Multicenter, Prospective, Double-blind, Randomized Trial of Laparoscopic Nissen vs Anterior 90º Partial Fundoplication FREE

Although medications that suppress acid achieve adequate symptom control for most patients with gastroesophageal reflux (GER) disease, some patients with more severe reflux have a poor response to medication. These patients will often benefit from surgery. In addition, fundoplication is also an effective treatment for many younger patients who do not wish to take tablets for the rest of their lives. The 360° fundoplication that was first described by Nissen remains the most commonly performed anti-GER procedure worldwide. It achieves excellent control of acid reflux although this is at the expense of a small, but nevertheless important, incidence of troublesome postoperative adverse effects.¹ To overcome this, technical aspects of this procedure have been progressively modified.

Partial fundoplication has the potential to produce a more physiological gastroesophageal junction and with this fewer adverse effects.^1- 2 While variants of posterior fundoplication are arguably the more common approach to partial fundoplication, the alternative anterior partial fundoplication procedure has the potential to reduce even further the risk of adverse effects.³ In 1999, the early outcomes of a randomized trial of Nissen vs anterior 180° fundoplication were reported by some of us.³ That study demonstrated the potential for an anterior partial fundoplication to produce adequate GER control and a low rate of postoperative adverse effects. Subsequent longer-term follow-up has confirmed the durability of the anterior 180° fundoplication procedure.⁴ Nevertheless, even this procedure is followed by a small incidence of troublesome adverse effects.

This provided impetus for the further refinement of the anterior fundoplication procedure to an anterior 90° partial fundoplication. Previously reported laboratory and clinical studies have confirmed the short-term effectiveness of this approach and its potential to achieve a very low rate of adverse effects.^5- 6 Before proceeding to wider clinical application, however, we chose to evaluate the new procedure within a multicenter, prospective, randomized, controlled clinical trial to compare the anterior 90° partial fundoplication procedure with a standard approach to Nissen fundoplication.

This multicenter study investigated the hypothesis that laparoscopic anterior 90º partial fundoplication could achieve effective control of GER symptoms, but with fewer adverse effects, compared with laparoscopic Nissen fundoplication. Fifteen surgeons from 9 university teaching hospitals in 6 Australian and New Zealand cities contributed patients to this study, with each surgeon aiming to contribute a quota of 10 patients to the study.

Patients undergoing laparoscopic fundoplication for GER disease were randomly assigned to undergo either a total fundoplication with division of short gastric blood vessels and full mobilization of all fundal attachments or an anterior 90º partial fundoplication. Informed consent was obtained from all participants, and randomization occurred in the operating theater, after commencing general anesthesia. Randomization was performed by opening 1 of 150 previously sealed opaque envelopes. The envelopes were prepared by a research officer (C.L.) before the trial began. Sets of 10 randomly selected envelopes were sent to each participating surgeon, and each surgeon opened an envelope at the time of the operation to determine the specific procedure to be performed. Patients were not stratified according to the operating surgeon or any other criteria.

Patients with proven GER disease who presented for primary antireflux surgery were considered for enrollment in this trial. Exclusion criteria were (1) an esophageal motility disorder that precluded a 360º fundoplication, (2) a planned concurrent abdominal procedure along with fundoplication (eg, cholecystectomy), and (3) previous antireflux surgery. Patients underwent preoperative investigation with esophageal manometry and endoscopy. In general, 24-hour pH monitoring was performed to confirm GER disease in patients who did not have unequivocal GER disease demonstrated by preliminary endoscopic and manometric studies.

Laparoscopic Nissen fundoplication was performed according to a common technique that was agreed to by the study participants before the trial commenced. This entailed posterior hiatal repair for all patients and full mobilization of the gastric fundus. The short gastric vessels were divided using ultrasonic shears, starting at the level of the inferior pole of the spleen, and progressing superiorly along the greater curvature of the stomach up to the left pillar of the esophageal hiatus. The uppermost short gastric vessel and all posterior attachments of the fundus were always divided, ensuring a very “floppy” wrap. Care was taken to ensure that the completed total fundoplication was not tight by having a 52F to 60F bougie within the lumen of the abdominal esophagus when constructing the fundoplication. Nonabsorbable sutures were used to secure a fundoplication that was between 1 and 2 cm in length.

A laparoscopic anterior 90º partial fundoplication was also performed according to an agreed on common technique. This has been described in detail in a previous report.⁵ The esophageal hiatus was dissected first using an identical technique to that used for total fundoplication, and the hiatus was repaired posteriorly in all patients. The 90º anterior fundoplication commenced with an esophagopexy suture between the posterolateral aspect of the right side of the esophagus at or just above the esophagogastric junction, and the posterior aspect of either the right pillar or both pillars. This stabilized a length of intra-abdominal length of esophagus. Two sutures were then placed between the left side of the esophagus and the adjacent gastric fundus to reconstruct and accentuate the angle of His. Next the gastric fundus was attached loosely over the front of the esophagus, using an apical suture that anchored the fundus to the anterior esophagus as it emerged through the esophageal hiatus, and to the apex of the hiatus in the 12-o’clock position. Finally, the inferior edge of the fundal fold lying in front of the abdominal esophagus was sutured to the anterior esophagus at the esophagogastric junction in the midline. This produced a loose fundoplication, covering the intra-abdominal esophagus from the apex of the angle of His to the anterior aspect of the esophagus in the midline. The short gastric vessels were left intact and an intra-esophageal bougie was not used for this procedure. With either procedure, if the laparoscopic procedure was converted to an open procedure because of intraoperative difficulties, the randomization schedule was still followed and the patient remained in the trial.

Before commencing this trial, we endeavored to standardize the operative techniques across all sites. This was attempted by applying several strategies. First, most of the surgeons participating in this study attended meetings of the Australasian Section of the International Society for Diseases of the Esophagus in December 10-11, 1998, and December 8-9, 2000. The operative techniques were discussed in detail, videotape demonstrations were shown, and the technical aspects of the operative techniques were discussed, refined, and agreed on. In addition, reference videotapes of the standard operative techniques were provided to surgeons participating in this study. Additional informal discussion occurred between the initiators of the trial and contributing surgeons at key time points. Because of limited funding and the large distances between centers, it was in general impossible for surgeons to travel to different centers to see other surgeons operate, or for surgeons from different cities to assist other surgeons with these procedures.

Patients were allowed oral fluids postoperatively on the evening of the day of surgery or the next day, and soft solid food soon after. Patients were instructed to maintain a soft diet for the first 3 to 4 weeks after surgery, and then to gradually increase the consistency of their diet.

Which procedure had been performed was concealed from patients during this initial period of follow-up. Patients had no direct access to case notes or trial records, and both laparoscopic procedures were performed through identical operative wounds. While operating surgeons were aware of the exact procedure performed, follow-up was obtained by a research assistant (C.L.) who was based at the Royal Adelaide Hospital and masked to the randomization of each patient. The research assistant was not involved in the initial surgery and remained unaware of the allocated group for each patient throughout the follow-up period. Final data analysis was performed by a surgeon investigator (D.I.W.). Raw data were circulated to all surgeons who contributed patients to this study, allowing the analysis to be independently checked by all surgeon participants.

Preoperative data were collected using a standard form. This was administered by the responsible surgeon before either surgery or before randomization was undertaken. Patients underwent a structured telephone interview that was performed by a research assistant (C.L.) 1, 3, and 6 months after surgery. Longer-term follow-up will be sought in due course. The presence or absence of each of the following symptoms was sought: heartburn; epigastric pain; regurgitation; dysphagia for lumpy solids, soft solids, and liquids; odynophagia; early satiety; inability to belch; epigastric bloating; anorexia; nausea; vomiting; wheezing; nocturnal coughing; increased flatulence; and diarrhea. The ability to relieve bloating and whether a normal diet was being consumed were also determined. Heartburn was also scored using a visual analog scale (0 [no heartburn] to 10 [severe heartburn]).

Dysphagia was scored by several methods. Visual analog scales (0 [no dysphagia] to 10 [total dysphagia]) were applied separately for solids and liquids, as well as a previously validated score (0 [no dysphagia] to 45 [severe dysphagia]) that combines information about difficulty swallowing 9 types of liquids and solids. This scoring system has been described in detail elsewhere.⁷ Overall outcome was determined using 3 further scales and a question. Patients were asked whether they thought that their initial decision to have a laparoscopic fundoplication was correct or not. They were also asked to rank the outcome of surgery using a modified Visick grading system (Table 1) and were asked to score the outcome as excellent, good, fair, or poor (Table 2). An overall assessment of satisfaction with the operative outcome was scored by a further visual analogue scale (0 [dissatisfied] to 10 [satisfied]).

Objective investigation with esophageal manometry, 24-hour pH monitoring, and endoscopy were performed 3 to 4 months after surgery. Investigation sought to assess lower esophageal sphincter function, control of GER, and postsurgical anatomy.

The primary clinical outcomes, which the trial was designed to evaluate, were postoperative dysphagia and control of GER symptoms. Before the trial commenced, it was determined that 120 patients (60 in each group) would be needed to demonstrate a 15% difference in these outcome measures at a statistical significance level of P<.05 and power of 80%. All analyses were performed on an intention-to-treat basis, with all patients remaining in their initial allocated group for this analysis. Before commencing this trial, it was intended to publish the initial outcomes and results of postoperative testing once all patients had been followed up for an initial 6-month period (this article). Longer-term outcomes will be reported once the follow-up duration is longer.

All data were entered in a computerized database (Filemaker Pro version 5.0; Filemaker Corp, Santa Clara, Calif)andanalyzed using statistical software (InStat version 3;GraphPadSoftware Inc, San Diego, Calif). The Fisher exact test was used to determine the significance of 2 × 2 contingency tables. A 2-tailed Mann-Whitney test was used to assess the significance of nonparametric data sets and an unpaired t test to determine the significance of data sets where it was reasonable to assume a parametric distribution (eg, weight). Statistical significance was accepted at P<.05. Unless otherwise stated, all data are reported as the percentage of the total patients in each group or as the mean (95% confidence intervals [CIs]).

The protocol for this study was approved by the human research ethics committee at each participating hospital. The study was conducted in accord with the World Medical Association Declaration of Helsinki (revised 1989) and the National Health and Medical Research Council of Australia’s guidelines on human experimentation.

From February 11, 2000, to February 26, 2003, 112 patients undergoing a laparoscopic fundoplication were enrolled in this trial. This fell short of the original target of 120 patients owing to recruitment difficulties in some centers. Fifty-two patients were randomized to undergo a Nissen fundoplication, and 60 to undergo anterior 90º partial fundoplication. Of these patients 96 (86%) were interviewed 1 month after surgery, 99 (88%) at 3 months, and 108 (96%) at 6 months. Missing data at the earlier time points were owing to an inability to contact patients at these specific follow-up time points. Only 4 patients did not provide clinical data 6 months after surgery. Two of these 4 could not be contacted then. They both had a satisfactory outcome at 3 months’ follow-up. Two patients withdrew from the study before 6 months and refused a follow-up interview at 6 months. As far as could be determined, they also had a satisfactory clinical outcome at 6 months and were free of GER symptoms. Only data that were obtained by telephone interview were included in the data analysis below.

Both study groups were well matched for demographic parameters (Table 3) and the presence or absence of various preoperative symptoms (Table 4 and Table 5), with the exception of a greater proportion of patients who underwent a laparoscopic Nissen fundoplication having undergone previous upper abdominal surgery. A significant proportion of patients in each group experienced preoperative dysphagia to some extent, with a preoperative incidence of 53% for the 90º partial fundoplication group and 56% for the laparoscopic Nissen group when assessed using the 0 to 45 dysphagia score (× 6).

Endoscopic grading of esophagitis before surgery was similar. Ten (17%) of the 52 laparoscopic Nissen group and 3 (6%) of the 60 anterior 90º partial fundoplication group had Barrett esophagus at preoperative endoscopy (P = .08). A hiatus hernia was seen preoperatively in 33 (63%) of the laparoscopic Nissen group vs 35 (58%) of the anterior 90º partial fundoplication group (P = .68).

Preoperative esophageal manometry outcomes (Table 6) were similar for most parameters, although basal lower esophageal sphincter pressure and the percentage of normal swallows at manometry were slightly lower in the anterior 90º partial fundoplication group. However, the actual magnitude of these differences was small. Twenty-four–hour ambulatory pH monitoring was performed in 70% of patients. The mean percentage exposure to an acid pH of less than 4 was 11.5% for the anterior 90º partial fundoplication group and 11.2% for the laparoscopic Nissen group (P = .95).

Fifteen surgeons participated in the study. All patients had a fundoplication constructed according to the randomization schedule. Operating time varied from 30 to 195 minutes (mean, 88 minutes; median, 80 minutes; 95% CI, 76-100) for anterior 90º partial fundoplication, vs 25 to 230 minutes (mean, 96 minutes; median, 87 minutes; 95% CI, 83-109; P = .30) for Nissen fundoplication. The corresponding operating room times were 47 to 270 minutes (mean, 121 minutes; median, 110 minutes; 95% CI, 106-137) vs 40 to 400 minutes (mean, 135 minutes; median, 115 minutes; 95% CI, 113-156; P = .40). The laparoscopic procedure was converted to open surgery in 1 patient in the anterior 90º partial fundoplication group because of intra-abdominal adhesions and in 2 patients in the Nissen fundoplication group owing to adhesions in one patient, and intra-abdominal obesity plus bleeding in the other. Operating surgeons were asked to rate the difficulty of the operative procedure using a scale from 1 to 10. Anterior 90º partial fundoplication was thought to be an easier operation; mean score for the anterior 90º partial fundoplication was 4.1 (95% CI, 3.4-4.7) vs 5.3 (95% CI, 4.6-6.0) for Nissen fundoplication (P = .01).

The periods between surgery and the commencement of oral fluids and solids and the length of postoperative hospital stay were not influenced by the type of laparoscopic fundoplication performed (Table 7). Patients took a mean of 2.6 weeks to return to normal physical activity following the 90º anterior 90º partial fundoplication and 2.9 weeks following laparoscopic Nissen fundoplication (P = .72). After the anterior 90º partial fundoplication, there was 1 of each of the following 5 complications: intraoperative pneumothorax, wound infection, urinary retention, pulmonary embolism, and small-bowel injury. The small-bowel injury was a complication of the use of a Veress needle for the commencement of insufflation, and it led to a laparotomy for peritonitis on the third postoperative day. Following laparoscopic Nissen fundoplication there was 1 of each of the following 4 complications: intraoperative pneumothorax, urinary retention, respiratory failure, and splenic infarction. The splenic infarct entailed the loss of blood supply to approximately 75% of the spleen following clipping of a bleeding vessel during division of the short gastric vessels. None of the complications following Nissen fundoplication required further surgical intervention.

A detailed analysis of the outcome of the masked standardized clinical assessment is summarized in Table 4, Table 5, Table 8, and Table 9. At the 1-month follow-up, the ability to belch and symptoms of epigastric bloating were better preserved following anterior 90º partial fundoplication. There were no other statistically significant differences seen for any of the other outcomes assessed. At the 3-month follow-up, the outcome following anterior 90º partial fundoplication was better for the symptoms of early satiety, epigastric bloating, and dysphagia for solid food. At 6 months after surgery, patients who underwent the anterior 90º partial fundoplication were less likely to experience dysphagia or flatulence.

The incidence and severity of heartburn assessed by the yes/no question and the visual analog scale was identical at the 1- and 3-month follow-up points (Table 4). However, at 6 months patients were more likely to report heartburn (assessed by yes/no question) after anterior 90ºpartial fundoplication. Outcomes were also similar at the 1- and 3-month follow-up intervals for measures of overall outcome, visual analog scale satisfaction score, outcome scale, and modified Visick grading system (Table 9). At 6 months, a greater proportion of the patients who underwent an anterior 90º partial fundoplication (98% vs 88%) indicated that they thought they had made the correct decision to have a laparoscopic fundoplication.

One patient in the anterior 90º partial fundoplication group underwent revision surgery at 5 months after the original fundoplication. This entailed conversion to a posterior partial fundoplication for the treatment of recurrent GER. None of the Nissen fundoplication group underwent further surgery during the 6-month follow-up period.

Seventy-three patients (65%) underwent postoperative endoscopy, 62 (55%) esophageal manometry, and 57 (51%) postoperative 24-hour pH monitoring. The clinical outcomes in patients who underwent postoperative investigation were similar to the outcomes in those patients who declined investigation. Endoscopy demonstrated an intact fundoplication in all patients who had undergone anterior 90º partial fundoplication, and in all but 1 patient following Nissen fundoplication. Following Nissen fundoplication 2 patients had ulcerative esophagitis compared with 4 patients after anterior 90º partial fundoplication.

Esophageal manometry outcomes following surgery are summarized in Table 6. Esophageal body motility parameters and lower esophageal sphincter parameters were similar for the 2 procedures, although there was a trend toward more complete sphincter relaxation with swallowing following anterior 90º partial fundoplication. Twenty-four–hour pH monitoring demonstratednormalization of acid exposure times in all but 6 patients (2 in the Nissen group and 4 in the anterior 90º partial fundoplication group). Three of these patients had symptoms of recurrent GER—all following anterior 90º fundoplication, and 3 had no GER symptoms (Nissen fundoplication group, 2 patients; anterior 90º partial fundoplication group, 1 patient). Overall postoperative exposure to acid pH (<4) was similar for the 2 groups—anterior 90º partial fundoplication group, 2.7% (95% CI, 0.6%-4.8%) and Nissen fundoplication group, 1.6% (95% CI, 0.5%-2.7%). 

While Nissen fundoplication and its various modifications have been in clinical practice for half a century, it continues to be associated with troublesome postoperative adverse effects in a small, but important, proportion of patients who undergo antireflux surgery.¹ Modification to a partial fundoplication has been recommended as a strategy with the potential to yield a better overall outcome. Worldwide, posterior partial fundoplication variants are the more usual surgical approach although anterior partial fundoplication has been gaining support recently.^3,8- 9

The outcomes of 5 prospective randomized trials of Nissen vs posterior partial fundoplication have been reported.^2,10- 13 Three of these demonstrated no difference in outcome, although in each instance the number of patients enrolled was small and the studies were insufficiently powered to demonstrate real differences.^10- 11,13 Hagedorn et al² reported a trial of 137 patients with follow-up extending for more than 10 years. Their study demonstrated a reduction in the gas-related adverse effects following posterior partial fundoplication, although the incidence and severity of dysphagia was not influenced by the surgical technique. In 2002 Zornig et al¹² reported the very early outcomes of a trial of 200 patients that showed a reduction in dysphagia at 4 months after posterior partial fundoplication. However, to our knowledge, longer-term outcomes have not yet been described.

The alternative of anterior partial fundoplication has been described in several articles. An anterior 120° partial fundoplication was reported in 1991 and the initial results of this procedure have been promising.¹⁴ In the laparoscopic era, this procedure was modified by some of us to an anterior 180° partial fundoplication.³ This included sutures that anchored the fundus of the stomach to the right side of the esophageal hiatal rim, a step which was not included in the anterior 120° partial fundoplication procedure. The 180° approach has been validated in a prospective randomized trial of 107 patients, at 6-month³ and 5-year follow-ups.⁴ This trial demonstrated effective GER control and a reduced incidence of dysphagia and other adverse effects following anterior 180° fundoplication. In 2003 Hagedorn et al¹⁵ reported the 12-month follow-up of a trial in which 95 patients were randomized to undergo either an anterior 120° partial fundoplication or a posterior partial fundoplication. The study results suggested that the anterior fundoplication provided less effective GER control than posterior fundoplication. However, the outcome for GER control for the anterior fundoplication in this trial was much worse than has been reported in other studies.^3,14

In an attempt to further reduce the adverse effects of antireflux surgery, some of us initiated laboratory⁶ and early clinical work⁵ to determine whether modification to an anterior 90° partial fundoplication could achieve a durable outcome but with even fewer adverse effects than the previous procedures. Initial testing in a porcine model demonstrated the short-term effectiveness of this approach,⁶ and an initial clinical study demonstrated effective GER control and a low rate of adverse effects.⁵ This supported further evaluation of this technique within a randomized trial. In addition, all previous randomized studies that compared partial with total fundoplication have been single-center studies, and this has limited the generalizability of the outcomes to community practice. For this reason, we commenced this multicenter study.

The results of our trial have demonstrated that the anterior 90° partial fundoplication procedure is followed by fewer postoperative adverse effects than Nissen fundoplication. In particular, the anterior 90° partial fundoplication procedure was associated with less gas-related adverse effects at all follow-up intervals and less dysphagia. While not all differences in the measures of dysphagia reached statistical significance, some did, and the trends for all other measures of dysphagia were toward less dysphagia following the anterior 90° partial fundoplication.

However, this better adverse effect profile was counterbalanced by a higher likelihood of postoperative GER symptoms. In particular, the responses to the direct yes/no heartburn question suggest a higher incidence of GER at 6 months after undergoing an anterior 90° partial fundoplication. However, this is a blunt tool for detecting further GER. It does not discriminate between mild and more troublesome symptoms, and an affirmative answer is not always associated with objective evidence of GER. Furthermore, effective control of GER was achieved for most patients, and the heartburn visual analog scale confirmed this in most patients in both study groups.

When considering the outcome of an antireflux procedure, it is important to consider the patient’s perspective as well as measures of technical success. Measures of overall outcome that balance control of GER against postoperative adverse effects are arguably more important to individual patients. The direct question that asked whether patients believed that they had made the correct decision to have a laparoscopic fundoplication confirmed a high rate of satisfaction 6 months after undergoing anterior 90° partial fundoplication (98%; 59 of 60 patients). This was significantly better than that following Nissen fundoplication. The outcome for the other measure (visual analog satisfaction score) was equally high in both patient groups.

A possible criticism of our trial is that it can be difficult to standardize technical aspects of the surgical procedures across multiple sites. However, this could also be a strength because the multicenter design of this study and the similar number of patients contributed by each surgeon aiming for a quota means that it should be possible to generalize the outcome to community practice with greater confidence. In addition, we endeavored to standardize both operative procedures by discussing techniques at face-to-face meetings and circulating a reference videotape. This ensured that the core aspects of each technique were performed in a similar way. Furthermore, follow-up bias was minimized by performing all follow-up interviews in a masked fashion. For 12 of the 15 surgeons the anterior 90° partial fundoplication was a new operation with the Nissen fundoplication being the operation with which they were most familiar. In other words, if bias exists in this study, it is probably against the anterior 90° partial fundoplication.

The outcome of this trial is similar to the results from the trial of Nissen vs anterior 180° partial fundoplication conducted previously at the Royal Adelaide Hospital,³ that is, there is a trade-off between the risk of adverse effects and the risk of recurrent GER. This tension between opposing outcomes must be weighed when determining what type of fundoplication to apply in clinical practice. The current trial has demonstrated that laparoscopic anterior 90° partial fundoplication provides effective GER control with a low rate of postoperative adverse effects at the 6-month follow-up, and that this technique is associated with a high rate of patient satisfaction. These early outcomes support the continued evaluation of this technique although longer-term follow-up is needed before this procedure can be recommended for routine clinical application.

Correspondence: David I. Watson, MD, Department of Surgery, Flinders University of South Australia, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia (david.watson@flinders.edu.au).

Accepted for Publication: March 16, 2004.

Funding/Support: This study was supported in part by funds from the National Heath and Medical Research Council of Australia, Canberra, and a grant from Astra Upper Gastrointestinal Research through the Royal Australasian College of Surgeons, Melbourne, Australia.

Acknowledgment: We acknowledge the assistance of Nicola Ascott and Tanya Ellis for their invaluable organizational and logistical support.