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Original Contribution |

Laparoscopic Antireflux Surgery vs Esomeprazole Treatment for Chronic GERD:  The LOTUS Randomized Clinical Trial FREE

Jean-Paul Galmiche, MD, FRCP; Jan Hatlebakk, MD, PhD; Stephen Attwood, MD, PhD; Christian Ell, MD, PhD; Roberto Fiocca, MD, PhD; Stefan Eklund, MD, PhD; Göran Långström, PhD; Tore Lind, MD, PhD; Lars Lundell, MD, PhD; for the LOTUS Trial Collaborators
[+] Author Affiliations

Author Affiliations: Department of Gastroenterology and Hepatology, Nantes University, and Centre d’Investigation Clinique INSERM, Nantes, France (Dr Galmiche); Institute of Medicine, Haukeland University Hospital, University of Bergen, Bergen, Norway (Dr Hatlebakk); Department of Surgery, North Tyneside General Hospital, North Shields, Tyne and Wear, England (Dr Attwood); Department of Gastroenterology, Dr Horst Schmidt Hospital, Wiesbaden, Germany (Dr Ell); Department of Surgical and Morphological Sciences, Anatomic Pathology Division, University of Genova, Genova, Italy (Dr Fiocca); AstraZeneca Research and Development, Mölndal, Sweden (Drs Eklund, Långström, and Lind); and Department of Surgery, Karolinska University Hospital, Huddinge, Sweden (Dr Lundell).


JAMA. 2011;305(19):1969-1977. doi:10.1001/jama.2011.626.
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Published online

Context Gastroesophageal reflux disease (GERD) is a chronic, relapsing disease with symptoms that have negative effects on daily life. Two treatment options are long-term medication or surgery.

Objective To evaluate optimized esomeprazole therapy vs standardized laparoscopic antireflux surgery (LARS) in patients with GERD.

Design, Setting, and Participants The LOTUS trial, a 5-year exploratory randomized, open, parallel-group trial conducted in academic hospitals in 11 European countries between October 2001 and April 2009 among 554 patients with well-established chronic GERD who initially responded to acid suppression. A total of 372 patients (esomeprazole, n = 192; LARS, n = 180) completed 5-year follow-up.

Interventions Two hundred sixty-six patients were randomly assigned to receive esomeprazole, 20 to 40 mg/d, allowing for dose adjustments; 288 were randomly assigned to undergo LARS, of whom 248 actually underwent the operation.

Main Outcome Measure Time to treatment failure (for LARS, defined as need for acid suppressive therapy; for esomeprazole, inadequate symptom control after dose adjustment), expressed as estimated remission rates and analyzed using the Kaplan-Meier method.

Results Estimated remission rates at 5 years were 92% (95% confidence interval [CI], 89%-96%) in the esomeprazole group and 85% (95% CI, 81%-90%) in the LARS group (log-rank P = .048). The difference between groups was no longer statistically significant following best-case scenario modeling of the effects of study dropout. The prevalence and severity of symptoms at 5 years in the esomeprazole and LARS groups, respectively, were 16% and 8% for heartburn (P = .14), 13% and 2% for acid regurgitation (P < .001), 5% and 11% for dysphagia (P < .001), 28% and 40% for bloating (P < .001), and 40% and 57% for flatulence (P < .001). Mortality during the study was low (4 deaths in the esomeprazole group and 1 death in the LARS group) and not attributed to treatment, and the percentages of patients reporting serious adverse events were similar in the esomeprazole group (24.1%) and in the LARS group (28.6%).

Conclusion This multicenter clinical trial demonstrated that with contemporary antireflux therapy for GERD, either by drug-induced acid suppression with esomeprazole or by LARS, most patients achieve and remain in remission at 5 years.

Trial Registration clinicaltrials.gov Identifier: NCT00251927

Figures in this Article

Quiz Ref IDGastroesophageal reflux disease (GERD) is a highly prevalent disorder caused by the reflux of gastric contents into the esophagus. It is a chronic, relapsing disease that negatively affects patients' health-related quality of life and reduces work productivity.13 Consequently, a long-term management plan is required for each individual patient. Maintenance treatment with proton pump inhibitor (PPI) therapy may be an option, offering high rates of symptom resolution and healing of esophagitis.46 However, some patients are reluctant to take long-term medication and may prefer to have antireflux surgery. A number of controlled studies have been undertaken comparing open antireflux surgery and laparoscopic antireflux surgery (LARS)7 or open antireflux surgery and pharmaceutical treatment,8,9 but few studies have compared pharmaceutical treatment with LARS, particularly over a longer term. Additionally, most of these comparisons included relatively small sample sizes and did not use optimized drug dosing or carefully controlled laparoscopic surgical techniques.1013

The LOTUS (Long-Term Usage of Esomeprazole vs Surgery for Treatment of Chronic GERD) trial compared maintenance therapy provided by esomeprazole (dose-adjusted when required) with standardized LARS in patients who responded well to acid-suppressive therapy. Herein, we report the final results of the 5-year follow-up for the LOTUS trial.

Study Design and Objectives

The LOTUS trial was an exploratory randomized, open, parallel-group, multicenter study conducted in 11 European countries between October 2001 and April 2009. The primary objective was to evaluate maintenance therapy with esomeprazole (in patients tested to be responsive to the medication) vs LARS performed by experts.

Patients were aged 18 to 70 years and had chronic symptomatic GERD. The diagnosis of GERD was established on the basis of typical clinical history and presence of esophageal mucosal breaks at endoscopy, classified by Los Angeles grade, and/or pathological pH-metry. Assessments included endoscopy with biopsy, 24-hour pH-metry and symptom response to esomeprazole. The participating centers had to be either academic units or affiliated with a university; each center participated in training sessions to ensure that operative procedures were conducted or supervised by a consultant surgeon who specialized in this type of laparoscopic upper gastrointestinal tract surgery; and surgical techniques were standardized14 across centers. All patients had to be eligible for both LARS and pharmaceutical therapy and were randomized in blocks of 4 consecutive patient numbers to either treatment. Participants were not permitted to switch treatment groups if they requested the alternative treatment; patients had to leave the study to receive the alternative treatment. Protocol approval for this trial was obtained from local ethics committees. Written informed consent was obtained from all patients.

Because sustained resolution of reflux symptoms with esomeprazole treatment occurs in approximately 70% of patients with GERD,15 a 3-month run-in period was required to verify the clinical response to esomeprazole, 40 mg/d, and only those who responded were randomized. Partial responders or patients refractory to treatment were excluded. This 3-month run-in period also allowed baseline assessments. Patients were required to have no more than Los Angeles grade B esophagitis at baseline and no more than mild heartburn or regurgitation at the end of 3 months of esomeprazole treatment to permit randomization. Symptom severity was classified as none, mild (awareness of symptoms but easily tolerated), moderate (discomfort sufficient to cause interference with normal activities), or severe (incapacitating, with inability to perform normal activities).

Responders were randomly assigned to undergo LARS or to receive esomeprazole, 20 mg once per day, increased stepwise to 40 mg once per day then 20 mg twice per day in case of incomplete control of heartburn and regurgitation. Full details of the protocol are described in the report of the interim 3-year results.16 Patients visited the clinic 6 months after randomization and every 6 months thereafter. Follow-up endoscopy was planned at 1, 3, and 5 years. At endoscopy, the esophagus, cardia region, stomach, and duodenum were examined and biopsies were repeated.17 Patients underwent pH-metry at baseline and again at 6 months and 5 years.18

Symptoms related to GERD were assessed at every visit, during which the investigator asked standardized questions about heartburn, acid regurgitation, epigastric pain, bloating, flatulence, diarrhea, and dysphagia severity. In addition, patients in the LARS group were asked about other gastrointestinal symptoms such as ability to vomit and ability to belch. Health-related quality of life and patient-reported symptoms were assessed by administering the validated Quality of Life in Reflux and Dyspepsia (QOLRAD) and Gastrointestinal Symptom Rating Scale (GSRS) questionnaires to patients at randomization and annually thereafter. Translations of the questionnaires into different languages were performed according to proposed guidelines and involved several independent translators.

During the follow-up period, patients in both treatment groups who experienced moderate to severe recurrent GERD symptoms for at least 3 consecutive days were instructed to contact the clinic. They were then questioned about their symptom control and need for other regular medication and were offered endoscopy.

Treatment End Points and Statistical Analyses

The main analysis was conducted using the intention-to-treat population comprising all randomized patients. Including patients randomized to undergo surgery but not operated on had little influence on the primary analysis because they were censored early.

The primary end point in this study, time to treatment failure, was defined as follows for the 2 study treatments.

In the esomeprazole group, the need for escalation in treatment for control of reflux disease was assessed at clinic visits by asking “Do you have sufficient control of your heartburn and acid regurgitation?” If the answer was no and the patient stated a need for other regular drug therapy, the dose of esomeprazole was increased to 40 mg once per day for 8 weeks and could be adjusted to 20 mg twice per day for a further 8 weeks if symptoms had not resolved. If this proved insufficient to control symptoms, the patient was classified as having had treatment failure.

Quiz Ref IDThe same questions were asked at clinic visits about symptom control in the LARS group, and if the answer was no and was backed up by a need for treatment with acid-suppressive drugs, the patient was classified as having had treatment failure. Patients were also classified as having had treatment failure if they had postoperative symptoms requiring medical action, perioperative death, postoperative death within 30 days of surgery, dysphagia requiring further treatment, or any other requirement to reoperate for symptom control. In the case of functional esophageal postoperative stenosis, 1 dilatation was allowed.

Time to treatment failure/censoring was defined as number of days between randomization and last visit for all participants within 5 years after randomization, regardless of reason for discontinuation or reason for visit. For patients who never returned for a visit, time of censoring was set as 0. As an exploratory analysis, the Kaplan-Meier method was used to estimate the proportion of patients in remission over time and, as specified in the study protocol, the log-rank test was used to test the statistical significance of the observed difference between the treatment groups. A per-protocol analysis was also performed on the primary end point and included all randomized patients except those with major protocol violations.16

In addition, to test the robustness of our main analysis, best- and worst-case outcomes scenarios were analyzed with censored patients considered to have had either treatment failures or treatment successes and after excluding censored patients.

Secondary variables were presented descriptively and analyzed only for the intention-to-treat population, without any analysis of missing data. There were no adjustments for multiple comparisons because of the exploratory character of the study.

In a post hoc analysis, severity of GERD symptoms (none = 0; mild = 1; moderate = 2; and severe = 3) reported at 5 years was compared between treatments using a 2-sided Wilcoxon rank sum test. The safety population included all patients who received at least 1 dose of study drug and from whom postdose data were available.

This study was not designed as a superiority or equivalence trial but, rather, was an exploratory study to estimate the efficacy of LARS and PPI treatment in PPI responders. The sample size was determined by assuming that the true rate of treatment success (ie, patients who did not experience treatment failure within 5 years) would be at least 70% for both treatments. With 275 patients in each group, the true difference between the treatments was estimated not to differ from the observed difference by more than 8 percentage points with a probability of 95%. Thus, the sample size was derived to give a specific length of the confidence interval (CI) between the proportions of treatment success in the 2 treatment groups. The computation is based on the normal approximation for a continuity-corrected interval.19 In an exploratory analysis, the log-rank test was used to test for the superiority of the observed difference between the treatment groups.

Statistical analyses were performed using SAS version 8.2 (SAS Institute Inc, Cary, North Carolina).

Study Population

A total of 626 patients completed enrollment for the study, of whom 554 were randomized, 288 to undergo LARS (40 of whom were not operated on) and 266 to receive esomeprazole. The reasons for the 40 patients who were not operated on were as follows: 29 withdrew consent or refused surgery; 4 were considered ineligible for surgery; 2 were not operated on within the time window after randomization; 2 were lost to follow-up; 1 was pregnant; 1 had a serious adverse event while waiting for surgery; and 1 had a death in the family. The demographic characteristics of these 40 patients did not differ substantially from the other randomized patients in the study. The flow of patients included in the study and reasons for withdrawal at each stage are summarized in Figure 1. Of the 248 patients in the LARS group, 180 (73%) completed the 5-year follow-up visit and 68 discontinued the study before the 5-year visit, 33 of whom met the primary end point of treatment failure. In the esomeprazole group, 192 of the 266 patients (72%) completed 5-year follow-up and 74 discontinued, 19 of whom had treatment failure. Thus, the total discontinuation rate at 5 years for participants randomized to the LARS group (including the 40 who did not undergo surgery) was 108 of 288 (38%) and for participants randomized to the esomeprazole group was 74 of 266 (28%). In violation of the protocol, 1 participant in the esomeprazole was operated on by a surgeon who was not aware of the study at a time when the investigator was on vacation. This patient was withdrawn from the study subsequently.

Place holder to copy figure label and caption
Figure 1. Patient Flow in the LOTUS Trial
Graphic Jump Location

LARS indicates laparoscopic antireflux surgery.

Demographic characteristics and GERD disease history for participants in each treatment group are presented in Table 1. The 2 groups were well matched with regard to both demographics and history and current symptoms of GERD.

Table Graphic Jump LocationTable 1. Patient Demographics and Baseline Characteristicsa
Treatment Efficacy

Time to Treatment Failure. Time to treatment failure, the primary efficacy variable, is presented as Kaplan-Meier plots for the intention-to-treat population in Figure 2. At 5 years, an estimated 85% (95% CI, 81%-90%) in the LARS group and an estimated 92% (95% CI, 89%-96%) in the esomeprazole group remained in remission (log-rank P = .048). There were 33 treatment failures in the LARS group (29 patients required other treatment to control reflux symptoms, 1 needed more than 1 dilatation, and 3 had postfundoplication adverse events including 1 gastric perforation and 2 with severe flatulence, bloating, and diarrhea) compared with 19 treatment failures in the esomeprazole group (all failures of symptom resolution). The results of the per-protocol analysis were similar: 85% (95% CI, 80%-90%) remission in the LARS group and 94% (95% CI, 91%-98%) remission in the esomeprazole group at 5 years (ie, 30 vs 12 treatment failures respectively; P = .004).

Place holder to copy figure label and caption
Figure 2. Time to Treatment Failure
Graphic Jump Location

LARS indicates laparoscopic antireflux surgery.

When best- and worst-case scenario case analyses were applied, the remission rates were 88.5% (95% CI, 84.1%-91.9%) in the LARS group and 92.9% (95% CI, 88.9%-95.5%) in the esomeprazole group, for a treatment difference of 4.3% (95% CI, −0.9% to 8.5%) when all censored patients were considered to have successful treatment. Corresponding rates when all censored cases were considered treatment failures were 61.5% (95% CI, 55.5%-67.1%) in the LARS group and 71.8% (95% CI, 65.9%-77.0%) in the esomeprazole group, for a treatment difference of 10.3% (95% CI, 2.2%-18.5%). When all censored patients were excluded from the analysis, the estimated remission rates were 84.3% (95% CI, 78.5%-88.8%) in the LARS group and 91.0% (95% CI, 86.0%-94.3% in the esomeprazole group, for a mean treatment difference of 6.7% (95% CI, −0.1% to 13.4%).

The percentages of patients in the esomeprazole group who required an increased dose of esomeprazole to control their symptoms were similar for each year during the study; at 5 years, 23.1% of patients were receiving an increased dose (16.5% were taking 40 mg once per day and 6.6% were taking 20 mg twice per day).

GERD and Postoperative Symptoms. The prevalence and severity of GERD symptoms reported by patients at each clinic visit throughout the study is shown in Figure 3. The esomeprazole group showed similar levels of heartburn and regurgitation from baseline up to 5 years, while both symptoms decreased in the LARS group after randomization. At 5 years, acid regurgitation was significantly worse in the esomeprazole group than in the LARS group (13% vs 2%, respectively; P < .001), although there was no significant difference between the groups in the severity of heartburn (16% vs 8%; P = .14), epigastric pain (18% vs 18%; P = .55), or diarrhea (15% vs 16%; P = .25). At 5 years, dysphagia remained significantly more common in the LARS group than in the esomeprazole group (11% vs 5%, respectively; P < .001), as did bloating (40% vs 28%, respectively; P < .001) and flatulence (57% vs 40%, respectively; P < .001).

Place holder to copy figure label and caption
Figure 3. Symptoms Reported by Each Treatment Group Throughout the Study as Mild, Moderate, or Severe
Graphic Jump Location

See definitions of mild, moderate, or severe symptoms in “Methods” section of text. GERD indicates gastroesophageal reflux disease; LARS, laparoscopic antireflux surgery.

Endoscopic Findings. At 5 years, esophagitis of Los Angeles grades A, B, or C was observed in 12, 5, and 1 patients in the LARS group and in 16, 7, and 2 patients in the esomeprazole group, respectively. The percentage of patients in the esomeprazole group with hiatal hernia remained consistent over 5 years and was present in 62% at 5 years compared with 6% in the LARS group. The presence of stricture decreased in both treatment groups throughout the study, with 5 reported during the run-in period (3 in the esomeprazole group and 2 in the LARS group) and 2 after operation in the LARS group.

Endoscopic suspicion of esophageal metaplasia was present in 11.1% (32/288) of the LARS group and in 10.5% (28/266) of the esomeprazole group at entry, and its prevalence at 5 years remained stable in both study groups (13.6% [22/162] and 9.3% [17/183], respectively).

pH-Metry. Complete pH data were available for approximately 70% of the participants who were still in follow-up at 5 years. Baseline intraesophageal acid exposure was similar for the 2 treatment groups; the median percentage of time that pH was below 4 (upright plus recumbent) was 8.6% in the LARS group and 8.8% in the esomeprazole group. At 5 years, exposure time had decreased to 0.7% in the LARS group and to 1.9% in the esomeprazole group. The mean percentage of time with raised intragastric pH (>4) increased from 12.1% at baseline to 62.1% at 5 years in the esomeprazole group, while in the LARS group it remained fairly stable, decreasing slightly from 12.4% at baseline to 11.4% at 5 years.

Health-Related Quality of Life. QOLRAD scores on the food and drink and vitality dimensions as well as scores on the GSRS reflux dimension were the most abnormal at entry and the most sensitive to change with treatment. The mean scores for all dimensions improved in both groups and remained close to values observed in a healthy population (eTable 1).

Safety

There was no perioperative mortality and only 3% of patients had in-hospital morbidity. Serious adverse events were reported by 28.6% of patients who underwent LARS (n = 248) and by 24.1% of the esomeprazole group (n = 266) over 5 years (Table 2). Five patients had serious adverse events during the study that led to death either during the study (3 patients in the esomeprazole group, 1 of whom had pneumonia and 2 of whom had pancreatic carcinoma) or after the study (1 patient in the LARS group who had a malignant lung neoplasm and 1 patient in the esomeprazole group who had a fall that led to traumatic brain injury and femur and pelvic fracture). Further details of serious adverse events are shown in eTable 2. Laboratory variables monitored throughout the study are summarized in Table 2. Mean gastrin and chromogranin levels were elevated in patients treated with esomeprazole, as expected after long-term acid suppression. They appeared to stabilize after 3 years. No clinically relevant changes were noted in other laboratory variables.

Quiz Ref IDThis large, multicenter randomized trial demonstrated that with modern forms of antireflux therapy, either by drug-induced acid suppression or after LARS, most patients remain in remission for at least 5 years. In an exploratory analysis, the estimated remission rates at 5 years were higher in the esomeprazole group (92%; 95% CI, 89%-96%) than in the LARS group (85%; 95% CI, 81%-90%; log-rank P = .048).Quiz Ref IDThere was more regurgitation with esomeprazole than with LARS. In contrast, dysphagia, bloating, and flatulence were more common after LARS vs with esomeprazole. Both treatments were well tolerated, with no surgery-related mortality and similar safety profiles for both.20

The high remission rates reported in this trial are at variance with previous randomized studies comparing long-term medical therapy vs antireflux surgery. There may be several reasons for these apparent discrepancies. Quiz Ref IDWith respect to drug therapy, earlier trials used drugs such as antacids, prokinetics, or histamine2 receptor antagonists that are now known to be of limited efficacy. Proton pump inhibitors are more potent acid-suppressive agents, reducing the intensity of esophageal acid exposure. In the present study, patients were treated with esomeprazole, which suppresses gastric acidity more effectively than omeprazole and other PPIs.21,22 Moreover, in our study, patients whose reflux symptoms were not adequately controlled by a standard maintenance regimen (ie, esomeprazole, 20 mg/d) were allowed to increase the dosage to 40 mg once per day and then to 20 mg twice per day. Dinnertime or split dosing can improve breakthrough nocturnal symptoms for some patients.23 Dose escalation or split dosing applied in the LOTUS study may have contributed to the improved remission rate (92%) compared with that reported in the SOPRAN study at 5 years (57%),9 in which patients received omeprazole and were not actively dose-titrated to the same extent. Most likely, LARS outcomes were better than reported in earlier studies because we recruited participating centers and surgeons with demonstrable expertise and standardized surgical technique, which has been shown to improve outcomes in other studies.24,25 The outcome from this approach was manifested by the absence of mortality and the very low morbidity rate in the LARS group. Only 1 patient had dysphagia requiring more than 1 endoscopic dilatation. One recent meta-analysis suggested better outcomes for LARS compared with open surgery, but the need for reoperation may be more frequent after LARS.7 In our experience, most patients (98%) did not experience long-term complications from LARS. The final endoscopic assessment did not show anatomical deterioration and hiatal repair was maintained, with only 5.6% of the LARS group having hiatal hernia after 5 years compared with 62.3% in the esomeprazole group, confirming similar observations from the SOPRAN study.9 Our LARS group showed slight deterioration in symptom control between 3 years (estimated remission rate, 90%) and 5 years (estimated remission rate, 85%), while the esomeprazole group remained more stable. Better long-term symptom control in the esomeprazole group might have been related to dose escalation.

Long-term acid suppression has been associated with complications.2628 The serious adverse events reported in this study20 (eTable 2) were similar between the LARS and esomeprazole groups, apart from slightly more cardiovascular complications in the esomeprazole group. However, there were no specific serious adverse events that were judged by the investigators to be attributable to acid-supressive therapy alone. Two hip fractures occurred during the study, 1 in the LARS group and 1 in the esomeprazole group that was caused by a serious fall that also resulted in femur fracture, brain trauma, and death. The few hip fractures we observed suggest that fractures are rare with PPI and that previous observational studies might have overestimated the risk of these events.29

Our trial has several limitations. First, we enrolled only PPI responders; our results do not generalize to patients who initially are partially or completely refractory to PPI therapy.30 These poor responders are a heterogeneous group of patients with many underlying causes for their nonresponsiveness to treatment. The most common cause is the absence of actual reflux disease, with symptoms being caused by nonreflux conditions. Assessing the role of surgery in nonresponders requires specific investigations such as pH impedancemetry to better classify patients. The choice of long-term PPI maintenance therapy or LARS in patients who initially respond to acid suppression is relevant to clinical practice.

Second, 14% of participants randomized to receive surgery were not operated on for various reasons. Despite our efforts, we were unable to follow up this patient cohort, who did not differ from participants at baseline but who declined surgery. For this reason, we performed a sensitivity analysis with best- and worst-case scenarios assuming that all participants not completing the study after randomization all either had treatment response or treatment failure. The results of this were similar to our overall findings. The number of participants randomized to receive surgery who did not undergo operation was considerably lower than the 38% of participants reported in the large UK REFLUX trial.13 When treatment failures were excluded, the dropout rate during the 5-year duration was consistent with rates observed in other studies of chronic conditions and better than in other previous antireflux surgery clinical trials.8,12,13

Third, this study was not designed as a superiority or equivalence trial but, rather, as an exploratory study to estimate the efficacy of antireflux surgery and PPI treatment in PPI responders. At the time the study was designed, there were no good estimates for long-term treatment efficacy of esomeprazole (or other PPIs) in this patient population, and the 70% estimate of success with surgery was based on results with nonlaparoscopic procedures. We therefore selected a more pragmatic strategy for sample size determination by estimating the size of the CI for a given difference in efficacy. Nonetheless, we did prespecify that the treatment success rates in each group would be compared using log-rank tests for the superiority of the observed difference between the treatment groups.

In summary, most patients with GERD who are initially responsive to PPIs achieve and remain in remission at 5 years with contemporary antireflux therapy using either LARS or esomeprazole in a dose-escalating manner when required.

Corresponding Author: Jean-Paul Galmiche, MD, FRCP, Department of Gastroenterology and Hepatology, Nantes University, CIC INSERM, Place Alexis Ricordeau, 44093 Nantes, France (jeanpaul.galmiche@chu-nantes.fr).

Author Contributions: Dr Lundell had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Galmiche and Hatlebakk contributed equally to the article's content.

Study concept and design: Galmiche, Hatlebakk, Attwood, Fiocca, Eklund, Lind, Lundell.

Acquisition of data: Galmiche, Hatlebakk, Attwood, Ell, Eklund, Lundell.

Analysis and interpretation of data: Galmiche, Hatlebakk, Attwood, Ell, Fiocca, Eklund, Långström, Lind, Lundell.

Drafting of the manuscript: Galmiche, Hatlebakk, Attwood, Ell, Eklund, Långström, Lind, Lundell.

Critical revision of the manuscript for important intellectual content: Galmiche, Hatlebakk, Attwood, Ell, Fiocca, Eklund, Långström, Lind, Lundell.

Statistical analysis: Långström.

Obtained funding: Galmiche, Hatlebakk, Lundell.

Administrative, technical, or material support: Galmiche, Hatlebakk, Attwood, Ell, Fiocca, Långström, Lind, Lundell.

Study supervision: Galmiche, Hatlebakk, Attwood, Lind, Lundell.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Galmiche reported that he is a consultant for several biomedical companies (AstraZeneca, Janssen-Cilag, Given Imaging, Xenoport, and Norgine) and that his institution receives grants for research from AstraZeneca, Given Imaging, and Mauna Kea Technology. He has prepared educational presentations for Shire Movetis. Dr Attwood reported that he has received honoraria for speaking at meetings sponsored by AstraZeneca. Dr Ell reported that he receives grants for research from several biomedical companies (AstraZeneca, Fujinon, Erbe, and Hitachi). Dr Fiocca reported that he has received travel and related expenses for attending study-associated meetings and his institution received a grant from AstraZeneca for central histological analyses. Drs Eklund, Långström, and Lind reported that they are employees of AstraZeneca. Dr Lundell reported that he receives consultancy and lecture fees from several biomedical companies including AstraZeneca and that his institution (Karolinska University Hospital) receives grants for research on his behalf.

LOTUS Trial Collaborators:Austria: Johannes Miholic (country coordinator), Univ Klinik für Chirurgie, Vienna; Rainer Hubmann, Jan Danis (country coordinator), Krankenhaus, Linz; Belgium: Jan Tack, Toni Lerut (country coordinator), UZ Gasthuisberg, Leuven; Hubert Piessevaux, UCL St-Luc, Jacques Devière, Clinique Universitaire Bruxelles Hôpital Erasme, Michel Buset, Centre Hospitalier Universitaire St-Pierre, and Cristiano Chioccioli, Clinique St-Jean, Brussels; Danny De Looze, UZ Gent, Gent; Jean-Claude Demoulin, Cliniques St-Joseph, and Edouard Louis, Centre Hospitalier Universitaire Sart Tilman, Liège; Jean-Michel Ghilain, Jean-Marc Maisin, CH Jolimont-Lobbes (Jolimont), Haine-Saint-Paul; Denmark: Peter Funch-Jensen (country coordinator), Århus Universitetshospital, Århus; Jørn Nielsen, Regionshospitalet Viborg, Viborg; Lars Christensen, Regionshospitalet Herning, Herning; Henning Antonsen, Kolding Sygehus, Kolding; Karsten Lauritsen, Odense Universitetshospital, Odense; Per Jess, Hillerød Hospital, Hillerød; Lene Wallin, Glostrup Hospital, Glostrup; Lars Naver, Hvidovre Hospital, Hvidovre; France: Jean-Paul Galmiche (country coordinator), Eric Letessier, CHU de Nantes–Hôtel Dieu, Nantes; Frank Zerbib, Groupe Hospitalier Saint André, Bordeaux; Bruno Bonaz, Richard Bost, CHU de Grenoble, Grenoble; Jean-Charles Delchier, Hôpital Henri Mondor, Creteil; Germany: Martin Fein, Jörn Maroske, Würzburg, Universitätsklinikum, Würzburg; Christian Ell, Dr Horst Schmidt Kliniken GmbH, Wiesbaden; Arnulf Hölscher, Uniklinik und Poliklinik für Visceral und Gefäßchirurgie, Köln; Carsten Zornig, Israelitisches Krankenhaus Hamburg, Hamburg; Joachim Helmut Schneider, Klinikum der Eberhard Karls Universität, Tübingen; Thomas Hüttl, München, Ludwig Maximilians Universität LMU, Chirurgie Poliklinikum, München; Markus Büchler, Universitätsklinikum Heidelberg, Heidelberg; Ursula Wehrmann, Universitätsklinikum Carl-Gustav-Carus an der TU Dresden, Dresden; Matthias Kemen, Herne, Ev Kkh, Chirurgie, Herne; Peter Layer, Hamburg Israelitisches Krankenhaus, Hamburg; Karl-Hermann Fuchs (country coordinator), St Markus Krankenhaus, Allgemeine Chirurgie Frankfurt/Main, Frankfurt; Solveig Kemen, Schwerpunktpraxis Gastroenterologie Praxis Kemen & Schmidt-Heinevetter, Bochum; Dieterich Hüppe, Internistische Praxisgemeinschaft, Herne; Iceland: Margrét Oddsdóttir (country coordinator), Bjarni Thjodleifsson (country coordinator), Landspitali, University Hospital, Reykjavik; Italy: Luigi Bonavina (country coordinator), Policlinico S Donato, San Donato Milanese; Ermanno Ancona, Policlinico Universitario di Padova, Padova; Mario Morino, Ospedale Le Molinette, Torino; Giusto Pignata, Alessandro Giurissa, Ospedale di Monfalcone, Monfalcone; Mauro Rossi, Ospedale S Chiara, Pisa; Riccardo Rosati, Istituto Clinico Humanitas, Rozzano; Renzo Cestari, Spedali Civili di Brescia, Brescia; Netherlands: Hein Gooszen (country coordinator), Universitair Medisch Centrum Utrecht, Utrecht; Norway: Jan Hatlebakk (country coordinator), Helse Bergen HF Haukeland Universitetssykehus, and Solomon Tefera, Haraldsplass Diakonale Sykehus AS, Bergen; Gjermund Johnsen, St Olav's Hospital HF, Trondheim; Jørgen Jahnsen, Aker Universitetssykehus HF, and Olav Sandstad, Ullevål Universitetssykehus HF, Oslo; Asbjørn Stallemo, Sørlandet Sykehus HF, Kristiansand; Jon Florholmen, Universitetssykehuset Nord-Norge HF, Tromsø; Geir Tollåli, Nordlandssykehuset HF, Bodø; Sweden: Cecilia Engström, Bengt Liedman, Lars Lundell (country coordinator), SU/Sahlgrenska Universitetssjukhus, Göteborg; United Kingdom: Chris Babbs, Stephen Attwood (country coordinator), Hope Hospital, Salford.

Funding/Support: The study was funded in total by AstraZeneca Research and Development, Mölndal, Sweden.

Role of the Sponsor: AstraZeneca contributed to the design of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript, in full collaboration with the independent statistician and the study steering committee. Madeline Frame, BSc, PhD, a medical scientist affiliated with AstraZeneca, provided medical writing support to the principal author in terms of drafting the methods and results and incorporating edits from all authors. All writing was done in close collaboration with the first author and the steering committee and they gave major input to the introduction, interpretation, and discussion sections.

Independent Statistical Analysis: Hans Wedel, PhD, emeritus professor in Epidemiology and Biostatistics at the Nordic School of Public Health, Gothenburg, Sweden, undertook an independent statistical analysis, of the data on behalf of AstraZeneca, for which he was reimbursed at standard rates. The results of his analyses are included in this article. His position as an academic faculty member working independent of AstraZeneca has been verified by the dean of the faculty, Anders Foldspang.

Additional Contributions: We thank all study site personnel who contributed to the study. This article is dedicated to Ola Junghard, PhD, our colleague and statistician for many years, who passed away in November 2009.

Kulig M, Leodolter A, Vieth M,  et al.  Quality of life in relation to symptoms in patients with gastro-oesophageal reflux disease—an analysis based on the ProGERD initiative.  Aliment Pharmacol Ther. 2003;18(8):767-776
PubMed   |  Link to Article
Wahlqvist P, Reilly MC, Barkun A. Systematic review: the impact of gastro-oesophageal reflux disease on work productivity.  Aliment Pharmacol Ther. 2006;24(2):259-272
PubMed   |  Link to Article
Camilleri M, Dubois D, Coulie B,  et al.  Prevalence and socioeconomic impact of upper gastrointestinal disorders in the United States: results of the US Upper Gastrointestinal Study.  Clin Gastroenterol Hepatol. 2005;3(6):543-552
PubMed   |  Link to Article
McQuaid KR, Laine L. Early heartburn relief with proton pump inhibitors: a systematic review and meta-analysis of clinical trials.  Clin Gastroenterol Hepatol. 2005;3(6):553-563
PubMed   |  Link to Article
Gralnek IM, Dulai GS, Fennerty MB, Spiegel BMR. Esomeprazole versus other proton pump inhibitors in erosive esophagitis: a meta-analysis of randomized clinical trials.  Clin Gastroenterol Hepatol. 2006;4(12):1452-1458
PubMed   |  Link to Article
Edwards SJ, Lind T, Lundell L. Systematic review: proton pump inhibitors (PPIs) for the healing of reflux oesophagitis—a comparison of esomeprazole with other PPIs.  Aliment Pharmacol Ther. 2006;24(5):743-750
PubMed   |  Link to Article
Peters MJ, Mukhtar A, Yunus RM,  et al.  Meta-analysis of randomized clinical trials comparing open and laparoscopic anti-reflux surgery.  Am J Gastroenterol. 2009;104(6):1548-1561
PubMed   |  Link to Article
Spechler SJ, Lee E, Ahnen D,  et al.  Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial.  JAMA. 2001;285(18):2331-2338
PubMed   |  Link to Article
Lundell L, Miettinen P, Myrvold HE,  et al; Nordic GERD Study Group.  Comparison of outcomes 12 years after antireflux surgery or omeprazole maintenance therapy for reflux esophagitis.  Clin Gastroenterol Hepatol. 2009;7(12):1292-1298, quiz 1260
PubMed   |  Link to Article
Mahon D, Rhodes M, Decadt B,  et al.  Randomized clinical trial of laparoscopic Nissen fundoplication compared with proton-pump inhibitors for treatment of chronic gastro-oesophageal reflux.  Br J Surg. 2005;92(6):695-699
PubMed   |  Link to Article
Anvari M, Allen C, Borm A. Laparoscopic Nissen fundoplication is a satisfactory alternative to long-term omeprazole therapy.  Br J Surg. 1995;82(7):938-942
PubMed   |  Link to Article
Mehta S, Bennett J, Mahon D, Rhodes M. Prospective trial of laparoscopic Nissen fundoplication vs proton pump inhibitor therapy for gastroesophageal reflux disease: 7-year follow-up.  J Gastrointest Surg. 2006;10(9):1312-1316
PubMed   |  Link to Article
Grant AM, Wileman SM, Ramsay CR,  et al; REFLUX Trial Group.  Minimal access surgery compared with medical management for chronic gastro-oesophageal reflux disease: UK collaborative randomised trial.  BMJ. 2008;337:a2664
PubMed   |  Link to Article
Attwood SE, Lundell L, Ell C,  et al; LOTUS Trial Group.  Standardization of surgical technique in antireflux surgery: the LOTUS trial experience.  World J Surg. 2008;32(6):995-998
PubMed   |  Link to Article
Castell DO, Kahrilas PJ, Richter JE,  et al.  Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis.  Am J Gastroenterol. 2002;97(3):575-583
PubMed   |  Link to Article
Lundell L, Attwood S, Ell C,  et al; LOTUS Trial Collaborators.  Comparing laparoscopic antireflux surgery with esomeprazole in the management of patients with chronic gastro-oesophageal reflux disease: a 3-year interim analysis of the LOTUS trial.  Gut. 2008;57(9):1207-1213
PubMed   |  Link to Article
Fiocca R, Mastracci L, Engström C,  et al; LOTUS Trial Collaborators.  Long-term outcome of microscopic esophagitis in chronic GERD patients treated with esomeprazole or laparoscopic antireflux surgery in the LOTUS trial.  Am J Gastroenterol. 2010;105(5):1015-1023
PubMed   |  Link to Article
Hatlebakk JG, Zerbib F, Bonavina L,  et al.  Control of acid reflux 5 years after laparoscopic anti-reflux surgery (LARS) compared to long-term treatment with esomeprazole 20-40 mg daily (ESO) in the LOTUS study.  Gut. 2010;59:(suppl 3)  A87
Fleiss JL. Statistical Methods for Rates and Proportions. 2nd ed. New York, NY: Wiley; 1981
Ell C, Lundell LR, Seiler CM,  et al.  Safety profile in GERD patients 5 years after laparoscopic antireflux surgery or long-term treatment with esomeprazole 20-40 mg daily in the LOTUS study.  Gastroenterology. 2010;138(5):(suppl 1)  S-654
Link to Article
Miner P Jr, Katz PO, Chen Y, Sostek M. Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a 5-way crossover study.  Am J Gastroenterol. 2003;98(12):2616-2620
PubMed   |  Link to Article
Röhss K, Lind T, Wilder-Smith C. Esomeprazole 40 mg provides more effective intragastric acid control than lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with gastro-oesophageal reflux symptoms.  Eur J Clin Pharmacol. 2004;60(8):531-539
PubMed   |  Link to Article
Hatlebakk JG, Katz PO, Kuo B, Castell DO. Nocturnal gastric acidity and acid breakthrough on different regimens of omeprazole 40 mg daily.  Aliment Pharmacol Ther. 1998;12(12):1235-1240
PubMed   |  Link to Article
Luostarinen MES, Isolauri JO. Surgical experience improves the long-term results of Nissen fundoplication.  Scand J Gastroenterol. 1999;34(2):117-120
PubMed   |  Link to Article
Oelschlager BK, Quiroga E, Parra JD, Cahill M, Polissar N, Pellegrini CA. Long-term outcomes after laparoscopic antireflux surgery.  Am J Gastroenterol. 2008;103(2):280-287
PubMed   |  Link to Article
Moayyedi P, Cranney A. Hip fracture and proton pump inhibitor therapy: balancing the evidence for benefit and harm.  Am J Gastroenterol. 2008;103(10):2428-2431
PubMed   |  Link to Article
Targownik LE, Lix LM, Leung S, Leslie WD. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss.  Gastroenterology. 2010;138(3):896-904
PubMed   |  Link to Article
Lodato F, Azzaroli F, Turco L,  et al.  Adverse effects of proton pump inhibitors.  Best Pract Res Clin Gastroenterol. 2010;24(2):193-201
PubMed   |  Link to Article
Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture.  JAMA. 2006;296(24):2947-2953
PubMed   |  Link to Article
Zaninotto G, Attwood SE. Surgical management of refractory gastro-oesophageal reflux.  Br J Surg. 2010;97(2):139-140
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Patient Flow in the LOTUS Trial
Graphic Jump Location

LARS indicates laparoscopic antireflux surgery.

Place holder to copy figure label and caption
Figure 2. Time to Treatment Failure
Graphic Jump Location

LARS indicates laparoscopic antireflux surgery.

Place holder to copy figure label and caption
Figure 3. Symptoms Reported by Each Treatment Group Throughout the Study as Mild, Moderate, or Severe
Graphic Jump Location

See definitions of mild, moderate, or severe symptoms in “Methods” section of text. GERD indicates gastroesophageal reflux disease; LARS, laparoscopic antireflux surgery.

Tables

Table Graphic Jump LocationTable 1. Patient Demographics and Baseline Characteristicsa

References

Kulig M, Leodolter A, Vieth M,  et al.  Quality of life in relation to symptoms in patients with gastro-oesophageal reflux disease—an analysis based on the ProGERD initiative.  Aliment Pharmacol Ther. 2003;18(8):767-776
PubMed   |  Link to Article
Wahlqvist P, Reilly MC, Barkun A. Systematic review: the impact of gastro-oesophageal reflux disease on work productivity.  Aliment Pharmacol Ther. 2006;24(2):259-272
PubMed   |  Link to Article
Camilleri M, Dubois D, Coulie B,  et al.  Prevalence and socioeconomic impact of upper gastrointestinal disorders in the United States: results of the US Upper Gastrointestinal Study.  Clin Gastroenterol Hepatol. 2005;3(6):543-552
PubMed   |  Link to Article
McQuaid KR, Laine L. Early heartburn relief with proton pump inhibitors: a systematic review and meta-analysis of clinical trials.  Clin Gastroenterol Hepatol. 2005;3(6):553-563
PubMed   |  Link to Article
Gralnek IM, Dulai GS, Fennerty MB, Spiegel BMR. Esomeprazole versus other proton pump inhibitors in erosive esophagitis: a meta-analysis of randomized clinical trials.  Clin Gastroenterol Hepatol. 2006;4(12):1452-1458
PubMed   |  Link to Article
Edwards SJ, Lind T, Lundell L. Systematic review: proton pump inhibitors (PPIs) for the healing of reflux oesophagitis—a comparison of esomeprazole with other PPIs.  Aliment Pharmacol Ther. 2006;24(5):743-750
PubMed   |  Link to Article
Peters MJ, Mukhtar A, Yunus RM,  et al.  Meta-analysis of randomized clinical trials comparing open and laparoscopic anti-reflux surgery.  Am J Gastroenterol. 2009;104(6):1548-1561
PubMed   |  Link to Article
Spechler SJ, Lee E, Ahnen D,  et al.  Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial.  JAMA. 2001;285(18):2331-2338
PubMed   |  Link to Article
Lundell L, Miettinen P, Myrvold HE,  et al; Nordic GERD Study Group.  Comparison of outcomes 12 years after antireflux surgery or omeprazole maintenance therapy for reflux esophagitis.  Clin Gastroenterol Hepatol. 2009;7(12):1292-1298, quiz 1260
PubMed   |  Link to Article
Mahon D, Rhodes M, Decadt B,  et al.  Randomized clinical trial of laparoscopic Nissen fundoplication compared with proton-pump inhibitors for treatment of chronic gastro-oesophageal reflux.  Br J Surg. 2005;92(6):695-699
PubMed   |  Link to Article
Anvari M, Allen C, Borm A. Laparoscopic Nissen fundoplication is a satisfactory alternative to long-term omeprazole therapy.  Br J Surg. 1995;82(7):938-942
PubMed   |  Link to Article
Mehta S, Bennett J, Mahon D, Rhodes M. Prospective trial of laparoscopic Nissen fundoplication vs proton pump inhibitor therapy for gastroesophageal reflux disease: 7-year follow-up.  J Gastrointest Surg. 2006;10(9):1312-1316
PubMed   |  Link to Article
Grant AM, Wileman SM, Ramsay CR,  et al; REFLUX Trial Group.  Minimal access surgery compared with medical management for chronic gastro-oesophageal reflux disease: UK collaborative randomised trial.  BMJ. 2008;337:a2664
PubMed   |  Link to Article
Attwood SE, Lundell L, Ell C,  et al; LOTUS Trial Group.  Standardization of surgical technique in antireflux surgery: the LOTUS trial experience.  World J Surg. 2008;32(6):995-998
PubMed   |  Link to Article
Castell DO, Kahrilas PJ, Richter JE,  et al.  Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis.  Am J Gastroenterol. 2002;97(3):575-583
PubMed   |  Link to Article
Lundell L, Attwood S, Ell C,  et al; LOTUS Trial Collaborators.  Comparing laparoscopic antireflux surgery with esomeprazole in the management of patients with chronic gastro-oesophageal reflux disease: a 3-year interim analysis of the LOTUS trial.  Gut. 2008;57(9):1207-1213
PubMed   |  Link to Article
Fiocca R, Mastracci L, Engström C,  et al; LOTUS Trial Collaborators.  Long-term outcome of microscopic esophagitis in chronic GERD patients treated with esomeprazole or laparoscopic antireflux surgery in the LOTUS trial.  Am J Gastroenterol. 2010;105(5):1015-1023
PubMed   |  Link to Article
Hatlebakk JG, Zerbib F, Bonavina L,  et al.  Control of acid reflux 5 years after laparoscopic anti-reflux surgery (LARS) compared to long-term treatment with esomeprazole 20-40 mg daily (ESO) in the LOTUS study.  Gut. 2010;59:(suppl 3)  A87
Fleiss JL. Statistical Methods for Rates and Proportions. 2nd ed. New York, NY: Wiley; 1981
Ell C, Lundell LR, Seiler CM,  et al.  Safety profile in GERD patients 5 years after laparoscopic antireflux surgery or long-term treatment with esomeprazole 20-40 mg daily in the LOTUS study.  Gastroenterology. 2010;138(5):(suppl 1)  S-654
Link to Article
Miner P Jr, Katz PO, Chen Y, Sostek M. Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a 5-way crossover study.  Am J Gastroenterol. 2003;98(12):2616-2620
PubMed   |  Link to Article
Röhss K, Lind T, Wilder-Smith C. Esomeprazole 40 mg provides more effective intragastric acid control than lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with gastro-oesophageal reflux symptoms.  Eur J Clin Pharmacol. 2004;60(8):531-539
PubMed   |  Link to Article
Hatlebakk JG, Katz PO, Kuo B, Castell DO. Nocturnal gastric acidity and acid breakthrough on different regimens of omeprazole 40 mg daily.  Aliment Pharmacol Ther. 1998;12(12):1235-1240
PubMed   |  Link to Article
Luostarinen MES, Isolauri JO. Surgical experience improves the long-term results of Nissen fundoplication.  Scand J Gastroenterol. 1999;34(2):117-120
PubMed   |  Link to Article
Oelschlager BK, Quiroga E, Parra JD, Cahill M, Polissar N, Pellegrini CA. Long-term outcomes after laparoscopic antireflux surgery.  Am J Gastroenterol. 2008;103(2):280-287
PubMed   |  Link to Article
Moayyedi P, Cranney A. Hip fracture and proton pump inhibitor therapy: balancing the evidence for benefit and harm.  Am J Gastroenterol. 2008;103(10):2428-2431
PubMed   |  Link to Article
Targownik LE, Lix LM, Leung S, Leslie WD. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss.  Gastroenterology. 2010;138(3):896-904
PubMed   |  Link to Article
Lodato F, Azzaroli F, Turco L,  et al.  Adverse effects of proton pump inhibitors.  Best Pract Res Clin Gastroenterol. 2010;24(2):193-201
PubMed   |  Link to Article
Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture.  JAMA. 2006;296(24):2947-2953
PubMed   |  Link to Article
Zaninotto G, Attwood SE. Surgical management of refractory gastro-oesophageal reflux.  Br J Surg. 2010;97(2):139-140
PubMed   |  Link to Article
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