We are actually going to continue with Dr. Thotta. Her next talk is entitled, The Next Logical Sequence, the PPI is not working. So what do you do then? What's next? When to consider endoscopic and surgical minimally invasive therapies incurred? As we have seen from the previous talk, about 10 to 50% of patients continue to have refractory symptoms in spite of PPI therapy. And then when they have symptoms, it is good to make a distinction about what exactly are the symptoms they have. One is refractory reflux like symptoms, where the symptoms may or may not be GERD related. And then the patients with refractory GERD symptoms, that is the patients have a prior diagnosis of GERD, and now they have persisting symptoms, which may or may not be related to ongoing reflux. So these are like the overlap syndromes. And then finally, refractory GERD itself, where there is persisting objective evidence of GERD, despite taking adequate PPI therapy, that is they have either erosive esophagitis on the endoscopy, or they have an abnormal pH test, or pH impedance test on PPI therapy. So these are the numbers which are good to know. For patients with persistent esophagitis on standard dose PPI therapy, in grade A esophagitis, 8% continue to have persistent esophagitis. In grade B, about 15%. And in grade C, about 20%. And in grade D esophagitis, almost 30% of the patients continue to have persistent esophagitis in spite of taking standard dose PPI therapy. So what are the causes of refractory PPI, GERD refractory to PPI? So it may be from several reasons. So one is that there is a true reflux going on. So there is a disrupted antireflux barrier, or there is increased transient TELUS relaxations, impaired esophageal clearance, or inadequate acid suppression, a significant hernia, obesity can contribute to refractory GERD. Then there is a reflux hypersensitivity, which we touched base on briefly before. So there is normal esophageal acid exposure, but physiologic reflux episodes cause the symptoms. And then there are patients who truly don't have GERD, but they have other esophageal disorders, which mimic GERD, like say, eosinophilic esophagitis, echolacea. And there could be underlying gastroparesis where patients continue to have acid regurgitation or food regurgitation going on in spite of taking PPIs, rumination where there is a voluntary regurgitation going on. And then the symptoms are functional, that is, it is not because of GERD or any other disease pattern. So here is a study, a randomized controlled trial published in a New England Journal of Medicine from Speckler, Speckler's group. So there are 366 patients who were screened for the study. And then ultimately there were only 78 patients who became, who are eligible to be candidates for the study, who went through the study. But look at this numbers over here. So on optimization of therapy, in those 366 patients on optimization of therapy, 42 patients responded with increasing the PPI therapy, giving them before meals and with the lifestyle modifications. Then another 23 patients among those, a minority of the patients had esophilic esophagitis or they had Echolacea or EGG outflow obstruction or so. And then 99 patients, so we are talking about almost 25% or so, they had functional heartburn. So how do we approach refractory GERD? And we went through this briefly too in the previous talk, is in patients who did not have a prior diagnosis of GERD, optimize the PPI therapy, if there is symptom relief, continue with that. If there is no symptom relief, get them off the PPIs, get them off the PPIs, do an endoscopy. So if it is an abnormal endoscopy, then treat for whatever is found. If it is a normal endoscopy, then reflux monitoring of the PPI therapies. And if there is no evidence of GERD, that is the pH is less than 4% of the time, then look for other causes. So abnormal endoscopy, so if there is erosive esophagitis or a long segment battered esophagus or so, that is almost diagnostic of GERD and no further evaluation is necessary. And then we can talk about either increasing the PPI therapy, adding the H2 blockers or discussing about endoscopic therapy or about the surgical options. And in patients with previously defined GERD who continue to have symptoms, again, if there is optimized therapy, and if there is unsatisfactory symptom relief or so, and if the primary symptom is regurgitation, consideration for fundoplication, TIF, or LYNX procedure in those patients, and then also performing the impedance testing on PPI-BID. And if it is normal, so where it is normal, the reflux episodes, less than 40 reflux episodes in a 24-hour period of time, that is considered as normal, so look for other causes. And if it is abnormal, then consider all the treatments that we talked about. So medical therapies, one thing we can add is to add Baclofen or H2 blocker at bedtime, and then considering the endoscopic or surgical interventions in these patients. So what are the surgical therapies we have? The standard surgical treatment for gastroesophageal reflux disease is fundoplication. So a fundoplication can be complete, that is a 360-degree wrap, which is a nascent fundoplication, or partial, this is what Dr. Iyer alluded to in his previous talk, it is either the tupe fundoplication or the door fundoplication. Then there is the gastric bypass surgery, run by gastric bypass in obese patients with absent peristalsis or so. Why is that? What exactly are you accomplishing with that? It is a parietal cell diverting procedure, because the majority of the stomach is not in continuity with the esophagus, there is less chance of reflux. And then the other one is a magnetic sphincter augmentation, or the LINX procedure. How do the LNF, stands for laparoscopic nascent fundoplication, versus the PPI therapy, how does it compare? This is a Lotus trial, and then 554 patients randomized to either the anti-reflux therapy or PPI therapy. Main thing to know is there are very few patients, probably around 10, 11 patients or so in each of the groups with grade C or grade D esophagitis. So when you look at these numbers, the PPIs seem to be almost equivalent to, or sometimes superior to fundoplication at the end of five years. So in 92% there is improvement in symptoms, in the anti-reflux group 85% improvement. Heartburn, regurgitation, much more improvement in the fundoplication group than in the PPI therapy group, is not significant. Dysphagia, more with the fundoplication group, as well as the bloating and the flatulence too. So when we are talking about fundoplication for patients with refractory reflux or so with severe reflux disease, we do have to mention about these possible after effects with fundoplication therapy. What are the indications of the fundoplication? It is in patients with severe reflux disease with grade C or grade D, large hiatal hernia. So it is an anatomic abnormality. This cannot be fixed with PPI therapy and in patients with troublesome regurgitation or so, fundoplication is more effective than PPI therapy. What are the other special circumstances when fundoplication is considered? A few things. One is long segment barrett's esophagus where it is refractory to radiofrequency ablation therapy. So this is from the Northwestern group and then patients who did not have complete eradication of intestinal metablasia after three ablation sessions, they went to the pH testing. And then that group of patients who had abnormal pH testing underwent antireflux therapy. And then in those, about 95% of the patients achieved complete eradication of intestinal metablasia. So that is something to be considered in this special group of patients. The other one to think about is lung transplant patients. In lung transplant patients, GERD is very common. So early fundoplication is indicated in this patient rather than late fundoplication because PPI therapy itself is not effective in this patient. The reason is if there is ongoing reflux or so, that leads to the rejection of the transplant. So when early in one study, when the early fundoplication is compared to the late fundoplication group, in the late group, the FEV1, the post-expiratory volume decreased by 8.9% at three years and then 40.7% at five years. So that is other indication we do fundoplication for lung transplant patients in our center. The third indication for fundoplication is in patients with achalasia who go through a Heller myotomy. If a Heller myotomy is done without any fundoplication or so, about 48% will have pathologic reflux afterwards. So when you do a partial fundoplication, like a door fundoplication, the 180 degree fundoplication, it decreases to about 9% or so. You do not want to do nascent fundoplication because it defeats the purpose. Patients will continue to have dysphagia. So here is that study I mentioned to you about refractory reflux looking at medical or surgical therapy. So among these patients, so 78 patients who had either a positive, who had either a positive pH impedance study, or they have a positive symptom association probability, or both. So they are randomized to these three groups. One is the fundoplication, and then active medical treatment with omeprazole and baclofen. And then neuromodulators could be added to in this regimen. And then the control medical therapy with the PPIs only. So what was found was about approximately 67% there was an improvement in the quality of life, as opposed to 28% with the combination of omeprazole, baclofen, or antidepressant therapy, and 12% with just the PPI therapy alone. So if patients have refractory heartburn on the testing, on PPI therapy, good idea to consider something else. And as I have mentioned to you, our practice is to add an antidepressant or so before suggesting fundoplication to the patients. Baclofen is not something which we commonly use, and the reason is because of the after effects. It causes a lot of drowsiness or so. So even though there is symptom response, the quality of life is not so good. Going on to the other surgical intervention which is available, the magnetic sphincter augmentation. It has recently emerged as a minimally invasive surgical option. And then when we look at this, the abnormal acid exposure normalizes in about 58% at one year. And then the PPI use decreases. So at baseline, all 100% of the patients are on PPI therapy. So these are patients with refractory reflux. And then it decreases and then stays the same up to year three. Remarkable improvement in regurgitation. So in patients with volume regurgitation or so, something to be thinking about. As opposed to fundoplication or so, one downside of this LYNX procedure is increased dysphagia. About 68% have dysphagia right after the procedure. The dysphagia is much more than what is seen with fundoplication or so. And then gradually over a period of time, the dysphagia does decrease. And there is a high patient satisfaction with the LYNX procedure, which seems to be sustained for up to three years or so. So in terms of the objective measures, these are the measures. When you look at the pH testing, in the average pH testing, pH time was 11 at baseline prior to the procedure, which decreased to 3.3. So that is normalization. Demister score has improved from 36.6 to 13.5 at the end of year one. So what are the outcomes at five years from the same randomized control trial, from the same trial is about, this is the good related quality of life questionnaire. Higher score means bad quality of life, lower scores, good quality of life. So at the baseline in patients without PPI therapy, the score was 27, which decreased to 11 with PPI therapy. And then at five years, it is still sustained. So good quality of life at five years with the LYNX procedure. And then same goes for the PPI usage to PPI usage in 11% of the patients. So compared to, compared to a LYNX procedure, comparing the Nissenfront application to the LYNX procedure, when we see there is a good improvement in the GERD questionnaire, there is this persistent dysphagia. And then in fact, the bloating is much less. The bloating is much less with the LYNX procedure as opposed to the Nissenfront application. And the patients are able to belch with the LYNX procedure. So that is advantage over Nissenfront application. A couple of things to remember though, is there is a, in view of troublesome symptoms or so, it has to be removed in about 16% of the patient. And the patient satisfaction is not so great compared to the Nissenfront application procedure or so. So at this time, what are the advantages of the magnetic sphincter augmentation over the Nissenfront application? Main thing is it is minimally invasive and then there is less bloating. However, dysphagia is more compared to the Nissenfront application. And at times, it has to be, device has to be removed too. So going on to the endoscopic therapies, I'm going to discuss about the main endoscopic therapies. One is STRETA. Second one is the TIFF, which has the best evidence so far. And then the antireflux resection and then the antireflux ablation, mucosal ablation or so. So the mechanism of action of STRETA, what does STRETA do is supposed to modulate the lower esophageal sphincter pressure. So is it because of fibrosis? The answer is no. It seems to decrease the transient ileus relaxations. So here is a demonstration of how STRETA is done. It is a catheter which is passed under endoscopic guidance to the gastroesophageal junction. And then there are these electrodes which come out, small needles, and then they deliver the radiofrequency energy at the lower esophageal sphincter. The distal two centimeters of the esophagus and the proximal two centimeters of the stomach or so. And then this leads to improvement in the lower esophageal sphincter pressures and then decrease the transient ileus relaxations. So here is a meta-analysis, which shows that including all these patients who underwent STRETA and then pre-STRETA, the esophageal acid exposure was about 10.3. After post-STRETA, it did not normalize. It was still about 6.5 or so. Improvement in the demister scores and then improvement in the basal ileus pressures or so. But a good improvement in the quality of life measurements. Then a repeat meta-analysis, including some of the trials which were not included in the previous meta-analysis, showed that there is no significant benefit of STRETA over the SHAM therapy. There was no change in the symptoms, no change in the lower esophageal sphincter pressure, no change in terms of discontinuing the PPI or so, or no change even in the quality of life measures. In addition, STRETA can be associated with some serious complications, and then aspiration pneumonia has been reported, and then gastroparesis. So, and because of these reasons, STRETA fell into disfavor, because there is no objective evidence of improvement in good. So going on to the TIF. So going on to the TIF, TIF or the transoral incision-less fundoplication or the endoscopic fundoplication using the esophagus device, what it does is it requires two operators, one passing the endoscope, one operating the esophagus device. What it does is it reconstructs the lower esophageal sphincter endoscopically. So it creates a two to four centimeter long valve with about a 270, almost complete, but not 360, about 270 degree fundoplication. And then the device is loaded onto the shaft of the endoscope, and then they're advanced into the stomach. And then the endoscope is retroflexed to look at the gastrocardia, and then the esophagus device, the fasteners are placed about one to three centimeters. Now the G-junction to fuse that distal wall of the esophagus and the proximal wall of the stomach. So this is a RESPECT trial, very elegantly done study with a placebo component. So the study group got the TIF and the placebo, whereas the control group got the sham procedure and then the PPI. And then the main primary outcome looking at was at the regurgitation, refractory to PPI therapy. So when you look at this value, so the orange is the TIF procedure. So the acid exposure time before the procedure was 9.3, after the procedure was 6.3. And then with the PPI therapy, before the treatment 8.6, after the treatment, it remained the same, 8.6% of the time, 8.9%. Then the GERD symptoms before the therapy is 3.1. And then after it went down to 0.6, this is a regurgitation we are looking at, whereas with the PPI therapy, that's the blue, before and after it remained roughly the same. So in terms of regurgitation response was noticed in 67% of patients, and then 45% on the PPI therapy immediately after the treatment, whereas at three months after the treatment, regurgitation improvement was noticed in 90% of the patients with TIF therapy and about 64% improvement in the PPI group. So what are the long-term results of the TIF? These are the TIF results, the five-year results of the TEMPO trial. So the troublesome regurgitation was eliminated in about 86% at five years. In terms of the atypical symptoms, about 80% resolution at five years. And there were about three reoperations within that five-year follow-up group. And at the end of five years, about 34% went back on daily PPIs. So one third of the patients, which is still not bad. One thing to remember is the fundoplication is also not a permanent fix, permanent cure. So it is a long-lasting measure to control the acid reflux, but it is not a permanent cure for acid reflux, which can last over the patient's lifetime or so. The patient should be counseled on that when we are discussing about the treatments. And also at five years with TIF, there is a great improvement in the quality of life. There is 22 at the start of the trial to 6.8 at the end of five years. So this is a meta-analysis by Richter's group looking at all the different therapies, TIF versus fundoplication versus the PPI therapy. So when you look at these numbers, these are the numbers to say the probability, like say the black is the fundoplication. So there's a 0.99 probability that the pH is improved. That's what this means. So the higher the number, the better it is. So LES pressure increase maximum with fundoplication. Here is the interesting part. So the improved quality of life measures, the best is with the TIF therapy. And also with the sham therapy too, you see, or the placebo, you see a significant effect. And in terms of the persistent esophagitis, at least with the fundoplication. So what they concluded is that the fundoplication is superior to TIF or to PPI therapy in terms of the persistent esophagitis, LES pressure increase, and then the improved acid exposure time. In terms of quality of life, TIF is better than PPI therapy or fundoplication. And the same goes for the placebo too. Placebo is significantly better than the PPI in terms of the improvement in the quality of life. Here is the outcomes that I have mentioned before. So going on to exciting procedures, which are simpler to do, is the antireflux mucosectomy. First reported by Inouye, the father of POEM procedure for Echolacea. So what was done is EMR was done of the fundus right below the G-junction at the gastric cardia. And then with this, the goal is removing this and leads to tightening a stricter formation to prevent the reflux eventually. So what he has noticed is an improvement in the heartburn score, the regurgitation score, and then a remarkable improvement in the acid exposure time. So 29% acid exposure time before to 3.1% after. So this is all the data we have for the antireflux EMR procedures. So at one year clinical success, what is success? Success is defined as symptom relief is about 61%, three-year clinical success is about 76%. And then about 60% of patients were able to get off the PPIs at one year. Overall adverse events, about 10%. The main thing is four perforations have been reported so far with this procedure. And then dysphagia requiring dilation in about 7% or so. Then the next procedure is the antireflux mucosal ablation treatments, very elegant procedure using APC therapy, using the Herbijet, the hybrid APC catheter, a creating a submucosal cushion at the gastric cardia, and then doing the ablation at the gastric cardia. So in this trial, 108 patients were recruited. And then the median acid exposure, the median time it took to do the procedure is about 35 minutes. And then the circumferential ablation was about 300 degrees. It's not a complete one. And about 14 patients required stricter dilation. So what we're seeing is an improvement in the acid exposure time from 18% to 19% to 3% or so. Improvement in the DEMISTER score from 42 to 9. And then improvement in the quality of life, GERD-related quality of life questionnaire scores from 36.5% to 10% or so. So here is the, after the ablation, about 300 degrees or so, and then completely healed afterwards. So here is the meta-analysis of all the patients who underwent mucosal ablation. So clinical success about 90% at one year and 72% at three years. About 68% of patients were off PPI therapy at one year. Overall adverse events about 13%. And then dysphagia requiring dilation in about 10% or so. So things to remember, who are the ideal candidates for these therapies are patients who truly have objective GERD in spite of being on PPI therapy. And then exclusion is things to remember. Patients with really severe GERD, that is grade C, grade D, esophagitis, battered esophagus, hiatal hernias more than two centimeters or so. And then heal well grade IV endosophageal dysmotility or contraindications at this point of time for either the endoscopic therapies of gastroesophageal reflux disease or for LYNX procedure too. So before contemplating either the endoscopic therapy or the surgical therapy, things to remember, optimize the PPI therapy. Make sure patients are compliant, taking 30 to 60 minutes before meals, switch to twice a day, switch to a different PPI, and then all the lifestyle modifications. Patients continue to have symptoms, then do the pH testing, do an endoscopy, look for all these different things, the battered esophagitis, if there is persistent esophagitis, size of the hiatal hernia, if there is any suggestion for eosinophilic esophagitis. Then do a high-resolution manometry to rule out echolacea or we're dealing with ineffective esophageal motility or the EGJ outflow obstruction. Multiple rapid swallows to assess for the contractile reserve. Then the pH testing to confirm the disease. And about 10% of patients with refractory GERD have gastroparesis, so if they have symptoms such as nausea, vomiting, early satiety, postprangial bloating, or so, consider doing a solid-phase gastric emptying test too. Thank you.

refractory GERD

PPI therapy

esophagitis

antireflux barrier

esophageal disorders

treatment options

patient selection