that it has a test, but it is surgery and the patient perceives that, and they may or may not wish to have an operation. Like all these treatments, they’re imperfect in terms of sometimes the long-term durability of some of these treatments. But also, I’m not sure how much it is at a physician level, but certainly at a third-party level, there are cost concerns in particular with that treatment.

Drs Rogers and MacDiarmid discuss data from feasibility and pivotal studies with eCoin, a tibial nerve stimulation device, and how it compares to other third-line treatments.

Implantable Tibial Nerve Stimulation: eCoin

We both like the tibial nerve. We’ve been treating patients through that nerve for a number of years. The tibial nerve stimulators, the implants, are hopefully here to stay. They’re coming soon. Could you talk about them in general first? Then we’ll be more specific.

 It’s pretty exciting. There are a lot in development. These will be a nice addition to the OAB [overactive bladder] toolbox or menu. There are devices that lie above the fascia in the leg, and devices that go under the fascia in the leg where the tibial nerve lies. There are devices that have a lead either antegrade-placed or retrograde-placed vs devices that are leadless. That’s different from what we’re used to with sacral neuromodulation leads.

The stimulation fields differ. One option, eCoin, has a more forgiving dome-like stimulation from a center cathode to an outer rim anode vs stimulation fields that perhaps are optimized by being flush to the tibial nerve. There are devices that have a primary battery that’s internal, in the body, like our sacral devices, vs devices that have an external power source. There are devices that have automatic therapy with no patient involvement vs devices that have patient management of external devices for therapy. And there are devices that need to be exchanged when the internal primary battery runs out vs those that don’t require any procedural change-out.

I’ll get some phone calls or colleagues ask me, and I agree with you. The big one is above the fascia and below the fascia. You and I have been involved with the Valencia [Technologies] device, eCoin, in its studies, and I like that it has a primary battery. You put it in, leave it alone, and it stimulates the nerve. I had to be educated on the fact that the electrode is facing down, and it can be a little more forgiving. It has a nice wide field that projects toward the nerve, so you’re above the fascia. The nerve is right underneath the fascia, and it stimulates the nerve nicely within approximately 6 mm or less.

The leads, which are going to be just like an InterStim lead in a sense, are similar. They’ll be placed next to the nerve. They have to be pretty close. They stimulate 360 degrees in terms of the pulse. The eCoin device is unidirectional, so you can turn it up pretty well to stimulate that nerve almost like a laser beam, and it’s not going to hurt the skin around it because it’s only going 1 direction deep and not stimulating the skin that’s more superficial, or the subcutaneous tissue. It’s about the size of a nickel and pretty easy to put in. We’ll talk about that a little later.

 I can comment a little on the research I’ve done for BlueWind [Medical]. Full disclosure, I wasn’t part of their trials, but I’m always excited to see all of these data coming out. It’s battery-free, so there’s no battery in the body. It’s an electrical power receiver implant that has 2 bipolar electrodes. There’s an external control unit anklet that’s managed by the patient. It seems like the variation of it has changed slightly, where for the feasibility [study], it was placed above the fascia and sutured in the vicinity of where that neurovascular bundle would be. Stimulation occurred for 30 minutes anywhere from 3 to 6 times a week, where the patient would tailor their treatment. And now with the pivotal [trial] per an ICS [International Continence Society] presentation, the fascia is incised and the nerve is directly viewed, and then the 4 wings next to the bipolar electrodes are sutured into that incised fascia. It seems to be a roughly 5-cm skin excision and the foreign body is underneath.

They have completed enrollment. Hopefully, we’ll be getting that data to the FDA this summer, that’s what they published in 

. That’s exciting to have many people involved.

You’ve already mentioned the device, but what are some of the data and what’s going on with the BlueWind device?

 I’ve been following the data. They initially had a feasibility trial where the 6-month results were encouraging in 36 implanted subjects. They had a 71% responder rate for all OAB syndrome symptoms of urgency, urge incontinence, and frequency. And they had a roughly 52% responder rate for urge urinary incontinence at 6 months. Forty-seven percent of the subjects experienced adverse events. There was preoperative nerve conduction testing performed as a screen prior to implant looking at nerve integrity.

The implant took 35 minutes. It was performed under local or general anesthesia at the discretion of the implanter. Interoperative testing was done at the physician’s discretion. And then the stimulation paradigm was 3 to 6 times per week for 30 minutes using an exterior power anklet. They followed these data for 3 years looking at 20 subjects, where the OAB syndrome complex, the responder rate was 75%, and the responder rate for urge urinary incontinence was 58% at 3 years per protocol.

They just finished enrollment for their OASIS study that’s being performed both in the United States and abroad. Their primary end point is urge urinary incontinence after 6 months of therapy. The estimated completion is roughly this summer, with the FDA then reviewing those data. There was also an abstract for the ICS [annual meeting] 2021 that I really enjoyed viewing where they talked about the implant procedure on these patients with wet OAB. The 3-cm implant is secured to the tibial nerve bundle where the fascia is incised and then these wings to these 2 bipolar electrodes are sutured down. That’s a little different from the feasibility trial, where it was sutured above the fascia. Interrogation was performed, and it was roughly a 20- to 30-minute procedure. They did daily sessions for 30 to 60 minutes. It was powered by a wearable cuff managed by the patient.

That’s my summary of the data that are out there, but it would be great to bring people who have been part of that study into the next 

Experts discuss tibial nerve stimulation, an emerging treatment for OAB.

Scott MacDiarmid, MD, FRCPSC

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