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CME / ABIM MOC

Updates on Emerging Data for the Treatment of Erosive Esophagitis

  • Authors: Prateek Sharma, MD, FACG, FACP
  • CME / ABIM MOC Released: 11/29/2022
  • Valid for credit through: 11/29/2023
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  • Credits Available

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    ABIM Diplomates - maximum of 0.50 ABIM MOC points

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Target Audience and Goal Statement

This activity is intended for gastroenterologists, primary care physicians (PCPs), nurse practitioners (NPs), physician assistants (PAs), and other clinicians who treat patients with acid-related gastrointestinal issues.

The goal of this activity is that learners will be better able to improve the evidence-based management of patients with erosive esophagitis including understanding how new/emerging treatments can be incorporated in treatment strategies.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Data from clinical trials for new/emerging potassium competitive acid blockers (PCABs)
  • Have greater competence related to
    • Diagnosing EE


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Faculty

  • Prateek Sharma MD, FACG, FACP

    Professor of Medicine
    University of Kansas School of Medicine
    Kansas City, Kansas

    Disclosures

    Sharma Prateek, MD, FACG, FACP has the following relevant financial relationships:
    Consultant or advisor for: Bausch; Boston Scientific Corporation; CDx Labs; Covidien LP; Exact Sciences; Fujifilm Medical Systems USA Inc.; Lucid; Medtronic; Olympus; Phathom; Samsung Bioepis; Takeda
    Research funding from: Cosmo Pharmaceuticals; Covidien LP; Docbot; ERBE USA Inc.; Fujifilm Holdings America Corporation; Ironwood Pharmaceuticals; Medtronic USA, Inc.; Olympus

Editor

  • Iwona Misiuta, PhD, MHA

    Medical Education Director, Medscape, LLC

    Disclosures

    Iwona Misiuta, PhD, MHA, has no relevant financial relationships.

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  • Yaisanet Oyola, MD

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Yaisanet Oyola, MD, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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CME / ABIM MOC

Updates on Emerging Data for the Treatment of Erosive Esophagitis

Authors: Prateek Sharma, MD, FACG, FACPFaculty and Disclosures

CME / ABIM MOC Released: 11/29/2022

Valid for credit through: 11/29/2023

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Speaker 1: Well, hello everyone and welcome to this program on updates on emerging data for the treatment of erosive esophagitis. I'm Prateek Sharma from Kansas City and it's my pleasure to host this MedScape educational event. I am based at the University of Kansas in Kansas City, and we will be discussing the treatment of erosive esophagitis and talking about the diagnosis, new guidelines, as well. You will be seeing a Q&A box on the right hand side of your screens. And so at the end of my presentation, we'll have the opportunity to go through your questions and discuss any new insights that you may have. So let's talk about endoscopy, reflux disease and heartburn. So here's a case of a middle-aged man who's had heartburn and regurgitation, which are the classic symptoms of gastroesophageal reflux disease, and undergoes an endoscopy. And you can find one of several things which are listed on the right hand side of your screen, which are the different endoscopic findings. So the question always comes up is how did reflux disease lead to the damage of the lining of the esophagus and lead to erosive esophagitis? So when you look at reflux esophagitis, the concept is that it is a chemical injury or an acid burn to the esophagus. Typically, these patients have had reflux symptoms for several months to years before they seek medical attention. Early signs include histologic changes of reflux esophagitis, and then severe reflux esophagitis, which can be healed by PPIs, return soon after stopping PPIs in this situation. And again, temporarily interrupting, PPIs can also induce reflux erosive esophagitis. So this is a chemical injury which happens and can lead to the presence of mucosal damage, which then is presented as erosive esophagitis. Now as gastroenterologists, most of us perform endoscopy in these patients and most of us have open access units, meaning that the patient gets referred to us with a diagnosis of reflux symptoms for us to perform the endoscopy. Now, on endoscopy, we try to classify these patients as having erosive GERD or non-erosive reflux disease. So now GERD, per the definition of the Montreal system, is a condition in which the reflux causes troublesome symptoms, so it's either a patient driven disease and/or complications such as erosive esophagitis or Barrett esophagus, which then becomes a sign of the disease. So the erosive changes are listed on the left and the non-erosive changes, which pretty much means that patients have symptoms of GERD, there's no mucosal damage, no erosive findings, but there is objective evidence of reflux disease. And we'll talk about what those objective evidence can mean as we go through the presentation. Now, these are different changes that you can see on endoscopy. On the extreme left of your screen is typical reflux induced erosive esophagitis, and that is characterized by the LA classification. On the next right, you see a patient who has reflux changes along with strict or scarring of the mucosa leading to a peptic stricture. Following that is Barrett's esophagus, which is the precancerous condition, which is again the complication of chronic gastroesophageal reflux disease. And of course, on the extreme right is the most dreaded complication, which is an adenocarcinoma arising in the setting of Barrett esophagus in the patient with chronic reflux symptoms. So if you look at the role of GI endoscopy, it's very important in the setting of dysphagia, odynophagia, as well as other alarm symptoms, you perform upper GI endoscopy because you want to rule out a complication. In the setting of typical reflux symptoms, and as I mentioned, the typical reflux symptoms are either heartburn or regurgitation, initially, a trial of acid suppressive therapy is given first, and then endoscopy could be performed in that situation. So when do you do endoscopy? How do you do endoscopy? And what are you looking for in endoscopy? So let's try to answer those questions. First and foremost, you do endoscopy when the patient has an incomplete response to PPI trial or if you're screening for Barrett's esophagus. So those could be when do you do endoscopy. And then the other question is you want to make sure that the patient is off of PPI therapy for at least about a week, if not longer. And the reason is that you can look at the reflux changes off of acid suppressive medications. Now, how do you do it and what do you look for? That's when it comes for inspecting for erosive esophagitis using the Los Angeles classification. You can see it's listed A, B, C, and D. A and B are considered as lower grades of erosive esophagitis. C and D are considered as higher grades of erosive esophagitis. And on those cartoons, you can see what those different gradings look like. This is extremely important because in your endoscopy reports you should be putting the LA classification. Multiple times, we get patients referred to us in which it says, "Mild esophagitis or redness is seen in the esophagus consistent with GERD." Again, those are all terms that you should avoid. You should put in very clearly that there was presence of either LA grade A, B, C, or D, or if none of those are present, then say, "There was no erosive esophagitis seen." And a negative finding is as important as a positive finding. During your endoscopy, inspect for erosive esophagitis and if it is present, grade it using the LA classification. Also inspect for eosinophilic esophagitis because that's a condition that we are seeing more and more of in our practices and that can be confused with gastroesophageal reflux disease. And then, of course, you want to assess for the hiatal hernia as well because that can be changing your treatment and the majority of patients with reflux or esophagitis will have either a small or large hiatal hernia. So it's important to do that as well. How do you approach these patients? We talked about that a little bit briefly. Now let's put it in the form of an algorithm because I like this. This is always very important for us to understand, but also it gives you a visual cue the next time you see a patient like this in endoscopy. You see erosive esophagitis, which is in the center. And on the right, this patient has gastroesophageal reflux disease. And so that becomes very clear in this specifically LA grade C and D esophagitis. On the left is a patient in which you do the endoscopy, you do a careful inspection, and again, I cannot emphasize careful inspection, because if you do a very quick examination, you can miss the presence of a hiatal hernia and you can also miss grade B erosive esophagitis, for example. So if you're sure there is no erosive esophagitis and the physiologic acid exposure doing pH testing is less than 4%, then the patient probably does not have GERD in all likelihood, and you should start considering non-GERD or other esophageal disorders. Keep sort of this algorithm in mind, and I will talk about this further as well when we start talking about management of patients with erosive esophagitis. That's the background on diagnosis, which is as important as treatment, because if you don't make an accurate diagnosis, you will struggle with the treatment as well. So now let's talk about the new guidelines and see what they talk about reflux disease as well as erosive esophagitis. So what's new about these guidelines? Well, pathogenesis of erosive esophagitis, talking about that you need to be doing prolonged pH monitoring, so we traditionally still call it 24-hour pH monitoring, but it should be now close to 48 or 96 hours pH monitoring. We have better imaging. We have high resolution manometry pH monitoring available as well as the Lyon consensus. Let's look at some of these things which have changed. We have a much clearer understanding on what is refractory reflux disease. We do have now level one evidence for fundoplication, magnetic sphincter augmentation, and some endoscopic successes as well. There's a major change in approach to PPI use as well as more data on PPI adverse events. So we go through some of these and just probably just telling you what's new rather than rehashing what's been known about for several years as well. Let's talk about endoscopy. We talked about endoscopy, doing it off of PPI therapy and then inspecting for erosive esophagitis, but also ruling out eosinophilic esophagitis. So remember this for endoscopy. Don't increase the dose or switch or do any of those things before a workup starts because then it will make you more confused about the actual diagnosis. Reflux monitoring should be performed off therapy for all patients who don't have either grade B, C or D erosive esophagitis or Barrett's esophagus. If you are doing it on PPI therapy, you should do it with impedance pH monitoring, but this is not to make a diagnosis of reflux. This is to have it in those patients who have objective documented evidence of gastroesophageal reflux disease. Extraesophageal GERD, just a one slide or one bullet point on that is perform objective workup. Don't put these patients on once daily, twice daily BID therapy for months and months. You know? But do a workup first so that again, you are treating the right patient with the right therapy, which is clear. What you don't want to do is send these patients for surgery again without any objective workup. I think this is what's new in the 2022 guidelines. For refractory reflux disease it’s do endoscopy off PPI therapy for at least a couple of weeks, specifically if the patient never had any objective evidence of gastro reflux disease in this patient population. How about surgery and endoscopic therapy? PPIs can be used in patients with well-documented grade C or D erosive esophagitis, early intervention when regurgitation is the primary symptom in your patient population, and then surgery is an option for these patients as well as endoscopic therapy, and we'll talk about that also. So this is just giving you a snapshot of what's new in the guidelines. Now again, let's come back to what I like, which is this algorithm. So here's a patient who's had heartburn or regurgitation, and again, key is without alarm symptoms. Everything changes once you have alarm symptoms because there, it's not just simple GERD you're talking about, but you're looking for a stricture, cancer, et cetera. Give them at least eight weeks of therapy. If the patient responds, then you know that GERD is likely. If there's incomplete relief, that's when you go to doing an upper endoscopy. If you have high grades or you have grade B, C or D erosive esophagitis or you have the presence of Barrett's esophagus, GERD or reflux disease is confirmed. So now you feel very comfortable freeing this patient with acid suppressive therapy. However, if the EGD is normal, then you want to make sure that you have more monitoring or diagnostic testing, which should be done in this patient population. Very sort of similar approach to extra esophageal reflux symptoms as well, in which you want to make sure that they get testing early on in the situation. Let's look at refractory reflux disease. And again, very similar as we discussed is that if the patient ... you've optimized PPI therapy, patient's still symptomatic, do the endoscopy. You don't find an objective evidence of reflux disease. Again, reminding you objective evidence of reflux disease includes Los Angeles, grade B, C, D, or the presence of Barrett esophagus. Then, you want to make sure that this is a patient who has reflux disease. If the patient does not have any of those criteria, then you perform pH monitoring. If the pH monitoring is abnormal, you know what the situation is. If it's normal, look for other causes and treat any coexisting functional symptoms or functional diseases that the patient may have. So those are important things for us to remember. Now let's move on to treatment and what's new in treatment, what sort of are the things that we are looking for. First and foremost, what's exciting is that we now have PCABs which are there for treatment, and now let's look and see how do they compare with PPI therapy? And depending as to what part of the world you are in today, you may have different PCABs which are available for treatment of reflux disease and unfortunately in some countries they're on the cusp and not there as yet. So let's look at that and look at what are the different mechanisms. First and foremost, let's talk about PPIs. And what are some of the features of PPIs? PPIs have this enteric coating. That's because they get degraded by gastric acid. Remember that they are prodrugs, so they need gastric acid in order for them to become active. And that's the reason, remember, they're given before a meal because they will be active with a meal when acid is being produced, they only inhibit the actively secreting parietal cells. They have very short plasma half life. And of course, we know that there may be variability in how they are excreted because of the CYP2C19 pathway that they look at in order to do it. However, on the other hand, if you look at the pharmacological features of these PCABs, or the potassium competitive acid blockers, right from the left, if you go, they're acid stable. So they do not require this coating. They're not prodrugs. They're active drugs, so they probably don't need this meal or this acid in your stomach in order to be active. They inhibit the hydrogen potassium ATPAs and they bind ionically to the hydrogen potassium pump. And because of that, they are able to inhibit all the proton pumps, not just the active proton pumps like the PPIs do, but both active and inactive and the primarily way of how they undergo metabolism is not by the CYP2C19 pathway. So that individual variability may be less. That's just to keep in mind about how they compare PCABs with PPIs. Now, one of the things to remember is that we do have a lot of data now on the proposed adverse effects of chronic PPI therapy. And you can see that we have everything which has been listed from cancer to Covid, to stroke, dementia. Everything has been reported. But if you pay attention to the center of the screen and in red highlight boxes, that's the key take home message. Most of these studies were observational studies, so they do not prove causality. If you look at the high quality studies, only a couple of things have been shown to be associated with PPIs, and one is enteric infections, for example. And this is important to remember because these adverse events of PPIs, because it's due to acid suppression, will probably pertain to PCABs, also, if you are already using them or if you start using them in the near future. Remember that those similar side effects are probably going to be likely with it, which are listed here in the center with red text boxes. So with that, let's look at some of the clinical data of PCABs because we are already very familiar with PPIs. So let's look at this. Just again, since we have a varied audience today, depending on where you are, you can look at this. That will not present, for example, in the US is approved for H pylori infection right now in the near future, perhaps for other indications. [00:20:30] You can see in Japan it's available for a variety of indications including for erosive esophagitis. Then you have revaprazan, tegoprazan, fexuprazan, and you can see that they are all approved outside of the US, primarily in Asian countries. So depending as to where you are, you may have access to one or more of these PCABs which are available. Well, what's exciting is that we do have now phase three data available for a trial of vonoprazan versus lansoprazole in the US and European patients with erosive esophagitis. In the past, the majority of the data with vonoprazan was in the Asian population. And the primary outcome here was a non-inferiority comparing lansoprazole resole versus vonoprazan. On the left is healing by week eight of erosive esophagitis, and you can see much higher numbers, 93% versus 85%. And the 24 hour heartburn free days were no different. Primarily the erosive esophagitis was driven by significantly higher healing of grade C and D erosive esophagitis. Now, as you know, GERD is a chronic disease, so you want to make sure, that there's also maintenance of healing so that it's not just at eight weeks, but can you do this also on the longer term with these medications? And this is looking at different doses of 20 and 10mg of vonoprazan compared to in the light gray shade of lensoprazole. And you can see again that there is higher healing. Or with 20 milligrams of vonoprazan, for example, and much higher, you can see on the right-hand side, when it comes to grade C and grade D erosive esophagitis. A lot of this is because of the higher healing with higher grades or more erosive esophagitis, which is grade C and D erosive esophagitis. Let's look at least partly some of the safety data which are available that they were able to show. And this is that the safety profile of 10mg and 20mg of vonoprazan is similar to that of lansoprazole for patients with healed erosive esophagitis. And you can see that treatment related AEs were very similar across the board with nasopharyngitis, which was the most common symptom in all of this. You can see that rightfully so, the mean serum levels of gastrin, pepsinogen one and two increased in all three arms. And of course, the greatest increase was seen with vonoprazan 20mg, probably reflecting the fact that it's a much more potent suppressor of acid as compared to 15 milligrams of lansoprazole. So that's for erosive esophagitis. Now this is a study which was just presented in randomized control trial at ACG literally a couple of weeks ago, and this looked at the use of on demand therapy versus placebo in patients with non-erosive reflux disease. Now again, non-erosive reflux disease is a whole new disease by itself, which is endoscopy negative, no presence of erosive esophagitis. And you can see that significantly higher primary outcome was achieved with vonoprazan, both 20 milligrams and 40 milligrams, as compared to placebo in a non on demand strategy. And that majority of the patients do use it on demand, which is complete and sustained relief within three hours of taking the medication. Now, there's data not just on vonoprazan but fexuprazan as well, and this is a study from South Korea, in which they took patients with, again, erosive esophagitis and randomized them to either fexuprazan 40mg or esomeprazole 4mg. And again, the primary goal was showing non-inferiority between this PCAB and this PPI, which was taken, they were able to show also with the PCAB that the fexuprazan showed significantly better control of heartburn relief in those who had moderate to severe symptoms. And also, there was some impact on cough, at least in this preliminary study which was conducted, so again, showing that perhaps more I potent acid suppression may be better in this patient population. Here's using tegoprazan, which is another PCAB, and it's listed here in different cohorts of patients. Again, you can see that this was a small study which was done looking at it, and they were able to show that it was generally well tolerated and that there was dose dependent gastric acid suppression with the use of tegoprazan, which is also a novel PCAB in this situation. Finally, to end up with some anti-reflux procedures for erosive esophagitis, and I'll run through these a little bit quickly, but just telling you is when should you consider that. There are certain guidelines here. Of course, a patient who does not want to take PPIs indefinitely. You have that discussion. But again, these should be patients who have proven reflux. Don't send patients for surgery or for an endoscopic procedure if there is no proven reflux. Patients who may have troublesome regurgitation because regurgitation may be a symptom difficult to control with PPI. Finally, PPI refractory heartburn is not an indication unless you prove there is objective evidence of reflux disease by either a positive pH test, which has been done, prolonged pH testing, which has been done, or the presence of endoscopic grade B, C or D erosive esophagitis. Now, the gold standard, which is amongst all of these anti-reflux procedures, is a fundoplication. It can be a complete wrap. It can be a partial fundoplication, which are shown here. So there are different ways of looking at these. Then you have this magnetic sphincter augmentation. Remember that there are no randomized control trials comparing it with the gold standard, which I just mentioned was a fundoplication, but it has been shown in observational studies to be effective in this patient population. It’s done laparoscopically. TIF, which is an endoscopic procedure, there are randomized control trials which have shown that this this help. And remember that if you have large hernias, you have severe grades of erosive esophagitis, this is not a procedure that you should be sending the patient to. Then of course, patients who have morbid obesity along with severe reflux, you can consider a Roux-en-Y bypass in this patient population. Sleeve gastrectomy or even endoscopic sleeve gastrectomy can actually worsen the reflux. So if you want to consider a bariatric procedure in your GERD population, think about Roux-en-Y bypass. So finally, to conclude, is endoscopy is king for making a diagnosis of erosive esophagitis. Make sure you grade it using the LA classification. You need objective evidence of erosive esophagitis or Barrett's or a positive pH before you consider either endoscopic or surgical procedures in your patient population. And finally, PCABs may offer several advantages over PPIs for reflux treatments specifically in those with grade C and D erosive esophagitis. So thank you all very much for your attention and we have a couple of minutes if you have questions. Please start putting them in the Q&A box, which are there. So I can already start seeing some of these. The first question is should one do biopsies to rule out eosinophilic esophagitis? So the answer to that is ... if the patient has some symptoms besides reflux such as intermittent dysphasia or the patient has a history of allergies to nuts or peanuts or some of these things and you see some furrows or rings, yes. You should biopsy. The second question is that when should you think about screening without alarm symptoms for Barrett's esophagus? The answer is ... if you have reflux for five or more years or other risk factors such as obesity, a family history, a smoker, Caucasian ethnicity, think about screening for Barrett's esophagus. That's the thing. The second question that I see is that how does the new drug or PCABs work and how effective it is in patients with chronic cough? The answer is we don't know yet, but hopefully studies will be done in the near future on PCABs in patients with extraesophageal GERD. I showed you one set of data in a small subset, which is there. The results appear promising. The next question is ... how do you avoid taking medicines for the rest of your life with GERD? Again, that's a very good question, and I would say that in some patients, especially with erosive esophagitis, it may be a long term treatment. But try to do, which is lifestyle modifications, which are extremely important, which go hand in hand with medical treatment, is try to make sure that your patients don't eat a heavy meal right before they go to bed. Make sure that they have at least a two or three hour window between their last meal and before they go to sleep, elevating the head end of their bed, losing weight, quit smoking. Again, lifestyle changes I think are extremely important in this patient population. The next question is ... when would you prescribe PCABs for erosive esophagitis? Again, a very good question. Specifically, I would say those patients who have higher grades of erosive esophagitis, right? Grades C or D, in which you know don't want to wait eight weeks with a PPI and see that the patients don't heal. I'd try to see if those are the patients that can go to PCABs. If a patient with grade B also or grade A or B is failing PPIs, I would definitely consider that. The new data on on-demand looks very exciting, and once that's really published and their data on that, we could definitely consider that as well. Another question is what natural treatments have shown help erosive esophagitis? I mean, again, I don't know what natural treatments mean, but again, lifestyle changes are really helpful to do that, and I would definitely encourage lifestyle changes that I mentioned along with your treatment. There's a question about what's the connection of cancer of the tonsils to erosive esophagitis? And again, if you look at the Montreal consensus, there was no connection there between having tonsillar cancer or reflux disease or erosive esophagitis. And finally, we are running out of time. So one last question that I could get to is ... please define failed or refractory gastroesophageal reflux disease. Again, a very interesting question. In the current era of PPIs, it's defined as having persistent symptoms despite eight weeks of PPI therapy. Now, whether it should be once a day therapy or twice a day therapy is up for debate. If you want to be a purist and go by what the FDA recommendation, it's on once daily therapy. So you would say that, but in my practice I usually use that if it's BID therapy or twice daily therapy with PPIs, that's when I would do it. There's some questions from Asia about the cost of these medications, and some of these drugs may be very expensive in some of these countries. There's a physician from Nepal who's asking that. And you're absolutely right. A lot of this is driven by the cost, and you'll just have to go with what's the best treatment which is available. And sometimes, unfortunately, the best treatment may be something which is a little bit more expensive than what the other treatments are. So again, a slew of questions. Thank you very much for these questions, which have been up and coming in that. Hopefully I've been able to answer a lot of these questions. And again, thank you for attending this webinar. Hope all of you found it interesting and challenging. Thank you.

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