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Medical treatment versus surgery for treatment of gastroesophageal reflux disease
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Medical Treatment Versus Surgery for Treatment of Gastroesophageal Reflux Disease Parth J. Parekh MD, David A. Johnson MD, MACG, FASGE, FACP
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Cite this article as: Parth J. Parekh MD, David A. Johnson MD, MACG, FASGE, FACP, Medical Treatment Versus Surgery for Treatment of Gastroesophageal Reflux Disease, Techniques in Gastrointestinal Endoscopy, http://dx.doi.org/10.1016/j. tgie.2015.02.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Medical Treatment Versus Surgery for Treatment of Gastroesophageal Reflux Disease
Parth J. Parekh, MD
Department of Internal Medicine Division of Gastroenterology and Hepatology Tulane University, New Orleans, LA United States David A. Johnson, MD MACG FASGE FACP Department of Internal Medicine Division of Gastroenterology and Hepatology Eastern Virginia Medical School, Norfolk, VA United States Authorship Contributions: Parekh PJ, Johnson DA contributed equally to this work Correspondence: David A. Johnson MD MACG FASGE, Professor of Medicine, Chief, Division of Gastroenterology and Hepatology, Eastern Virginia Medical School, Norfolk, VA 23510, United States. ([email protected]) Relevant conflict of interest: PJ Parekh: none DA Johnson: Consultant: Pfizer, LINX, Janssen Speaker bureau: Takeda Keywords: Gastroesophageal reflux disease, treatment of gastroesophageal reflux disease, surgery for gastroesophageal reflux disease, proton pump inhibitors, medical therapy for gastroesophageal reflux disease
Abstract: Gastroesophageal reflux disease (GERD) has significant and profound impact on the population at large. This increasingly prevalent disease has been shown to have adverse effect on quality of life, work productivity, interference with daily living, much less the direct and indirect diagnostic and therapeutic costs. Effective medical and surgical therapies are available. This discussion focuses on evidence for justifying therapy – both with a risk and reward assessment of outcomes. Best practice recommendations and caveats for each pathway of therapy are discussed.
Introduction to the Treatment of GERD Gastroesophageal reflux disease (GERD) is characterized by troublesome symptoms of heartburn and regurgitation and/or complications that are caused by the reflux of stomach contents into the esophagus. [1] This is a common condition affecting approximately 10–20% of the population in the western world [2] and its symptoms can negatively impact patients’ health‐related quality of life (HR‐QOL) and well‐being, as well as productivity at work, resulting in substantial societal burden and employer costs. [4]
Proton pump inhibitors (PPIs) are considered to be the most effective form of
pharmacological therapy for GERD. Although surgical treatment of GERD is a well‐established option, when done by an expert surgeon, current GERD treatment guidelines recommend the use of PPIs as the preferred method of disease management of patients with moderate or severe manifestations. [4] However, 20 to 40% of patients with GERD continue to experience persistent and intense reflux symptoms while receiving standard‐dose PPI therapy. [5,6] This chapter will review and compare the published literature for both surgical and medical treatment of GERD and highlight best practice recommendations for both approaches. Goals of Therapy According to the most recent consensus definition of GERD [4], the disease is defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. According to this definition, “troublesome” symptoms are those that adversely affect an individual’s well being. The goal of therapy is to control symptoms and prevent complications. “Typical GERD” symptoms (such as heartburn and acid regurgitation) and their frequency in order to be “troublesome” have also been defined. [1] The typical symptoms, e.g. heartburn and acid regurgitation, have been defined by consensus only and currently lack adequate validation. [1] The attempt of the Montreal process to define an overall sensitivity and specificity of these two symptoms for the diagnosis of GERD has failed, for the most part due to the lack of a gold standard and non‐homogeneity of the trials. Therefore, the definition and diagnosis of typical GERD are based solely on expert consensus. Symptoms that may accompany typical GERD symptoms includes
epigastric pain, sleep disturbances, dyspepsia, dysphagia, odynophagia, nausea, vomiting, and others. “Atypical GERD” involves signs or symptoms considered to be associated with or caused by GERD such as non‐cardiac chest pain, chronic cough (especially nocturnal), chronic laryngitis and asthma. The main complications of GERD can include reflux esophagitis, the development of strictures, Barrett’s esophagus, and esophageal adenocarcinoma. In rare cases, esophagitis may also lead to clinically significant bleeding. Despite its potentially serious sequelae, GERD usually presents as a relatively benign condition. The vast majority of patients with GERD experience non‐progressive disease (i.e. the progression from non‐erosive to erosive disease, to severe erosive disease, to Barrett’s esophagus, and ultimately esophageal adenocarcinoma or other complications), and thus GERD has been traditionally viewed as a non‐progressive disease without significant associated mortality. New Concepts of Pathophysiology There are several underlying mechanisms working individually or in concert contributing to the pathogenesis of GERD. If envisioned to be a single plumbing circuit, as described by Stein et al [7], the esophagus acts as an antegrade pump, the lower esophageal sphincter (LES) a valve, and the stomach a reservoir. Abnormalities can stem from any or all components of the system and ultimately contribute to the pathogenesis of GERD and its sequelae. The impact of esophageal dysfunction [8] and resultant damage to pre‐epithelial [8,9], epithelial [8], and post‐epithelial [8] defense mechanisms, LES dysfunction [10], abnormal LES pressures [11‐5], and structural abnormalities (e.g. hiatal hernia) [16‐18] has been well demonstrated in the pathogenesis of GERD. Emerging data has shifted focus on to the role of transient lower esophageal sphincter relaxations (TLESR) and the acid pocket as a potential underlying mechanism in the pathogenesis of GERD. Transient Esophageal Sphincter Relaxation The most common mechanism implicated in the pathogenesis of GERD is TLESR. Under normal circumstances, the LES relaxes following a swallow or subsequent to primary or secondary to peristalsis to allow for passage of a bolus. In the face of a normal LES pressure, TLESR occurs spontaneously independent of pharyngeal stimulation or esophageal peristalsis. [19] There is an on‐
going debate as to whether an increase in duration [20] versus an increased frequency [21,22] of LES relaxation is responsible for the pathogenesis of GERD. Other studies indicate that neither the frequency nor duration of LES relaxation is the culprit, but rather dysfunction in the motor responses that normally promote esophageal clearance of refluxate. [23‐25] Acid Pocket Intragastric pH has been demonstrated to be highest after a meal, owning to the buffering effect of food. [26] The fact that most a majority of symptoms related to GERD occur during the postprandial period [27] led many investigators to further investigate this paradox. In 2001, Fletcher et al detected an area at the gastroesophageal junction of highly acidic, unbuffered gastric content, which he termed the “acid pocket”. [28] Subsequent studies have demonstrated the location and size of the acid pocket to differ in patients suffering from GERD as compared to the healthy cohorts [29‐31]. In patients with GERD the “acid pocket” acts as a reservoir and is prone to upward migration of the proximal margin onto the esophageal mucosa which may be a factor contributing to the mucosal pathology. [32] In addition, the acid pocket has been demonstrated to move in conjunction with a hiatal hernia to supradiaphragmatic location increasing the propensity for GERD symptoms by mechanisms previously discussed. [29,33,34] Medical Therapy Medical intervention and lifestyle modifications, if applicable, are considered the first line therapy for patients with GERD. This section will focus on the available medical therapies and the recommended lifestyle modifications in the treatment of GERD. Figure 1 outlines an algorithmic approach to the medical treatment of GERD. Lifestyle Modifications Several lifestyle and dietary modifications are commonly recommended to patients in the clinical realm, however for lifestyle and dietary modifications the evidence for efficacy of these recommendations is mostly anecdotal. The general consensus appears to be that of the lifestyle and dietary modifications only weight loss, elevation of the head of the bed, and avoidance of postprandial recumbency has been shown to somewhat consistently improve esophageal pHmetry
and / or GERD symptomatology. [35‐38]. Jacobsen et al found a dose‐response relationship across all categories of BMI, noting that an increase of >3.5 in BMI increased the risk of GERD symptoms by more than a factor of 2 and conversely a decrease in BMI of >3.5 resulted in nearly a 40% reduction of symptoms compared to women whose BMI remain unchanged (odds ratio 0.64; 95% CI 0.42‐0.97] [35]. Current American College of Gastroenterology (ACG) guidelines recommends weight loss for patients with a BMI>25 or patients with recent weight gain. [4] Three trials to date have demonstrated improvement in esophageal pH values and GERD symptoms with head of bed elevation [39‐41], which led the ACG to recommend the use of head of bed elevation for patients suffering with nocturnal GERD. [4] Avoidance of late evening meals has been demonstrated to improve nocturnal gastric acidity [42,43] and thus the ACG recommends avoiding eating meals particularly with high fat content within 3 hours of reclining. [4] Acid Suppressive Therapy Histamine type 2 receptor antagonists (H2RAs) are currently first line agents for patients with mild to moderate GERD. H2RAs act by competitively inhibiting histamine from binding to H2 receptors found on parietal cells, thus reducing acid production. In addition, they act to reduce pepsin and volume of gastric acid. [44] There are currently 4 available H2RAs, 3 of which are available over the counter. As a class, the differences in pharmacokinetics and pharmacodynamics are negligible. [45] Although, recent studies have suggested clinical superiority of nizatadine compared to other H2RAs despite there being no difference in the level of acid suppression amongst H2RAs as a class owning to its unique ability to inhibit the rate of TLESR and acid reflux during those episodes not demonstrated. [46] The advent of proton pump inhibitors (PPIs) in the 1980’s revolutionized approach to GERD management [37], emerging to become the first line therapy for patients with moderate to severe GERD. [47] PPIs irreversibly antagonize the hydrogen/potassium/adenosine triphosphatase enzyme (i.e. the gastric proton pump) ultimately preventing the secretion of hydrogen ions into the gastric lumen. [48] There are currently 6 available PPIs, 3 of which are available now available to patients without the need of a medical prescription by a health care provider. Recognizably the prescription strength dosages are higher (with the exception of 20mg omeprazole); patients are more likely to
adhere to a prescription regimen as compared to those who are over the counter consumers. [49] As a class, the differences in pharmacokinetics, pharmacodynamics, and symptomatic relief are negligible. [50,51] A 2010 meta‐analysis totaling 9,989 patients with GERD demonstrated the placebo response in GERD clinical trials to be 18.85% (lower in patients with erosive esophagitis (11.87%)) and placebo response significant lower in studies using PPIs versus studies of H2RA therapy (14.51% vs. 24.69%, respectively; p=0.05). [52] Several other studies have demonstrated the use of to be associated with superior healing rates and decreased relapse rates when compared to H2RAs and placebo for patients with erosive [53‐55] and non‐erosive reflux disease [56]. As previously described, more attention is being paid to the gastric acid pocket as a potential source of symptomatic GERD. A recent study by Rohof et al evaluated the therapeutic effect of PPIs on the acid pocket in patients with GERD. [57] Thirty‐six patients with GERD (18 taking PPIs, and 18 not taking PPIs) underwent high‐resolution manometry and pH‐impedance after ingesting a standardized meal. Scintigraphy post intravenous administration of (99m) technetium‐pertechnetate was used to visualize the acid pocket. In patients taking PPI, the acid pocket was noted to be smaller and more frequently located below the diaphragm. In addition, the mean pH of the acid pocket was significantly higher in those patients taking PPIs as compared to those who were off PPIs. The authors concluded that the acid pockets of patients in GERD appears to act as a reservoir for refluxate and that PPIs may play a role in affecting the size, acidity, or position of the acid pocket resulting in symptomatic relief. NonAcid Related Therapy The most commonly utilized surface agents for symptomatic GERD are sucralfate and bismuth. They act by binding to gastric mucosa and ulcerated tissue favoring healing [58] and providing cytoprotective effects. [59] Current guidelines, however, state that there is no role for sucralfate in the non‐pregnant GERD patient owing to the availability, efficacy, and safety profile of H2RAs and PPIs. [4]
Alginate rafts are polysaccharide polymers that upon contact with gastric acid precipitate to
form a low‐density viscous gel, which have been reported to form at the acid pocket. [60] Rohof et al
recently sought to evaluate the location of alginate formulation in relation to the acid pocket and the corresponding effects on reflux parameters and acid pocket position in 16 patients with GERD. [61] In this prospective, single‐center study, 16 patients with symptomatic GERD and large hiatal hernias were randomized to receive either radiolabeled alginate‐antacid (n=8) or an antacid (n=8) after a standard meal. Postprandial scintigraphy was performed to analyze the relative position of the acid pocket. High‐resolution manometry and pH‐impedance monitoring were used to detect reflux episodes. Patients receiving alginate‐antacid were significantly less likely to experience acid reflux episodes compared to those receiving an antacid (3.5 vs. 15, respectively; p=0.03), and time to reflux was significantly increased in patients receiving alginate‐antacid compared to those receiving antacid (63 minutes vs. 14 minutes, respectively; p=0.01). In addition, the acid pocket was located below the diaphragm in 71% of patients versus 21% of patients who received alginate‐antacid and an antacid, respectively (p=0.08). There was an inverse correlation between acid reflux and the subdiaphragmatic position of the acid pocket (r=‐0.76; p<0.001) which led to the conclusion that alginate‐antacid raft localizes to the post prandial acid pocket and displaces it below the diaphragm ultimately reducing postprandial reflux. Thus, the acid pocket is likely to play a significant role in the pathogenesis of GERD and establish the role of an alginate‐antacid in the management of postprandial GERD. Success with Typical Versus Atypical GERD Therapeutic efficacy differs in patients who present with typical symptoms as compared to those with an atypical presentation. Patients with atypical GERD are often more difficult to treat and thus have an unpredictable response to acid‐suppressive therapy, which may in part own to the misdiagnosis of GERD. Figure 2 depicts the estimated efficacy of PPI therapy for various manifestations of GERD, both typical and atypical, based on available randomized control data. [37,62] Long Term Safety Issues with Medical Intervention In the past few years, data has accumulated on the potential risks of long‐term use of PPIs in patients with GERD. The reports were initially sporadic, but a stream of publications has claimed a variety of
adverse effects that may afflict patients who are chronically treated with PPIs, raising concerns among physicians and patients. In response to such publications, many physicians altered their usual approach to the care of patients on chronic anti‐reflux treatment for GERD. To date, all of the reported studies have been case controlled studies. Summary reviews on the potential harm by long term PPI use have noted that all of the reports have been case‐controlled studies and there have not been any prospective studies with stratified risk balance to validate any of these reported harms. Furthermore, the pathogenesis of these proposed associations is not clear in most cases and the evidence base to support a clear association for harm is extremely variable. These potential interactions have ranged from alteration of absorption of vitamins and minerals, metabolic effects on bone density, alteration of pharmacokinetics or pharmacodynamics and related drug interactions, or alterations of intended effect, infection risk, and hypersensitivity response with consequent organ damage. [63‐65] The clinical risk/benefit of any medical intervention or therapy always should be evaluated for each patient and appropriate use of therapy should be accordingly directed. Because PPIs are overprescribed in many patients, in particular for continued long‐term use, the clinical effects always should be reviewed and attempts should be justified to stop any therapy that may not be needed. Mechanisms of PPI Failure There are several underlying mechanisms though to contribute to PPI failure. Patients ought to be instructed to take PPIs half hour prior to breakfast in order to maximize acid inhibition. [66] Studies have demonstrated that upwards of 50% of patient were improperly taking their PPIs. [67] Compliance remains an issue with patients requiring PPI therapy. It has been demonstrated at the end of 1 and 6 months of PPI therapy, only 55 and 30% of GERD patients consume their PPI once daily as initially instructed [68]. There is a multitude of reasons resulting in PPI non‐compliance [69,70], thus proper patient education on disease process and the importance of compliance remains imperative.
Studies evaluating patients who fail to respond to twice daily PPI therapy have
demonstrated that close to 60% of patients have functional heartburn, thus making it the most
common mechanism of PPI failure. [71,71] Other mechanisms thought to contribute to PPI failure include bile acid reflux [73], Helicobacter pylori status [74,75], and concomitant psychological comorbidities (e.g. anxiety and depression) [76‐78]. Surgical Therapy Patients with GERD are commonly referred for surgical evaluation for several reasons such as desire to discontinue medical therapy due to non‐compliance or associated side effects, the presence of a large hiatal hernia, symptoms or sequelae of GERD refractory to medical therapy. [4] This section will focus on the available surgical therapies available for the treatment of GERD. Fundoplication In a surgical fundoplication, be it open or laparoscopic, the gastric fundus is wrapped around the lower end of the esophagus and stitched in place reinforcing the LES. This can be done completely, known as a Nissen, or partially, known as a Belsey (270 degrees anterior transthoracic), Dor (anterior 180‐200 degrees), or Toupet (posterior 270 degrees posterior) depending on indication. A recent meta‐analysis sought to compare the posterior approach to an anterior approach in controlled reflux symptoms. [79] The investigators found the posterior approach to be associated with significant reduction in heartburn and thus concluded that the posterior approach is a better alternative for controlling GERD symptoms.
Recent data indicates that fundoplication may not be efficacious in patients with GERD who
are non‐responders or partial responders to PPI therapy [80,81]. In a recent large, single center prospective study, Hamdy et al sought to evaluate the outcome of a laparoscopic Nissen fundoplication in patients that are non‐responders to PPI therapy. [80] Three hundred and seventy patients were enrolled, 296 were good responders to PPI while 74 patients were non‐responders. Patients who were prior to PPI responders prior to surgery reported relief of heartburn (p=0.01) and regurgitation (p=0.04) in comparison to non‐responders. In addition, the integrity of the wrap was higher in PPI responders (p=0.04). This led to the conclusion that a thorough assessment is mandatory to confirm a GERD diagnosis, but that PPI non‐responders should not be precluded from receiving a fundoplication. A significant portion of PPI non‐responders shows good response to
fundoplication, albeit significantly less than PPI responders, and thus the likelihood of poor outcome post procedure should be discussed with each individual patient. Transoral Endoscopic Incisionless Fundoplication Surgical fundoplication is an essentially blind approach and as a result is associated with significant postoperative morbidity, namely dysphagia (up to 50%) and recurrent heartburn (upwards of 60%), resulting in reoperation rates in up to 15% of patients. [82] A transoral endoscopic approach allows for direct visualization of the esophageal and gastric lumen, which theoretically allows for increase efficacy and decreased morbidity.
Approved in 2007, transoral incisionless fundoplication (TIF) is an innovative approach to
treat GERD. [83] TIF bridges the treatment gap between medical therapy and move invasive surgical fundoplication by reconstructing the dynamics of the natural antireflux barrier. It is a full thickness gastroesophageal plication utilizing transmural fasteners, that if unsuccessful may be safely revised with laparoscopic anti‐reflux surgery. [84]
Currently there is limited long‐term data comparing the efficacy and safety of TIF to surgical
fundoplication, however the available data indicates that the efficacy and safety is comparable. [85‐ 87] Recently, Trad et al evaluated the efficacy and durability of TIF in patients who were partial responders to high dose PPI therapy. [85] This multicenter trial included 63 patients (3 lost to follow up) who were randomized to TIF (n=39) or high dose PPI (n=21), later crossed over at 6 month follow up. In the cross over group, TIF improved control of regurgitation and atypical symptoms, with 65% reporting global elimination of troublesome regurgitation and atypical symptoms post TIF and off PPIs. Seventy‐one percent of cross over patients were off PPIs six months following TIF. In the TIF cohort, 77% of patients achieved global elimination of symptoms, 82% ceased PPI therapy, and 100% healed esophagitis 12 months post TIF. This led the authors to conclude that patients with symptoms refractory to high dose PPI may provide further elimination of symptoms with TIF.
The largest study to date comes from Bell et al. [86] This multicenter, prospective study
included over 100 patients who underwent TIF. More than 50% of patients reported improvement in symptoms and daily PPI use decreased approximately 60%. In patients amenable to post operative testing, esophagitis was healed in 75% of patients with normalization of esophageal acid exposure in
greater than 50% of patients, which led the authors to conclude that TIF safely achieved sustained symptomatic control in two‐thirds of patients over a 2 year period with a virtual absence of de novo side effects. Sphincter Augmentation In 2012, the United States Food and Drug Administration (FDA) approved the use sphincter augmentation as an alternative to fundoplication in patients with GERD. [88,89] This novel procedure involves placement of magnetized titan pellets around the LES allowing for passage of food bolus but prevent reflux.
Ganz et al first evaluated the use of sphincter augmentation in a prospective study involving
100 patients with GERD. [88] There was reported normalization of esophageal acid exposure of a greater than 50% decrease at 1 year follow up in approximately 64% of patients. In addition, there was a greater than 50% reduction in the use of PPIs in the majority of patients with a significant improvement in quality of life scores. Subsequent studies echoed the findings of Ganz et al, suggesting that sphincter augmentation ought to be considered first‐line surgical therapy in appropriately selected patients due to its favorable side effect profile and in order to avoid unnecessary dissection and preserve native gastric anatomy. [89‐94]
The largest study to date comes from Riegler et al, who evaluated the efficacy and safety
profile of sphincter augmentation. [90] This multicenter center, prospective study involved 249 patients (202 who underwent magnetic sphincter augmentation and 47 who underwent laparoscopic fundoplication). The improvement in quality of life scores was comparable between patients who underwent magnetic sphincter augmentation and those who underwent laparoscopic fundoplication. There was a significant different in improvement of moderate to severe regurgitation between patients who underwent magnetic sphincter augmentation and those who underwent laparoscopic fundoplication from 58.2 to 3.1% and 60.0 to 13.0% (p=0.014), respectively. In addition a significantly greater proportion of patients were able to discontinue PPI therapy in the sphincter augmentation cohort as compared to the fundoplication cohort. Lastly, reoperation rates were lower in the sphincter augmentation group, which ultimately led investigators to conclude that magnetic
sphincter augmentation should be considered as first‐line surgical option in appropriately selected patients.
The LINX® is one such reflux management system that is designed to augments the sphincter
barrier with a laparoscopic sphincter which preserves gastric anatomy and is easily reversible. [94] To date, there have been two single group trials that have demonstrated this device to decrease esophageal acid exposure, improve reflux symptoms and quality of life, and ultimately allow cessation of PPI therapy in a majority of patients. [88,95] Success with Typical Versus Atypical GERD The advent of impedance‐pH monitoring has allowed clinicians to select patients who demonstrate good symptom correlation with reflux events. [96] Although both have been shown beneficial, initial data indicate that for patients with long‐standing and/or complicated GERD anti‐reflux surgery is more effective in improving symptoms, endoscopic signs of reflux esophagitis in the short term [97‐ 99], and may be more cost effective in the long term [100]. Studies have demonstrated that patients with typical symptoms of heartburn and/or regurgitation with a good response to PPIs or abnormal pH studies with good system correlation are the most likely to respond to surgical therapy [101], thus it is essential to properly evaluate a patient with pH‐impedance and esophageal manometry prior to surgical intervention to best maximize outcomes. Long Term Safety Issues with Surgical Intervention Even skilled surgeons have complications following fundoplication be it open or laparoscopic, thus it is essential that a patient undergo surgery at a high‐volume highly experienced center. Fortunately, the mortality rate is low (less than 1%) with a majority of postoperative complications occurring within the first 2 years of surgery with up to 15% requiring reoperation. [82] The most common postoperative complications include gas‐bloat syndrome in upwards of 85% of patients, dysphagia (10‐15%), diarrhea in up to 33% of patients, and recurrent heartburn in nearly 2/3rds of patients. The most common adverse event of sphincter augmentation and the LINX® system is dysphagia, which occurs in up to 70% of patients. [88,95] Dysphagia was generally mild and self‐
limited and the majority resolved by 3 months without any postoperative reports of food impaction or inability to eat when resumed on a normal diet. Medical Therapy in Post Fundoplication Patients Emerging data indicate that the rate of patients requiring PPIs post anti‐reflux surgery may be significant higher than previously thought and thus should be made aware that long term PPI therapy is often necessary despite surgical intervention. [102] Previously, the risk of PPI use post fundoplication was thought to be up to 44% with follow up periods up to 12 years, with a tendency of increased PPI use with longer follow up. Recently, Lødrup et al. performed a retrospective analysis of 3,465 patients who underwent antireflux surgery during 1996‐2010. They found the 5‐, 10‐, and 15‐ year risks of taking long term PPI to be 29.4%, 41.1%, and 56.6%, respectively, with female gender, elderly, recent antireflux surgery, previous use of PPI and non‐steroidal anti‐inflammatory drugs or antiplatelet therapy to have the highest propensity towards long term PPI therapy. Admittedly, the use of PPI can only serve as a proxy for inadequate symptomatic relief after antireflux surgery thus patients should be made aware that long term PPI therapy is often necessary despite surgical intervention. Surgical Versus Medical Therapy It is difficult to assess the optimal therapy for GERD by measuring treatment outcomes seeking to compare the medical and surgical therapeutic approaches to GERD intervention. In particular for the surgical reports, the majority of these trials of therapy have had several issues that limit the extrapolation of the reported data. These include: 1. Lack of standardization of the inclusion/ exclusion criteria. 2. The therapeutic outcomes are not clearly defined “a priori”. 3. Rarely are power calculations done to justify the study primary objectives. 4. Rarely are validated measures used to assess the primary or secondary outcomes.
5. Lack of an appropriate control/sham comparison group to provide comparison outcome with no active treatment intervention. Additionally, for most of GERD therapeutic trials, variable efficacy endpoints have been targeted. These endpoints include: 1. Esophageal pH monitoring 2. Esophageal manometry 3. Endoscopic identification of esophagitis 4. Patient symptom response 5. Quality‐of‐life assessment 6. Quantification of medication usage In 1992, Spechler et al sought to evaluate the long‐term outcomes of medical therapy (lifestyle modifications and up to four medications) and surgical therapy (Nissen fundoplication) in 247 patients who randomly assigned to receive continuous medical therapy, medical therapy for symptoms only, or surgical therapy. [97] They found that while medical therapy is effective in men with complicated GERD, surgery is significantly more effective in improving the endoscopic signs of esophagitis and GERD symptoms for up to two years. More recently, Galmiche et al sought to evaluate laparoscopic antireflux surgery versus esomeprazole therapy in patients with chronic GERD. [103] Patients were randomized to receive esomeprazole (20‐40 mg daily allowing for dose adjustments, n=266) or undergo laparoscopic antireflux surgery (n=248), of which 372 completed 5‐year follow up (esomeprazole, n = 192; laparoscopic antireflux surgery, n = 180). This multicenter trial demonstrated that antireflux therapy beit? surgical or medical with esomeprazole to be beneficial with most patients achieving and remaining in remission at 5 year follow up. “Refractory GERD” – Recognizing and Managing
A non‐satisfactory response to GERD therapy is typically centered on the incomplete or lack of response to PPI therapy. Partial responders should be defined analogously to the general inclusion criteria. This means that a significant, and “typical” (both heartburn and regurgitation, with one of them being the most bothersome or severe symptom) symptom burden should exist at inclusion that is considered to be troublesome by the patient. The definition of PPI non‐responders may be difficult, as this would require a standardized comparison of symptom burden before and after PPI therapy, which is usually not available in clinical practice. Cost effectiveness of GERD Treatment The economic impact of GERD is significant and complicated. [104] To fully understand, one must consider both direct and indirect costs. Direct health care costs include those incurred during office visits, diagnostic testing, medical or surgical treatment and hospital admissions. Indirect costs include those from missed work, diminished productivity, and impairment in performing daily activities. The indirect costs due to GERD related impacts have been shown to be profound, yet responsive to effective treatment. [104] Very few randomized controlled trials (RCTs) have compared laparoscopic Nissen fundoplication to PPI management for patients with chronic GERD. Larger RCTs have been relatively short in duration, and have reported mixed results regarding symptom control and effect on quality of life (QOL). Economic evaluations have reported conflicting results. The central theme is that surgery, if done by an expert surgeon, is cost effective in particular for more troublesome symptoms. The key variable is the cost of the PPI, which when now available at generic as well as over the counter pricing, makes this a dominant strategy for cost effectiveness and safety. [105‐107] Conclusions Medical therapy has been extremely “successful” in the treatment of symptoms and complications of GERD. Recognizably, the methods to assess treatment outcomes for GERD have been extremely variable among medical and surgical therapies. Comparison between or even within classes of treatments cannot be accurately assessed without standardization of patient demographics, scientific
design, and treatment assessment. Evidence based comparisons of treatment outcomes between trials without this study design is inappropriate. Medical therapy offers a distinct advantage as it relates to risk versus the surgical therapeutic strategies for GERD. Clearly, medical therapy has been shown to be the safest and most cost‐effective strategy compared with surgery, especially now with low cost PPI pricing with generic and over the counter options. Available data from RCTs demonstrates equal efficacy for up to 5‐year follow up for both approaches. True “medical failures” are rare and these patients should be thoroughly evaluated before considering surgical anti‐reflux therapy option. The response of patients to PPI therapy, as well as the expertise of the surgeon is extremely important for best GERD surgical outcomes. Anti‐reflux surgery is a better treatment for durable control of the patients whose primary troublesome symptom is volume regurgitation. Surgery for GERD should never be recommended to patients as a better way to prevent esophageal cancer related to GERD. Despite continued improvements in the ability to suppress acid via even more potent PPIs, there remain, however, opportunities for improvement. These would be in the arena of accelerating the onset of action so that PPIs could provide more rapid symptom “on demand” symptom relief. Additionally, medical and or surgical therapies to better deal with ongoing symptoms for patients on PPIs with non‐acidic reflux are needed.
Figure legends. Figure 1. Algorithmic approach to medical treatment of GERD Figure 2. Therapeutic efficacy of PPI therapy on various manifestations of GERD (modified from Boeckxstaens et al. ref 37)
References
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Medical Treatment Versus Surgery for Treatment of Gastroesophageal Reflux Disease Parth J. Parekh MD, David A. Johnson MD, MACG, FASGE, FACP
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Cite this article as: Parth J. Parekh MD, David A. Johnson MD, MACG, FASGE, FACP, Medical Treatment Versus Surgery for Treatment of Gastroesophageal Reflux Disease, Techniques in Gastrointestinal Endoscopy, http://dx.doi.org/10.1016/j. tgie.2015.02.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Medical Treatment Versus Surgery for Treatment of Gastroesophageal Reflux Disease
Parth J. Parekh, MD
Department of Internal Medicine Division of Gastroenterology and Hepatology Tulane University, New Orleans, LA United States David A. Johnson, MD MACG FASGE FACP Department of Internal Medicine Division of Gastroenterology and Hepatology Eastern Virginia Medical School, Norfolk, VA United States Authorship Contributions: Parekh PJ, Johnson DA contributed equally to this work Correspondence: David A. Johnson MD MACG FASGE, Professor of Medicine, Chief, Division of Gastroenterology and Hepatology, Eastern Virginia Medical School, Norfolk, VA 23510, United States. ([email protected]) Relevant conflict of interest: PJ Parekh: none DA Johnson: Consultant: Pfizer, LINX, Janssen Speaker bureau: Takeda Keywords: Gastroesophageal reflux disease, treatment of gastroesophageal reflux disease, surgery for gastroesophageal reflux disease, proton pump inhibitors, medical therapy for gastroesophageal reflux disease
Abstract: Gastroesophageal reflux disease (GERD) has significant and profound impact on the population at large. This increasingly prevalent disease has been shown to have adverse effect on quality of life, work productivity, interference with daily living, much less the direct and indirect diagnostic and therapeutic costs. Effective medical and surgical therapies are available. This discussion focuses on evidence for justifying therapy – both with a risk and reward assessment of outcomes. Best practice recommendations and caveats for each pathway of therapy are discussed.
Introduction to the Treatment of GERD Gastroesophageal reflux disease (GERD) is characterized by troublesome symptoms of heartburn and regurgitation and/or complications that are caused by the reflux of stomach contents into the esophagus. [1] This is a common condition affecting approximately 10–20% of the population in the western world [2] and its symptoms can negatively impact patients’ health‐related quality of life (HR‐QOL) and well‐being, as well as productivity at work, resulting in substantial societal burden and employer costs. [4]
Proton pump inhibitors (PPIs) are considered to be the most effective form of
pharmacological therapy for GERD. Although surgical treatment of GERD is a well‐established option, when done by an expert surgeon, current GERD treatment guidelines recommend the use of PPIs as the preferred method of disease management of patients with moderate or severe manifestations. [4] However, 20 to 40% of patients with GERD continue to experience persistent and intense reflux symptoms while receiving standard‐dose PPI therapy. [5,6] This chapter will review and compare the published literature for both surgical and medical treatment of GERD and highlight best practice recommendations for both approaches. Goals of Therapy According to the most recent consensus definition of GERD [4], the disease is defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. According to this definition, “troublesome” symptoms are those that adversely affect an individual’s well being. The goal of therapy is to control symptoms and prevent complications. “Typical GERD” symptoms (such as heartburn and acid regurgitation) and their frequency in order to be “troublesome” have also been defined. [1] The typical symptoms, e.g. heartburn and acid regurgitation, have been defined by consensus only and currently lack adequate validation. [1] The attempt of the Montreal process to define an overall sensitivity and specificity of these two symptoms for the diagnosis of GERD has failed, for the most part due to the lack of a gold standard and non‐homogeneity of the trials. Therefore, the definition and diagnosis of typical GERD are based solely on expert consensus. Symptoms that may accompany typical GERD symptoms includes
epigastric pain, sleep disturbances, dyspepsia, dysphagia, odynophagia, nausea, vomiting, and others. “Atypical GERD” involves signs or symptoms considered to be associated with or caused by GERD such as non‐cardiac chest pain, chronic cough (especially nocturnal), chronic laryngitis and asthma. The main complications of GERD can include reflux esophagitis, the development of strictures, Barrett’s esophagus, and esophageal adenocarcinoma. In rare cases, esophagitis may also lead to clinically significant bleeding. Despite its potentially serious sequelae, GERD usually presents as a relatively benign condition. The vast majority of patients with GERD experience non‐progressive disease (i.e. the progression from non‐erosive to erosive disease, to severe erosive disease, to Barrett’s esophagus, and ultimately esophageal adenocarcinoma or other complications), and thus GERD has been traditionally viewed as a non‐progressive disease without significant associated mortality. New Concepts of Pathophysiology There are several underlying mechanisms working individually or in concert contributing to the pathogenesis of GERD. If envisioned to be a single plumbing circuit, as described by Stein et al [7], the esophagus acts as an antegrade pump, the lower esophageal sphincter (LES) a valve, and the stomach a reservoir. Abnormalities can stem from any or all components of the system and ultimately contribute to the pathogenesis of GERD and its sequelae. The impact of esophageal dysfunction [8] and resultant damage to pre‐epithelial [8,9], epithelial [8], and post‐epithelial [8] defense mechanisms, LES dysfunction [10], abnormal LES pressures [11‐5], and structural abnormalities (e.g. hiatal hernia) [16‐18] has been well demonstrated in the pathogenesis of GERD. Emerging data has shifted focus on to the role of transient lower esophageal sphincter relaxations (TLESR) and the acid pocket as a potential underlying mechanism in the pathogenesis of GERD. Transient Esophageal Sphincter Relaxation The most common mechanism implicated in the pathogenesis of GERD is TLESR. Under normal circumstances, the LES relaxes following a swallow or subsequent to primary or secondary to peristalsis to allow for passage of a bolus. In the face of a normal LES pressure, TLESR occurs spontaneously independent of pharyngeal stimulation or esophageal peristalsis. [19] There is an on‐
going debate as to whether an increase in duration [20] versus an increased frequency [21,22] of LES relaxation is responsible for the pathogenesis of GERD. Other studies indicate that neither the frequency nor duration of LES relaxation is the culprit, but rather dysfunction in the motor responses that normally promote esophageal clearance of refluxate. [23‐25] Acid Pocket Intragastric pH has been demonstrated to be highest after a meal, owning to the buffering effect of food. [26] The fact that most a majority of symptoms related to GERD occur during the postprandial period [27] led many investigators to further investigate this paradox. In 2001, Fletcher et al detected an area at the gastroesophageal junction of highly acidic, unbuffered gastric content, which he termed the “acid pocket”. [28] Subsequent studies have demonstrated the location and size of the acid pocket to differ in patients suffering from GERD as compared to the healthy cohorts [29‐31]. In patients with GERD the “acid pocket” acts as a reservoir and is prone to upward migration of the proximal margin onto the esophageal mucosa which may be a factor contributing to the mucosal pathology. [32] In addition, the acid pocket has been demonstrated to move in conjunction with a hiatal hernia to supradiaphragmatic location increasing the propensity for GERD symptoms by mechanisms previously discussed. [29,33,34] Medical Therapy Medical intervention and lifestyle modifications, if applicable, are considered the first line therapy for patients with GERD. This section will focus on the available medical therapies and the recommended lifestyle modifications in the treatment of GERD. Figure 1 outlines an algorithmic approach to the medical treatment of GERD. Lifestyle Modifications Several lifestyle and dietary modifications are commonly recommended to patients in the clinical realm, however for lifestyle and dietary modifications the evidence for efficacy of these recommendations is mostly anecdotal. The general consensus appears to be that of the lifestyle and dietary modifications only weight loss, elevation of the head of the bed, and avoidance of postprandial recumbency has been shown to somewhat consistently improve esophageal pHmetry
and / or GERD symptomatology. [35‐38]. Jacobsen et al found a dose‐response relationship across all categories of BMI, noting that an increase of >3.5 in BMI increased the risk of GERD symptoms by more than a factor of 2 and conversely a decrease in BMI of >3.5 resulted in nearly a 40% reduction of symptoms compared to women whose BMI remain unchanged (odds ratio 0.64; 95% CI 0.42‐0.97] [35]. Current American College of Gastroenterology (ACG) guidelines recommends weight loss for patients with a BMI>25 or patients with recent weight gain. [4] Three trials to date have demonstrated improvement in esophageal pH values and GERD symptoms with head of bed elevation [39‐41], which led the ACG to recommend the use of head of bed elevation for patients suffering with nocturnal GERD. [4] Avoidance of late evening meals has been demonstrated to improve nocturnal gastric acidity [42,43] and thus the ACG recommends avoiding eating meals particularly with high fat content within 3 hours of reclining. [4] Acid Suppressive Therapy Histamine type 2 receptor antagonists (H2RAs) are currently first line agents for patients with mild to moderate GERD. H2RAs act by competitively inhibiting histamine from binding to H2 receptors found on parietal cells, thus reducing acid production. In addition, they act to reduce pepsin and volume of gastric acid. [44] There are currently 4 available H2RAs, 3 of which are available over the counter. As a class, the differences in pharmacokinetics and pharmacodynamics are negligible. [45] Although, recent studies have suggested clinical superiority of nizatadine compared to other H2RAs despite there being no difference in the level of acid suppression amongst H2RAs as a class owning to its unique ability to inhibit the rate of TLESR and acid reflux during those episodes not demonstrated. [46] The advent of proton pump inhibitors (PPIs) in the 1980’s revolutionized approach to GERD management [37], emerging to become the first line therapy for patients with moderate to severe GERD. [47] PPIs irreversibly antagonize the hydrogen/potassium/adenosine triphosphatase enzyme (i.e. the gastric proton pump) ultimately preventing the secretion of hydrogen ions into the gastric lumen. [48] There are currently 6 available PPIs, 3 of which are available now available to patients without the need of a medical prescription by a health care provider. Recognizably the prescription strength dosages are higher (with the exception of 20mg omeprazole); patients are more likely to
adhere to a prescription regimen as compared to those who are over the counter consumers. [49] As a class, the differences in pharmacokinetics, pharmacodynamics, and symptomatic relief are negligible. [50,51] A 2010 meta‐analysis totaling 9,989 patients with GERD demonstrated the placebo response in GERD clinical trials to be 18.85% (lower in patients with erosive esophagitis (11.87%)) and placebo response significant lower in studies using PPIs versus studies of H2RA therapy (14.51% vs. 24.69%, respectively; p=0.05). [52] Several other studies have demonstrated the use of to be associated with superior healing rates and decreased relapse rates when compared to H2RAs and placebo for patients with erosive [53‐55] and non‐erosive reflux disease [56]. As previously described, more attention is being paid to the gastric acid pocket as a potential source of symptomatic GERD. A recent study by Rohof et al evaluated the therapeutic effect of PPIs on the acid pocket in patients with GERD. [57] Thirty‐six patients with GERD (18 taking PPIs, and 18 not taking PPIs) underwent high‐resolution manometry and pH‐impedance after ingesting a standardized meal. Scintigraphy post intravenous administration of (99m) technetium‐pertechnetate was used to visualize the acid pocket. In patients taking PPI, the acid pocket was noted to be smaller and more frequently located below the diaphragm. In addition, the mean pH of the acid pocket was significantly higher in those patients taking PPIs as compared to those who were off PPIs. The authors concluded that the acid pockets of patients in GERD appears to act as a reservoir for refluxate and that PPIs may play a role in affecting the size, acidity, or position of the acid pocket resulting in symptomatic relief. NonAcid Related Therapy The most commonly utilized surface agents for symptomatic GERD are sucralfate and bismuth. They act by binding to gastric mucosa and ulcerated tissue favoring healing [58] and providing cytoprotective effects. [59] Current guidelines, however, state that there is no role for sucralfate in the non‐pregnant GERD patient owing to the availability, efficacy, and safety profile of H2RAs and PPIs. [4]
Alginate rafts are polysaccharide polymers that upon contact with gastric acid precipitate to
form a low‐density viscous gel, which have been reported to form at the acid pocket. [60] Rohof et al
recently sought to evaluate the location of alginate formulation in relation to the acid pocket and the corresponding effects on reflux parameters and acid pocket position in 16 patients with GERD. [61] In this prospective, single‐center study, 16 patients with symptomatic GERD and large hiatal hernias were randomized to receive either radiolabeled alginate‐antacid (n=8) or an antacid (n=8) after a standard meal. Postprandial scintigraphy was performed to analyze the relative position of the acid pocket. High‐resolution manometry and pH‐impedance monitoring were used to detect reflux episodes. Patients receiving alginate‐antacid were significantly less likely to experience acid reflux episodes compared to those receiving an antacid (3.5 vs. 15, respectively; p=0.03), and time to reflux was significantly increased in patients receiving alginate‐antacid compared to those receiving antacid (63 minutes vs. 14 minutes, respectively; p=0.01). In addition, the acid pocket was located below the diaphragm in 71% of patients versus 21% of patients who received alginate‐antacid and an antacid, respectively (p=0.08). There was an inverse correlation between acid reflux and the subdiaphragmatic position of the acid pocket (r=‐0.76; p<0.001) which led to the conclusion that alginate‐antacid raft localizes to the post prandial acid pocket and displaces it below the diaphragm ultimately reducing postprandial reflux. Thus, the acid pocket is likely to play a significant role in the pathogenesis of GERD and establish the role of an alginate‐antacid in the management of postprandial GERD. Success with Typical Versus Atypical GERD Therapeutic efficacy differs in patients who present with typical symptoms as compared to those with an atypical presentation. Patients with atypical GERD are often more difficult to treat and thus have an unpredictable response to acid‐suppressive therapy, which may in part own to the misdiagnosis of GERD. Figure 2 depicts the estimated efficacy of PPI therapy for various manifestations of GERD, both typical and atypical, based on available randomized control data. [37,62] Long Term Safety Issues with Medical Intervention In the past few years, data has accumulated on the potential risks of long‐term use of PPIs in patients with GERD. The reports were initially sporadic, but a stream of publications has claimed a variety of
adverse effects that may afflict patients who are chronically treated with PPIs, raising concerns among physicians and patients. In response to such publications, many physicians altered their usual approach to the care of patients on chronic anti‐reflux treatment for GERD. To date, all of the reported studies have been case controlled studies. Summary reviews on the potential harm by long term PPI use have noted that all of the reports have been case‐controlled studies and there have not been any prospective studies with stratified risk balance to validate any of these reported harms. Furthermore, the pathogenesis of these proposed associations is not clear in most cases and the evidence base to support a clear association for harm is extremely variable. These potential interactions have ranged from alteration of absorption of vitamins and minerals, metabolic effects on bone density, alteration of pharmacokinetics or pharmacodynamics and related drug interactions, or alterations of intended effect, infection risk, and hypersensitivity response with consequent organ damage. [63‐65] The clinical risk/benefit of any medical intervention or therapy always should be evaluated for each patient and appropriate use of therapy should be accordingly directed. Because PPIs are overprescribed in many patients, in particular for continued long‐term use, the clinical effects always should be reviewed and attempts should be justified to stop any therapy that may not be needed. Mechanisms of PPI Failure There are several underlying mechanisms though to contribute to PPI failure. Patients ought to be instructed to take PPIs half hour prior to breakfast in order to maximize acid inhibition. [66] Studies have demonstrated that upwards of 50% of patient were improperly taking their PPIs. [67] Compliance remains an issue with patients requiring PPI therapy. It has been demonstrated at the end of 1 and 6 months of PPI therapy, only 55 and 30% of GERD patients consume their PPI once daily as initially instructed [68]. There is a multitude of reasons resulting in PPI non‐compliance [69,70], thus proper patient education on disease process and the importance of compliance remains imperative.
Studies evaluating patients who fail to respond to twice daily PPI therapy have
demonstrated that close to 60% of patients have functional heartburn, thus making it the most
common mechanism of PPI failure. [71,71] Other mechanisms thought to contribute to PPI failure include bile acid reflux [73], Helicobacter pylori status [74,75], and concomitant psychological comorbidities (e.g. anxiety and depression) [76‐78]. Surgical Therapy Patients with GERD are commonly referred for surgical evaluation for several reasons such as desire to discontinue medical therapy due to non‐compliance or associated side effects, the presence of a large hiatal hernia, symptoms or sequelae of GERD refractory to medical therapy. [4] This section will focus on the available surgical therapies available for the treatment of GERD. Fundoplication In a surgical fundoplication, be it open or laparoscopic, the gastric fundus is wrapped around the lower end of the esophagus and stitched in place reinforcing the LES. This can be done completely, known as a Nissen, or partially, known as a Belsey (270 degrees anterior transthoracic), Dor (anterior 180‐200 degrees), or Toupet (posterior 270 degrees posterior) depending on indication. A recent meta‐analysis sought to compare the posterior approach to an anterior approach in controlled reflux symptoms. [79] The investigators found the posterior approach to be associated with significant reduction in heartburn and thus concluded that the posterior approach is a better alternative for controlling GERD symptoms.
Recent data indicates that fundoplication may not be efficacious in patients with GERD who
are non‐responders or partial responders to PPI therapy [80,81]. In a recent large, single center prospective study, Hamdy et al sought to evaluate the outcome of a laparoscopic Nissen fundoplication in patients that are non‐responders to PPI therapy. [80] Three hundred and seventy patients were enrolled, 296 were good responders to PPI while 74 patients were non‐responders. Patients who were prior to PPI responders prior to surgery reported relief of heartburn (p=0.01) and regurgitation (p=0.04) in comparison to non‐responders. In addition, the integrity of the wrap was higher in PPI responders (p=0.04). This led to the conclusion that a thorough assessment is mandatory to confirm a GERD diagnosis, but that PPI non‐responders should not be precluded from receiving a fundoplication. A significant portion of PPI non‐responders shows good response to
fundoplication, albeit significantly less than PPI responders, and thus the likelihood of poor outcome post procedure should be discussed with each individual patient. Transoral Endoscopic Incisionless Fundoplication Surgical fundoplication is an essentially blind approach and as a result is associated with significant postoperative morbidity, namely dysphagia (up to 50%) and recurrent heartburn (upwards of 60%), resulting in reoperation rates in up to 15% of patients. [82] A transoral endoscopic approach allows for direct visualization of the esophageal and gastric lumen, which theoretically allows for increase efficacy and decreased morbidity.
Approved in 2007, transoral incisionless fundoplication (TIF) is an innovative approach to
treat GERD. [83] TIF bridges the treatment gap between medical therapy and move invasive surgical fundoplication by reconstructing the dynamics of the natural antireflux barrier. It is a full thickness gastroesophageal plication utilizing transmural fasteners, that if unsuccessful may be safely revised with laparoscopic anti‐reflux surgery. [84]
Currently there is limited long‐term data comparing the efficacy and safety of TIF to surgical
fundoplication, however the available data indicates that the efficacy and safety is comparable. [85‐ 87] Recently, Trad et al evaluated the efficacy and durability of TIF in patients who were partial responders to high dose PPI therapy. [85] This multicenter trial included 63 patients (3 lost to follow up) who were randomized to TIF (n=39) or high dose PPI (n=21), later crossed over at 6 month follow up. In the cross over group, TIF improved control of regurgitation and atypical symptoms, with 65% reporting global elimination of troublesome regurgitation and atypical symptoms post TIF and off PPIs. Seventy‐one percent of cross over patients were off PPIs six months following TIF. In the TIF cohort, 77% of patients achieved global elimination of symptoms, 82% ceased PPI therapy, and 100% healed esophagitis 12 months post TIF. This led the authors to conclude that patients with symptoms refractory to high dose PPI may provide further elimination of symptoms with TIF.
The largest study to date comes from Bell et al. [86] This multicenter, prospective study
included over 100 patients who underwent TIF. More than 50% of patients reported improvement in symptoms and daily PPI use decreased approximately 60%. In patients amenable to post operative testing, esophagitis was healed in 75% of patients with normalization of esophageal acid exposure in
greater than 50% of patients, which led the authors to conclude that TIF safely achieved sustained symptomatic control in two‐thirds of patients over a 2 year period with a virtual absence of de novo side effects. Sphincter Augmentation In 2012, the United States Food and Drug Administration (FDA) approved the use sphincter augmentation as an alternative to fundoplication in patients with GERD. [88,89] This novel procedure involves placement of magnetized titan pellets around the LES allowing for passage of food bolus but prevent reflux.
Ganz et al first evaluated the use of sphincter augmentation in a prospective study involving
100 patients with GERD. [88] There was reported normalization of esophageal acid exposure of a greater than 50% decrease at 1 year follow up in approximately 64% of patients. In addition, there was a greater than 50% reduction in the use of PPIs in the majority of patients with a significant improvement in quality of life scores. Subsequent studies echoed the findings of Ganz et al, suggesting that sphincter augmentation ought to be considered first‐line surgical therapy in appropriately selected patients due to its favorable side effect profile and in order to avoid unnecessary dissection and preserve native gastric anatomy. [89‐94]
The largest study to date comes from Riegler et al, who evaluated the efficacy and safety
profile of sphincter augmentation. [90] This multicenter center, prospective study involved 249 patients (202 who underwent magnetic sphincter augmentation and 47 who underwent laparoscopic fundoplication). The improvement in quality of life scores was comparable between patients who underwent magnetic sphincter augmentation and those who underwent laparoscopic fundoplication. There was a significant different in improvement of moderate to severe regurgitation between patients who underwent magnetic sphincter augmentation and those who underwent laparoscopic fundoplication from 58.2 to 3.1% and 60.0 to 13.0% (p=0.014), respectively. In addition a significantly greater proportion of patients were able to discontinue PPI therapy in the sphincter augmentation cohort as compared to the fundoplication cohort. Lastly, reoperation rates were lower in the sphincter augmentation group, which ultimately led investigators to conclude that magnetic
sphincter augmentation should be considered as first‐line surgical option in appropriately selected patients.
The LINX® is one such reflux management system that is designed to augments the sphincter
barrier with a laparoscopic sphincter which preserves gastric anatomy and is easily reversible. [94] To date, there have been two single group trials that have demonstrated this device to decrease esophageal acid exposure, improve reflux symptoms and quality of life, and ultimately allow cessation of PPI therapy in a majority of patients. [88,95] Success with Typical Versus Atypical GERD The advent of impedance‐pH monitoring has allowed clinicians to select patients who demonstrate good symptom correlation with reflux events. [96] Although both have been shown beneficial, initial data indicate that for patients with long‐standing and/or complicated GERD anti‐reflux surgery is more effective in improving symptoms, endoscopic signs of reflux esophagitis in the short term [97‐ 99], and may be more cost effective in the long term [100]. Studies have demonstrated that patients with typical symptoms of heartburn and/or regurgitation with a good response to PPIs or abnormal pH studies with good system correlation are the most likely to respond to surgical therapy [101], thus it is essential to properly evaluate a patient with pH‐impedance and esophageal manometry prior to surgical intervention to best maximize outcomes. Long Term Safety Issues with Surgical Intervention Even skilled surgeons have complications following fundoplication be it open or laparoscopic, thus it is essential that a patient undergo surgery at a high‐volume highly experienced center. Fortunately, the mortality rate is low (less than 1%) with a majority of postoperative complications occurring within the first 2 years of surgery with up to 15% requiring reoperation. [82] The most common postoperative complications include gas‐bloat syndrome in upwards of 85% of patients, dysphagia (10‐15%), diarrhea in up to 33% of patients, and recurrent heartburn in nearly 2/3rds of patients. The most common adverse event of sphincter augmentation and the LINX® system is dysphagia, which occurs in up to 70% of patients. [88,95] Dysphagia was generally mild and self‐
limited and the majority resolved by 3 months without any postoperative reports of food impaction or inability to eat when resumed on a normal diet. Medical Therapy in Post Fundoplication Patients Emerging data indicate that the rate of patients requiring PPIs post anti‐reflux surgery may be significant higher than previously thought and thus should be made aware that long term PPI therapy is often necessary despite surgical intervention. [102] Previously, the risk of PPI use post fundoplication was thought to be up to 44% with follow up periods up to 12 years, with a tendency of increased PPI use with longer follow up. Recently, Lødrup et al. performed a retrospective analysis of 3,465 patients who underwent antireflux surgery during 1996‐2010. They found the 5‐, 10‐, and 15‐ year risks of taking long term PPI to be 29.4%, 41.1%, and 56.6%, respectively, with female gender, elderly, recent antireflux surgery, previous use of PPI and non‐steroidal anti‐inflammatory drugs or antiplatelet therapy to have the highest propensity towards long term PPI therapy. Admittedly, the use of PPI can only serve as a proxy for inadequate symptomatic relief after antireflux surgery thus patients should be made aware that long term PPI therapy is often necessary despite surgical intervention. Surgical Versus Medical Therapy It is difficult to assess the optimal therapy for GERD by measuring treatment outcomes seeking to compare the medical and surgical therapeutic approaches to GERD intervention. In particular for the surgical reports, the majority of these trials of therapy have had several issues that limit the extrapolation of the reported data. These include: 1. Lack of standardization of the inclusion/ exclusion criteria. 2. The therapeutic outcomes are not clearly defined “a priori”. 3. Rarely are power calculations done to justify the study primary objectives. 4. Rarely are validated measures used to assess the primary or secondary outcomes.
5. Lack of an appropriate control/sham comparison group to provide comparison outcome with no active treatment intervention. Additionally, for most of GERD therapeutic trials, variable efficacy endpoints have been targeted. These endpoints include: 1. Esophageal pH monitoring 2. Esophageal manometry 3. Endoscopic identification of esophagitis 4. Patient symptom response 5. Quality‐of‐life assessment 6. Quantification of medication usage In 1992, Spechler et al sought to evaluate the long‐term outcomes of medical therapy (lifestyle modifications and up to four medications) and surgical therapy (Nissen fundoplication) in 247 patients who randomly assigned to receive continuous medical therapy, medical therapy for symptoms only, or surgical therapy. [97] They found that while medical therapy is effective in men with complicated GERD, surgery is significantly more effective in improving the endoscopic signs of esophagitis and GERD symptoms for up to two years. More recently, Galmiche et al sought to evaluate laparoscopic antireflux surgery versus esomeprazole therapy in patients with chronic GERD. [103] Patients were randomized to receive esomeprazole (20‐40 mg daily allowing for dose adjustments, n=266) or undergo laparoscopic antireflux surgery (n=248), of which 372 completed 5‐year follow up (esomeprazole, n = 192; laparoscopic antireflux surgery, n = 180). This multicenter trial demonstrated that antireflux therapy beit? surgical or medical with esomeprazole to be beneficial with most patients achieving and remaining in remission at 5 year follow up. “Refractory GERD” – Recognizing and Managing
A non‐satisfactory response to GERD therapy is typically centered on the incomplete or lack of response to PPI therapy. Partial responders should be defined analogously to the general inclusion criteria. This means that a significant, and “typical” (both heartburn and regurgitation, with one of them being the most bothersome or severe symptom) symptom burden should exist at inclusion that is considered to be troublesome by the patient. The definition of PPI non‐responders may be difficult, as this would require a standardized comparison of symptom burden before and after PPI therapy, which is usually not available in clinical practice. Cost effectiveness of GERD Treatment The economic impact of GERD is significant and complicated. [104] To fully understand, one must consider both direct and indirect costs. Direct health care costs include those incurred during office visits, diagnostic testing, medical or surgical treatment and hospital admissions. Indirect costs include those from missed work, diminished productivity, and impairment in performing daily activities. The indirect costs due to GERD related impacts have been shown to be profound, yet responsive to effective treatment. [104] Very few randomized controlled trials (RCTs) have compared laparoscopic Nissen fundoplication to PPI management for patients with chronic GERD. Larger RCTs have been relatively short in duration, and have reported mixed results regarding symptom control and effect on quality of life (QOL). Economic evaluations have reported conflicting results. The central theme is that surgery, if done by an expert surgeon, is cost effective in particular for more troublesome symptoms. The key variable is the cost of the PPI, which when now available at generic as well as over the counter pricing, makes this a dominant strategy for cost effectiveness and safety. [105‐107] Conclusions Medical therapy has been extremely “successful” in the treatment of symptoms and complications of GERD. Recognizably, the methods to assess treatment outcomes for GERD have been extremely variable among medical and surgical therapies. Comparison between or even within classes of treatments cannot be accurately assessed without standardization of patient demographics, scientific
design, and treatment assessment. Evidence based comparisons of treatment outcomes between trials without this study design is inappropriate. Medical therapy offers a distinct advantage as it relates to risk versus the surgical therapeutic strategies for GERD. Clearly, medical therapy has been shown to be the safest and most cost‐effective strategy compared with surgery, especially now with low cost PPI pricing with generic and over the counter options. Available data from RCTs demonstrates equal efficacy for up to 5‐year follow up for both approaches. True “medical failures” are rare and these patients should be thoroughly evaluated before considering surgical anti‐reflux therapy option. The response of patients to PPI therapy, as well as the expertise of the surgeon is extremely important for best GERD surgical outcomes. Anti‐reflux surgery is a better treatment for durable control of the patients whose primary troublesome symptom is volume regurgitation. Surgery for GERD should never be recommended to patients as a better way to prevent esophageal cancer related to GERD. Despite continued improvements in the ability to suppress acid via even more potent PPIs, there remain, however, opportunities for improvement. These would be in the arena of accelerating the onset of action so that PPIs could provide more rapid symptom “on demand” symptom relief. Additionally, medical and or surgical therapies to better deal with ongoing symptoms for patients on PPIs with non‐acidic reflux are needed.
Figure legends. Figure 1. Algorithmic approach to medical treatment of GERD Figure 2. Therapeutic efficacy of PPI therapy on various manifestations of GERD (modified from Boeckxstaens et al. ref 37)
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