Proton Pump Inhibitor Failure Research Articles

Comparison of the Degree of Duodenogastroesophageal Reflux and Acid Reflux Between Patients Who Failed to Respond and Those Who Were Successfully Treated With a Proton Pump Inhibitor Once Daily

The objective of this study was to compare the degree of esophageal acid exposure and duodenogastroesophageal reflux (DGER) during treatment between gastroesophageal reflux disease (GERD) patients who responded fully to proton pump inhibitor (PPI) once a day and those who failed to respond. Gastroesophageal reflux disease patients who continued to report symptoms 3 times a week for 3 months while on PPI once a day were assigned to the PPI failure group. GERD patients who were asymptomatic on PPI once a day for 3 months were assigned to the PPI success group. All patients underwent upper endoscopy to assess esophageal mucosal injury. Subsequently, all patients underwent simultaneous 24-h esophageal Bilitec 2000 and pH testing while on treatment. Patients recorded GERD-related symptoms during the test. Twenty-four patients were enrolled in the PPI failure group and 23 patients were enrolled in the PPI success group. Endoscopy was normal in 63% of PPI failure patients and 76% of PPI success patients. Abnormal DGER was documented in 82% of PPI success patients vs. 67% of PPI failure patients (P=NS). All pH testing and Bilitec parameters in the PPI failure group were similar to those in the PPI success group (P=NS). Of the 34 GERD symptoms recorded by the PPI failure group, 64% were associated with acid reflux and 41% were associated with DGER (P<0.05). There is no difference in the degree of DGER and acid exposure during treatment between patients who failed to respond and those who achieved complete symptom resolution on PPI once daily. GERD symptoms in the PPI failure group are more commonly associated with acid reflux than with DGER.

Proton Pump Inhibitor Failure—What Are the Therapeutic Options?

Proton pump inhibitor (PPI) failure is very common and may affect up to one-third of the PPI consumers. Identifying the underlying mechanisms for PPI failure in each individual patient is essential for treatment success. For residual acid reflux, increasing the PPI dose to twice daily; switching to another PPI, or adding an histamine 2 receptor antagonist could be a successful therapeutic strategy. In patients with duodenogastroesophageal reflux, weak acidic/alkaline reflux and hypersensitivity to acid reflux, therapeutic modalities that reduce transient lower esophageal sphincter relaxation or visceral pain could be entertained. Treatment of PPI failure due to delayed gastric emptying should be focused on improving gastric motor activity. Psychological management may supplement any medical or surgical approach toward PPI failure.

Preface

In the past few years, data have accumulated on the potential risks of long-term use of proton pump inhibitors (PPIs) in patients with gastroesophageal reflux disease (GERD). The reports were initially sporadic, but we have recently noticed a stream of publications claiming a variety of adverse effects that may afflict patients who are chronically treated with PPIs. These studies have raised concerns among physicians and patients alike. In response to such publications, many physicians have altered their usual approach to the care of patients on chronic antireflux treatment for GERD. Thus far, however, there are no clear guidelines on how to manage GERD sufferers who are using PPIs on a daily basis. This clinical gap was the impetus for developing this supplement. We have assembled a highly reputable group of experts to discuss the full range of adverse events that have recently been attributed to long term PPI use. The authors were instructed to provide a detailed review incorporating all currently available publications on their relevant topic. Additionally, each expert was asked to critically evaluate these publications. Karl Insogna, an endocrinologist with expertise in calcium metabolism, discusses the effect of PPI therapy on mineral metabolism, and Kenneth McColl, a gastroenterologist with expertise in acid-peptic disorders, evaluates the effect of long term PPI use on vitamin and iron absorption. The relationship between PPI use and enteric infections is examined by Sandra Dial, a critical care physician with expertise in epidemiology. Nimish Vakil, a gastroenterologist with expertise in acid-peptic disorders, reviews the relationship between acid inhibition and infections outside the gastrointestinal tract. Loren Laine, also a gastroenterologist with expertise in acid-peptic disorders, provides a critical review of the relationship between PPI therapy and hip fracture. The overutilization of PPIs in clinical practice is discussed by Joel Heidelbaugh, a primary care physician with expertise in family medicine, and colleagues. Finally, Ronnie Fass, a gastroenterologist with interest in both acidpeptic disorders and gastrointestinal motility, describes therapeutic options for patients who failed PPI treatment. This timely supplement provides a critical review of the growing number of publications linking a variety of adverse events to long-term PPI treatment. The authors attempt to put into perspective all these publications and propose proper management of such patients. Clearly, in the face of overutilization of PPIs, concerns about adverse effects, and the increasing phenomenon of PPI failure, experts agree that PPIs should be used only in the proper patient population and for the duration required. CONFLICT OF INTEREST Guarantor of the article: Ronnie Fass, MD. Specific author contributions: Dr Fass conducted the research and wrote the preface and chapter entitled “Proton Pump Inhibitor Failure — What Are the Therapeutic Options?” Financial support: This work was supported by Glaxo Smith Kline. Potential competing interests: Dr Fass conducts research for Wyeth, Takeda, and AstraZeneca. He is a speaker for AstraZeneca and a consultant for AstraZeneca, Glaxo Smith Kline, Eisai, Takeda, Proctor & Gamble, Vecta, Addex, and Pfizer.

Functional Heartburn: What It Is and How to Treat It

Functional heartburn is considered one of the most common functional esophageal disorders. The disorder is more common in young women and is associated with other functional bowel disorders and psychological co-morbidity, primarily somatization. The etiology of functional heartburn remains unknown. Most patients, however, demonstrate esophageal hypersensitivity. Functional heartburn has been identified as the main cause for proton pump inhibitor (PPI) failure in patients with heartburn. Treatment is still a challenge, and patients should be started with PPI treatment. In non-responders, escalation of the PPI dose could be attempted and, if unsuccessful, pain modulators should be prescribed.

Potential reasons for proton pump inhibitor failure in the treatment of gastroesophageal reflux disease

The introduction of proton pump inhibitors (PPI) has facilitated the successful management of patients with gastroesophageal reflux disease (GERD). In a minor, but still relevant proportion of patients with GERD-like symptoms, PPI therapy has also proved to be ineffective. In such cases, the first question to be answered is if the symptoms and complaints are related to GERD indeed, or another disorder should be searched for. If GERD is still the most likely diagnosis, patients' compliance should be thoroughly investigated before any further diagnostic and therapeutic measure is taken. If PPI failure is not a result of inadequate management of GERD, there are several other disorders to be ruled out. In our review, we summarize the most important differential diagnostic issues of PPI failure.

Refractory GERD: What is it?

Refractory gastroesophageal reflux disease (GERD) is very common and may affect up to 40% of patients who use a proton pump inhibitor (PPI) once daily. Refractory GERD can present as incomplete or lack of response to PPI therapy. The disorder is clearly driven by patients, who present with a wide range of symptom severity and frequency while on PPI treatment. Poor compliance and improper timing of PPI consumption should always be excluded before further evaluation of this patient population. The putative mechanisms for refractory GERD include weakly acidic reflux, duodenogastroesophageal/bile reflux, visceral hypersensitivity, delayed gastric emptying, psychological comorbidity, and concomitant functional bowel disorders. Reduced PPI bioavailability, rapid PPI metabolism, PPI resistance, nocturnal reflux, and Helicobacter pylori infection status have very limited roles in refractory GERD. The contribution of eosinophilic esophagitis to refractory GERD is still unknown. Pill-induced esophagitis, Zollinger-Ellison syndrome, achalasia, and other disorders are rarely responsible for PPI failure and usually are not confused with GERD.

Clinical trial: acupuncture vs. doubling the proton pump inhibitor dose in refractory heartburn

The current standard of care in proton pump inhibitor failure is to double the proton pump inhibitor dose, despite limited therapeutic gain. Aims To determine the efficacy of adding acupuncture vs. doubling the proton pump inhibitor dose in gastro-oesophageal reflux disease patients who failed symptomatically on proton pump inhibitors once daily. Thirty patients with classic heartburn symptoms who continued to be symptomatic on standard-dose proton pump inhibitors were enrolled into the study. All participants underwent upper endoscopy while on proton pump inhibitors once daily. Subsequently, patients were randomized to either adding acupuncture to their proton pump inhibitor or doubling the proton pump inhibitor dose over a period of 4 weeks. Acupuncture was delivered twice a week by an expert. The two groups did not differ in demographic parameters. The acupuncture + proton pump inhibitor group demonstrated a significant decrease in the mean daytime heartburn, night-time heartburn and acid regurgitation scores at the end of treatment when compared with baseline, while the double-dose proton pump inhibitor group did not demonstrate a significant change in their clinical endpoints. Mean general health score was only significantly improved in the acupuncture + proton pump inhibitor group. Adding acupuncture is more effective than doubling the proton pump inhibitor dose in controlling gastro-oesophageal reflux disease-related symptoms in patients who failed standard-dose proton pump inhibitors.

Heartburn refractory to proton-pump inhibitors

The most appropriate diagnostic and therapeutic approach to patients with heartburn that persists despite the use of proton-pump inhibitor (PPI) therapy currently is not known. In general, patients with heartburn refractory to PPIs may have more than one explanation for their persistent symptoms. These include uncontrolled esophageal acid exposure ("PPI failure") in a small subset of patients, as well as other potential etiologies in the majority of patients who have controlled esophageal acid exposure on PPI therapy ("PPI success"). Some potential explanations for persistent heartburn in this latter group include hypersensitivity to acid reflux, nonacidic or duodenogastric esophageal reflux, as well as functional heartburn. Patients who present with heartburn refractory to PPIs should be investigated further to determine the potential cause. We believe the diagnostic modality with the most clinical usefulness is 24-hour pH and multichannel intraluminal impedance monitoring with symptom index performed while the patient is on high-dose PPI therapy. This approach allows the patient to be properly categorized and also identifies a substantial proportion of patients who will have functional heartburn, a condition that should discourage the use of endoscopic or surgical therapies. Therapeutic options for patients with heartburn refractory to PPIs are limited and have not been thoroughly studied. As a result of the paucity of information, we favor a therapeutic approach based on the outcome of diagnostic testing.

Proton-Pump Inhibitor Therapy in Patients with Gastro-Oesophageal Reflux Disease

Proton-pump inhibitor (PPI) failure in gastro-oesophageal reflux disease (GORD) patients has become the main reason for referral of these patients to gastroenterology specialists. It is estimated that 30% of GORD patients requiring a PPI once daily will experience treatment failure. Patients with non-erosive reflux disease are the most common GORD-related group in which once-daily PPI therapy fails. Various mechanisms have been suggested to underlie PPI failure in GORD patients. The most pertinent include weakly acidic reflux, duodenogastro-oesophageal reflux, visceral hyperalgesia, delayed gastric emptying, psychological co-morbidity and concomitant functional bowel disorders, as well as others. Because of the importance of PPI failure as a target for future drug development, further understanding of the most relevant underlying mechanisms is needed.

The Value of Upper Endoscopy in Patients with Gastroesophageal Reflux Disease (GERD) Who Failed Proton Pump Inhibitor (PPI) Therapy

Background: PPI failure is a growing clinical dilemma in GI practice. It is estimated that up to 30% of the patients receiving PPI once a day will continue to report GERD symptoms. Thus far, the value of an upper endoscopy in this important patient population has not been assessed. Aim: To determine the value of an upper endoscopy in GERD patients who failed symptomatically PPI treatment (PPI failure) as compared to GERD patients who are symptomatically controlled on PPI (PPI success). Methods: This is a case-controlled study that included GERD patients undergoing an upper endoscopy because of PPI failure that were matched by age, gender and PPI dose to GERD patients who were well controlled on PPI.

Proton pump inhibitor failure in gastro‐oesophagel reflux disease – what about eosinophilic oesophagitis? Authors’ reply

Proton pump inhibitor failure in gastro‐oesophagel reflux disease – what about eosinophilic oesophagitis? Authors’ reply

Proton pump inhibitor failure in gastro‐oesophageal reflux disease – what about eosinophilic oesophagitis?

Proton pump inhibitor failure in gastro‐oesophageal reflux disease – what about eosinophilic oesophagitis?

Introduction: the evolving role of 24‐h oesophageal pH monitoring

Publication data Accepted 12 December 2005 Since the introduction of 24-h pH testing about a half century ago, the procedure has gained general popularity and has established itself as an important tool in evaluating patients with suspected gastro-oesophageal reflux disease (GERD). While initially praised as the gold standard for diagnosing GERD, over time the clinical value of the pH test has changed primarily due to the recognition of its inherent limitations. Regardless, the tool provides a unique opportunity to assess the extent of oesophageal acid exposure at different levels of the oesophagus and to determine the relationship between patients’ symptoms and acid reflux events. The role of pH testing in GERD has evolved over the years, the result of the introduction of potent medical antireflux treatment as well as improvement in surgical techniques. Recent studies have shown that the main indications for referrals for pH testing are failure of proton pump inhibitor (PPI) therapy or presurgical evaluation. 2 However, the yield of pH testing in evaluating patients who failed PPI therapy appeared to be very low. The traditional test that utilizes a pH probe has been shown to be poorly tolerated by a subset of patients who are undergoing pH testing. More disconcerting was the effect of the pH probe on patients’ normal daily activities, which may lead to a marked reduction in reflux-provoking activities. However, by miniaturizing the pH test, patients are able to better tolerate the procedure, and longer duration of oesophageal pH measurements can be achieved. The introduction of the wireless pH capsule resulted in resurgence in the popularity of the technique. Furthermore, the easy placement of the pH capsule after an upper endoscopy increased the utilization of the test by community-based gastroenterologists. An important contribution of the pH test is the finding that a significant number of patients with non-erosive reflux disease (NERD) have normal oesophageal acid exposure. Other intraoesophageal stimuli have been suggested to cause heartburn that is not related to an acid reflux event. They include weakly acidic reflux, duodenogastro-oesophageal reflux, and motor events. Visceral hypersensitivity has been suggested as an important underlying mechanism for symptoms in these patients, regardless of the type of stimulus. In this supplement, we address the evolving role of pH testing in GERD with a series of articles by experts in the field. We discuss the value and type of information generated by intragastric vs. intraoesophageal pH testing. Additionally, we evaluate the new position of the pH test with the introduction of novel techniques that can assess non-acid-related reflux events, such as the intraluminal multichannel impedance and the Bilitec. We also discuss potential new indications for the pH test in GERD with the introduction of the wireless pH system; this is because studies have demonstrated that the pH capsule Alimentary Pharmacology & Therapeutics

The Value of Ambulatory 24 hr Esophageal pH Monitoring in Clinical Practice in Patients Who Were Referred with Persistent Gastroesophageal Reflux Disease (GERD)-Related Symptoms While on Standard Dose Anti-Reflux Medications

To determine the value of pH testing in clinical practice in gastroesophageal reflux disease patients who failed anti-reflux treatment. Patients resistant to standard dose proton pump inhibitor or an H2-blocker underwent pH testing. Randomly selected patients from the proton pump inhibitor failure group underwent the modified acid perfusion test as compared to patients with non-erosive reflux disease. In the proton pump inhibitor failure group (n = 70), 63.8% had a normal pH test as compared to 29% in the H2-blocker group (n = 31) (P = 0.007). Sensory intensity rating and acid perfusion sensitivity score were significantly higher in the non-erosive reflux disease control group than the proton pump inhibitor failure group (P < 0.05). Most patients who continued to be symptomatic on proton pump inhibitor once daily demonstrated a normal pH test and overall lack of increased chemoreceptor sensitivity to acid.

Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease - where next?

Proton-pump inhibitor failure has become a common clinical dilemma in gastrointestinal clinics and has been increasingly encountered at the primary care level as well. Underlying mechanisms are diverse and may overlap. Most patients who have proton-pump inhibitor failure are likely to originate from the non-erosive reflux disease phenotype. Currently, available diagnostic modalities provide limited clues to the exact underlying cause. Treatment relies primarily on escalating dosing of proton-pump inhibitors. However, new insights into the pathophysiology of proton-pump inhibitor failure are likely to provide alternative therapeutic options.

Treatment of Helicobacter pylori Eradication Failures.

Even with the current most effective treatment regimens, about 10% to 20% of patients will fail to eradicate Helicobacter pylori infection. Therefore, in designing a treatment strategy, we should not focus on the results of primary therapy alone but also on the final (overall) eradication rate. The choice of a second-line treatment depends on which treatment was used initially, because retreatment with the same regimen is not recommended. Therefore, it seems that performing culture after a first eradication failure is not necessary and assessing H. pylori sensitivity to antibiotics only after failure of the second treatment is suggested in clinical practice. Different possibilities of empirical treatment are suggested. After failure of proton pump inhibitor (PPI)-amoxicillin-clarithromycin, quadruple therapy has been generally used. More recently, replacing the PPI and the bismuth compound by ranitidine bismuth citrate has also achieved good results. After PPI-amoxicillin-nitroimidazole failure, retreatment with PPI-amoxicillin-clarithromycin has proved to be effective. Finally, the first therapy should not combine clarithromycin and metronidazole in the same regimen because of the problem of resistance against both antibiotics. Recently, rifabutin-based rescue therapies have been shown to constitute an encouraging strategy for eradication failures because they are effective for H. pylori strains resistant to antibiotics.

Review article: Helicobacter pylori "rescue" regimen when proton pump inhibitor-based triple therapies fail.

Even with the currently most effective treatment regimens, about 10-20% of patients will fail to obtain eradication of Helicobacter pylori infection. Therefore, in designing a treatment strategy, we should not focus on the results of primary therapy alone, but also on the final (overall) eradication rate. The choice of second-line treatment depends on which treatment was used initially, as re-treatment with the same regimen is not recommended. Therefore, it is not necessary to perform culture after the first eradication failure. Assessment of the sensitivity of H. pylori to antibiotics only after failure of the second treatment is suggested in clinical practice. Different possibilities of empirical treatment have been suggested. After failure of proton pump inhibitor-amoxicillin-clarithromycin, quadruple therapy has generally been used. More recently, replacement of the proton pump inhibitor and the bismuth compound by ranitidine bismuth citrate has also achieved good results. After proton pump inhibitor-amoxicillin-nitroimidazole failure, re-treatment with proton pump inhibitor-amoxicillin-clarithromycin has been proven to be effective. Finally, first-line treatment should not combine clarithromycin and metronidazole in the same regimen, because of the problem of resistance to both antibiotics. Recently, rifabutin-based rescue therapies have been shown to constitute an encouraging strategy for eradication failures, as they are effective against H. pylori strains resistant to antibiotics.