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This activity is based on the lectures of John E. Pandolfino, MD, and John W. Devlin, PharmD. This program is available as read only and with accompanying audio.
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Slide 3: Dr. Devlin: Welcome to “Atypical Presentations of GERD in Older Patients: Strategies for Early Identification and Treatment to Limit Disease Progression.” This activity is sponsored by Princeton CME and is supported through an educational grant from TAP Pharmaceutical Products, Inc. I am Dr. John Devlin, Associate Professor of Pharmacy Practice at the Northeastern University School of Pharmacy and Adjunct Associate Professor at Tufts University School of Medicine in Boston.
I will be your presenter along with Dr. John Pandolfino, Associate Professor of Medicine at the Feinberg School of Medicine at Northwestern University in Chicago. Please remember that to receive continuing education credit following the conclusion of this activity, each participant must complete the post-test and evaluation form. These forms can be easily completed online for immediate receipt of credit at www.princetoncme.com.
Slide 4: Thank you, again, for joining us. Now, to begin with our case. A 76-year-old retired school teacher presents to his primary care provider complaining that over the past 4 weeks he has found it increasingly more difficult to swallow pills and any meal that is not cut into very fine pieces. On physical exam, he is found to be 5’10” tall and weigh 75 kg. His blood pressure is 135/73, and he has a heart rate of 93. His physical exam was otherwise unremarkable. His medical history includes chronic atrial fibrillation, intermittent gout, and occasional heartburn.
Slide 5: His current medications include warfarin 2.5 mg PO daily, and his most recent INR was noted to be 2.1; controlled release diltiazem 240 mg PO daily. He has a social history that includes a 38 year pack history of smoking; however, he did quit smoking 20 years ago and moderate alcohol use. And he says that he usually consumes 1 to 2 beers a day. His family history was deemed to be noncontributory.
Slide 6: I would like you to consider the following questions for this patient as you listen to today’s presentation. Should this patient be sent to a gastroenterologist for further evaluation? Can this patient have GERD if he only has occasional heartburn? Could his current medications be contributory to his current GI symptoms, or place him at higher risk for further GI-related sequelae? What pharmacologic and nonpharmacologic treatment options are available for this patient? And then finally, if acid suppressant therapy is warranted, what is the optimum dosing regimen? As you listen to the main presentation, think about what therapy should be considered for older patients with GERD.
Slide 7: I would now like to welcome and introduce you to Dr. John Pandolfino for his presentation on strategies for early identification and treatment to limit disease progression in older patients with GERD. Dr. Pandolfino.
Dr. Pandolfino: Well, thank you, Dr. Devlin. This is an important topic for both clinical and managed care pharmacists because of the severity and burden of the disease in the elderly. So let’s begin.
Slide 8: Before we can uncover the hidden burden of GERD, we first need to define and understand the disease itself. A comprehensive definition for GERD was provided by the Genval Working Group in 1997 and published in Gut. For the purpose of this talk, we will define GERD as all individuals exposed to the physical complications from gastroesophageal reflux or who experience clinically significant impairment of health-related quality of life.
Slide 9: Given this vague definition, it is not surprising that GERD is a heterogeneous disorder. It classically presents with objective endoscopic findings such as inflammation, esophagitis, and more rarely stricture, Barrett’s esophagus, and adenocarcinoma.
The majority of people, however, present with endoscopy-negative disease, which really only impairs the quality of life. In addition, the extraesophageal symptoms, such as laryngitis, cough, asthma, etc, typically are associated with a negative endoscopy.
Slide 10: Now, the data supporting the heterogeneous endoscopic presentation of GERD can be found in this study looking at endoscopic findings in the general practice. This study is from Jones et al and was published in the European Journal of General Practice in 1995.
As you can see, the majority of patients have normal mucosa, or nonspecific erythema, which is not pathognomonic of GERD. Most esophagitis patients have mild, nonconfluent esophagitis, while only 4% of patients actually have ulcer, stricture, Barrett’s esophagus, or circumferential disease.
Today I would say that severe GERD is even less common when we look at endoscopic findings, such as esophagitis, and 70% of subjects most likely have a negative endoscopy, probably due to the early use of proton pump inhibitor therapy.
Slide 11: Whether symptoms or injuries occur is related to a delicate balance between the
aggressive and defensive forces that protect the esophagus against reflux. Now, these
defensive and aggressive forces can be seen in the next slide, which kind of shows this balance.
The aggressive factors consist of the number of reflux events along with the caustic nature of the reflux acid. In addition, the defensive factors protecting the esophagus include acid clearance and the esophageal mucosal resistance.
Although GERD is considered primarily an acid-related disease, it is really more a manifestation of abnormal motor events and anatomy. In fact, if you took 100 GERD patients and 100 normal subjects, their acid secretion would be quite similar. The things that separate them are the anatomic and motor abnormalities that lead to an increased number of acid reflux events and poor acid clearance.
Slide 12: Now when you look at the next slide, this really depicts the impaired esophageal clearance, acid sensitivity, and reduced saliva. These are mechanisms whereby esophageal acid clearance will be decreased.
The transient lower esophageal sphincter relaxations are the most common mechanism of gastroesophageal reflux disease. And hiatus hernia, of course, is probably the most important anatomical deficiency at the esophageal gastric junction. Most of the reflux events that are associated with acid are related to hiatus hernia and transient lower esophageal sphincter relaxation, with a very small minority of them being associated with swallow-induced reflux.
Delayed gastric emptying and increased gastric volume are important factors when you are dealing with patients who have gastroesophageal reflux disease and poor gastric emptying, which is what we see in some of our diabetic patients.
Slide 13: Now, given the focus of GERD pathophysiology on motility, let’s examine how motility changes with age can predispose patients to reflux and increase asset exposure time in the esophagus. A very recent study from Lee et al reported that acid exposure in the elderly is more severe, and they noted a 1.1% increase in acid exposure. Now, that is an extra 16 minutes of acid sitting in the esophagus for every decade of life. And, of course, this is more pronounced in the recumbent position.
A few interesting findings were that this increased acid exposure was not due to an overall increase in the number of reflux events, but a longer duration of acid exposure in the elderly.
Slide 14: There are a number of potential motility changes that could predispose aging patients to reflux. Ter et al’s study suggests that while lower esophageal sphincter pressure does not routinely fall with aging, there is a decrease in the length of the sphincter that does occur.
In addition, hiatal hernia, or hiatus hernia, is also more common with aging, a factor that may contribute to the potential increase in reflux with aging. This reduces both the acid clearance and certainly can increase the number of acid-related reflux events.
Slide 15: Aging has several effects on the physiology of the esophagus in terms of the esophageal body. Secondary peristalsis and the ability of the esophagus to clear a reflux bolus declines with aging. Some, but not all, studies have suggested a failure of peristalsis in at least a subset of older patients, the so-called presbyesophagus.
Decreased salivary function will also predispose patients to worse acid clearance, and data suggest that the salivary function does decrease with age. Now, as mentioned previously, it is also clear that older patients experience a decline in the ability to sense esophageal acid and experimentally to sense balloon distention.
Slide 16: Now, this slide shows the results of a study of 25 patients under the age of 60 and 23 patients over the age of 60. The patients had symptomatic GERD with at least 3 episodes per week of heartburn or acid regurgitation in the last 3 months.
In this study by Fass et al, published in Age and Ageing in 2000, they used the modified acid profusion test, or the Bernstein test, to evaluate patients older and younger than 60. The acid profusion test involves instilling normal hydrochloric acid at a 0.1% normal concentration, or saline, into the distal esophagus. A positive response is recorded when the patient reports heartburn while the acid is in contact with the esophagus but no symptoms when saline is profuse.
Now, of course, patients will have a disconnect between the Bernstein test. And that is why this is done in a blinded fashion.
This study demonstrated that older patients were less sensitive to acid and certainly took longer to perceive symptoms after acid profusion than patients under the age of 60. The older patients experience a lower level of sensitivity, and perhaps more importantly had a longer lag time between the start of profusion and the onset of symptoms.
Slide 17: And as we saw earlier, the prevalence of GERD symptoms is higher in the general population of older patients. But as we saw here, their sensitivity is certainly different from the young.
The next section will focus on the presentation of GERD in the elderly. It certainly is more severe and certainly atypical. Data support that the overall burden of GERD is similar between young and elderly.
Slide 18: In a study by George Triadafilopoulos [and R. Sharma] that was published in the American Journal of Gastroenterology in 1997, they show that the odds of having various stages of GERD is similar in the young and elderly. But that being said, the burden of disease in both groups is substantial, with an estimated annual direct cost being greater than $10 billion in 2002.
Now, although the prevalence in this particular study was similar between the age groups, severity is certainly not. And it does appear that elderly patients are more likely to present with severe esophagitis.
Slide 19: Geriatric patients are less likely than younger patients to report heartburn as their primary complaint. Instead, they may report regurgitation, vomiting, difficulty swallowing, or even noncardiac chest pain as the main symptom. However, elderly patients are more likely to have the complications of reflux disease, such as erosive esophagitis, Barrett’s esophagus, which is considered intestinal metaplasia of the mucosa at the lower esophagus.
Slide 20: Now, this study from Pilotto et al highlights the phenomenon of the disconnect between heartburn symptoms and esophagitis severity in the elderly. As you can see, the percentage of GERD patients presenting with heartburn decreases as you get older. Now this is clearly depicted on the left.
Now, when you look at the study in general, you can see on the far right elderly patients are more likely to have grade III and IV esophagitis, the most severe grades. So once again, even though they report heartburn in terms of less with regard to frequency, they tend to have more severe esophagitis.
Slide 21: Now, in this same study it was shown that the elderly patients with reflux esophagitis had less typical and more nonspecific symptoms than young or adult patients. Clinicians caring for older patients should be aware of nonspecific presentations. And the potential that the severity of reflux in this patient population that is elderly can be quite severe.
Anorexia, anemia, weight loss, and vomiting are common presenting symptoms of GERD in the elderly population. And once again, these are considered warning signs and should prompt endoscopy.
Slide 22: Now, this slide depicts the warning signs and symptoms that we typically see with complicated GERD. These are continued pain, especially in the context of ongoing PPI therapy, dysphasia, odynophagia, bleeding, unexplained weight loss, and choking. Whenever you elicit a history of any of these warning signs, it is extremely important to send these patients for endoscopy, as they may have significant complications.
Slide 23: This slide represents endoscopic images of the classic grades of esophagitis. The grading scheme focuses on small mucosal breaks, or erosions, and is considered the Los Angeles classification system. It has the best inter- and intraobserver reproducibility. Los Angeles Grade A esophagitis consists of 1 or more mucosal breaks no longer than 5 mm. Los Angeles B esophagitis is really an extension of Los Angeles A esophagitis where the mucosal breaks are longer than 5 mm.
Now, once the erosions start to bridge, or the tops of the mucosal folds begin to bridge, it starts to become more severe, and Los Angeles C and D esophagitis are the most severe forms of esophagitis. And you can clearly see that they involve bridging of the lesions with a circumferential involvement. If it is <75%, it is Los Angeles Grade C. If it is >75%, it is Los Angeles Grade D.
Slide 24: Now the prevalence of moderate or severe erosive esophagitis does significantly increase with age. This is a wonderful study from Johnson and Fennerty that was published in Gastroenterology in 2004, and it represents data for results of a post-hoc analysis of baseline data pulled from 5 prospective, randomized controlled clinical trials that assess the effects of PPI on healing of erosive esophagitis.
The trial involved a total of 11,945 patients ages 18 and older with GERD and erosive esophagitis. In this large compilation of patient registry trials, there was a clear association between age and the proportions of patients that were diagnosed with moderate or severe esophagitis, once again, Los Angeles Grade C or D.
In this group of untreated patients, moderate or severe erosive esophagitis was less prevalent in the younger age groups and became progressively more common as you increased in age.
Slide 25: Looking at the same data, it was also apparent that around 40 years of age, you start to see a decrease in the presentation of severe heartburn and an increase in the prevalence of severe esophagitis, once again, highlighting the fact that although elderly patients may present with less severe symptoms, or atypical symptoms, their disease in terms of esophagitis is much more severe.
Slide 26: Another additional facet of this is the fact that GI bleeding occurs more commonly in older patients using esophagitis or looking at esophagitis as a cause. In this study from Zimmerman et al, that was published in the Scandinavian Journal of Gastroenterology, you can clearly see that when you get above the age of 80, esophagitis as a cause of bleeding is much more significant or substantial than in the age group from 60 to 69.
Now, this may be due to the fact that there is more severe esophagitis, but we also cannot forget the fact that elderly patients are more likely to be on aspirin and NSAID therapy, and certainly this can complicate the issue.
But once again, severe bleeding from esophagitis is certainly seen more commonly in the elderly population.
Slide 27: Now, as we mentioned previously, Barrett’s esophagus and adenocarcinoma are also commonly seen in the elderly at a much greater rate than young patients. Barrett’s is defined as specialized intestinal metaplastic tissue, seen here on the path specimen in the upper right. Endoscopically it presents as a salmon-colored mucosa that takes the shape of a regular tongue-like projection off the squamocolumnar junction. This is in the top left-hand corner.
You can clearly see that the squamish mucosa is pearly white, and you can clearly see the mucosa extending up from the stomach that has a salmon color. The most severe complication related to GERD, of course, is adenocarcinoma, and this can be seen in the 2 endoscopic pictures in the below left-hand corner.
Once again, the scope is in full view in the retroflect view, and you can see that this is adenocarcinoma at the esophageal gastric junction.
Slide 28: In this study by Blankenstein, one can see that the prevalence of Barrett’s esophagus increases with age and certainly is more common in males. The 2 top lines represent males, and the 2 bottom lines represent females. The only difference in the 2 lines is the fact that intestinal metaplasia on biopsy, meaning that there’s pathologic confirmation of Barrett’s esophagus, is slightly less than what we see on endoscopy, and that is because once again endoscopy does not diagnose Barrett’s esophagus. Barrett’s esophagus is diagnosed with pathology. But, as you can see in both males and females, as you increase in age, there certainly is an increased prevalence of Barrett’s esophagus.
Slide 29: Now, the data, of course, are well accepted now and support that the more severe GERD symptoms you have, the higher the risk of developing adenocarcinoma. In fact, if you look at the specific study, if you have simple reflux, your odds of developing adenocarcinoma increase about 1.7 in terms of the hazard ratio. Esophagitis is 2.2.
Once you get to the point where you have developed Barrett’s esophagus, your risk is almost 10-fold or greater to develop adenocarcinoma. So once again, highlighting the fact that the more severe your symptoms are, the more severe your presentation is, the more likely you are to develop adenocarcinoma of the esophagus.
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Slide 31: Now, our typical approach to the management of GERD has been updated in the ACG guidelines by Dr. Ken DeVault and Don Castell. Patients presenting with classic symptoms such as heartburn and regurgitation can be started on acid suppressive therapy.
Now, it’s preferable that a PPI be started, and we also institute lifestyle modification. If the patients have atypical symptoms or warning signs, like many of our elderly patients do, they would certainly require an immediate response and referral for endoscopy.
So if they also fail to respond to therapy after a 4-week trial, they also should be referred for further testing. If they do respond and their symptoms are typical, they can be started on maintenance antireflux therapy.
Slide 32: Now, this next slide represents the typical diagnostic algorithm for GERD testing. Patients are initially sent for upper endoscopy when they are failing PPI therapy. When this is negative, that is when they are sent for pH monitoring and reflux monitoring. If the pH study does reveal that patients have excessive esophageal acid exposure, they are diagnosed with nonerosive reflux disease if the upper endoscopy is negative.
Of course, if the endoscopy is positive, we have a pretty good idea that they already have reflux disease and they’re not responding to the PPI therapy. Those patients who still have esophagitis despite PPI therapy will require an escalation in PPI dose.
Now, if the overall excessive esophageal acid exposure is negative on the pH study but they have a good symptom correlation between reflux and symptoms, then those patients are deemed to have a hypersensitive esophagus. Once again, this is true acid-related disease, and these patients may require an escalation of therapy, or actually an alteration in the therapeutic algorithm.
Now, if the pH monitoring study is negative in terms of the overall acid exposure and symptom correlation, the patient likely has either functional heartburn or the very controversial nonacid reflux.
Slide 33: Now, on-demand therapy is a reasonable approach to patients whose symptoms resolve on acid suppressive therapy and do not have complicated disease such as esophagitis C and D. Remember, if patients have severe esophagitis like Los Angeles C and D, they will require lifelong PPI therapy.
Now, the argument for on-demand therapy focuses on the fact that symptomatic GERD is really not that progressive a disorder. In addition, on-demand therapy is easy and user-friendly. It stimulates the patient’s sense of responsibility and self-control, and patients definitely enjoy this in terms of their own management.
It also focuses on symptom control, so that is the primary goal of GERD therapy—to reduce symptoms. In addition, on-demand therapy has been shown to be the most cost- effective regimen in patients with mild-to-moderate uncomplicated GERD.
As I mentioned, some patients with very low-grade erosive esophagitis, like Los Angeles A and B, may also respond to on-demand therapy.
Slide 34: Now, this next slide represents the supportive data for on-demand therapy. Now, this looks at 3 different PPIs at various doses, and you can see that patient discontinuation due to inadequate symptom control is extremely low, and much less than placebo.
Thus, this compilation of data does support that on-demand therapy can be used to treat nonerosive reflux disease. Now, of course, after an initial acute treatment period of continuous PPI to control symptoms, asymptomatic patients were enrolled, and therefore, when you look at these particular studies, you really have to treat people acutely with a continuous PPI dose to control their symptoms and use on-demand therapy as a maintenance routine.
Slide 35: Now, going back to our diagnostic algorithm and how we address patients who are not responding to medical therapy. Typically after the patient is sent for endoscopy and it comes back as a negative endoscopy, we increase their PPI dose to BID and see if symptoms improve. If it does not, or if their symptoms are still present, there is very good data to support that the patient who has continued symptoms, despite double-dose PPI therapy, is unlikely to have abnormal acid exposure on PPI therapy.
Now, this is a study that was published from the Cleveland Clinic Group by Charbel et al, and you can clearly see from this study only 7% of patients who have typical symptoms of heartburn or regurgitation who were on a BID dose of PPI will have abnormal acid exposure in the esophagus.
If you look at our patients with atypical symptoms, the so-called extraesophageal symptoms—noncardiac chest pain, laryngitis, chronic cough—if these patients are on double-dose PPI therapy and still having symptoms, the chances that they have abnormal acid exposure is on the order of 1%.
So the double-dose PPI therapy in and of itself not only treats the symptoms but also can be used as a diagnostic test with a very good negative predictive value for acid-related symptoms.
Slide 36: Another issue in dealing with GERD in the elderly is noncardiac chest pain. Certainly GERD can cause chest pain and is an important consideration. But that is only after cardiac disease is ruled out. 30% of patients undergoing cardiac cath with angina have a normal angiogram. And thus, it’s estimated that about 40% to 50% of these patients may actually have GERD as a cause of their so-called noncardiac chest pain.
Now, features suggestive of noncardiac chest pain that may be related to the esophagus are that they are merely related or nocturnal pain can last for hours, the retrosternal pain without lateral radiation, concomitant GERD symptoms or pain coinciding with a reflux event, and pain that is relieved by antacid pharmacotherapy. All of these factors suggest noncardiac chest pain. But once again, in the elderly patient population, it is extremely important to rule out cardiac disease before you attempt an aggressive course of antireflux therapy.
Slide 37: Once again, the PPI test at a double dose is a very helpful test in ruling out and ruling in GERD as a potential cause. This study by Locke et al was published in Gastroenterology in 1997 and showed that omeprazole at a 40-mg dose BID was much better at diagnosing GERD than manometry, 24-hour pH testing, and endoscopy.
Now, this is a very well-done study and really highlighted the fact that even though we are using double-dose PPI therapy to treat patient symptoms, it is also very helpful as a diagnostic tool.
Slide 38: Another important issue to remember when dealing with the elderly, especially when they present with noncardiac chest pain or atypical GERD symptoms, is pill esophagitis. This certainly can mimic GERD, and the motility issues related to poor esophageal clearance certainly do make the elderly patients predisposed to pill-induced esophageal injury.
The pills can typically get caught in the proximal esophagus just below the striated muscle portion. This is usually due to cardiomegaly or the aortic arch. Those can certainly complicate that. Also, they are found in the lower area by the hiatus hernia or at the esophageal gastric junction.
Now, this study by Abid et al highlights some of the common players. Certainly NSAIDs are the most important contributors to pill esophagitis, and it really needs to be highlighted that these are a very common medicine, and sometimes they even go underrecognized in terms of a cause for pill esophagitis because they are ubiquitous.
We all know that tetracycline is also a big player. It’s very common to see young patients come in with acne who are on tetracycline and develop pill esophagitis. But certainly in the elderly population, if they are undergoing H pylori treatment and so forth, they can develop pill esophagitis. Alendronate and potassium chloride are also big players, and certainly other antibiotics, quinidine and ascorbic acid.
Slide 39: Now, some tips to prevent pill-related GI injury in the elderly population are to reinforce the importance of medication administration schedules and directions. They always need to take the medication upright, and they always need to swallow a little bit of water just prior to taking the medication and at least 4 ounces afterwards. Now, they don’t have to gulp that. They just have to take very small sips.
In addition, you need to educate patients on signs and symptoms of esophageal injury and dysphagia so that when they present, you can treat their pill esophagitis. I typically treat pill esophagitis with carafate slurries mixed to a 1-g concentration about once or twice a day. Use of alternative medication formulas in high-risk patients is also important, especially in the elderly who have trouble with pills or capsules. You can use chewable, liquid, or crushable forms.
In addition, another important aside is that we should be very cognizant of the elderly patient’s risk for gastric and duodenal ulceration if they are on concomitant NSAIDs and aspirin. And it’s always very important to be cognizant of the gastric and duodenal risks of patients who are on multiple NSAIDs, especially the elderly.
Slide 40: Well, now we are going to shift gears a little bit and focus specifically on the management of GERD in older patients. But what we will find is that it is very similar to younger patients. But once again, you just need to be a little bit more vigilant.
Slide 41: Now, what are typical treatment goals when it comes to GERD? Well, first off, we want to alleviate or eliminate the patient symptoms. We also want to use the most appropriate administration option for antireflux therapy, depending on the older patient’s ability to swallow.
We also want to decrease the frequency, recurrence, and duration of GERD symptoms, and we certainly want to promote healing of the injured mucosa, because certainly that will cause ongoing symptoms and possibly can degenerate into stricturing and food impactions. That is, once again, why we want to prevent the development of complications of esophagitis, because they can be severe in the elderly, such as stricture, and as we saw in the previous studies, bleeding.
Slide 42: Now, the algorithm that we are putting forth here in older patients is very similar to the ACG guidelines. And it is really just a derivation of those guidelines put forth by Dr. Ken DeVault and Don Castell.
The other thing that it really highlights, as opposed to the other figure, is the fact that once symptoms are controlled, we can step the therapy down to a maintenance dose. Now, this can either be a lower dose, a half dose, or we may even switch patients to on-demand treatment if they have uncomplicated gastroesophageal reflux disease.
Once again, this algorithm highlights that if the patient has persistent symptoms, we certainly should investigate them with endoscopy and possibly 24-hour pH manometry.
Now, surgery is an option for refractory patients, but as you can see, surgery is still associated with slight surgical risks, and these are certainly increased in our elderly population. So surgery should only be thought of as a last resort in our elderly population with reflux disease.
Slide 43: Now, what are some of the over-the-counter medications for the treatment of GERD? Well, certainly we have numerous antacids, H2RAs, and we do also have an over-the-counter PPI, omeprazole. The H2RAs that we typically see are cimetidine, famotidine, nizatidine, ranitidine. And as I mentioned, the PPI is omeprazole 20 mg/day for 14 days.
Now, the limitation of 14 days is really due to the fact that they want patients to see a physician if they are struggling with constant reflux symptoms.
Slide 44: Now, in terms of promotility agents, even though GERD is considered predominantly a motility disease, we really do not have a very safe and effective promotility agent for reflux. We can use metoclopramide at very low doses, but this is certainly limited by side effects of fatigue, sedation, lethargy, anxiety, hopefully not tardive dyskinesia and tremors.
In addition, there are many drug interactions that make these medicines difficult to use in the elderly. Thus, promotility agents have limited utility in older patients with GERD due to intolerance. That being said, I do occasionally use metoclopramide at very low doses in my patients who have concomitant gastroparesis and reflux disease.
Slide 45: In terms of healing esophagitis, there was a very nice meta-analysis that was published by Chiba et al in Gastroenterology which showed the superiority of PPIs. One can clearly see that the PPIs are much more effective at healing esophagitis than both H2RAs and placebo at 12 weeks of therapy.
Slide 46: In addition, there was a very nice meta-analysis of PPIs versus H2RAs for erosive esophagitis healing. Once again, this showed that PPIs were superior to ranitidine for healing of esophagitis at 8 weeks. This study was published in Clinical Therapeutics in 2001, and once again supports the original Chiba meta-analysis.
Slide 47: Now, certainly there are a number of FDA-approved alternative PPI formulations and administration options. You can use capsule granules sprinkled on selective soft foods, capsule granules mixed into selective beverages, NG tube administration, intravenous formulation, oral suspension packets, and orally disintegrating tablets.
Now, it is very important to realize that you should not have the patients chew or crush the contents of PPI capsules or tablets, as they are delayed release.
Now, as you can see, esomeprazole, lansoprazole, omeprazole, and pantoprazole all have some alternative formulations. Unfortunately rabeprazole does not have any alternative options. And if you do have a patient that is having difficulty with this medicine, you may have to switch that PPI.
Slide 48: Now, there is an FDA-approved PPI that is mixed with sodium bicarbonate. And the important concept behind this is that this is the only PPI that can be taken on an empty stomach before one goes to sleep. It can also be taken at least 30 minutes to 1 hour before meals like the other PPIs, but it is important to remember that all enteric coated PPIs should be administered 30 minutes before breakfast and a half hour before dinner (if you are going to use a BID dosing schedule).
Slide 49: Now, in terms of the comparison of efficacy studies with PPI therapy, you can see that these medicines are excellent. Proton pump inhibitors really rewrote the book in terms of treating acid peptic disorders. And you can expect anywhere from an 85% to 90% response rate with any of the enteric-coated PPIs depicted in this slide from multiple different studies looking at esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole.
Not a real huge difference. You can see that there is some statistical difference between esomeprazole and lansoprazole, but once again, the question whether this is clinically relevant is definitely under debate.
Slide 50: Now, what is the rationale for continuous PPI therapy in GERD? We did talk a little bit about on-demand therapy in patients with uncomplicated reflux. But if patients have severe erosive esophagitis, especially those with Los Angeles C and D, they will require long-term continuous PPI therapy.
In addition, patients who have complications of GERD, such as esophageal ulcer, stricture, and Barrett’s esophagus, will also require long-term continuous PPI therapy. These patients tend to have the highest levels of acid exposure in the esophagus and have the most dramatic defects of the antireflux barrier. They tend to have a low LES pressure and sometimes very large hiatus hernia.
Now, in terms of on-demand therapy with PPI and H2 blockers, they are not appropriate for these patients because they will relapse if you discontinue their medicine for even brief periods of time. So once again, on-demand therapy is not appropriate for patients with severe and complicated disease.
Slide 51: Now, esophagitis is a chronic condition that is likely to relapse. This is a very nice study from Lars Lundell that was published in Gut in 1999 that showed that if you stopped PPI therapy after obtaining remission, almost uniformly these patients will relapse at 6 months. In fact, the relapse rate does increase, especially at 3 months, when you go to more severe forms of endoscopic grades of esophagitis.
Slide 52: In addition, when you look at this other study from Robinson et al, published in the Annals of Internal Medicine in 1996, you see the same theme. Maintenance of healing of erosive esophagitis in terms of severity does highlight the fact that there is a difference if you have grade II, III, or IV esophagitis, you are almost uniformly going to relapse in terms of your esophagitis.
In contrast, using either doses of lansoprazole 15 or 30 mg, you can see that even with grade IV esophagitis, you can remain in remission in a very high proportion of patients.
Slide 53: Now, what is the occurrence of GERD symptoms that we could expect in terms of relapse rates of medical therapies? This was a very nice study that was published in the Cochrane Database Systematic Review in 2005 by Donnellan et al, and when you look at the relapse of symptoms, you can clearly see that the PPI healing dose and the PPI maintenance dose are far superior to H2RAs in terms of maintaining symptom resolution and remission.
So once again, if you are going to take a patient and treat them long term with maintenance therapy, PPI therapy is more effective than H2RAs, and that is likely due to the fact that H2RAs do develop tachyphylaxis.
Slide 54: Now, there are multiple PPI drug interactions that you need to be aware of, but these are usually pretty mild and not very complicated. And we are going to focus on a few specific interactions.
Slide 55: Now, in terms of omeprazole and diazepam, there is a decrease in the clearance of diazepam by 25% to 50% with concomitant PPI therapy. This does have a potential in older patients for increased sedation and an increased risk of falls, which certainly we are risk-averse with in the elderly population. They are more predisposed to hip fractures and falls, and certainly we would like to do something to not increase this risk.
In terms of omeprazole and phenytoin, it does decrease the clearance of phenytoin by 15% to 20%. Patients requiring higher serum concentrations of phenytoin may be at risk for developing symptoms of toxicity, such as nystagmus, unsteady gait, slurred speech, confusion, respiratory depression, and seizure generation.
Once again, these are going to highlight the fact that we are very nervous about fall risk in our elderly patient population. And some of these things can certainly increase that risk.
Phenytoin serum concentration should be measured with any dose change and signs of toxicity or addition of therapy when patients are on concomitant PPI therapy.
Slide 56: In terms of omeprazole and warfarin, this is a very important issue, because we see a lot of our elderly patients on warfarin or aspirin and warfarin for either mechanical valves or atrial fibrillation.
We certainly know that there is a decrease in clearance of the R isomer, 5 times less potent than the S isomer. Interaction is likely only clinically important in patients requiring elevated INRs, such as mechanical valves, but you need to be cognizant about the fact that certainly these medicines can be used inappropriately, and compliance with warfarin is always suspect.
There certainly is a potential for an elevated PT and INR, which can be dangerous, once again, in older patients that are at risk for fall. In terms of lansoprazole and theophylline, there is an increase in the metabolism of theophylline by 10%. The potential exists for increased dose requirements of theophylline for appropriate bronchial dilation in certain patients. This interaction has been deemed to be of little clinical significance, but theophylline serum concentrations can be obtained to ensure levels remaining within the predetermined range for the particular patient.
Slide 57: In terms of PPI drug interactions that could be potentially related to the acid suppressive state, certainly bismuth, digoxin, and nifedipine and ketoconazole can have some adverse absorption due to the hypochlorhydric state. But once again, these are very variable, and you need to be very cognizant of this when you are looking at patients who are on multiple medications.
Other drugs, such as aspirin, ddI, midazolam, and furosemide, have been reported in the literature as having increased absorption potential. So once again, you need to keep this in mind when you are seeing patients who may be HIV-positive or on lasix or diuretics, aspirin products, or midazolam.
Slide 58: In terms of the safety of long-term PPI therapy, there have been a number of issues that have been raised over the years that have been addressed. The first one focuses on gastric malignancy. In terms of gastric malignancy, there were 2 particular malignancies that were looked at, carcinoid tumors and gastric atrophy, and its relationship to adenocarcinoma.
Now, the evidence suggests that there certainly is a link between elevated serum gastric concentrations and ECL cell hyperplasia. However, there is no clinical evidence of progression to higher grades of hyperplasia or gastric ECL cell tumors.
In terms of gastric atrophy and its relationship to adenocarcinoma, atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated with long-term PPI therapy. However, there may be an interaction with H pylori (Helicobacter pylori), and that is why it is important to look for H pylori in patients who are on long-term PPI therapy.
And I would treat H pylori because the only good H pylori is a dead H pylori. It has a 15% to 20% increase of peptic ulcer disease and also is the primary etiologic agent of adenocarcinoma and gastric lymphoma. So if you find H pylori, you are obligated to eradicate it.
Slide 59: In terms of infection, the enteric infections in particular, there is an increased risk of C difficile, colitis, or infection in PPIs. Now, you have to realize that this risk is increased from 0.02% to 0.06%. So the absolute risk is really only 0.04%.
Now, although this is clinically important if you look at huge numbers of patients, on a day-to-day basis it is really not that important, and it should not ever be used as a reason to stop someone’s PPI who is appropriately being treated for symptomatic GERD.
In terms of pneumonia, there was a study that was published in JAMA that was, in essence, a flawed study. They did not control for important confounders. We already knew that patients with reflux disease had a significant increase in pulmonary complications, especially aspiration. And although the adjusted relative risk was 1.89 with PPI therapy, we really do not look at this study as being appropriate or validated because they really did not control for GERD symptoms and the presence of hiatus hernia.
In terms of osteoporosis, there is a slight increased risk of hip fractures. And this adjusted odds ratio is 2.65. So once again, we need to be vigilant regarding osteoporosis. And there have been case reports of rebound symptoms in terms of PPI use. But once again, this is more of a physiologic phenomenon and really not a clinically relevant phenomenon.
But if you do stop PPI therapy, after around 7 days to 14 days there will be a rise in acid secretion. But once again, we’re unsure of the clinical relevance of these rebound symptoms.
Slide 60: In terms of once again going back to the hypochloridia, or the decrease in acid suppression and absorption, just like medications, we are also going to be focused on nutrient absorption.
Now, there was a 4-year study of patients on continuous PPI therapy. And they show that these patients had normal digestion of protein, normal calcium absorption, and normal iron homeostasis.
The one vitamin that everyone is concerned about is vitamin B12. And certainly a minority of patients on long-standing therapy may develop a slight reduction in B12 concentrations. These patients at risk include, of course, the elderly, vegetarians, and some of our very malnourished cancer patients or chronic alcoholics.
Slide 61: Now, what is the rationale for better acid suppression, similar to when we move up to double-dose or BID PPI therapy? Well, certainly in our severe erosive esophagitis and complicated GERD patients, we know that these patients tend to have the highest esophageal acid exposure. So certainly we want to treat people aggressively with severe esophagitis, Barrett’s esophagus, and stricture.
In addition, we also know that patients who have nocturnal GERD tend to have the most severe reflux during the night-time period, and this is usually associated with hiatus hernia. So multiple dosing with PPI is often required to cover nocturnal acid breakthrough more effectively.
Slide 62: Now, in terms of developing a pharmaceutical care plan for the older patient with GERD, of course, it is very similar to the younger patients. We want to eliminate symptoms and we want to use lifestyle modifications as appropriate, pharmacologic therapies. We want to choose the appropriate administration option for the patient, and certainly use other studies or other tests to make sure that we are aggressively treating these people.
Antireflux surgery and procedures are not very good options for the elderly patient population because of the underlying surgical mortality/morbidity that is related to the elderly population. In addition, we should always try to treat and heal the underlying pathology. We need to ensure compliance and appropriate timing of doses and educate healthcare professionals on the most effective agents and the fact that there are other available preparations such as chewable, liquid, etc.
In addition, we want to avoid additional complications, and that is where maintenance therapy comes in. And that can certainly prevent complications of disease in patients with severe symptoms or severe esophagitis.
And we always want to minimize potential adverse effects and drug interactions. And although these are not common with PPIs, there are a lot of very subtle interactions that we need to be aware of and we need to make sure our patients are aware of.
Well, now we will turn back to Dr. Devlin for a discussion of the case presented at the beginning of this activity. Thank you very much.
Slide 64: Dr. Devlin: I would like to review the case. A 76-year-old retired school teacher presents to his primary care provider complaining that over the past 4 weeks he has found it increasingly more difficult to swallow pills in any meal that is not cut into very fine pieces. Let’s now attempt to answer the questions I posed at the beginning of today’s presentation regarding this patient and develop a treatment plan to optimize his care.
Slide 65: This patient should be referred to a gastroenterologist given that the worsening dysphasia he is experiencing may be related to Barrett’s esophagus, esophageal strictures, or cancer, and not just GERD. The gastroenterologist workup could include an upper EGD. Typical GERD symptoms, such as heartburn, are less frequently seen in elderly patients such as this patient. Diltiazem may worsen GERD in this patient by decreasing lower esophageal sphincter pressure. Esophagitis is associated with far more bleeding in the elderly than nonelderly.
Although this patient’s most recent INR is within the normal therapeutic range, use of warfarin could further increase risk for bleeding if esophagitis is present.
Slide 66: So what is the optimal therapeutic plan for this patient? Well, he should be booked to see a gastroenterologist. He should consider alternatives to diltiazem for ventricular rate control, such as a beta-blocker. His warfarin therapy should be held until seen by a gastroenterologist. He should avoid ingesting alcohol. The head of his bed should be elevated 4 to 8 inches. He should begin a trial of a PPI. He should avoid any PPI that may not be used in conjunction with warfarin, for example, omeprazole. He should use a formulation of a PPI that does not require a tablet or capsule to be swallowed. And finally, his response to therapy should be evaluated based on the recommendations of a gastroenterologist.
Thank you for your participation.
