It's a great honor and privilege to introduce our next speaker, Dr. Gary Falk, Professor of Medicine and Director of Physiophagology and Swallowing Center at University of Pennsylvania. Now that we know how to diagnose GERD, we are going to learn how to treat refractory GERD. Thank you, Dr. Falk. Good morning. Thank you. And I'd like to thank the course organizers for having me come. Thank you all for being here, both in person and virtually. And Felice's talk, I can eliminate most of my slides. We're going to actually amplify from these first two talks and just build on this a little bit more and deal with the patient with refractory GERD. My disclosure is here. And the learning objectives are as follows. What is the definition of refractory GERD? How common is this a problem? What are the potential causes? What's the optimal diagnostic approach, especially hearing what you've just heard? And how do you approach this therapeutically? So there are a few times I'll pause here that things that are critical to remember. This is one is our definition of what's refractory GERD because there's refractory GERD and refractory GERD symptoms. And a lot of this is covered in a brief manner in the guideline that Felice is a co-author and it's a wonderful guideline that the ACG put out this year. A more in-depth paper comes from the ANMS and the European Society that was published last year. And I'm going to spend a lot of time going through some of this, which is covered briefly in the ACG guideline and quite in-depth here. And this document gives you, I think, everything you need to know about refractory GERD. But let's start. There's a difference between what's refractory GERD and what's refractory GERD symptoms. So starting with symptoms. So and let me stop for a moment. I'm talking purely now of heartburn, acid regurgitation. We're going to take off the table all the extra esophageal stuff and unexplained chest pain. So this whole talk is going to be about heartburn and acid regurgitation, not the other stuff. So this is the persistence of symptoms on stable therapy for eight weeks in someone who has prior objective evidence of reflux from all those metrics that you've just heard about from Felice. The esophagitis, peptic stricture, Barrett's, abnormal acid exposure time off of therapy. It's amazing how much confusion continues to be whether you do pH testing on or off therapy. But unless you have a diagnosis of GERD, you've got to do your pH testing off of therapies. That's symptoms. So what's refractory GERD? It's persisting objective evidence of GERD, not just symptoms, but persisting objective evidence despite medical therapy, erosive esophagitis. Now B is included for this. Abnormal acid exposure time on therapy and abnormal number of reflux events greater than 80. It can be any combination and it should only be considered in clinical practice after BID dosing. So that's after BID dosing of your PPI of choice for eight weeks. So refractory GERD is someone who has a previous objective evidence of gastroesophageal reflux disease who's failed eight weeks of therapy. A lot of people call refractory GERD as actually refractory GERD symptoms. So how common is this problem? A nice population-based study was published in Gastroenterology two years ago. This used the PROMIS form. This is a survey of 71,000 individuals in the United States. 40% ever had GERD symptoms. One in three had GERD symptoms in the past week. But importantly, persistent GERD symptoms in patients taking at least once a day PPI was seen in 54%. So it's a common, common problem. And there's some factors that are associated with this, including more common in females, Latinos, and younger individuals. And other factors can include interesting low BMI, not high BMI, concomitant dyspepsia and IBS symptoms, nocturnal symptoms, and sleep disturbance. So what are the potential causes of refractory GERD? So anytime you see someone in the office, this is kind of like your epic smart list about things that you should be thinking about in someone with refractory GERD. So first of all, is it actually GERD? And the mechanical issues of the GE junction, we'll spend a little bit more time amplifying what's been said. Is there someone with a hiatal hernia? Is there someone who's obese? Is there someone who has increased TLSRs? Is a driver of reflux? Is it related, as mentioned earlier, to noncompliance of PPIs or PPI potency, which is going to be a critical point I'm going to make later? Is it related to reflux hypersensitivity or functional heartburn? So that's within the GERD spectrum. On the alternative diagnosis, you never want to miss a motility abnormality. We're talking about the major ones here, achalasia being the most important, EGJ-alpha obstruction. But the major motility abnormalities, EOE, of course, can present this way rarely, rumination and supragastric belching, as has been mentioned by Felice. Now I'm going to talk more about PPIs in a moment, but PPI efficacy in GERD, the important thing to remember with that is that PPIs are exceed, or excel in healing of erosive esophagitis. But other than that, their efficacy decreases. So for heartburn relief, with or without esophagitis, it's only about 56%. For heartburn relief without esophagitis, it drops down to 40%. And regurgitation relief, about 47%. Regurgitation is the Achilles heel of PPIs. And that is an important thing to remember in refractory GERD, is that if it's regurgitation predominant, it's not surprising that PPIs are not going to necessarily work. So given these factors, what is the optimal diagnostic approach, including what you've just heard about the endoscopic exam and the toolbox that you just saw? Well, again, I want to emphasize something that Felice said, is that when you approach GERD, since there is no single diagnostic test, it's really you're putting the pieces of the puzzle together. And what she said about the story is really important. And I always tell the fellows who work with me in my clinic, is that an Aforga clinic is all in the story. And usually, if you can't figure it out in the first five minutes, you're going to have trouble figuring it out. So when someone says they have reflux, the next question you have to ask is, what exactly do you mean? And the answers are quite, quite varied, as I think you'll see, is that it's critical to say, when you say you have heartburn, what do you mean? When you have regurgitation, what do you mean? And a lot of times, things are north of the neck that they're describing. And that will give you clues. So it's pieces of the puzzle. And you're going to utilize your various testing. You saw this just now. And I think this is a critical slide. This is really your infrastructure of how you approach this and the conclusive evidence you've heard about. The borderline or inconclusive evidence are esophagitis, LA grades A or B, that acid exposure time between 4% and 6%, and that reflux events between 40% and 80%. And then there's the adjunctive supporting aspects, which are part of that puzzle that's really important. So in terms of histopathology, that's not going to help you. In terms of the reflux symptom association, that's a part of the puzzle. But you can't hang your hat on it. And also things like low MNBI is also part of the puzzle. But you can't necessarily hang your hat on it. And the number of reflux events, part of the puzzle. And then finally, on the far right, that issue of anatomy. What does the GE junction look like? Is there a hiatal hernia? And manometry can give you supportive information, but is not diagnostic. So in terms of the approach to reflux, both refractory, non-refractory, that Leon consensus really gives you the best infrastructure how to approach it. Now you've heard of endoscopy in two things. I want to just give you a little bit of a different spin. You heard about that part, recurrent peptic strictures. Hiatal hernia size was mentioned. So when someone puts in a report, moderate, large, minimal hiatal hernia, I have absolutely no idea what's meant. And that's a problem. And that again gets to the first talk that we heard of the importance of language. It's very, very important because it's very simple to measure the length of a hiatal hernia. And the Hill classification is something that most people don't use. Again, you don't hang your hat on it. It's part of the puzzle. So Felice showed this in a table. Here it is in the graph. And it's okay not to remember this. In my endoscopy room, we have all of these classifications on laminated images in the room. And other than the esophageal doctors at Penn, other people don't use it or can't remember it. So LA classification, greater than five or less than five millimeters without breaks, LA grade C is when breaks cross folds involving less than 75%, LA grade D greater than 75%. It's fine to hold up these images, have these images in your endoscopy unit. Hiatal hernia configurations, I think the type 1, 2, 3, 4 is not important. It's really describe what you see. Is there a sliding hiatal hernia? Namely, the GE junction goes above the diaphragm, the fundus is in place. A parasophageal hernia, the GE junction is in place and the fundus slides adjacent to that. A mixed hernia is when you have both the GE junction and the fundus above. That starts getting into interthoracic stomach. And the rarest type of hiatal hernia, when you have other viscera accompanying things. You're going to have trouble describing type 4s in endoscopy. That ancillary imaging is going to help you with that. So the Hill classification was mentioned by the previous two speakers, but what exactly is it? Again, it's remarkable how few people use it. And again, as a standalone thing to hang your hat on, it's not enough. And in terms of that puzzle of refractory GERD, it gives you useful information. Image A is the normal flap valve. So what you see here is the valve is snug to the scope. It extends three to four centimeters along the lesser curve. To the right is a Hill 2, where the valve is less snug and there's space between the scope and the valve that opens with respiration. Hill 3, which I find to be the hardest to cut, it's the most variable, is that you've lost the valve and the EGJ completely does not close around the scope. And then finally, an obvious hernia, which is a Hill 4. So a Hill 1 is totally normal, a Hill 4 is totally abnormal, and a Hill 2 or 3 are in between. And those are useful, again, in putting the pieces of the puzzle together. It's easy to do. It's fine to hang the image, or you can go to Google and look at it any time in your unit. The PROG you've heard about, again, it's still remarkable in this day. And Pratik authored this paper now 16 years ago, how infrequently the PROG classification is shown in endoscopy reports. It's really not that hard. It's the three landmarks that have been mentioned, the diaphragmatic height pinch, the top of the folds, and the square about kilometer junction. And why do we use it? It's not because we're just trying to hammer people with it. It's reproducible, and anything less than one centimeter is not reproducible. So again, in the approach to refractory reflux disease, use the terminology correctly. Remember to put those pieces of the puzzle together nicely. pH testing has already been mentioned, and again, some key points to make. If someone's seen you with refractory GERD symptoms, by definition, they have had a test, but a lot of people haven't. So if someone has symptoms of heartburn or acid regurgitation, and they've not gotten better, and they don't have proven GERD, they need testing, and it should be pH monitoring off of therapy. If it's proven GERD, pH monitoring should be done on therapy, and if you have any of these metrics, you have a diagnosis of reflux. So if it's greater than 6%, again, it's conclusive, 4 to 6 is inconclusive, and then that reflux episodes greater than 80 is an ancillary criteria. This is now on therapy. Now what hasn't been mentioned, I just want to, again, focus on the right-hand side of the slide, is that remember how you use your pH testing to classify individuals. So let's just focus on therapy. So on the far right, if you still have abnormal acid exposure on therapy, you have reflux. Then if you look at normal acid exposure and a negative symptom association, that's considered functional heartburn. If you have normal acid exposure and a positive symptom association, that's reflux hypersensitivity. This phenotyping has implications on how you're going to approach the patient. The functional heartburn patient is not going to get better with all the PPIs in the world, and the person who has reflux is then you're going to think about other approaches to it. Now there's some pH testing pearls that I want to amplify that comes from Prakash's paper on the Leon classification 2018. So again, optimal testing should be done off therapy in someone who has not had testing done before. A symptom index is a measure of effect size, and a symptom association probability is a probability measurement. They measure different things, and as Felice said, they're not perfect, but they're parts of the puzzle. And a combination of both a positive SI and SAP provides the best evidence of a clinically relevant association. Usually that's not the case. You have one or the other that's positive, and then you're still not sure what to do. So it's nice when they come together like that. And it's need to have at least three episodes of symptom reporting to have any utility. So if there's one episode or two, I don't even report it out. It's not going to tell me anything. This is an example here of supragastric belching, especially on the right. You can just see that quick increase in the impedance pattern that you see with air with belching. And then what you can see with rumination, which is usually described on manometer, but you can also see it on impedance pH, is that the postprandial period is shown at the top. Here is the meal. And then you have these rapid postprandial regurgitation events that occur, nonacid reflux that occurs with rapid clearance after a meal. These are challenging patients to identify. High resolution manometry is also part of the approach to refractory reflux. It's not a diagnostic test for reflux, but it excludes major motility abnormalities. It gives you some information on EG junction anatomy as well as function. And it will also give you information about disorders associated with reflux, but not necessarily diagnostic. So if you see ineffective esalvageal motility, that will give you some, again, pieces of the puzzle. The last important point here in the approach is that you can have bonafide reflux, but you can have hypersensitivity or functional heartburn overlying that. What do I mean by that? Someone has diagnosed reflux off therapy, on therapy you fit into on pH testing with continuing symptoms, your pH testing shows either reflux hypersensitivity or functional heartburn. So again, these categories are not necessarily mutually exclusive. So finally, let's turn to how do you approach these patients therapeutically? So there's some simple things that cost nothing. One of them is hard to do, namely weight loss, but it does reduce acid exposure. The postural measures are, again, things to go over with a patient. The issue of elevating the head of the bed is not necessarily easy to do. It's not necessarily good for marital bliss either. And simpler things can be used, like avoiding a meal close to bedtime. Elevation of the bed, you can use something just for one person, not the other. And then sleeping in the left lateral decubitus position, at least trying to do that, can decrease acid exposure. Now again, when you talk about points to remember from this talk, the issue of PPI optimization is really, really important. So oftentimes, people with refractory symptoms or GERD are not dosing their PPI correctly. And BID dosing does control intragastric pH more effectively than once a day dosing. But here's the kicker, and this is a beautiful article from David Graham now from four years ago. We've said forever that all PPIs are created equally, but in fact, they're not. And this is really a systematic review of the PPI literature, looking at the potency of PPIs, looking at omeprazole equivalents. So if you look at omeprazole, 20 in the middle. So 20 of omeprazole is your standard here. So what is 20 of omeprazole? So 20 of pantoprazole, the most favorite PPI of the insurance company, is the equivalent of 4 and 1 half milligrams of omeprazole. Lanzoprazole, it's the equivalent of 13 and 1 half milligrams. And esomeprazole, more potent. And ribeprazole, something that people don't use often, is even more potent. So all PPIs are not necessarily created equally. And one of the key things that I see are people on pantoprazole, if you switch to something else, may do much better than if you're just on, may do better if you switch them to something like omeprazole or ribeprazole. The other point to make here that's very important is that people will go from 20 of omeprazole a day to 40 of omeprazole a day. Bad idea. It's better to split your dosing as 20 BID versus 40 once a day. And this is shown here on the top graphic, where you look at the bottom line. That's once a day dosing. If you look at 40 of omeprazole given once a day versus 40 of omeprazole as 20 BID, the BID dosing regimen gives you greater intragastric acid reduction than the 40 once a day. So it's best to try to split dosing versus going to a double dose. And it's no better if you go to triple dosing than BID dosing. So the issue of PPIs, the bottom line is as follows. BID dosing is preferred to high dose once a day dosing. Omeprazole is best avoided unless it's working for the patient. So the paper that was referred to by Reina that the AHA clinical practice update came out regarding pharmacotherapy and GERD phenotypes, there's some adjunctive things you can do. Alginates are good for breakthrough symptoms. It neutralizes the postprandial acid pocket. This is available through Google as Gaviscon advanced through Europe. Nocturnal S H2 blockers are good to be used intermittently, but it's limited by tachyphylaxis. So daily use of a nocturnal H2 blocker is best avoided. Baclofen may be used for regurgitation or belching, but it's limited by adverse events. And prokinetics only if there's documented gastroparesis, it really has no role in most people with reflux. What about the mechanical approaches? Antireflux surgery, be it traditional or with magnetic sphincter augmentation will improve refractory GERD symptoms, especially if it's regurgitation predominant in individuals with proven GERD. A Roux-en-Y is a good approach for individuals who are obese with refractory GERD. As far as TIF goes, it provides short-term improvement in regurgitation and limited long-term data right now. However, there is no improvement in acid exposure time compared to PPIs alone. And radiofrequency ablation, I think the benefits are mixed and probably should be best avoided. And finally, what do you do for people who don't fit in those categories? Functional heartburn, reflux hypersensitivity, hypervigilance, or behavioral disorders such as supragastric belching or rumination. While pharmacologic neuromodulation may help for some, but cognitive behavioral therapy is critical, especially for things like supragastric belching and rumination. Hypnotherapy may work and diaphragmatic breathing is part of that package along with relaxation strategies. Just a word on von Oppersam, where that's going to fit in the future is unclear. It is a potassium competitive acid blocker. It blocks the potassium channel of the pump. It's independent of food in contrast to PPIs. It's reversible. It has a very rapid onset of action, and it leads to very prolonged and consistent elevation intragastric acid. So is this the answer to the patient's problems? We don't know yet. And in a meta-analysis looking at this, you can see that when you look at compared to standard dose PPIs, lansoprazole, or esomeprazole, really there is a variable gain. And the key thing is that it's rapid, and symptom resolution is more rapid. You can see it the one week. But in terms of healing, it may be more rapid. But the gain is unclear that what we're going to get with this. So to summarize, refractory GERD symptoms applies only to patients with prior objective evidence of reflux. Refractory GERD is persistent objective evidence of GERD despite being on a BIDPPI. It's a common clinical problem, and pH monitoring is critical to phenotyping patients correctly. And phenotyping patients will guide your therapy. Remember the pieces of the puzzle concept. I thank you all for your attention. I look forward to questions at the end of the session.

refractory GERD

treatment

GERD

prevalence

diagnostic approaches

therapeutic approaches