PeVD: bridging gaps in pelvic vein insufficiencies for enhanced patient care and outcomes

Episode Transcript

Recorded live from the Cook booth at SIR and featuring leading experts in the field of interventional radiology discussing a wide range of IR-related topics, this is the Cook@ SIR podcast series.

Welcome to SIR 2024 in Salt Lake. We are live with the Cook Medical team and our podcast team to start talking about pelvic venous disorders. We’re going to be talking about bridging the gaps in pelvic venous insufficiencies for enhanced patient care and outcomes. I have two amazing guests that are joining us today. One will be familiar, and that’s Dr. Neil Khilnani. And then the other one we have remotely is Dr. Ron Winokur. I’m going to have each of you guys introduce yourselves, and then we’ll go from there. One of the things that I’m really excited—

Did you want to go first?

I’m going to actually really introduce is—there’s some exciting things that have happened since last year’s podcast talking about the enhancements in venous disorders, but also I’m incredibly pleased to start talking about the announcement that’s going to be made tomorrow about pelvic venous disease and the EMBOLISE trial that particularly is near and dear to Dr. Winokur. So let’s get Neil. I’d love to have you introduce yourself and say a few words from what’s happened from SIR.

Yeah, no, thanks, Ram. It’s great to be back at SIR. It’s the energy again. This year is even better than last year, so it’s nice to be back at in-person meetings. And again, thank you to Cook for giving us the opportunity to talk about pelvic venous disorders, which we do think is something important. So I’m Neil Khilnani, and I’m a professor of clinical radiology at Weill Cornell and NewYork-Presbyterian in New York City. My involvement in the pelvic venous disorder issue goes way back, but notably I was the lead IR on the research consensus panel that we put together with the SIR Foundation back in 2017, and I am running a study to develop a patient-reported outcome measure for pelvic venous disorder, specifically venous-origin chronic pelvic pain, funded by SIR Foundation, and then I am a co-PI on the EMBOLISE trial, which Dr. Winokur can talk about in just a second.

Dr. Winokur.

Thanks, Neil.

Yeah, please, tell us about yourself.

It’s exciting to be here and have this discussion as a group. Obviously this is an important topic, and I’ve been lucky enough to— for Neil and I, for Dr. Khilnani and I, to be together for pretty much my entire career, early years, but I am on faculty and a professor of clinical radiology at Weill Cornell also. We work together at the vein treatment center and focus in on patients with venous disease and have over the years seen lots of patients who have venous-origin chronic pelvic pain, and trying to understand this patient population and improve upon how we treat these patients, how we identify the best treatments. So I’m a professor of clinical radiology at Weill Cornell, and we work together and see a large number of patients that are in the process of opening up the EMBOLISE trial to look at ovarian vein, pelvic vein embolization, and outcomes from that specific treatment strategy.

Excellent. Well, my name is Ram Chadalavada. I’m an associate professor of radiology and surgery at University of Cincinnati. Pelvic venous disorders is a passion of mine, and one of the perfect ways to convey this is through Ashley. It’s a patient replica or memoir that was created through Cook—a video team—sharing her experiences of a patient that I was able to be involved in her care. So hopefully many of you have a chance to review through that video as well that’ll be associated with this. But let’s get started. Neil, Ron, what’s happened in the last year since we met in Phoenix, particularly related to venous disorders? Any particular literature or any punchlines that you’d like to share? Obviously we heard about the clinical trial that’s coming forward, but what would you say?

I’d like to say that our understanding of the disease process has dramatically changed, but I think there’s more progress that we need to make to really identify the patient who has venous-origin chronic pelvic pain. And Neil, I’m sure you’ll have a good bit to say about that, because I think it’s an important component of what you’re working on and things that we are working hard nationally to understand well. How are patients affected by this, and how do dilated veins in the pelvis lead to symptoms, and what type of symptoms are the predominant symptoms in these patients?

Great. Neil, let’s transition this. So why don’t we just do the intro part as to what is PEVD and why is it so important?

Yeah, no, thanks. I think the way that we answer that question now is different than maybe the way we answered it a few years ago, and I think it’s for the better. If I can make an observation: In the last year, having attended many meetings in multiple disciplines that focus on venous disease, nobody uses the term pelvic congestion anymore. And I’m very happy about that, because the pelvic congestion term was a term loaded with baggage. First off, gynecologists, when they hear that term, immediately it triggers a set of thinking that is skeptical and not really open to consideration. And in many ways that’s because pelvic venous congestion is a very messy term. It’s including multiple pathophysiologies leading to potentially one of only four of the potential clinical presentations that pelvic venous disorders can be. Ultimately, pelvic venous disorders are caused by venous hypertension in the veins in the pelvis, and that can lead to what we, I think—is better described as venous-origin chronic pelvic pain, but it also can lead to pelvic varicosities that communicate with varicosities in the leg or in the genital area in men and women, but particularly vulvar varicose veins in women. And so lower extremity varicose veins of pelvic origin would be the second clinical presentation, or lower extremity and genital varicose veins of pelvic origin. We know that vein compression can lead to leg symptoms, specifically swelling, and in some patients venous claudication. That would be the third presentation of pelvic venous disorder. And the pelvic venous system includes the left renal vein, and the left renal vein can be compressed, as we know, and that compression can lead to both pelvic—sorry—venous-origin flank pain and venous-origin hematuria. But if the gonadal vein is incompetent, it could also lead to venous-origin chronic pelvic pain, which underscores how the physiology—similar physiologies can cause different clinical presentations depending on how they’re linked together.

Yeah. Neil, one of the beautiful articles that you were involved with is the article that came out in May 2021, the special article that came out in Journal of Vascular Surgery. I believe there were at least 17 team members that went and contributed. Do you mind just referencing that article? And how did that come together? Because I think that’s very special. It’s something that I reference and I share with everyone about this particular disease.

Yeah, so you’re specifically talking about the SVP paper, or symptoms, varices, and pathophysiology. So SVP, si vous plaît, is— one of our contributors was from France. That was a product again of the research consensus panel that we had in 2017. One of the priorities that the panel identified was the need to develop some sort of clinical tool to classify venous disorders of the pelvis, much like the CEAP classification does for lower-extremity varicose veins. And so we—as a result of that, RCP assembled physicians from multiple different specialties, both in interventional radiology—and this is internationally—vascular surgery, which included an international flavor for that too. Gynecologists were also part of this group. And we talked about various strategies of classification and ultimately came up with this, much like other classification systems that are a little cumbersome to use. But once you start to use it, it actually works very well, and it’s something that you can sort of read like a sentence and create in that way—the acronyms that relate to specific things. And the reason it’s so important for pelvic venous disorders is a little related to what I had said before—is that different clinical presentations can have different pathophysiologies, but sometimes the same clinical pathophysiology can lead to different clinical presentations. And conversely, the same clinical presentation may come from multiple different pathophysiologies. So the more specific you are in defining your population, ultimately the better you’ll be in terms of caring for the patients—and then later in terms of research, classifying your patients, making sure you have homogeneous populations.

I’m sure many of you see—

It’s important to bring up just the disease-specific quality-of-life tools like this are so critical in how you see these patients in the office and the conversations that you have to understand what is predominantly affecting them. And that way you can target treatment strategies and set goals for patients in very clear outcomes and clear expectations post-procedure for these patients, which ends up being good discussions, especially in our interventional space.

Yeah, absolutely. One of the things that often comes up is patients being under-recognized, therefore possibly leading to undertreatment and so on. Can you guys talk about the recognition of the disease or potentially the diagnosis component? Ron, do you want to take that?

Sure. The diagnosis component can be very challenging, and there’s so many overlapping conditions that these patients present to other providers with. And so having those referrals and having knowledge, let’s say, in the gynecological space or the pelvic-floor physical-therapy space to understand the different types of disease entities that can cause chronic pelvic pain and what the stimulating factors might be for those different conditions so that they can identify venous-origin pelvic pain as a specific source is useful for patient identification. And I think that’s what helps differentiate those that have venous-origin chronic pelvic pain that may occur more as postcoital pain or withstanding and pressure and heaviness that ends up with reflux down into the pelvic reservoir. And so when we’re thinking about those and we see escape points, let’s say, to the vulvar region or the low extremity, it sometimes is easier to identify these patients and make that association.

Yeah. Neil, do you want to add anything about why it’s so under-recognized? You referenced gynecologists. Do you want to share a little bit about that interdisciplinary and what’s happening in their literature and bulletins and updates?

Yeah, I think ultimately it comes down to—the acceptance of this by the population that controls these patients, which is really the gynecologist, will come down to data. And when we start actually publishing some data that proves both that venous conditions can cause chronic pelvic pain and then secondarily treating venous conditions can improve pain in women who have it, then we will get more buy-in from the gynecologist. And so they are skeptical, and they do point to the fact that our literature at this point, as much as it is fairly longstanding, is really just a bunch of large case series. There is a lot of heterogeneity in that data too in the context of how procedures were done and how symptoms were defined and ultimately how symptoms were improved in terms of the definitions that were used. And so I think ultimately our—from a public health point of view, if we’re going to make an impact in the area of chronic pelvic pain that will be substantial, we need to produce data that will convince gynecologists to consider a venous origin in the appropriate scenario and refer a patient to a vascular provider, usually an interventional radiologist.

Sure. So, let’s—

I think the past has confusion of that. I think that’s where that struggle comes in, that they may have referred patients for, let’s say, ovarian vein embolizations in the past, and based on the way the data was produced, or the lack of data that was out there, or the way the procedures were performed, let’s say, with lack of true consistency, unilateral treatment, or treatment of the ovarian vein without necessarily treatment of the pelvic reservoir, that can lead to inconsistencies of the outcomes from an individual patient basis. And then without us producing this kind of quality data and research with large values of numbers, then they have a harder time believing those outcomes. And so that obviously affects referrals. And then patients are primarily being treated, let’s say, with pelvic-floor physical-therapy treatment or surgical intervention, hysterectomy, other things, because they don’t have the quality of information that they truly need.

Yeah, absolutely. Why don’t we talk about this underappreciated presentation of PEVD? And walk me through a patient that typically comes into your clinic. How do you analyze them, and how do you work it up? Because I think we have a lot of interventional radiologists that are learning more, or have been brought up to the literature, making the transition. Let’s walk through this workup and the clinical evaluation. I would love to see your explanations of patients.

Yeah, I think this depends a great deal on how the patient comes to you. And I think, unfortunately, nowadays, most of the patients that come to us are patients that have been—and this is an observation that I think is fairly consistent—have seen multiple different providers and have been given multiple different diagnoses and have had treatments for those specific diagnoses with temporary but not longstanding benefits. And then at some point somebody notices that they have big veins, and after exhausting all the other potential treatments that could be offered, someone says—or if the patient concludes themselves by doing their own internet research—”I need to go find a physician who takes care of abnormal veins in the pelvis,” and then ultimately comes to us. Those patients may be very different—maybe parenthetically saying here—than a patient that might just for the first time present to a gynecologist with a pain condition that might have been nice to have identified as a venous origin at the beginning.

And so outcomes in that patient population might be very different than the patient population that we see ultimately, because once patients have pain of any form—whether it’s gynecologic pain, musculoskeletal pain, neurologic pain—they change. Their biology changes, depression is common, central sensitization becomes common, and then they become a substrate that’s not as amenable to treatment. So you may end up treating the primary pain generator and not improving them as much. But I think the classic patient who comes in—we’re looking for symptoms that suggest a venous origin, and those generally are symptoms that are pelvic discomfort, pressure, pain that’s not present in the morning but gets worse over the day, that gets worse with activity, that gets better when they lie down, gets better overnight, and can be provoked, in addition to bioactivity, after intercourse, with prolonged discomfort. And presumably that’s because a lot of blood came into the pelvis, and it’s taking time for that blood to dissipate.

What I’ve learned working with the gynecologist on my patient-reported outcome-measure trial is that many patients with pelvic floor myalgia also have those symptoms. So it may be that pelvic floor myalgia and pelvic venous disorders have very similar clinical phenotypes, so we need to keep that in mind. That raises two thoughts: One, maybe many of our patients with pelvic venous disorders are being sent to pelvic floor therapists, and so that’s a potential group to work with to find patients. And then what we also know is that pelvic floor tightening and pelvic floor muscle contractions—much like when you have an orthopedic injury in your shoulder, your back starts to hurt, your neck starts to hurt—the same thing happens in the pelvis: The pelvis muscles start to react to the pain. And maybe pelvic floor myalgia is secondary to pelvic venous disorders. So these are things that come up.

What I’ve learned from the gynecologist is—who are a part of our study who think that we can enhance the specificity of our diagnosis with a physical exam—their points are that in—the physical exam of a patient with pelvic floor myalgia will be very different than the physical exam of a patient with pelvic venous disorders. And pelvic floor myalgia—when you do the exam, specific muscle groups will be very tender: the pudendal, the obturator, the—maybe moving the pelvis itself may generate pain; pushing on the abdomen may generate pain. In patients with pure pelvic venous disorders, you won’t have that. They will have pain when you push on the cervix or push on the uterus or push on the ovary where the varicose veins are. That’s how you’ll elicit the kind of pain that they’re complaining about. And so from their point of view, this is just like in medicine anywhere else: Our diagnosis may be a combination of history, physical exam, and then a confirmatory imaging test.

Sure.

And I think that’s where we’re going to probably get with time.

Got it. Ron, can you elaborate a little bit about the imaging workup? I think Neil touched upon the physical exam findings and clarification between the myalgia very nicely, so can you help talk through us the imaging workup?

Yeah, I think that’s a great point. I think what Neil brought up and the way he described the clinical presentation and workup of this patient group and how it’s changing over time is critical. Obviously imaging is a large part of how all of these patients are worked up by the gynecological community of different backgrounds. So as soon as there’s a patient who has recurrent pelvic pain—let’s call it postcoital pain—the first thing that’s going to happen, let’s say, is ultrasound imaging of the pelvis, and if you have a pelvic ultrasound or if you look at pelvic ultrasounds and you find pelvic varices, you probably need more data to support this and show locations of those pelvic varices, diameters of those pelvic veins, that indicate that this is abnormality. But I think we can all recognize parauterine veins and when those parauterine and periovarian veins are larger than expected and not normal vasculature that’s normally emptying and draining the pelvic reservoir. We know that this patient population is going through menstrual cycles, and they’re going to have cycles every 30 days, and they’re going to have increased flow during that cycle. And so, sure, these are going to dilate, but how do they stay dilated in between cycles, or how do they become larger than normal size? That’s important for us to understand, and we need to publicize that. We need to gather more data to find the true indication of this disease process from that imaging diagnosis and from that very identifiable source.

Ron—

I think we—yeah—

Oh, go ahead. I was going to ask you about the cross-sectional imaging that you—is there a transition that you make? What would be the specific exam? And maybe let’s say you’re in a facility—what kind of protocol is a must? How would you simplify that?

Yeah, I mean I can talk about—my preference is to do transabdominal ultrasounds in these patients. I think we can really get good visualization in most of this patient population. We can see the IDC; we can see the iliacs. We want to look at different disease entities, so are we looking at iliac vein compression versus primary ovarian vein reflux versus renal vein compression leading to ovarian vein reflux? And so we can identify that pretty easily with ultrasound. And so quality ultrasound assessment will help us along those lines. But as you mentioned the EMBOLISE trial earlier, one of the goals of that trial is going to be to assess different types of imaging workup of these patients, and how do we do with CT venography? How do we do with CT upfront? And how does that compare to ultrasound? And can we assess diameters of different vessels to predict which ones have valvular incompetence, which ones are going to lead to reflux, which ones are going to lead to dilated varices in the parauterine/periovarian space, that we think are so highly associated with pelvic venous symptoms?

Great. One of the things that I always get asked about is—depending on the type of clinical scenario or clinic setup you have—is what imaging do you want us to order? Or the way we would like to work in our clinical basis is we want to see them in clinic. We will kind of collate through all the imaging. Sometimes they come from CT imaging that’s been done, multiphasic, MRI imaging that’s been done. How do you handle those particular patients and—who’ve been told something else with images that was interpreted by others? Ron, do you want to take that?

Sure, yeah, I was waiting to see if Neil wanted to make a comment. But, yeah, I mean, look, we have lots of different sources of imaging backgrounds that we can utilize, and I think they’re all useful to help us identify abnormalities of dilated veins in the pelvic reservoir. Personally, I like ultrasound, because I think we can see it live, and we can pressurize the system, but we don’t have necessarily all the data supporting that thing—[that] we need to do transabdominal or transvaginal ultrasounds in all these patients. But it is helpful in identifying this large pelvic reservoir in the parauterine/periovarian space. I think the individual images that we get, let’s say, on CT or MR, although they can be good, ultrasound, I think, gives us a little more live information, and we can ask patients, let’s say, to pressurize it, or we can change insulation, have them stand—do lots of things to modify and to get maybe better results.

Okay.

Now ultimately, I think our paradigms will change. I think—I hope studies like the EMBOLISE trial will demonstrate benefit for patients who get embolization for chronic pelvic pain related to a venous origin. And ultimately I think that is our best chance for gynecologists to start referring patients to us by thinking about the diagnosis first and then doing a preliminary workup and then sending us patients based on that. I’m hopeful that at some point we’ll see gynecologists evolve to listening for specific things, doing a physical exam, and thinking about venous-origin pain and then doing transvaginal ultrasound as a screening test. And it’s not going to find all the patients, and I think ultimately this will be something we’ll need to study, but many of the patients who will have chronic pain of a venous origin will have dilated veins in the pelvis, and that should be very easily seen with transvaginal ultrasound. Also flow direction. And ultimately that would be the mechanism by which patients are screened and referred to the IR, and then the IR may choose to do another imaging test to work out the pathophysiology, to look at the iliac vein, the renal vein, the gonadal veins, as well as the pelvic varicosities.

And again, the cost-effective way to do that would be with ultrasound. The skill for that kind of ultrasound is actually not that hard to acquire. I think that’s always been intimidating, and I think we have in our community a concern that most of those scans are not diagnostic, but as it turns out, most are diagnostic primarily because most of the women with pelvic venous disorders tend to be very thin. So the scans are good. But yes, I agree with Ron. We often have patients come in with CT and MR, and then we do our ultrasound to actually troubleshoot the areas that aren’t quite clear on the CT and MR.

Let’s start transitioning into—

I think it’s interesting and I’m curious: What do you guys think? There’s variability depending on what the hydration status is of the patient that particular day and sometimes the variety of diagnostic elements. Is this iliac compression that’s leading to reflux in the internals? Is this renal vein compression? Is this primary ovarian vein reflux? All these potentially could be the source of excessive pressure in the pelvic reservoir, and how we image that and the timing and the prep of the patient to that particular moment can be challenging, and so we have to be mindful of it. And I think ultrasound offers a lot of value there, that we can discuss that with the patient, we may be able to change patient positioning, we may be able to prep patients before they come in and do differentiating assessments. So I think it is useful to understand that particular process.

Great, thank you. I think I want to—let’s start transitioning into treating reflux disease with the embolization and potentially tying it also to the EMBOLISE trial. So how do you manage or how do you treat the reflux disease, especially if it’s a single-vessel disease situation or a multi-vessel disease? Neil, do you want to take that one?

Yeah, I think this whole approach has changed over the years, and as a result we see that much of the literature is very heterogeneous in terms of what is treated and how it’s treated and then also how it’s assessed. But I think the original papers were a lot more single-vessel treatments without treating the pelvic varicosities. If we extrapolate from treating varicosities in the leg, we know that patients’ symptoms get substantially better when we not only treat the saphenous vein that’s causing the varicose veins, but the varicose veins as well.

Absolutely.

And so although we don’t have convincing evidence to support the idea that treating the ovarian veins and the pelvic reservoir is better, it seems logical that it would be. And for the context of clinical trials, particularly early in this sort of “let’s prove with science what we’re doing is actually benefiting patients,” it’s probably beneficial for us to do more—in other words, be a more total and complete embolization, treat the ovarian veins, treat the reservoir of pelvic varicosities in the pelvis, and then study the internal iliac veins and then potentially treat any varicose veins that are coming off the internal iliac veins.

The reason for that is we really want to prove embolization works, and then later we could do some clarifying studies to see if we need to do all of that or if part of that is necessary. So I think as we move toward the EMBOLISE trial—and I’ll let Ron in a second take over— the concept that went into doing the trial was “let’s do more, because we think there’s some signal suggesting treating the pelvic reservoir and the refluxing varicose veins adds benefit over just treating one or both of the ovarian veins.” And so, with that said, Ron, did you want to talk a little bit about your logic behind a particular patient and how you decide what to treat?

Yeah, and how to treat.

Yeah, it’s a great point. I think the way you describe that is perfect in the sense that we want to try to treat this dilated pelvic reservoir. We know from external experience in venous disorders that we treat—let’s say we’re talking about lower extremity varicose veins—we know that if we treat a source of reflux, but we leave the varicosities alone, that those patients are at risk for recurrence. So if you translate that and think about that in the pelvic reservoir, if we treat the source of reflux like treating the ovarian vein but not the source of pelvic pain, the dilated varices in the parauterine/periovarian space, then you’ve left this reservoir behind that’s going to sump from somewhere else and create recurrence of disease. And I think—at least my logic on this—one of the reasons that we’ve seen recurrence, looking back at old data in the way it was published over the last, let’s say, 20, 30 years of data—one of the lacking elements is that completeness of therapy treating both the source of reflux plus the pelvic reservoir.

And so one of our goals as part of this EMBOLISE trial is to say, “If we are complete, if we treat the entire pelvic reservoir, we get into the parauterine/periovarian veins, and we treat those veins with some sort of treatment strategy—we can use sclerosant, we can use gel foam, we can use other tools to treat that pelvic reservoir—and we cause those veins to completely shut down and close, then we can coil the ovarian veins in completeness, and we can prevent recurrent flow that’s going to reopen that venous reservoir.” If we think about how this was done and the failure points of these prior studies, one of the things that was done was—okay, you can get into the ovarian vein, and you can coil that vein, but you don’t put any sclerosant into the pelvic reservoir. Well, now you’ve left a dilated reservoir of vein behind, and that reservoir could be a sump source or somewhere that’s going to recruit blood from some other venous system.

So let’s say if only one ovarian vein was treated rather than bilateral, then now all of a sudden the right ovarian can become refluxing and valvular-incompetent and recurrence of disease, or we know that the internal iliacs are connected to this pelvic system as well, and not only the internals plus the ovarians are draining the pelvic-reservoir veins, but we know that there’s probably other veins that drain the system in addition. And so if you’re limited in your treatment and you’re only coiling a refluxing vein, you’re leaving a dilated segment in the pelvis that can be a recruitment source from anywhere, and that can lead to recurrence of disease and recurrence of pain and recurrence of dilation. And so at least the thought process in this trial is, how do we completely treat this pelvic reservoir? And if we can, we can treat it directly plus treating the primary sources of pressure. So whatever is refluxing—call it unilateral ovarian, call it bilateral ovarian, call it bilateral ovarian plus internal iliac—all of this could be strategies that you need to do in order to prevent recurrence.

What Ron’s talking about isn’t just hypothetical, but it’s actually observable. In patients that we’ve studied with ultrasound before, we’ll find that the left ovarian vein is refluxing, filling a pelvic vascular reservoir around the uterus with some what we’ll call left-to-right shunting across the uterus and then out the internal and up the other ovarian. And then after embolization, during venography of the right internal iliac vein, then you start to see the right internal iliac vein is now refluxing. It’s small, and it’s only refluxing a little bit, but it’s communicating with the reservoir if you don’t treat the reservoir at the same time.

Sure.

And so these flow shifts can already be identified even at the time of the embolization, and then that flow shift with time will eventually allow that ovarian vein on the right side to enlarge and potentially repressurize that pelvic reservoir and lead to recurrent symptoms.

I think you guys make a great point about how sometimes this is dynamic, and you see in real time the shifts happening as you’re evolving into the treatment pattern as well. I’m going to give you a scenario. How do you decide if it’s reflux or iliac vein obstruction that’s more important lesion? When you have a two-for-one or three-for-one, what kind of order do you think about it—whether it—Neil or Ron, if you want to take this, and actually, Neil—

Maybe I’ll start and then Ron can fill in the gaps. But I think that’s a very interesting question, and as it turns out, it’s a very common problem. We’ll find patients with multiple things going on, and then it’s the—the question is what’s causing the symptoms? Once you’ve defined they have some sort of vein-related symptom, then the pathophysiology is the next step. So I think some of the things that we rely on are inferential. So, for instance, patients with reflux-related symptoms tend to be older and multiparous. Patients with obstruction can be younger, but they can also be older. And this has been demonstrated with data already, looking at cohorts of patients who’ve been studied. You’ll see a bimodal sort of presentation with patients with obstruction, with patients during their reproductive years being mostly the reflux patients—particularly multiparous, reproductive-year women.

But sometimes it’s still challenging to know. Many times I think the argument will go, the treatment should be directed toward what seems to be the most obvious lesion. So if you have a minimally refluxing ovarian vein filling small pelvic varicosities, but you have this really tight iliac obstruction leading to collaterals that are actually going through the uterus and with reflux in the ipsilateral internal iliac vein, then it sounds like the iliac obstruction is potentially the more impactful thing to treat. We don’t know if the symptoms from iliac vein obstruction are different than the symptoms from gonadal vein reflux. They may be different. It may relate to the different collateral pathways that patients with obstruction have compared to the pathways that the reflux patients have in terms of the dilated veins. And so the presentations more with the back pain and the big collaterals may also signal more of an iliac vein lesion.

And then in contradistinction, somebody with a relatively mild—let’s just say anatomically 50% diameter or 50% area reductions of the iliac vein—but have a very big ovarian vein with lots reflux filling down and across and up, then I think the reflux is probably the one that’s leading to what’s important. One of our colleagues, Dr. Meisner, puts a lot of emphasis on looking at the flow pattern in the internal iliac vein. And so he’ll start actually with—if a pre-procedure ultrasound or cross-sectional imaging suggests the coexistence of a left common iliac obstruction and a left renal—left ovarian vein, rather, reflux, he’ll start with a left internal iliac vein venogram, and depending on the flow, will make a decision as to whether he thinks the reflux is more important or the obstruction is more important. With situations where when you inject the internal iliac vein, if you see some flow go up the ovarian vein and then come down the ovarian vein, that speaks for the ovarian vein maybe not being as important of a backward-flow contributor to the pelvis as one where you never visualize with venography the left ovarian vein.

Yeah.

Ron, did you want to chime in with some additional ideas?

Yeah, I mean, I like what you were saying, and I agree. I think we’re on the exact same page as far as how to assess these patients and how do we figure out is it reflux or obstruction that we’re going after, and which one should be the target for the patient? And part of it can be a conversation and patient-dependent. Do we want to have permanent iliac venous stent placement for common iliac vein compression is always a challenge. It’s always a challenge from a one-to-one basis conversation with the patient as well as from a medical perspective—what should we be doing for these patients, and what does our data show, and the conversation that just—the presentation that was just presented in detail. So I think there are some challenges that we need to learn more about, and our data and our research will help us in really strong ways to guide our patients who won’t understand this in the highest way. So I think that’ll be really strong. That being said, iliac vein compression is real. May-Thurner is a real lesion that we’ve all encountered, and when those are real, and we get reflux in the internal that’s pressurizing the venous reservoir and the parauterine/periovarian vein, and these patients have typical chronic pelvic pain or venous-specific pelvic pain or the type of symptoms that we’re accustomed to, then it becomes hard to avoid that treatment of that May-Thurner lesion.

That’s great. Ron, I’m going to transition to—

But I think the—

Yeah.

I’m sorry?

Yeah, no, no. Great points. I’m going to actually give you an associated scenario as well. How about a situation where you have the left renal vein compression and that’s associated with LOV reflux. How do you go about handling that scenario?

I think that one’s really important to understand at the greatest level possible. I think we have—we probably have more to understand, and there’s been some good publications in recent years looking at pressure differentials in the left renal vein, which are critical. At least for me, there can be lots of collaterals for the left renal vein, and sometimes they do have left renal vein compression, reflux down the left ovarian, plus many paralumbar collaterals, and they have normal renal function, and if they have normal renal function, then that renal vein compression isn’t true. It has no negative consequence that you need to have surgical correction of their nutcracker first. You—their symptoms are really associated with the dilated vasculature that’s collateralizing around the obstruction. We need more data down that pathway as well. But that’s an interesting point to make and something we need to understand well. I think a lot of us will measure pressures in the left renal vein and put temporary occlusion balloon in the ovarian vein to mimic like we’re doing in ovarian vein embolization. And this is a pelvic pain population, so let’s say this patient’s coming in with typical pelvic pain symptoms, postcoital ache, and we think this is truly vulvar veins that are the predominant source of their pain, and we’re going to go ahead before we do ovarian vein embolization—because if we embolize the ovarian, we’re embolizing the collateral network. We don’t want to do that. So we want to check that, okay? That’s the important component we need to understand.

What’s your threshold for our audience that may be asking? What are you looking for? What’s that gradient?

I mean, I usually say one to three millimeters of mercury. I usually will use the three millimeter mercury cutoff. Neil, I don’t know if you would do anything differently. I think we’ve talked—

Yeah, no, the three millimeter cutoff comes from literature that actually came from our group and one of our mentors, Dr. Tom Sos, when he was doing a lot of renal-vein renin measurements, he would also, as part of that, measure pressures, and ultimately they came to the conclusion that the normal renal vein had a gradient of less than three. So any pressure of three or more is abnormal. What you would probably expect to find in somebody who had a, let’s say, critical renal vein obstruction leading to left gonadal vein reflux—which is where it gets tricky. I think in a straightforward nutcracker, if you do a left renal vein compression—I mean a left renal vein venogram—you’ll just see a number of hilar collaterals, and you’ll do a pressure gradient, and there’ll be a positive gradient, and then you can be confident that that’s what’s leading to potentially those symptoms of flank pain and hematuria that the patient may have.

But in the case of a coexistent ovarian vein that’s refluxing, you won’t see a pressure gradient. And so putting the balloon up in the renal—in the ovarian vein, simulating as Ron said what the physiology will be like after you do the embolization—if you measure the pressure gradient before and after and it jumps dramatically, particularly more than three, then that, I think, is a strong predictor that the renal vein is probably driving the left ovarian vein reflux, and embolizing the left ovarian vein may lead to left flank pain and hematuria if you do the embolization—the data on that is, at this point, not very strong, so these are inferences that we’re making—and may—although this is probably a small risk, but a real risk—lead to a renal vein thrombosis. So these are the two concerns we have, and it’s hard to know how important they are, but these are the reasons to be cautious in those situations.

Great. Thank you. Ron—

I think it’s important for patient education and patient—to describe to them in advance of these procedures so that they’re aware of what they’re being prepared for and what to expect on the other side.

Perfect transition to you. A question for you, Ron: Why are we doing these trials? If you had to give me a one-liner—and then tell me a little bit about what’s so unique to your trial, this particular trial that’s being supported.

Yeah, great question and great point that we need data to prove the efficacy of the type of treatment that we’re talking about. We’ve had outcomes, and we’ve showed that patients respond to intervention in small patient populations. And there’s been these small studies that have been published out in different areas of literature, but we have yet to do a randomized controlled trial of embolization of the ovarian vein and pelvic reservoir. And so the goal of the EMBOLISE study is that we want to prove that doing complete treatment of the pelvic reservoir plus the refluxing ovarian vein segments—and we’re open to other—as part of the study, there are options to treat from the internal iliac veins—additional treatment of the pelvic reservoir as well—that you have complete treatment of all of the pelvic varices.

And we’re going to look at, at least now, good outcome time. So we’re looking at six month timelines. But ideally we’ll have longer- term data over time—that we’re going to get long-term data at a year, two years, five years potentially, to look at how these patients do over time once we get rid of the source of their pain, the source of their venous hypertension within the pelvic reservoir. If we were to talk historically, we know and we’ve seen the historic information for varicose veins of the lower extremities—that we’ve seen positive outcomes. So why couldn’t we follow that same type of pathway and say if we eliminate these dilated veins in the parauterine and periovarian or vulvar space and the associated varicose veins, let’s say, in the leg, then if we eliminate that source of pressure and symptoms all around go away, I think we’re going to have really strong long-term outcomes.

Yeah, no, Ron, I have to commend you and your partners and all the team members that are involved in this and creating an opportunity for a comparative outcome study, and especially with the long-term follow-up so that we can also use it to educate our patients, but also referrers and ultimately the payers as well. So as we come to a close, obviously, I’m going to turn to each of you to—a call to action and words of wisdom related to PEVD. And let’s start with Neil and then Ron, we’ll also finish with you.

Oh, interesting. Call to action. It’s probably—we can summarize, I think we should probably all be familiar with and conversant with the SVP classification. We should now be using new nomenclature rather than describing the problem as pelvic congestion. We should speak specifically about venous-origin chronic pelvic pain or lower-extremity varicose veins of pelvic origin and consider subgroups and how to manage them. I think doing that in the long run will allow us to think about these patients a little differently. They’re all a little different. We’ve already alluded to the fact that what used to be called pelvic congestion can come from left ovarian vein reflux, but it can come from left renal vein compression with left ovarian vein reflux, and those are two different things. Or it can come from ovarian vein reflux on the right side and internal iliac vein reflux.

And so these are all different things. They may all require different treatments, and ultimately we need to be familiar with that language and then incorporate those concepts into whatever clinical trials we use. And I too want to commend Ron on putting together the team that’s putting together this clinical trial. I think this is something for all of us to track. This will be a very critical outcome study. It’s in many ways the first that I can think of in interventional radiology where we have a placebo arm. This is going to be a group of patients that are going to have venography in IVUS and won’t have an embolization and won’t know what treatment they had. So both the treatment group and the control group won’t know if they got treated or if they just had a venogram. And we’re going to take great steps to try to make sure that they don’t learn, because obviously the biases that can come from having the knowledge of what treatment arm you’re in can play a big role. So these are the things, I think, to keep in mind in 2024 and forward.

Yeah. Ron, I think this is a perfect transition to your beautifully positioned trial. So how would you leave and close this call?

Thanks so much. I mean, that’s an amazing comment and much appreciated, and I’m excited for where we are going in this disease process and the understanding that we’ve developed over time and understanding the source of pelvic pain in this female population. And I think as time goes on and as we complete this study and enroll patients and randomize them to different treatment outcomes and—or treatment options that they will not know—they’re blinded. And so we’re going to have really strong data supporting—hopefully, and I expect—supporting embolization and proper treatment of the ovarian veins, but we are randomized, and so these patients really won’t know what they’re undergoing. And by not knowing what they’re undergoing, we’re going to get true, clear data on procedural strategies that we’re going after and that we’ve all done for many years on this patient population. So I think there’s lots of amazing options to come, and I think we’re going to learn a lot about this patient population, about the types of symptoms that they have on start, as well as post-procedure, and what the outcomes are expected to be. We expect very positive results post-embolization based on the historical data that we know about, but it’ll be good to have this blinded control arm and really understand it well and know where we should go in the future.

Absolutely. I think one of the beauty of interventional radiology is, I think, the very thoughtful multidisciplinary approach. And so I want to draw it back to the patient as well, because a lot of this data will have to be complemented with the partnerships we’ll have with gynecology. Also, there’s other specialties that’ll be involved dealing with this particular patient population and disease as well—whether psychiatry, the primary care physicians, or others. So I think there’s a tremendous value here. And so, yeah. Any other last words? Otherwise we’ll wrap this up.

No, I think this is just another step on the course of—as Dr. Vedantham pointed out earlier today—in the maturation of our specialty, we start with a clinical idea. Some people treat these patients. They get better. And now we as a community have recognized that this is our responsibility to actually gather the evidence to prove what we’re doing is making a difference. And this trial, like some of the other trials that Dr. Vedantham talked about this morning in his innovator award acceptance speech, is another feather in the cap of the interventional radiology community. And a big thanks goes out to SIR Foundation. This model of identifying a clinical problem, developing a clinical research consensus panel about it, and then focusing on the recommendations of the research consensus panel, and then having a very logical step-by-step process to dealing with the research that’s needed to demonstrate value is the model that we need to continue with with all of what we do in interventional radiology.

Absolutely. Perfect, Neil. Thank you. I want to thank our guests, Dr. Neil Khilnani and Dr. Ron Winokur. It’s a pleasure of mine, as Ram Chadalavada, and I want to thank the Cook Medical team for hosting this year’s podcast series. They’re just wonderful to listen to. I learned so much, and I’ve learned so much again at this session. So thank you all. Have a great meeting.