William D. Chey, MD: Hello. I'm William Chey, Professor of Medicine at the University of Michigan Health System in Ann Arbor, Michigan. I'd like to welcome you to this Medscape CME Spotlight panel discussion, "Contemporary Issues in GERD: The Economic and Clinical Burden of Disease." This program will address the clinical and economic burden of disease attributable to gastroesophageal reflux disease, or GERD, including the impact of GERD symptoms on patients' quality of life and strategies in medical management.

I'm joined today by my colleagues, Dr. Joel Heidelbaugh, Clinical Associate Professor in the Department of Family Medicine at the University of Michigan Medical School in Ann Arbor, Michigan, and also by Dr. Michael Vaezi, Professor of Medicine and Clinical Chief at Vanderbilt University Medical Center in Nashville, Tennessee. Welcome.

Let's go ahead and start by providing some background and context with regard to the discussion that will follow. Acid-related disorders, such as GERD, are prevalent conditions that are associated with significantly impaired health-related quality of life and considerable economic and clinical burden. Since 2006, GERD has been the most common gastrointestinal (GI)-related diagnosis made in outpatient office visits. Its prevalence is increasing, as are the costs to the healthcare industry, as well as to employers.

Possible explanations for the increasing prevalence of GERD include obesity as well as changes in sleep and an aging population. For example, a study in 1992 found that approximately 13% of respondents reported at least weekly heartburn in the prior year, whereas a more recent study performed in 2004 reported this to be greater than 23%.

In addition to symptoms, GERD can lead to a number of important clinical consequences, including erosive esophagitis, stricture formation, Barrett's esophagus, and esophageal adenocarcinoma.

Patient groups that can present greater challenges to providers include those with more severe grades of erosive esophagitis, patients with persistent reflux symptoms despite maintenance proton-pump inhibitor (PPI) therapy, obese and elderly patients, and patients with Barrett's esophagus.

The economic burden of GERD is considerable. GERD is a chronic disease and so it causes significant economic impact due to the expenses of long-term management. A study on the burden of chronic GI disorders found that GERD was the most expensive, with direct and indirect costs totaling approximately $10 billion per year.

So, Joel, many times payers dismiss GERD as a lifestyle illness -- the implication being that if a disease doesn't lead to mortality it may not be worth paying for. Can you provide us with information and insights that might help to put the effect of GERD on quality of life into perspective?

Joel J. Heidelbaugh, MD: Bill, in primary care, GERD accounts for approximately 5% of all visits. That is 1 out of 20 patients. We are seeing an increased severity and frequency of GERD symptoms that's associated not only with more concomitant diseases but a much lower reported health-related quality of life and lower work productivity. This is significant and this is what brings a lot of patients into primary care offices. Therefore, patients with even moderate, severe, or frequent symptoms have more concomitant disease and a lower quality of life compared with those with milder disease. This has been shown both in patients who have had endoscopy and in patients who haven't had endoscopy.

Some quality-of-life issues that we see in our practices include decrease in work productivity, absenteeism, and sleep disruption, which is a more common issue related to GERD and has an impact on psychosocial functioning and next-day functioning. Subjects with untreated GERD have lower health-related quality of life than the general population. In fact, one study found that patients with GERD even have lower reported health-related quality-of-life scores on standardized questionnaires than patients with diabetes and congestive heart failure. Enjoying food, eating out, family activities, socializing, exercise, and intimate time with a spouse, as well as hobbies, have all been affected and implicated [by GERD symptoms].

[As mentioned,] Validated questionnaires have shown all of this multiple times. Therefore, in primary care, it's been a challenge to manage [GERD and these quality-of-life issues] effectively. Surveys in the community further highlight disrupted sleep and reduced concentration at work, and interference with physical activity, especially the inability to even engage in physical activity because of poorly controlled GERD, is significant.

Primary care providers are often the first point of contact for patients who experience acid-related disorders. Now that many medications are available over the counter, some patients may opt to self-treat before they even come to their primary care physician. Therefore, primary care physicians are in a unique position to improve health-related quality of life and help reduce the economic burden through appropriately diagnosing and targeting management.

Dr. Chey: It seems pretty clear that this really is mostly a primary care disorder. So with this in mind, what advice do you have for your primary care colleagues about when to refer a patient to a gastroenterologist?

Dr. Heidelbaugh: It's very reasonable for a primary care physician to offer at least an 8-week trial of standard-dose PPI therapy before considering it to be a failure of treatment. This, of course, is in the absence of common alarm signs or symptoms that we would be worried about, which would prompt immediate endoscopy and referral. But if a patient has failed [to respond to] standard therapy with a PPI, it's reasonable at that point to consider referring to a gastroenterologist. The other challenge we have is making the correct diagnosis. Oftentimes, GERD and dyspepsia are confused.

Patient-reported outcome instruments can provide a better understanding of patients' experience with their disease, and mild symptoms can even have an impact on quality of life. This all underscores the importance of incorporating an assessment tool in primary care to manage GERD and properly evaluate GERD, especially for newly diagnosed patients.

Dr. Chey: Now that we have discussed the clinical and economic ramifications of GERD, let's move on to issues surrounding the management of GERD. Given our time constraints, we'll try to focus on medical management. Mike, what do you feel are the key points to managing patients with GERD?

Michael F. Vaezi, MD, PhD: Thanks, Bill. What we need to know is that reflux is a spectrum of disease and that patients present often with different manifestations.

Oftentimes, patients have heartburn/regurgitation but many may not. Many may have extraesophageal symptoms, some may have cough or asthma, and when we do diagnostic testing, such as endoscopy, we may or may not find erosive disease. Therefore, patients may have nonerosive disease and, in fact, in the past we used to think that nonerosive disease was only prevalent in about 50% of patients. Now we know that it is probably as high as 70%-80%.

So what we need to know is that symptoms overlap. The patient who may have mild disease symptom-wise may actually have severe disease when we look endoscopically; thus, objective tests and subjective measures don't necessarily correlate in this area. This is why we depend on tests such as pH monitoring and endoscopy for patients who may present with either partial or lack of response to PPI therapy.

We also need to know that the presentation of reflux is changing. We know that over-the-counter medications are now more common. There are histamine-2 receptor antagonists (H2RAs) and PPIs. We now have 3 PPIs available over the counter, and because of this, many patients present with nonerosive disease when we do endoscopy. I know it is the case in my practice, as I am sure it is in yours as well, that patients aren't presenting with symptoms that we can actually treat and resolve completely. The patients who commonly present to me, for example, are those who have partial [response] or nonresponse to the conventional dose of PPI therapy.

Dr. Chey: Thanks, Mike. What would you consider the target goals of medical therapy for GERD?

Dr. Vaezi: In a simple way, if a patient presents with heartburn/regurgitation, if we suspect that reflux is the cause of the patient's symptom, we need to acutely treat that patient. The goal of that acute treatment is to make the patient asymptomatic, to affect the quality of life, as Joel highlighted. And then chronically, we need to make sure they maintain that acid suppression, at the minimum dose [possible[, but to also make sure that their symptoms, [as well as any] objective findings of esophagitis, are resolved. Thus, that is acute therapy followed by maintenance and chronic therapy.

We also know that most of our patients have already tried over-the-counter antacids or H2 blockers, so the face of reflux, if you will, is changing. PPIs are more effective in acid suppression than what patients may have tried before. In fact, the reason for the empiric trial of PPIs, which is what everyone recommends as the initial treatment, is because of how effective they are. H2RAs are good when one tries to reduce the dose of acid suppression to see whether patients can get off of the PPIs once we have established a diagnosis of reflux empirically.

There is a need for increased acid suppression, and the reason for this is that there is no good gold standard. We can't perform a [diagnostic] test that is 100% sensitive and specific. We rely on PPIs as a test as well as treatment for reflux disease. Many patients do well. In fact, when we look at studies with PPIs, we know that healing of esophagitis is achieved in approximately 85%-95% of these patients. Many of our patients do well with PPIs as far as response to therapy, but what we also need to know, [as reflected in the] recent American Gastroenterological Association (AGA) survey that came out, that about 30%-40% =of patients, despite taking PPIs, need to take over-the-counter antacids or H2 blockers. Some even double the dose* of their PPI; as we know, this is not FDA approved but is often done. Therefore, there is an unmet need for increased acid suppression to provide better coverage for our patients.

So what are some of these unmet needs? I think they stem from the fact that we don't have a medication at this time that suppresses acid in a prolonged manner. We need increased acid suppression, more prolonged [acid suppression].[In addition], there are recent data [on nocturnal reflux], as you are aware and you [Bill] were part of many of these studies. [They show] that patients are experiencing nighttime heartburn, they are awakening, their sleep is affected, they don't sleep, and so this [highlights] that there is clearly an unmet need for these patients as well.

Dr. Chey: Mike, can you tell us a bit more about the available PPIs -- both the traditional PPIs as well as the newer formulations aimed at altering the pharmacodynamics of PPI therapy?

Dr. Vaezi: PPIs are the cornerstone of treatment for reflux, both affecting esophagitis and healing of esophagitis for patients, as well as [for improving] quality of life, as Joel alluded to. The conventional PPIs are also known as the delayed-release PPIs. In the order that they were released by the FDA, they include omeprazole, lansoprazole, rabeprazole, pantoprazole, and then esomeprazole. These delayed-release compounds are enteric coated. The enteric coating is to protect them from gastric acid destruction. The peak plasma concentration for these agents occurs about an hour and a half to 2 hours post-ingestion, and the important thing to remember about PPIs is that they work on the active [proton] pump. Thus, there are active pumps and there are inactive pumps. When these delayed-release compounds are taken, they only work on the active pumps; they don't act on inactive pumps. Therefore, there is the potential for patients to have initial acid suppression followed by more acid in the stomach, which might result in increasing symptoms. So, although the conventional PPIs have done a great job in helping patients, there are clearly times during the day, whether at night or later in the afternoon, when there is increased acid suppression that is not covered [by the actions of these delayed-release PPIs].

With respect to the newer generation [of PPIs,] there is immediate-release omeprazole, which is omeprazole without the enteric coating, protected from intragastric activation by sodium bicarbonate. The rationale [for this formulation] is that it there is a much faster time to onset of action and plasma concentration. The bicarbonate may actually serve to activate the proton pump; therefore, the omeprazole will then suppress the acid.

The most recent [of these newer-generation PPIs] is a dual-delayed-release formulation, dexlansoprazole. Lansoprazole is a combination of the R and the S enantiomers, and dexlansoprazole is the R enantiomer. What is unique about this compound is that it is a mixture of 2 types of enteric-coated granules. The first peak occurs an hour and a half to 2 hours after ingestion; the second peak, which is a much larger peak, actually happens about 4 to 5 or 6 hours later. So there is potential, pharmacokinetically -- as well as, hopefully, clinically -- for a dual action, and hopefully this leads to better patient care and symptom relief.

The conventional PPIs are important for what they have done [therapeutically]. Studies clearly show that they are beneficial, but one of the things we have to tell our patients if they take the conventional PPIs is that they need to take them 30-60 minutes prior to meals to allow them to be in the active site so that when activated, they block the pump. What is important to know is that proton pumps are regenerated; therefore, the conventional PPIs don't do as good a job [in covering those pumps] that have been regenerated.

Newer PPI formulations that allow for that prolonged concentration might be better at giving you more lasting acid suppression during the 24-hour period.

Dr. Chey: So Mike, we talked a lot about acid suppression. It clearly has a role in the treatment of GERD and is highly effective in many patients, but there are many patients who are still symptomatic, despite acid suppression [with the current agents]. Therefore, are there other forms of therapy in development that may be useful for clinicians to know about?

Dr. Vaezi: You are absolutely right, so there is a search for the "ideal PPI," if you will. They want more acid suppression because of the unmet needs, as we discussed, for patients and for coverage of their symptoms and esophagitis. Some [of these strategies] that have been explored and abandoned have included the potassium competitive-acid blockers and the potassium channel blockers, also called the PCABs.* [Other agents under investigation include] extended-release rabeprazole;* there is not a whole lot going on right now that I'm aware of as far as studies, but this is out there, especially in Europe. What has [been perhaps most] exciting are the gamma-aminobutyric acid (GABA) receptor agonists,* and the main reason for this is, as we all know, that the predominant mechanism for reflux is the transient lower esophageal sphincter relaxation; these GABA agonists help us with that mechanism. Thus, we are awaiting studies on these novel strategies, but right now, there is no FDA approval for any of these agents and we are not using them in clinical care at this time.

Dr. Chey: Thank you. So, Mike, there seems little doubt that PPIs provide effective relief for GERD symptoms in many patients. However, as I mentioned, many patients and doctors remain concerned about the safety of PPI use, particularly when used chronically. Can you briefly update us on this controversial area about long-term use of PPI therapy?

Dr. Vaezi: Yes. This is a major issue. I'm sure we've all gotten emails and phone calls from patients who are on PPIs and whose physicians have said, "Stop the PPI" because of something that may have been published. So there are concerns. These concerns include pneumonia, the development of pneumonia in patients who are on chronic therapy; vitamin B₁₂ malabsorption or lack thereof, resulting in anemia or osteoporosis; and calcium absorption issues. What has received the most interest most recently and [resulted in a] lot of phone calls from our patients is [the potential interaction] with clopidogrel. We all know that clopidogrel is a prodrug and has to be activated when it goes through the cytochrome P450 pathway, which is the same pathway that the PPIs go through. So there is that potential that clopidogrel, if taken along with a PPI, won't get activated.

Thus, the issue to remember in all of these cases is that these are epidemiologic data, they're interesting, and they may suggest association but not a causal link. There are no randomized controlled studies showing association or causal link between PPIs and any of these. The most important thing to remember is that the strength of association is weak. The odds ratio for many of these studies is between 1.1 and 1.8 and the data are inconsistent. Some reports find an association and some do not and, to me, as a physiologist, the most important is the biological plausibility. Is it possible that PPIs might cause pneumonia or be associated with it? I think it is a bit simplistic to think that, because taking a PPI once daily does not suppress all of the acid in the stomach. The likelihood [for the association] might be there, but the biological plausibility, given the lack of consistent data... I would say that, overall, based on what I know from the literature, PPIs are clearly effective in what they need to do and from a side-effect perspective. If patients have side-effect profiles we'll see it immediately -- headaches, diarrhea, cramping -- but [these drugs] are safe in the short and long term, based on my review of the [available] data.

Dr. Chey: I think, too, it's clear that even if there is a risk, it's really small on the basis of those epidemiologic studies you talked about. And if you look at the most recent data on that very sticky issue of the interaction between PPI and clopidogrel, probably the best, most robust evidence that's recently been published suggests that there doesn't appear to be a clinically meaningful effect. So I think this is something for our listeners to be aware of.

Mike, as doctors we tend to focus -- some would say overly so -- on the use of medications to treat GERD. Patients often want a more holistic approach to therapy. What dietary and lifestyle recommendations do you offer to your patients who suffer with GERD symptoms?

Dr. Vaezi: Yes, this is one of those areas that I think is very important. You know, as primary care physicians or subspecialists we often have a list of things -- I call them the list of don'ts -- that we give patients: don't eat this, don't drink that, do this, lose weight. The problem is as I reviewed the data (and we recently had this in the AGA guidelines for treating reflux disease), there are really no strong data to suggest that any of the lifestyle modifications [are effective], short of weight loss for obesity, which has become an important issue. There is really no evidence, so to tell someone "don't drink soda, don't drink coffee, no orange juice, no pasta, but while you're at it lose 40 pounds" is a bit problematic. In my opinion, we have to tailor what we tell patients to that individual patient. There may be a patient for whom drinking a cup of coffee causes reflux and makes reflux symptom worse, and for that patient we would say "don't drink your cup of coffee." However, there may be another patient that we have to tell otherwise. Head of the bed elevation -- there is no compelling evidence [that it helps improve symptoms] because most patients have normal esophageal acid clearance. Where the data are compelling is in regard to weight loss because of the association, as you highlighted, with BMI and reflux disease. Clearly, there are data suggesting that weight loss might contribute to decreasing esophageal acid exposure and, hopefully, reflux symptoms.

Dr. Chey: Mike, can you [comment further on] that [relationship between weight gain and reflux] -- that is, in regard to this issue, is it any obesity or is it a certain type of obesity that causes problems with GERD?

Dr. Vaezi: That's a good point. There are some data that actually suggest that it's abdominal obesity predominantly; perhaps it's the pressure effect that might be causing increasing reflux. At this year's Digestive Disease Week (DDW) meeting, we also present that it is not a uniform increase in acid reflux -- that as you go from being normal weight to overweight, the risk is actually much higher than if you go from overweight to obesity. So the relationship is complex, but as you highlighted, the data suggest that abdominal obesity might have more of a role.

Dr. Chey: Joel, from a primary care perspective, is that a standard recommendation? When you're dealing with a patient with GERD, do you always recommend that somebody who is overweight lose weight?

Dr. Heidelbaugh: We do, and like Mike pointed out, there are various types of obesity. These [recommendations] may not work, but they certainly don't cause any harm and there may be other health benefits.

Dr. Chey: Couldn't agree with you more. Very important point for our listeners today. Thanks for that great review, Mike. Would you mind summarizing the key points from that very nice discussion?

Dr. Vaezi: The key to remember is that not all reflux is created equal: A patient might present with cough, may have laryngitis, may have asthma, or may have reflux disease despite not having concomitant symptoms of heartburn. And reflux presentation and severity don't necessarily translate to objective findings at endoscopy. It is also important to know that there is a driving force for us to have better acid suppression, which is the unmet need, as we discussed. We need newer agents to get us to a point where we can provide that medication to a patient and that patient feels better 100%, not 70%-80%.

Overall, given the recent concern on safety and what I have reviewed, if the patient needs a PPI to suppress acid and to feel better, great -- please provide that. Don't keep that [medication] away from [the patient]. However, at the same time, once we have achieved the goal of acid suppression, we should always start tapering the dose to the minimum acid suppression that the patient might need.

Dr. Chey: Thanks so much, Mike and Joel, for those really thoughtful comments. I think our listeners will have gained a lot of insight and information from your excellent discussions.

Let me take a moment to summarize what I take away as the key points from both of your discussions today.

First, GERD is a prevalent condition associated with significantly impaired health-related quality of life, as well as considerable economic and clinical burden. Increasing severity and frequency of GERD symptoms is associated with more comorbid disease, lower quality of life, lower work productivity, and increased healthcare utilization. Effective treatment of patients with GERD is challenging, and patients may experience persistent GERD or other GI-related symptoms despite treatment.

Therefore, we need better individualized treatment for GERD patients that will help improve clinical outcomes.

The currently approved conventional formulations of PPIs are all effective, but there is opportunity for improvement. To offer improved benefit over current PPIs, new strategies that offer prolonged duration of acid suppression and that enhance dosing flexibility may offer improved clinical utility.

Recently published professional societal guidelines on GERD, as authored by Dr. Vaezi and others, provide an evidence-based resource for primary care physicians and specialists caring for affected patients. These resources are a great place to go with your questions concerning the treatment of patients with gastroesophageal reflux disease.

We hope you have enjoyed today's discussion and thank you for participating in this activity. I'd like to ask you to now please continue on to the post-test to obtain CME credit for this program. Thank you again for joining us.

*The US Food and Drug Administration has not approved this medication/dosage for this use.