The talk is entitled, The Best and Worst of PPIs, Perls in the Medical Management of Gastroesophageal Reflux. Are we all good? Yes. Go ahead. Okay. So no additional disclosures, I've not developed any in the past 30 minutes. So GERD is one of the most common GI diagnosis in the United States. The annual direct cost of GERD is about 12 billion in 2004, and it has increased to 18 billion by 2015 or so. So PPIs are one of the most common given prescriptions after the statins only. And then the peak expenditure for the PPIs was in 2008, 2009 period, remember the time of Great Recession. So it peaked up to 36.7 billions. And then afterwards with the availability of the generic PPIs or so, the expenditure has come down to approximately 20 billion or so in the year 2016 to 17. However, the overall proportion of the PPI users have increased, used to be around 5.7 20 years back. And then the latest figures we have available about 6.7% of the US population use PPIs. What are proton pump inhibitors? These block the terminal step of the acid secretion. For them to be effective, they have to be acid active proton pumps. So that happens when we are eating or so. But the problem with that is the PPI absorption may be diminished by four. So they need to be entry coated. The half-life of PPIs are short, and then the half-life of pump is long. So you will not have an immediate onset of action. It would take about five to seven days of PPI therapy to reach a steady state. So and also the acid pumps in the stomach regenerate once they're gone. So the drug must be taken daily for them to be effective. And a couple of other things to know about PPI therapy is that these are metabolized by the cytochrome P450, the 2C19. And then because of the polymorphisms, there are different variations, individual variations in the pharmacokinetics and the pharmacodynamics of the PPIs, different PPIs in different patients. Main thing to know is acid control equates to esophagitis healing. Now here is an elegant study by Dr. Katz. So on the x-axis is the percentage of time when there is acid control, that is the pH is more than four in the stomach. And then on the y-axis is the proportion of patients with healed esophagitis. So the longer that is acid control within the stomach, the greater the esophagitis healing. And then with the different PPIs, we see that the healing of the erosive esophagitis is over 85% or so. And then we see with the isomiprazole or the Nexium, this healing is slightly somewhat better than the other PPIs such as the omeprazole, lansoprazole, and then the phantoprazole. The incremental effect seems to be about 5% or so compared to the other PPIs. However, PPIs are not as good for healing of LA grade C and grade D esophagitis. And then what we see is much lower values with other PPIs, usually within the 70 to 80% range or so. And then with Nexium, approximately 80 to 90% range or so. And in terms of the symptom resolution, there is a disconnect between the subjective findings as well as the subjective features, subjective symptoms, as well as the objective findings or so. So a symptom resolution is not necessarily as good as we see in terms of the healing of the erosive esophagitis or so. So for most of this PPIs, it is within the 60 to 75% range. When it comes to the acid suppression, when we look at H2, the histamine receptor blockers versus the proton pump inhibitors, they're really good. The 12-week freedom with H2 blockers in terms of symptoms is about 50%. And in terms of the PPI therapy is about 80% or so. In terms of the healing of the erosive esophagitis, histamine receptor blockers are not as good, approximately 50% as opposed to 90%, 80 to 90% or so. And in speed of healing too, there's a difference, 6% healing per week with H2 blocker therapy versus 12% healing with the PPI therapy. And then with the PPIs, the frequency of dosage matters too. So when you look at the acid control, when once a day dose is given, so 66% of the time there is acid exposure within the stomach. And then when it is given before the dinner in about 31% of the time, there is acid exposure going on within the stomach, intragastric pH. And then, but when that 40 milligram dose is split, so 20 milligrams before breakfast and 20 milligrams before dinner, that acid exposure time in the stomach gets down to about 20% or so. So in patients who are not responding to once a day PPI therapy, it is entirely reasonable to split the dose and split it into twice a day therapy before meals. And then, but the control at night is not as good with the PPI therapy, even with the once daily dose. And as you see here, it is the nocturnal exposure, when there is a nocturnal abnormal acid exposure over 60% or so with a morning dose of PPI therapy, which decreases to about 40% or so with the evening dose. And with the BID dose, it decreases much more, approximately about 30% or so. And the other thing to know is that the PPIs do not decrease the reflux episodes when we do a 24-hour pH study. So what they do is on PPI therapy, what happens is the number of non-acid or the weakly acidic reflux episodes increase. So the total number of reflux episodes are the same on or off PPI therapy, but the proportion of the non-acid and the weakly acidic reflux episodes increase on PPI therapy. And then the other thing to know is that the PPIs are not effective for reducing the regurgitation. And the reason is because the regurgitation is an anatomical defect at the gastroesophageal junction because of the hiatal hernia or because of the weak LES, lower esophageal sphincter or so. And then here is a study comparing the LYNX procedure or the magnetic sphincter augmentation to twice-daily PPI therapy. And then the people who had control or no regurgitation is only about 3% with the PPI therapy, whereas it is approximately 80% with the LYNX procedure or the magnetic sphincter augmentation procedure. However, recently there have been several news reports, observational studies in the past decade about the adverse events with PPI therapy, myocardial infarction, chronic kidney disease, dementia, ischemic stroke, asthma risk to pregnant mothers, visual hallucinations, macular degeneration, fractures, interaction with plavix, increased risk of pneumonias, C. diff. So PPIs have been known to be associated with various adverse effects in various systems or so. However, this is the latest summary of the increased risk associated with PPIs recently published in the ACG guidelines on gastroesophageal reflux disease. Some we know the underlying mechanisms and some we do not know. But what we see is if you look at the hazard ratios or the ARDS ratios, the numbers are very small. These are mostly from the observational studies or so. So in terms of the cardiovascular events, what we know is that the PPIs, the block, the metabolism of what is called ADMA or asymmetric dimethyl arginine, and the increased levels have shown to be a strongest risk factor beyond the traditional risk factors for cardiovascular events and then cardiovascular mortality in patients with coronary artery disease. So PPIs seem to block the metabolism of this chemical. And then the reason mechanism underlying the interaction with plavix is that PPIs are metabolized by the cytochrome P452C19, which is needed to activate plavix. Then the acute interstitial nephritis is thought to be an aureosyncratic drug reaction. Then the increased risk of C. diff and then the enteric infections is because of the decreased gastric acidity, which led the enteric pathogens thrive. And the same is the mechanism for SIBO, which is the small bowel bacterial overgrowth, and then the spontaneous bacterial peritonitis. And then these are all the various other adverse events purported to be associated with PPI therapy or so. However, one thing to remember is that most likely there are confounders by indication, which surprisingly is not addressed in most of these observational studies or not. What to remember is that these patients on PPIs are sicker than the patients who are not. And in these papers, we do not know what is the indication for the PPI use. And then, so the confounders are not controlled for in these observational studies. And then association does not necessarily prove that the PPIs are causing these adverse events. So the one thing reassuring news about the PPIs is based on the two recent randomized control trials. One is the ASPECT trial. So the ASPECT trial has 2,550 patients with varicose esophagus followed for almost nine years. And then the patients are divided into four groups. One is, there is a low dose Nexium 20 milligrams a day, a high dose Nexium 80 milligrams a day. So that is 40 milligrams twice a day, and then plus or minus aspirin. So there is a 20 milligram Nexium, no aspirin, there's a 20 milligram Nexium plus aspirin, and then there is a 80 milligrams Nexium, no aspirin, and an 80 milligrams Nexium plus aspirin. So when we look at the side effects in all these four groups, there is no significant difference in terms of any of the possible side effects, including the cardiac events or so. And then here is a total amount of side effects in each of these groups with the low dose PPIs, the high dose, or plus or minus aspirin. And then related to aspirin and then isomiprazole are very minute numbers that we see here. So this is reassuring to know that there are no statistical significant difference in terms of the various side effects with or without the low dose Nexium or the high dose Nexium. The second one is the recent trial, the COMPASS trial for patients, approximately 17,600 patients with cardiovascular disease or peripheral vascular disease. And then they're randomized to this different rivaraxaban, aspirin, and then received either pantoprazole or placebo. And then they were followed for a median of about three years or so. And then in these patients, there is essentially no difference with or without aspirin. So look at this ARS ratios. Of course, the ARS ratio for C. diff is high. The P value is not significant, but look at the number of events with pantoprazole, nine events on the placebo group, only four events. So there seems to be a slight trend towards enteric infections, which is expected. P is 0.04. But other than that, there is no significant differences in all this purported side effects of PPI therapy. So the other thing is the interaction with clopidogrel. And then this interaction came into news probably about 10, 11 years ago. And then the FDA recommendations at that time was to avoid omeprazole and isomeprazole with clopidogrel and prefer lansoprazole or pantoprazole because it has no effect on the C2 cytochrome P450 to C19. And then after the FDA warning, the gastroenterology groups and the cardiology groups got together and then recommended PPI therapy in those with history of upper GI bleeding and who are at high risk for GI bleeding or so. This is advanced age, the patients who are on anticoagulants, TDRs or NSAIDs and patients with history of H. pylori infection. And it is not recommended for patients at lower risk of upper GI bleeding. Now, the current consensus about using clopidogrel is it is the same whether patients are on Plavix or not, is see if the symptoms can be controlled with H2 blockers or so. But if it is a patient with erosive esophagitis or battered esophagus and they need to be on Plavix, it is reasonable to give a PPI therapy too, because we do not know what the extent of the, what the clinical significance of this interaction is. Here is a recent systematic review of the PPI therapy and the concomitant PPI therapy and clopidogrel therapy. It includes 156,000, 157,000 patients, MAIS stands for Major Adverse Cardiovascular Events. And then when you look at this numbers, there is a slight increase in the patients on concomitant PPI and then clopidogrel therapy. However, when the subgroup analysis was restricted to the randomized control trials, it was not significant at all. So this is reassuring to know in terms of the interaction with clopidogrel and also in terms of the, all the other side effects, which were noted in the observational studies. Coming to the other interventions for medical management, gastroesophageal reflux disease, lifestyle modifications, use of prokinetics, antacids, baclofen. And one of the new drugs is the potassium acid channel blockers, which are an improvement over PPI therapy. So but at this time, they're not available in US, but there are trials going on to look at patients with erosive esophagitis or so. So what are the different lifestyle modifications? One is weight loss, avoiding late night meals, avoiding fatty meals, carbonated beverages, then avoiding alcohol, stop smoking, and then sleeping with the head elevated and then sleeping with the, on the left side, because when you sleep on the left side, the gastroesophageal junction is above the dependent portion of the stomach. So is there any strong evidence? The answer is no. But is it recommendable? The answer is yes, because they are easy to do and then patients do have symptom relief. So here is a study of the MedKline pillow or the nocturnal positioning device. And it does seem to decrease the esophageal acid exposure by 87% when compared to sleeping flat or on an incline in normal volunteers. So this is a study, a small study on patients with nocturnal reflux symptoms. And after two weeks of use, there is an improvement in the quality of life nocturnal GERD questionnaire, as well as in the 24 hour GERD quality of life questionnaire too. Regarding the other medications, Baclofen is a GABA amino butyric acid agonist. And then what does it do? It reduces a transient LES relaxations. So that's the main mechanism behind the reflux episodes. So it is good to add in patients who have refractory reflux and then a belching or so. A nighttime H2 receptor blockers, they decrease the nocturnal acid breakthrough on patients on PPIs from 64% to 17%. And then there is an improvement in the intragastric pH from 31.5% to 18%. Prokinetics, among the prokinetics, metoclopramide is not recommended. Think of tardive dyskinesia. Dampyridone has symptom relief, but there is no objective evidence to suggest that. Recently, the procaliprite, which is used for treating constipation, seemed to reduce acid exposure time from 3.4 to 1.7 in a short case series or so. That is something, a potential possibility. Alginate can provide symptomatic relief and sucralfate also provides symptomatic relief, but there is no comparative data with PPI therapy or so. So going on to this potassium channel acid blockers, in contrast to PPIs, they provide a very fast inhibition of acid production. They bind both to the active and inactive forms of the proton pump. Remember, the PPIs bind only to the active forms, and then you can get a full effect from the first dose. And then they are meal-independent and we don't have to worry about the pharmacokinetics being affected by the C2-19 polymorphisms. So wonaprazone is a potassium channel acid blocker, and this is a study from Japan, comparing it to the Prilosec. And when you see erosive esophagitis or so, a 99% healing with wonaprazone as opposed to about 95% healing with lansoprazole. However, when you look at grade C and grade D esophagitis, there is a vast difference. So that may be a potential possibility in the future for medical treatment of grade C and grade D esophagitis. So in terms of the PPIs, things to remember is that these are overall, they're safe, and then they improve the quality of life. And in patients who require PPI therapy for control of good, the only other alternator is surgery. So in terms of the treatment for gastroesophageal reflux disease, depends on the patient, and then it's reasonable to start with the PPI or H2 blocker. And then if there is no response, do not continue, may require evaluation, re-evaluation. And then if the patient is not better with optimizing the PPI therapy, so making sure that the patient is taking it before meals, then switching it from once a day to twice a day, or switching to a different PPI are all reasonable. And if there is no response, proceed with EGD, with esophageal pH monitoring. And then if the patient truly are not responsive to optimized PPI therapy, and if they have objective evidence of good, that is a pH more than 6% on pH monitoring, they're good candidates for endoscopic treatments or surgical evaluation. And if the patients do not have objective evidence of good, then get them off the PPI therapy. And then do not be afraid of using long-term PPIs in right patients, that is patients with erosive esophagitis or battered esophagus. And that's it. Thank you.

PPIs

GERD

acid secretion

esophagitis

adverse effects

alternative treatments