Guidelines for the Diagnosis and Management of Gastroesophageal Reflux Disease

The usage of baclofen is another alternative for refractory GERD patients. Baclofen, a GABA(b) agonist, has been demonstrated to be effective in GERD by its ability to reduce transient LES relaxations (80), and reflux episodes (81). Baclofen has also been demonstrated to decrease the number of post-prandial acid and non-acid reflux events (82), nocturnal reflux activity (83), and belching episodes (84). Given the limited treatment options for GERD symptoms refractory to PPIs, a trial of baclofen at a dosage of 5-20 mg three times a day can be considered in patients with objective documentation of continued symptomatic reflux despite optimal PPI therapy, based on two short-term randomized controlled trials that demonstrated symptomatic improvement with this agent (82,83). The clinician should be aware that there has not been long-term data published regarding efficacy of baclofen in GERD. Usage is limited by side effects of dizziness, somnolence, and constipation. Baclofen is not approved by the FDA for the treatment of GERD.

Surgical Options for GERD

Recommendations

1. Surgical therapy is a treatment option for long-term therapy in GERD patients. (Strong recommendation, high level of evidence)

2. Surgical therapy is generally not recommended in patients who do not respond to PPI therapy. (Strong recommendation, high level of evidence)

3. Preoperative ambulatory pH monitoring is mandatory in patients without evidence of erosive esophagitis. All patients should undergo preoperative manometry to rule out achalasia or scleroderma-like esophagus. (Strong recommendation, moderate level of evidence)

4. Surgical therapy is as effective as medical therapy for carefully selected patients with chronic GERD when performed by an experienced surgeon. (Strong recommendation, high level of evidence)

5. Obese patients contemplating surgical therapy for GERD should be considered for bariatric surgery. Gastric bypass would be the preferred operation in these patients. (Conditional recommendation, moderate level of evidence)

6. The usage of current endoscopic therapy or transoral incisionless fundoplication cannot be recommended as an alternative to medical or traditional surgical therapy. (Conditional recommendation, moderate level of evidence)

Summary of the Evidence

Potential surgical options for GERD include laparoscopic fundoplication or bariatric surgery in the obese. Reasons to refer GERD patients for surgery may include desire to discontinue medical therapy, non-compliance, side-effects associated with medical therapy, the presence of a large hiatal hernia, esophagitis refractory to medical therapy, or persistent symptoms documented to be caused by refractory GERD. With the introduction of esophageal pH-impedance monitoring, patients found to have abnormal amounts of non-acid reflux on PPI therapy with good symptom correlation may be considered for surgery (85). Refractory dyspeptic symptoms including nausea, vomiting, and epigastric pain are less likely to demonstrate symptomatic response. The highest surgical responses are seen in patients with typical symptoms of heartburn and/or regurgitation that demonstrate good response to PPI therapy or have abnormal ambulatory pH studies with good symptom correlation (86). In this patient cohort, long-term remission rates can be expected to be comparable and in some cases statistically superior to medical therapy. In a long-term follow-up of a Veterans Affairs Cooperative cooperative randomized controlled trial comparing medical to surgical therapy for GERD, 92% of the patients in the medical arm were using medical therapy compared with 62% of the surgical cohort at 10 years (87). In a 12-year long-term follow-up of patients randomized to fundoplication compared with omeprazole, 53% of the surgery cohort were in remission compared with 45% of the medically treated patients (P=0.02), although symptoms of gas-bloat syndrome remained more common in the surgical cohort (88).

Patients choosing to undergo surgical therapy for GERD may face some additional risks including increased short-term risk of mortality. The most common adverse events associated with fundoplication include the gas-bloat syndrome in 15-20% of patients. A recent meta-analysis concluded that the prevalence of postoperative dysphagia and inability to belch were significantly lower in patients undergoing partial fundoplication compared with patients undergoing total fundoplication (89). In a Cochrane review, four randomized trials with over 1,200 subjects randomized to medical or surgical therapy were included (90). All four studies reported significant improvements in GERD-specific QOL after surgery compared with medical therapy although data were not combined. There was evidence to suggest that symptoms of heartburn, reflux, and bloating were improved more after surgery compared with medical therapy, but a small proportion of participants reported persistent postoperative dysphagia. Overall rates of postoperative complications were low, but fundoplication was associated with a potential for adverse postoperative events.

Outcomes in patients with extraesophageal symptoms undergoing Nissen fundoplication have been less encouraging. In patients enrolled in a VA Cooperative study, no significant change in pulmonary function tests were demonstrated after 1 year of surgery, even in patients with abnormal baseline pulmonary function tests (91). A randomized controlled trial of cimetidine vs. fundoplication and placebo for asthma symptoms demonstrated equivalent efficacy for medical and surgical therapy compared with placebo but no significant change in FEV1 at 6 months (92). In a 2003 Cochrane review, medical or surgical antireflux therapy was not associated with improvement in pulmonary function, asthma symptoms, or use of medication (93). Although surgery can be effective in carefully selected patients with extraesophageal or atypical symptoms, response rates are lower than in patients with heartburn (86). It is particularly important to carefully evaluate patients with so-called laryngopharyngeal reflux before considering fundoplication. A response to PPI is critical. In the absence of a PPI response, surgery is unlikely to be effective even with an abnormal pH study (94).

Given the increasing prevalence of obesity in the US, gastric bypass has become a more common procedure compared with Nissen fundoplication. A 2009 review assessed the efficacy for surgical therapies for obesity on gastroesophageal reflux (95). In studies assessing Roux-en-Y gastric bypass surgery, GERD symptoms improved when assessed postoperatively via questionnaire. Roux-en-Y was more effective compared with gastric banding in one study. Of the eight studies assessing vertical banded gastroplasty, one study showed improvement in GERD symptoms, but the other studies demonstrated no change or an increase in reflux symptoms. The effects of gastric banding on GERD symptoms in eight studies were conflicting.

Endoscopic therapies for GERD have been developed but have not demonstrated long-term efficacy. These therapies included radiofrequency augmentation to the lower esophageal sphincter, silicone injection into the lower esophageal sphincter, and endoscopic suturing of the LES. None of these therapies demonstrated long-term improvement in esophageal pH levels or the ability for patients to stop antireflux therapy and were subsequently removed from the US marketplace (96). Recent alternative approaches have included transoral incisionless fundoplication, a suturing device designed to create a full thickness gastroesophageal valve from inside the stomach. Unfortunately long-term data regarding efficacy of this device are limited to a small number of subjects and short duration of follow-up (97). A recent study suggested that at 36 months of follow-up, the majority of patients had required additional medical therapy or a revisional fundoplication (98).

Sphincter augmentation using the LINX Reflux system constructed of titanium beads has shown efficacy up to 4 years in the reduction of the amount of pathologic esophageal acid exposure in a small number of subjects (99). This device has been approved by the FDA based on a clinical study in 100 GERD patients. This study found that performance of LINX resulted in consistent symptom relief and pH control with markedly fewer side effects than traditional laparoscopic fundoplication in well-selected patients. More data are required before widespread usage can be recommended.

Potential Risks Associated with PPIs

Recommendations

1. Switching PPIs can be considered in the setting of side effects. (Conditional recommendation, low level of evidence)

2. Patients with known osteoporosis can remain on PPI therapy. Concern for hip fractures and osteoporosis should not affect the decision to use PPI long-term except in patients with other risk factors for hip fracture. (Strong recommendation, moderate level of evidence)

3. PPI therapy can be a risk factor for Clostridium difficile infection and should be used with care in patients at risk. (Strong recommendation, moderate level of evidence)

4. Short-term PPI usage may increase the risk of community-acquired pneumonia. The risk does not appear elevated in long-term users. (Conditional recommendation, moderate level of evidence)

5. PPI therapy does not need to be altered in concomitant clopidogrel users as clinical data does not support an increased risk for adverse cardiovascular events. (Strong recommendation, high level of evidence)

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Summary of the Evidence

Potential adverse events associated with PPI therapy have included headache, diarrhea, and dyspepsia in <2% of users. Switching to another PPI can be attempted in these patients or in patients who fail to respond to an initial PPI, although data supporting this practice are limited. Other potential adverse associations have included vitamin and mineral deficiencies, association with community-acquired infections including pneumonia and diarrhea, hip fractures and osteoporosis, and increased cardiovascular events in patients using concomitant clopidogrel therapy. The FDA issued warnings regarding the potential for wrist, hip, and spine fractures among PPI users in 2010 and warnings regarding potential for adverse cardiovascular events among clopidogrel users taking PPI therapy in 2009. Because of these concerns, multiple meta-analyses and systematic reviews have been published.

The reason for concern regarding potential vitamin B12 deficiency in PPI users derives from the fact that the first step in cobalamin absorption requires gastric acid and pepsin in order to release cobalamin from dietary proteins. In two recent reviews, there was no supporting clinical evidence to document the development of B12 deficiency in chronic PPI users (100,101). However, recent studies have suggested that in elderly institutionalized long-term PPI users, B12 deficiency is more likely to develop and should be considered in this cohort.

Gastric acid is necessary to allow absorption of non-heme iron and also enhances iron salt dissociation from ingested food. Iron deficiency anemia has been reported in patients with atrophic gastritis, gastric resection, or vagotomy. There currently is no data demonstrating the development of iron deficiency anemia in normal subjects on PPI therapy (100).

By their effects in increasing gastric pH levels, the usage of PPIs may encourage growth of gut microflora and increase susceptibility to organisms including Salmonella, Campylobacter jejuni, Escherichia coli, Clostridium difficile, Vibrio cholerae, and Listeria. A systematic review published in 2011 found an increased susceptibility in PPI users for Salmonella infections (adjusted RR ranging from 4.2-8.3 in two studies), Campylobacter (RR 3.5-11.7 in four studies) and C. difficile infections (RR 1.2-5.0 in 17 out of 27 studies demonstrating a positive association) (102). The studies failing to demonstrate an association were predominantly in older patients >65 years of age where because of the presence of co-morbid conditions and associated hypochlorhydria, the addition of PPI therapy did not raise the risk of infection. On the basis of the available evidence, PPI usage can be a risk factor for Clostridium difficile and other enteric infections and should be used with care in patients at risk.

An increased risk for community-acquired pneumonia cannot be clearly documented in association with PPI therapy. A systematic review identified 31 studies (five case-control studies, three cohort studies, and 23 randomized controlled trials) (103). A meta-analysis of the eight observational studies showed that the overall risk of pneumonia was higher among patients using PPIs (adjusted odds ratio (OR) 1.27, 95% CI 1.11-1.46) and H2RAs (adjusted OR 1.22, 95% CI 1.09-1.36). However, when the randomized controlled trial data were analyzed, only use of H2RAs was associated with an elevated risk of hospital-acquired pneumonia (RR 1.22, 95% CI 1.01-1.48) A more recent meta-analysis (six nested case-control studies) found an increased risk of community acquired pneumonia (CAP) associated with PPI usage (OR 1.36, 95% CI 1.12-1.65), but the results were confounded by significant heterogeneity (104). In exploratory subgroup analysis, short duration of use was associated with an increased odds of CAP (OR 1.92 (95% CI 1.40-2.63), P=0.003), whereas chronic use was not (OR 1.11 (95% CI 0.90-1.38), P<0.001). Other studies have also demonstrated an increased risk of CAP associated only with short-term PPI usage (105,106). In summary, PPI therapy should not be withheld in patients requiring therapy due to a potential risk of CAP; however, the diagnosis of pneumonia and timing of initiation of PPI therapy deserves further study.

Reduction in gastric acid has been associated with decreased release of ionized calcium from calcium salts and protein-bound calcium. Although some physiologic data have suggested that PPIs might inhibit osteoclast-mediated bone resorption, clinical studies have rendered mixed results. In the Manitoba Bone Mineral Density Database, the study with the longest follow-up to date (107), cases with osteoporosis at the hip or lumbar vertebrae were matched to three controls with normal bone mineral density. PPI use over the previous 5 years was not associated with having osteoporosis at either the hip (OR 0.84; 95% CI, 0.55-1.34) or the lumbar spine (OR 0.79; 95% CI, 0.59-1.06), and it was concluded that the association between PPI use and hip fracture was probably related to factors independent of osteoporosis. A 2010 case-control study demonstrated that the excess hip fracture risk among PPI users was only present in persons with at least one other risk factor (108). Two meta-analyses published in 2011 demonstrated small increases in risk of hip fracture (OR 1.2) but were limited by substantial heterogeneity among studies included (109,110).

In 2009, the FDA issued a warning regarding the potential for increased adverse cardiovascular events in concomitant users of PPI and clopidogrel therapy, particularly among users of omeprazole, lansoprazole, and esomeprazole. The concern arises from the fact that the antiplatelet activity of clopidogrel requires activation by CYP 2C19, the same pathway required for metabolism of some PPIs. Initial studies raised concern for a potential interaction based on in vitro tests demonstrating that clopidogrel's ability to inhibit platelet aggregation was decreased in the presence of PPIs (111,112). Subsequent retrospective studies yielded conflicting results with some publications suggesting an increased risk for cardiovascular events (113,114,115) and others showing lack of effect (116,117). In two randomized controlled trials, PPIs did not increase the risk of adverse events in patients receiving clopidogrel (118,119). Meta-analyses have demonstrated that the strength of potential interactions is dependent upon the assessment of clinical outcomes, adjustment for confounders, and data quality. For example, in a meta-analysis including 26 studies (16 published articles, 10 abstracts), the authors divided the analyses between primary outcomes (myocardial infarction, stroke, stent occlusion, or death) and secondary outcomes (re-hospitalization for cardiac symptoms or revascularization procedures) (120). Clinical data from the two randomized controlled trials which included usage of all PPIs except for dexlansoprazole did not show an increased risk for adverse cardiovascular events (risk difference, RD 0.0, 95% CI ?0.01, 0.01). The meta-analysis of primary outcomes showed a RD of 0.02 (95% CI 0.01, 0.03) for all studies. The meta-analysis for secondary outcomes yielded a RD of 0.02 (95% CI 0.01-0.04) based on 19 published papers and abstracts. When primary and secondary outcomes were combined, the meta-analysis for published papers yielded an overall RD of 0.05 (95% CI 0.03-0.06). The authors concluded that in patients using concomitant clopidogrel and PPI therapy, the risk of adverse cardiac outcomes was 0% based on data from well-controlled randomized trials. Data from retrospective studies and the addition of probable vascular events significantly increased the RD estimates, likely due to lack of adjustment for potential confounders (76). Subsequent meta-analyses have concluded that the data from two randomized trials did not support an adverse effect, and that analysis of cardiovascular events from the remainder of the studies was limited by moderate-substantial heterogeneity (121,122).

Extraesophageal Presentations of GERD: Asthma, Chronic Cough, and Laryngitis

Recommendations

1. GERD can be considered as a potential co-factor in patients with asthma, chronic cough, or laryngitis. Careful evaluation for non-GERD causes should be undertaken in all of these patients. (Strong recommendation, moderate level of evidence).

2. A diagnosis of reflux laryngitis should not be made based solely upon laryngoscopy findings (Strong recommendation, moderate level of evidence).

3. A PPI trial is recommended to treat extraesophageal symptoms in patients who also have typical symptoms of GERD. (Strong recommendation, low level of evidence)

4. Upper endoscopy is not recommended as a means to establish a diagnosis of GERD-related asthma, chronic cough, or laryngitis. (Strong recommendation, low level of evidence)

5. Reflux monitoring should be considered before a PPI trial in patients with extraesophageal symptoms who do not have typical symptoms of GERD. (Conditional recommendation, low level of evidence).

6. Non-responders to a PPI trial should be considered for further diagnostic testing, and are addressed in the refractory GERD section below. (Conditional recommendation, low level of evidence)

7. Surgery should generally not be performed to treat extraesophageal symptoms of GERD in patients who do not respond to acid suppression with a PPI. (Strong recommendation, moderate level of evidence)

Summary of the Evidence

The spectrum of clinical presentations attributed to GERD has expanded from typical esophageal symptoms of heartburn and regurgitation, to an assortment of extraesophageal manifestations including respiratory and laryngeal symptoms. Several epidemiological studies have identified an association between GERD and these extraesophageal symptoms, but causality cannot be inferred from these studies. A systematic review of 28 studies found that symptoms of GERD and abnormal 24-h pH monitoring were present in 59% and 51% of asthma patients, but concluded that there was little data to clarify the direction of causality in this association (123). Cohort studies suggest that GERD may be the cause in 21-41% of chronic nonspecific cough (124). A large VA population case-control study found increased odds ratios for pharyngitis (OR 1.60), aphonia (OR 1.81), and chronic laryngitis (OR 2.01) in cases with esophagitis or esophageal stricture compared with controls (125). The Montreal Consensus recognized established associations between GERD and asthma, chronic cough, and laryngitis, while acknowledging that these disorders frequently have a multi-factorial etiology and that gastro-esophageal reflux may be a co-factor rather than a cause. The Montreal consensus also recognized the rarity of extraesophageal syndromes occurring in isolation without concomitant typical symptoms of GERD (3). Currently available diagnostic tools to establish GERD as the cause of extraesophageal symptoms have serious limitations, and recent placebo-controlled trials have failed to show a clear therapeutic benefit of PPIs in treating all-comers with extraesophageal symptoms. Therefore, patients with asthma, chronic cough, or laryngitis should have careful evaluation for non-GERD causes. GERD should be viewed as a possible contributing factor in some but not all patients presenting with these clinical entities.

Diagnosing GERD as the cause of extraesophageal symptoms has proven to be very challenging. Upper endoscopy can document the presence of GERD when erosive esophagitis is present, but it is found in only one third of patients with GERD symptoms (126) and is even rarer after treatment with PPIs (59). Even when present, finding erosive esophagitis does not establish a diagnosis of GERD-related asthma, chronic cough, or laryngitis.

Ambulatory reflux monitoring can confirm the presence of GERD by documenting a pathological amount of gastroesophageal reflux. Current consensus is that the total percentage of time the pH is <4 is the most useful single discriminator between physiologic and pathologic reflux (127). There is great variability in the reported prevalence of abnormal pH monitoring in patients with asthma (123), chronic cough (128), and laryngitis (129). Similar to the finding of erosive esophagitis on endoscopy, documentation of pathological reflux on ambulatory monitoring does not establish GERD as the cause of the extraesophageal symptoms. On the other hand, a negative reflux monitoring test should direct the diagnostic effort toward non-GERD etiologies. Beyond establishing the presence of pathological reflux, ambulatory reflux monitoring may be used to determine whether the patient's symptoms are due to reflux. The two most commonly used methods to evaluate the temporal association between reflux episodes and symptoms are the symptom index (SI) (130) and the symptom-association probability (SAP) (131). Both methods rely on precise and timely symptom recording by the patient, along with accurate reflux detection by the testing device. Symptom association analysis performed during reflux monitoring may document a temporal association between reflux episodes and asthma attacks or cough events. The sensitivity and specificity of symptom association analysis tools is limited and there are no outcome studies to support treatment of extraesophageal GERD based on this parameter alone (127). A recent study of 237 patients with extraesophageal reflux symptoms that were refractory to PPI, found that the presence of heartburn or abnormal acid exposure on pH monitoring predicted response to escalation of therapy, but the SI, SAP, or impedance variables did not (132). The recent development of ambulatory reflux-cough monitoring by combining impedance-pH to measure reflux (acid or nonacid) along with acoustic detection of cough, which eliminates the subjectivity of patient-reported cough, has enabled a more accurate assessment of the relationship between reflux and cough; a recent study using this approach was able to document reflux-induced cough as well as cough-induced reflux (133). Whether these technical improvements increase the yield of symptom association analysis in patients with cough attributed to reflux requires further studies.

Laryngoscopic findings, especially edema and erythema, are often used to diagnose reflux-induced laryngitis (134). It should be pointed out that laryngoscopy revealed one or more signs of laryngeal irritation in over 80% of healthy controls in a well-done prospective study (135). Moreover, in a study of five ENT (ear, nose, and throat) physicians who blindly evaluated 120 video recordings of laryngoscopy exams, concordance among physicians was low for edema, erythema, as well as likelihood and severity of laryngopharyngeal reflux; similarly, intra-rater reliability was extremely variable for these findings (136). It is important to keep in mind that signs of laryngeal irritation may also be the result of non-GERD etiologies such as allergy, smoking, or voice abuse. Therefore, it is recommended that a diagnosis of reflux-induced laryngitis not be made based on laryngoscopy findings alone.

A course of action that is often pursued in clinical practice is to empirically prescribe acid suppression with PPIs, especially in patients with concomitant typical symptoms of GERD. Two randomized controlled trials have shown that PPIs result in improvement of various asthma outcomes (137,138). However, a meta-analysis of 11 randomized controlled trials concluded that PPI therapy in adults with asthma results in a statistically significant but overall only a small improvement in peak expiratory flow rate, that is unlikely to be of meaningful clinical significance. Thus, there is insufficient evidence to recommend PPIs for routine asthma treatment when other GERD symptoms are absent (139). Improvement in peak expiratory flow was greater, though still modest, in the eight studies that required evidence of GERD (by symptoms, endoscopy, or reflux monitoring) compared with the three studies that did not require evidence of GERD. A meta-analysis of nine randomized controlled trials found no advantage for PPI compared with placebo for total resolution of cough (OR 0.46, 95% CI 0.19 to 1.15), although sensitivity analysis found significant improvement in cough scores in those receiving PPI (standardized mean difference ?0.41, 95% CI ?0.75 to ?0.07) (140). The experience with treating laryngeal symptoms attributed to reflux disease is comparable. A meta-analysis of eight randomized controlled trials found that PPI therapy had no significant advantage over placebo in achieving improvement of symptoms of suspected GERD-related chronic laryngitis (RR 1.28, 95% CI 0.94 to 1.74) (141).

There are no high-quality randomized controlled trials evaluating the effectiveness of laparoscopic fundoplication for the treatment of extraesophageal symptoms of GERD. A recent Agency for Healthcare Research and Quality review on the comparative effectiveness of GERD treatments summarized the available data on fundoplication for asthma, cough, and laryngitis (142). As explained in detail in this review, all the data on surgery for extraesophageal GERD come from surgical cohort studies with wide variation in population treated, severity of symptoms, outcome measures, surgical intervention, and duration of follow-up. Although some of these studies may show benefit, the conclusion of the review was that the strength of the evidence was insufficient, and no consistent benefit could be attributed to surgery.

On the basis of the information summarized above, PPI therapy seems reasonable in patients with asthma, chronic cough, and laryngitis who also have typical symptoms of GERD or objective evidence of GERD by endoscopy or reflux monitoring. In these patients, acid suppression with PPIs has proven to be beneficial to heal esophagitis and treat typical symptoms; whether the extraesophageal symptoms will improve is less predictable. We have few well-defined markers to predict which patients will respond to therapy. Empirical treatment for patients without typical symptoms or objective evidence of GERD thus cannot be routinely recommended. The historic recommendation is to treat patients with higher dose PPI (twice daily) than patients with typical GERD symptoms; however, this is based on uncontrolled and observational data only (143,144). Patients who are treated with PPI and who do not respond to a 2-3 month course of acid suppression can be evaluated and managed as proposed in the «refractory GERD» section. The importance of pursuing non-GERD etiologies in this group of patients is critical.

GERD Refractory to Treatment with PPIs

Recommendations

1. The first step in management of refractory GERD is optimization of PPI therapy. (Strong recommendation, low level of evidence)

2. Upper endoscopy should be performed in refractory patients with typical or dyspeptic symptoms principally to exclude non-GERD etiologies. (Conditional recommendation, low level of evidence)

3. In patients in whom extraesophageal symptoms of GERD persist despite PPI optimization, assessment for other etiologies should be pursued through concomitant evaluation by ENT, pulmonary, and allergy specialists (Strong recommendation, low level of evidence)

4. Patients with refractory GERD and negative evaluation by endoscopy (typical symptoms) or evaluation by ENT, pulmonary, and allergy specialists (extraesophageal symptoms), should undergo ambulatory reflux monitoring (Strong recommendation, low level of evidence)

5. Reflux monitoring off medication can be performed by any available modality (pH or impedance-pH) (Conditional recommendation, moderate level of evidence). Testing on medication should be performed with impedance-pH monitoring in order to enable measurement of nonacid reflux. (Strong recommendation, moderate level of evidence)

6. Refractory patients with objective evidence of ongoing reflux as the cause of symptoms should be considered for additional antireflux therapies that may include surgery or TLESR inhibitors. (Conditional recommendation, low level of evidence). Patients with negative testing are unlikely to have GERD and PPI therapy should be discontinued. (Strong recommendation, low level of evidence)

Summary of the Evidence

We are seeing increasing numbers of patients treated empirically with PPIs for symptoms that are suspected to be due to GERD who do not respond to these medications. The term refractory GERD encompasses a heterogeneous group of patients that may differ in symptom frequency and severity, PPI dosing regimen (once or twice daily), and response to therapy (from partial to absent). Although there is no established consensus regarding the definition of refractory GERD in terms of symptom burden, degree of therapeutic response, and PPI dose at which failure occurs, we should accept that refractory GERD is a patient-driven phenomenon (145). Not surprisingly, refractory GERD has a significant impact on QOL. A recent systematic review of nine studies found that persistent reflux symptoms on PPI therapy are associated with reduced physical and mental health-related QOL (10). Therefore, any patient who seeks consultation for bothersome symptoms that are attributable to GERD and that persist despite treatment with a PPI merits evaluation and management. As not all patients who fail to respond to PPIs will have GERD, the most important goal of the diagnostic evaluation in these patients is to differentiate those with persistent reflux as the cause of the ongoing symptoms, from those with non-GERD etiologies.

The reported proportion of patients with heartburn who do not respond to PPIs varies among studies, likely due to differing definitions of failure, dissimilar patient groups, and different medication dosing. It has been estimated that failure to control symptoms occurs in up to 40% of patients treated with a PPI (146). A recent systematic review found persistent, troublesome typical symptoms of GERD (heartburn and regurgitation) in 32% of patients in randomized primary care trials and 45% of patients in observational studies (147). The proportion of patients with extraesophageal presentations of GERD that do not respond to medication is less well documented, but the success rate of treating extraesophageal reflux symptoms is lower than that for typical symptoms (139,140,141). A recent comparison of PPI responders and non-responders found that PPI failure appears to be significantly more common in those with atypical symptoms. Additional factors associated with PPI failure were longer duration of disease, poor compliance, and obesity (63).

The first step in the management of refractory GERD is to optimize PPI therapy by confirming compliance and ensuring appropriate dosing. Poor compliance is associated with lack of response to PPI (63). Furthermore, adherence to PPI therapy was found in only 60% of patients with GERD in a large population-based VA study (148). The efficacy of PPIs (as discussed above) is generally maximized when PPIs are taken before a meal (149). Optimal PPI dosing (before meals) was seen in only 46% of 100 patients who were referred for persistent GERD symptoms despite treatment (66). A survey of 491 physicians found that nearly 70% of primary care physicians and 20% of gastroenterologists in the US advised patients to take the PPI dose at bedtime or did not believe that the relationship to meals was important (150). Therefore, any patient with refractory symptoms should be instructed regarding optimal dosing of the PPI being used. Once compliance and appropriate dosing are ensured, a single trial of a different PPI can be considered. Recent evidence from a multicenter randomized trial showed this strategy to be helpful in some patients (67). A randomized controlled trial in patients with persistent GERD symptoms despite a single daily dose of PPI, showed that increasing PPI to twice daily or switching to another PPI both resulted in symptomatic improvement in roughly 20% of patients, without a clear advantage for either strategy (151).

Patients with persistent symptoms despite optimization of PPI therapy require further work-up (Figure). Those with typical, esophageal symptoms should undergo endoscopy principally to exclude non-reflux esophageal disorders such as EoE, which can present with esophageal symptoms refractory to PPI and to look for the rare patient with erosive esophagitis, a finding that provides evidence of ongoing acid reflux. Although the prevalence of EoE in patients with refractory GERD in the US has not been studied, a recent Markov model found that obtaining esophageal biopsies to diagnose EoE in refractory GERD patients is cost-effective only when the prevalence of EoE is 8% or greater (152). If endoscopy is negative, as is frequently the case, the next step is to perform reflux monitoring to quantify reflux and assess the relationship between reflux episodes and the patient's symptoms. Reflux monitoring should also be considered in patients with extraesophageal symptoms that persist despite PPI optimization and in whom non-GERD etiologies have been ruled out through pulmonary, ENT, and allergy evaluation.

Algorithm for the evaluation of refractory gastroesophageal reflux disease (GERD).

ENT, ear, nose, and throat; PPI, proton pump inhibitor

Reflux monitoring enables further characterization of the refractory patient, as the study may reveal: (a) PPI failure with ongoing acid reflux, which will require escalation of therapy to control acid reflux (b) adequate acid control but ongoing symptomatic non-acid reflux, which may respond to specific therapy or (c) no reflux. Among refractory GERD patients with a negative reflux monitoring study, those with heartburn may be classified as having «functional heartburn» while those with extraesophageal symptoms (asthma, cough, laryngitis) will need additional or repeat work-up for non-GERD (pulmonary, allergic, ENT) etiologies.

Two key issues to consider are whether reflux monitoring should be performed after stopping PPI therapy or while on medication, and what technique to use (catheter-based pH, wireless pH, or impedance-pH). At the present time there are limited data and no clear consensus regarding the optimal testing methodology for refractory GERD. The approach to testing may be chosen based on the patient's clinical presentation and pretest likelihood of GERD, as well as on the available technology and expertise. Reflux monitoring both off as well as on PPI offers important and clinically useful information as outlined below.

Reflux monitoring off PPI (7 days after cessation of PPI) can be performed with any of the available techniques (catheter or wireless pH, or impedance-pH). If reflux monitoring off medication is negative (normal distal esophageal acid exposure and a negative symptom-reflux association), GERD is very unlikely. In a patient with a negative test off therapy, PPIs can be stopped and the diagnostic effort should be steered toward non-GERD etiologies. On the other hand, a positive test after PPI cessation offers objective evidence of GERD but it does not provide insight regarding the reason for the failure to respond to treatment.

Reflux monitoring on PPI should be performed with impedance-pH monitoring to enable measurement of nonacid reflux. The yield of pH monitoring without impedance in a patient taking a PPI is very low because in acid-suppressed patients reflux becomes predominantly nonacid (153). In fact, pH monitoring revealed normal acid exposure in 96% of patients with refractory GERD that were tested on twice daily PPI (154). Although rare, an abnormal pH test in a patient taking a PPI (i.e. ongoing acid reflux despite treatment) is evidence of therapeutic failure or noncompliance. A negative pH test in treated patients makes ongoing acid reflux as the cause of their symptoms very unlikely, but it cannot account for the possibility of nonacid reflux, which can be measured using impedance-pH monitoring. A study that used the SI to evaluate 144 patients refractory to twice daily PPI therapy found that ongoing symptoms were related to non-acid reflux in 37% and acid reflux in 11% (155). In the remaining 52% of patients, there was no association between reflux (either acid or non-acid) and symptoms. A positive SI was more common in patients with typical symptoms (heartburn, regurgitation, and chest pain) compared with those with an atypical presentation (55% vs. 25%). A different study using the SAP in patients who were symptomatic despite PPI therapy found an association between reflux and symptoms in 37% of 60 patients; the SAP was positive due to nonacid reflux in 17%, acid reflux in 5%, and acid plus nonacid reflux in 15% (156). As demonstrated by these studies, impedance-pH testing covers all possible scenarios for persistent symptoms in a treated patient: ongoing acid reflux, ongoing non-acid reflux, or no reflux. Furthermore, a systematic review that quantified acid and nonacid (both weakly acidic and weakly alkaline) reflux in studies of GERD patients taking a PPI, found that weakly acidic reflux underlies the majority of reflux episodes in these patients and is the main cause of persistent symptoms despite PPI therapy (157). Finally, a negative impedance-pH test on medication strongly supports that the patient's complaints are not due to reflux of any type. Needless to say, the full context of the patient (including clinical presentation, presence of hiatus hernia, endoscopy findings, and/or degree of response to therapy) always needs to be considered.

Studies comparing the yield of «off vs. on» therapy reflux monitoring in refractory GERD patients are limited. Hemmink et al. (158) concluded that testing should be performed off PPI. In contrast, Pritchett et al. (159) found that reflux monitoring on PPI may be the preferred strategy. At present no single approach can be recommended due to the heterogeneous group of patients. A recent technical review on this topic suggested that, in the absence of high-quality studies to guide this decision, the method of testing may be chosen based upon the patient's clinical presentation (127). In patients with a low likelihood of GERD (for instance, atypical presentations without concomitant typical GERD symptoms) pH monitoring off medication may be preferred as it will enable ruling out GERD. Patients with a higher likelihood of GERD (typical symptoms, at least partial response to PPI) can be tested with impedance-pH testing on medication in search of ongoing reflux (either acid or non-acid) despite PPI. Clearly, more studies are needed to bring clarity to this issue.

Finally, it is important to stress the importance of stopping PPI therapy in patients with refractory symptoms in whom all testing is negative. In a recent study, after a negative evaluation for refractory GERD that included normal endoscopy and impedance-pH monitoring, 42% of 90 patients reported continued use of PPI despite negative results (160). This study underscores the importance of educating the patient about the need to stop PPIs once GERD has been ruled out.

There are few studies in which refractory GERD patients with documented ongoing reflux have been treated with either medication or surgery. Patients with abnormal frequency of non-acid reflux can be considered for treatment with the GABA B agonist, baclofen as this drug has been shown to decrease reflux episodes and symptoms due to all types of reflux (81,82). Unfortunately, high-quality controlled trials evaluating the role of baclofen in refractory symptoms are not available. Small uncontrolled studies have demonstrated a benefit for baclofen when used for refractory duodeno-gastro-esophageal reflux in patients with persistent symptoms on PPI therapy (81). A small observational study with limited follow-up suggested a positive symptom response to surgery in this group, but improvement in reflux control was not objectively documented (161). A more recent prospective, uncontrolled study found that 3 months after fundoplication, both the number of reflux episodes and typical symptoms of GERD (heartburn and regurgitation) improved in patients who were PPI-nonresponders (162). However, it must be pointed out that these patients are carefully selected and were not in a controlled trial. High-quality, controlled trials evaluating surgery in patients unresponsive to PPIs are lacking, so this approach is not recommended except in highly individual circumstances. In this context, performing a reflux monitoring test off PPI can confirm the presence of pathological reflux before surgery. Finally, there is no data to support the use of transoral incisionless fundoplication, or other endoscopic therapy in refractory GERD.

What are the Complications Associated with GERD?

Recommendations

1. The Los Angeles (LA) classification system should be used when describing the endoscopic appearance of erosive esophagitis (Strong recommendation, moderate level of evidence). Patients with LA Grade A esophagitis should undergo further testing to confirm the presence of GERD. (Conditional recommendation, low level of evidence)

2. Repeat endoscopy should be performed in patients with severe ERD after a course of antisecretory therapy to exclude underlying Barrett's esophagus. (Conditional recommendation, low level of evidence)

3. Continuous PPI therapy is recommended following peptic stricture dilation to improve dysphagia and reduce the need for repeated dilations. (Strong recommendation, moderate level of evidence)

4. Injection of intralesional corticosteroids can be used in refractory, complex strictures due to GERD. (Conditional recommendation, low level of evidence)

5. Treatment with a PPI is suggested following dilation in patients with lower esophageal ring (Schatzki) rings. (Conditional recommendation, low level of evidence).

6. Screening for Barrett's esophagus should be considered in patients with GERD who are at high risk based on epidemiologic profile. (Conditional recommendation, moderate level of evidence)

7. Symptoms in patients with Barrett's esophagus can be treated in a similar fashion to patients with GERD who do not have Barrett's esophagus. (Strong recommendation, moderate level of evidence)

8. Patients with Barrett's esophagus found at endoscopy should undergo periodic surveillance according to guidelines. (Strong recommendation, moderate level of evidence)

Summary of the Evidence

Numerous «complications» have been associated with GERD including erosive esophagitis, stricture, and Barrett's esophagus. Obesity has been demonstrated to be a risk factor for symptoms, ERD, BE, and adenocarcinoma (17). It may be that the presence of an abnormal waist-to-hip ratio is the greatest risk factor for the presence of BE (163). Although many classification systems for erosive esophagitis have been used in the literature, a classification system, introduced in 1994, appears to be most logical to use in practice. Using an A, B, C, D system to describe esophageal erosions, this system has been used in the largest and most modern trials. In contrast to other systems (164), the LA classification system has been tested and shown to have good inter and intraobserver variability (27). This system offers a commonality of language among endoscopists for grading this complication of GERD and is recommended as the system of choice for reporting. Erosive esophagitis is seen in a minority of patients with symptomatic GERD, with the majority of the patients having LA grade A or B esophagitis present. LA grades C and D have been described as «severe» and have the lowest healing rate with PPIs (54,165). Severe erosive esophagitis (grades C and D) is more common in the elderly and in general would relapse if maintenance therapy is not instituted. There are limited data to suggest that a columnar lined esophagus (Barrett's esophagus) can be obscured by any grade of erosive esophagitis, most commonly it is obscured by grades C and D (166,167). On the basis of these data, a repeat endoscopy after a minimum 8-week course of PPI therapy is recommended in patients with grades C and D esophagitis and can be considered in lower grades. In patients not found to have BE on repeat endoscopy and in patients with a normal initial endoscopic examination, the utility of repeated examinations to screen for the development of BE has not been demonstrated (168). Other than the above clinical scenarios, repeating an endoscopy in GERD patients who do not demonstrate new symptoms is not recommended.

Peptic strictures are infrequent in practice, likely related to the widespread use of antisecretory therapy. Strictures tend to occur most often in Caucasians, older patients with a longer duration of untreated symptoms, and in the setting of abnormal esophageal motility (169,170). With rare exceptions (e.g. the presence of an inlet patch), true peptic strictures occur at the squamocolumnar junction. A stricture elsewhere should raise suspicion for another etiology. PPIs are clearly superior to H₂-receptor antagonists and when used in a maintenance fashion improve dysphagia, decrease the need for repetitive dilations and/or prolong the interval between dilations (171,172).

Intralesional corticosteroids (40?mg of triamcinolone injected in four 1?ml aliquots) in a four quadrant pattern can be considered in peptic strictures refractory to dilation. The limited randomized controlled trials support the efficacy of steroid injection in conjunction with antisecretory therapy and dilation in tough strictures (173,174). The availability of so-called removable stents has generated enthusiasm in patients with benign esophageal strictures. These should be rarely necessary and are associated with stent migration and complications that preclude routine use in a benign peptic stricture. There appears to be no role for endoscopic incision in a typical benign peptic stricture.

Lower esophageal rings (Schatzki) are felt by many to be linked with GERD, raising the question of whether antisecretory therapy should be part of the treatment approach. Dilation remains the mainstay of treatment; however, one trial found that no patient with documented GERD (endoscopy or pH) had a recurrent Schatzki ring on PPI therapy post dilation. The same group randomized 30 patients without proven GERD to PPI or placebo and found a statistical decrease in recurrence of rings (mean follow up 43 months) in PPI-treated patients (175). This prompts many to recommend PPIs in patients with Schatzki ring, particularly if they recur.

Barrett's esophagus is the only complication of GERD with malignant potential. Barrett's can be found in 5 to 15% of patients who have endoscopy for symptoms of GERD (176) and tends to be seen at the higher end of this range in patients with long duration of symptoms, who are over the age of 50, male, and Caucasian. The difficulty in risk stratification is highlighted by the fact that 25% of patients with Barrett's are women or under the age of 50 (177,178). Despite the well-identified epidemiologic risk factors there is no clear profile that mandates screening. As such, these guidelines can only recommend consideration of screening perhaps concentrating on those of higher epidemiologic risk but more importantly with an informed discussion with the patient. Although there is debate about the value of surveillance, current guidelines recommend that patients with endoscopically confirmed Barrett's esophagus be enrolled in a surveillance program (179).

References

1. Atkins D, Best D, Briss PA et al. Grading quality of evidence and strength of recommendations. BMJ 2004; 328:1490-1494.

2. Atkins D, Briss PA, Eccles M et al. Systems for grading the quality of evidence and the strength of recommendations II: pilot study of a new system. BMC Health Serv Res 2005; 5:25-36.