Review article: alternative approaches to the long-term management of GERD

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1 Aliment Pharmacol Ther 2005; 22 (Suppl. 3): Review article: alternative approaches to the long-term management of GERD M. B. FENNERTY Division of Gastroenterology, Oregon Health and Science University, Portland, OR, USA Accepted for publication 15 September 2005 SUMMARY Although proton-pump inhibitors are highly effective for the treatment of gastro-oesophageal reflux disease, there are issues with long-term maintenance therapy: not all patients require full daily dose for maintenance treatment, some patients are reluctant to take long-term daily medication, and long-term PPI therapy is inadequate for some patients. This article aims to review alternatives to daily protonpump inhibitor therapy for the long-term management of gastro-oesophageal reflux disease, including intermittent or on-demand proton-pump inhibitor use, as well as endoscopic and surgical options. On-demand proton-pump inhibitor therapy has demonstrated efficacy in achieving acceptable symptom control, healing and maintenance of quality of life for a proportion of patients with gastro-oesophageal reflux disease. Endoscopic antireflux procedures can reduce the need for proton-pump inhibitor therapy, but safety and durability of these procedures require more study. Surgical treatment of gastro-oesophageal reflux disease in properly selected patients has demonstrated efficacy in reducing symptoms and the need for proton-pump inhibitor therapy; however, long-term follow-up suggests that it is not a permanent solution for many patients. While daily proton-pump inhibitor therapy remains the main treatment regimen option for most patients with gastro-oesophageal reflux disease, on-demand therapy may prove effective for many patients. Endoscopic anti-reflux therapies and surgery are options for patients who prefer nonpharmacological treatment, but experience is limited at this point in time for the former. INTRODUCTION Proton-pump inhibitors (PPIs) are highly effective therapeutic agents for symptom relief, healing and maintenance of remission in patients with gastrooesophageal reflux disease (GERD). 1, 2 However, daily use of PPIs is not universally effective in the relief of GERD symptoms or as maintenance therapy. In contrast, despite GERD being a chronic disease in most individuals, many patients with GERD do not require continuous daily therapy for their disease. Additionally, Correspondence to: Dr M. B. Fennerty, Division of Gastroenterology, Oregon Health and Science University, Mail Code PV-310, 3181 SW Sam Jackson Park Road, Portland, OR , USA. fennerty@ohsu.edu not all patients are comfortable with the concept of having to take daily or intermittent medication for the rest of their lives and many are interested in nonpharmacological options for managing their reflux disease. This paper reviews some of the alternatives to daily PPI therapy for the long-term management of GERD, including intermittent or on-demand PPI use, as well as surgical and endoscopic options (Table 1). ON-DEMAND PPI USE Until recently, PPI regimens rarely deviated from daily use due to several reasons. For one, GERD is a chronic, debilitating disease that adversely affects the patient s quality of life (QOL) and therefore, maintenance of Ó 2005 Blackwell Publishing Ltd 39

2 40 M. B. FENNERTY Table 1. Comparison of alternative strategies for the long-term management of GERD Long-term PPI On-demand PPI Surgery Endoscopic therapy Efficacy Numerous short- and long-term high quality trials Short-term studies only Few high-quality trials Few short-term high-quality trials; little long-term data Safety No issues No issues Measurable morbidity and mortality Measurable morbidity and mortality Operator dependent No No Yes very dependent Yes likely very dependent Ability to adjust Yes Yes No, although can repeat Probably yes Learning curve No No Yes Probably yes GERD, gastro-oesophageal reflux disease; PPI, proton-pump inhibitor. remission (both symptomatic and healing) has been the cornerstone of therapy for many years. GERD is a chronic condition, any breakthrough of symptoms should be avoided to optimize patient QOL, and the chronic nature of the disease is one reason why intermittent therapy (a defined length of therapy by a doctor) or on-demand therapy (a defined length of therapy by a patient) of PPIs has only been recently studied. Several studies have demonstrated that patients with GERD on standard or high-dose delayed-release PPI therapy could either decrease or eliminate their PPI regimen without experiencing breakthrough GERD symptoms. 3, 4 Additionally, a growing number of controlled trials investigating alternatives to daily PPI therapy have shown that intermittent or on-demand therapy is effective in achieving acceptable symptom control, healing and maintenance of QOL for many GERD patients For example, Bytzer et al. assessed the ability of on-demand rabeprazole 10 mg daily compared with placebo for the maintenance of remission of GERD symptoms in patients who had previously responded to daily PPI therapy in an acceptable symptom range. 10 At the end of the 6-month observation period, only 6% of the PPI on-demand group had discontinued the trial because of unacceptable heartburn control compared with 20% of the placebo-treated patients. Those who remained in the trial had continued normalization of their QOL scores compared with those who discontinued the study. Talley et al. demonstrated similar results using esomeprazole. 7 Rates of discontinuation for inadequate heartburn control in the ondemand group were 5% for esomeprazole 20 mg, 8.5% for esomeprazole 40 mg and 36% for placebo. Other trials of this therapeutic strategy generally demonstrate similar results. Healing of oesophagitis can be achieved, and patient QOL improved among patients with GERD through the use of alternative PPI regimens. On-demand or intermittent therapy is also appealing due to the cost savings that result from minimizing medication use. It is speculated that a substantial portion of the GERD population will benefit from on-demand or intermittent PPI regimens; however, the exact number is not known. Further studies along with doctor and patient education on alternative PPI regimens are needed. ENDOLUMINAL (ENDOSCOPIC) THERAPIES FOR GERD Traditionally, GERD has been treated with either an antisecretory agent such as a PPI or using anti-reflux surgery. PPI therapy is effective in nearly all patients when escalating doses are used for initial suboptimal symptom response to a single daily dose. In fact, as demonstrated in the on-demand studies, many GERD patients can be managed without taking PPIs chronically. Anti-reflux surgery is also effective in 85% or more of patients with GERD. 11 In patients where pharmacological therapies or anti-reflux surgeries are not viable treatment choices (i.e. unwillingness to use medications or the invasiveness and associated morbidity with surgeries) less invasive endoscopic anti-reflux procedures are a potential alternative. There are three FDA-approved endoscopic antireflux devices (Stretta, Curon Medical, Freemont, CA, USA; EndoCinch, Bard, Murray Hill, NJ, USA; Plicator TM, NDO Surgical, Mansfield, MA, USA), as well as one with approval expected shortly (Gatekeeper; Medtronic, Minneapolis, MN, USA) and one which has recently been withdrawn (Enteryx, Boston Scientific, Natick, MA, USA; for further information please see gov/cdrh/safety/ enteryx.html). Several other endoscopic anti-reflux devices are in various stages of engineering or clinical development. Although thousands of patients have undergone these procedures,

3 REVIEW: LONG-TERM MANAGEMENT OF GERD 41 both in clinical trials and in clinical practice, published data on the efficacy, long-term safety and mechanism of action of these therapies are still limited. Radiofrequency energy application (Stretta) to the deep muscle layer of the oesophagogastric junction (EGJ) was the first of these techniques to be applied. This technique is actually not an endoscopic technique as the endoscope is removed after carefully measuring the location of the squamocolumnar junction (SCJ) and then the energy application is applied blindly by a special catheter system inserted to various depths and rotations based on this initial endoscopic measurement. An open-labelled study suggested that over 80% of patients with GERD showed a decrease in reflux symptoms such that, at 12 months, PPI use could be decreased by more than 50% or eliminated. 12 However, sham-controlled results prove otherwise. Corley et al.,in the very first endoscopic anti-reflux therapy sham trial, demonstrated no decrease in the need for daily medication between the Stretta and sham-treated patients, despite significant improvements in symptoms and QOL with active treatment. 13 Furthermore, there was no significant decrease in oesophageal ph exposure in either the treatment or sham groups. While Stretta was effective in improving symptom in nearly two-thirds of patients, the sham procedure was also effective in almost one-third of the patients. The 80% or more of patients responding in the initial open-label studies clearly overestimated the true response rate and emphasizes the importance of performing sham trials for endoscopic therapies despite the difficulty and expense in doing such studies. Endoscopic suturing or plication (EndoCinch) was the next device studied as an endoscopic anti-reflux procedure. A modified endoscope is used to apply a series of sutures, two of which that can then be joined into any number of two-suture plications at and near the EGJ. Filipi et al. reported that despite an improvement in PPI use in patients undergoing this procedure, there were no differences in rates of oesophagitis or oesophageal acid exposure pre- and post-procedure. 14 A single-center, sham trial reported less than impressive results and the durability of results with Endo- Cinch was limited. 15, 16 Thus, this device, as it is presently being applied, appears to be the least effective of the currently available endoscopic antireflux devices. The deep intramural implantation of a biopolymer (Enteryx now withdrawn) was the next endoscopic anti-reflux device available on the market. It consists of a solution of ethylene-vinyl alcohol, dimethyl sulphoxide (DMSO), and a radio-opaque tantalum powder that is injected under fluoroscopic and endoscopic guidance into the deep muscle layer in the region of the cardia and SCJ. The DMSO then dissipates, allowing polymerization of the ethylene vinyl alcohol that forms a spongy mass thought to provide the therapeutic effect as it elicits an inflammatory and fibrotic response thereby stiffening the cardia. Open-label studies have demonstrated an elimination or decrease in PPI use in 80% or more GERD patients with Enteryx therapy at 6 and 12 months with the effect appearing to have sustained durability out to 2 years. 17, 18 A recent sham-controlled trial of Enteryx also resulted in an approximate 80% patient response with 68% able to discontinue PPIs (Figure 1). 19 However, 41% of the sham group also discontinued PPIs, indicating a much smaller magnitude treatment effect than suspected based on the initial open trial data. The most recent entry into this therapeutic management field has been the full thickness plication of the cardia (Plicator). Open-label trial results, from this serosal to serosal-implanted suture plication, indicate that approximately 80% of patients are able to decrease or eliminate their PPI use. 20 The sham-controlled trial of this device is completed but not yet published. It is likely that the response rates will be lower than that observed in the open-label trial as has been seen with the other devices. Patients (%) * Enteryx group (n = 32) Sham group (n = 32) > 50% reduction in PPI use Discontinuation of PPI use Figure 1. Reduction or elimination of proton-pump inhibitor (PPI) use at 3 month follow-up in a randomized sham-controlled, multicentre trial of Enteryx implantation for gastro-oesophageal reflux disease (n ¼ 64). *P ¼ 0.023, **P ¼ Based on data from Deviere et al. 19 **

4 42 M. B. FENNERTY All the procedures that have been mentioned were associated with serious complications that included perforation, bleeding, pleural effusions, pericardial effusions, pneumonia, severe chest pain, persistent dysphagia and death. Chest pain and dysphagia are common after these procedures (chest pain in 80% or more of those receiving Enteryx); they are usually transient, but occasionally can be prolonged and cause significant complications. In addition to safety concerns, the number of experienced endoscopists skilled in performing endoluminal therapies is limited. As noted above, most of the data on efficacy of these devices (i.e. efficacy in 80% or more of treated patients) were derived from open-label trials. However, efficacy reported in open-label studies almost always overestimates the true treatment effect (the absence of a control group and blinding invariably results in an inflated treatment effect), and it is only recently that a true measure of the magnitude of the treatment effect for these devices (at least for Stretta and Enteryx) has been established in sham-controlled trials. 13, 19 These trials have demonstrated a treatment response rate of 65% with active treatment compared with 35% with sham procedures, for an absolute benefit of 30% and a number-needed-to-treat of 3 4. No long-term controlled trials accurately address the questions of durability and safety. We can only rely on data from continuation trials of previous open-label studies, which suggest that when the procedure is initially effective, the effect remains durable in most patients for at least 1 2 years and late adverse effects do not appear to be frequent. 12, 17, 18 Uncontrolled data on efficacy and safety cannot be extrapolated to suggest either a permanent effect or an absence of long-term safety issues following application of these therapies. The only way these outcomes likely can be established is through large-scale registries of patients undergoing these procedures, which can measure meaningful outcomes over many years. Until then, patients undergoing these procedures can at least now be informed of the magnitude of the treatment effect (30%) but they should also be informed that the length of treatment effect and its long-term safety are yet to be established. Additionally, patient types, other than those with mild to moderate typical GERD symptoms enrolled in the trials of these devices, have not been evaluated and cannot be assumed to have similar response rates. These procedures are technically demanding and likely require substantial training and experience before optimal efficacy and safety is achieved. SURGICAL ANTIREFLUX THERAPIES The criteria for considering anti-reflux surgery in patients with GERD are a confirmed diagnosis of GERD with a good response to pharmacological therapy, the availability of an experienced and skilled surgeon who has demonstrated good outcomes in performing the procedure, as well as a healthy patient able to withstand the physiological stresses of surgery. Importantly, a poor response to pharmacological therapy predicts a poor response to surgical therapy, as this suggests that the symptoms may be due to causes other than acid reflux. A study by Vakil et al., in which only 61% of patients were satisfied with the procedure, showed that 46% of surgically treated patients had pursued surgery because of inadequate symptom relief with medication. 21 Moreover, only 17% of the patients had an appropriate indication for the procedure in that they did not want to take long-term medication. The remaining patients (other than the 46% who had a suboptimal symptom response to medication) thought that it would either cure their disease or prevent cancer (neither of which it does). The poor results of this study are not surprising given the poor patient selection in this study, and this clearly demonstrates that proper patient selection remains a problem with surgical antireflux therapy. When a skilled surgeon performs surgery, using appropriate candidates, 85% or more of patients can be expected to achieve a good symptomatic outcome. 22 Moreover, although there are only limited data, both open and randomized trials have consistently shown surgery to be as effective as medical therapy (either H 2 RA antagonists or PPIs) over a 2 5 year observation period. 11, 23 However, for many patients, surgery is not a permanent solution to their reflux symptoms. A 9 10 year follow-up of participants from a randomized study found that two-thirds of surgically treated patients were back on antisecretory therapy, with a third using PPIs. 24 So while surgery is effective and durable in many patients with GERD, it is still associated with an appreciable failure rate over time in a substantial proportion of patients, and this is an important issue to inform patients of if their goal was to avoid chronic use of medical therapy for the rest of their lives.

5 REVIEW: LONG-TERM MANAGEMENT OF GERD 43 SUMMARY AND CONCLUSIONS There are a number of alternatives to daily PPI therapy for the long-term management of GERD, including intermittent or on-demand PPI use, as well as surgical and endoscopic options (Table 1). Long-term PPI use has been demonstrated to be safe and effective in a number of high-quality studies. Intermittent or on-demand therapy appears to be effective in a significant proportion of patients with GERD; however, well controlled studies are limited and long-term efficacy trials investigating the success of this strategy are needed. Endoscopic anti-reflux therapies have moderate efficacy demonstrated in high-quality sham studies, with apparent durability for some of the devices (Enteryx, Stretta) based on limited data from lower quality studies. There are substantial safety issues that need to be addressed with this form of therapy as well as determining which of the many available devices will be the optimal choice for an individual with GERD seeking a nonpharmacological yet nonsurgical form of therapy for their disease. Surgical therapy has been demonstrated to be an effective short- and long-term therapy in a limited number of high-quality randomized trials, but durability remains an issue as well as peri-operative morbidity associated with this management option. In summary, daily PPI therapy remains the main treatment regimen for patients with GERD, and while on-demand therapy may prove effective for some patients, further studies and patient education are required. Endoscopic anti-reflux therapies are available but currently inadequately studied, and doctor and patient knowledge of these techniques is limited. Surgery is an effective therapeutic option for GERD but is often avoided because of its invasive nature and associated morbidity. DISCUSSION QUESTIONS What role might intermittent or on-demand PPI dosing play in the long-term management of GERD? Most of the evidence for on-demand PPI therapy comes from Europe, where this strategy is frequently recommended. It has not been extensively studied in the USA, but data would suggest that it is inappropriate or less effective for people with erosive oesophagitis because it has been demonstrated to be inferior to daily PPI maintenance therapy in terms of maintaining remission of erosive GERD. Data from a prescription database show that among patients on maintenance PPI therapy, the average daily dose is about 7 mg/day, which suggests that about two-thirds of the time patients are not taking their PPIs. So patients are already using on-demand therapy in clinical practice. Thus, there is both controlled trial and clinical evidence that on-demand PPI therapy may be effective for many patients, and it should probably be the goal in most patients to individualize therapy and determine the minimal effective dose. How well could an immediate-release PPI perform as an on-demand therapy? Immediate-release omeprazole [(IR-OME) (Zegerid powder for oral suspension; Santarus, Inc., San Diego, CA, USA)] would likely perform as well or better than delayed-release PPIs as an on-demand treatment. IR PPIs could be hypothesized, based on pharmacological data, to be more effective in an on-demand use than the delayed-release agents and thus in comparative trials, IR-OME may outperform delayed-release PPIs because of the faster onset of action of IR-OME. Increasing concerns about cost will increasingly drive patients towards on-demand use of PPIs. The various delayed-release PPIs are likely to all demonstrate similar efficacy when used as on-demand therapy, while IR- OME may show an advantage at least for some patients. Which, if any, of the alternative therapies for GERD are ready for widespread clinical use? While long-term once-daily PPI therapy currently remains the gold standard for treatment, it is clear that half-dose or on-demand strategies are effective for many patients. Given this, on-demand strategies are worth attempting in many patients. Surgical therapy has been an accepted alternative for over a decade, but patients should be properly selected and it may not be a longterm answer. The endoscopic anti-reflux procedures require further study. However, in the hands of a welltrained doctor, these techniques may be viable options in properly selected patients, although long-term safety and efficacy are not yet known. REFERENCES 1. Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux

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