Laparoscopic Nissen fundoplication versus 90° and 180° fundoplication for gastroesophageal reflux disease

Laparoscopic Nissen fundoplication (LNF) is standard care for surgical treatment of gastroesophageal reflux disease (GERD) in adults. The main disadvantage is the compression of the food passageway, affecting the ability to belch and vomit, and causing swallowing difficulties. Therefore, partial fundoplication methods encircling esophagus as little as 90° and 180° have been developed. Previous studies have been inconclusive. The aim was to assess the effectiveness of LNF compared to laparoscopic anterior 90° and 180° fundoplication. Randomized controlled trials were searched for in MEDLINE, Embase, CINAHL, the Cochrane Library, and Web of Science, and in eligible studies’ reference lists and relevant reviews. Outcomes of interest were 5-year heartburn, medication use, dysphagia, reoperation, and satisfaction. Dichotomous data were calculated as risk ratios (RR). Subgroup analyses were performed to compare each comparator separately with LNF. The meta-analyses were conducted using a random-effects model with an inverse variance statistical method and a significance level of 0.05. Four eligible trials were included with 398 participants, of which half compared LNF with 90°. At 5 years there was higher risk of dysphagia for solids after LNF compared to 90° and 180° fundoplication (RR 1.68 [1.14, 2.49]). However, LNF was associated with a significantly lower risk of medication use compared to laparoscopic anterior 90° fundoplication (RR 0.23 [0.09, 0.58], subgroup analysis). No differences between treatments in terms of heartburn, reoperation, and satisfaction were found. The limited evidence fails to provide an unequivocal method of choice, but rather indicates a trade-off between reflux control and complications.


Introduction
Gastroesophageal reflux disease (GERD), commonly with symptoms of heartburn and regurgitation, is 66 Laparoscopic Nissen fundoplication versus 90°and 180°fundoplication for gastroesophageal reflux disease K review Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the process from identification to inclusion of studies a prevalent digestive disorder worldwide [1][2][3]. Productivity loss and decreased wellbeing are associated with GERD as well as the risk for other conditions such as esophagitis and Barrett's esophagus [2,3].
LNF and the shorter fundoplication methods (90°a nd 180°) have been studied in reviews at followups ranging from set timepoints to indefinite or indeterminate periods [8-10, 12, 19]. This range raises some doubt about the validity of assuming independent events. Furthermore, long-term follow-up at a specific timepoint, such as 5 years after surgery, has seldom been studied. Being an invasive treatment option, it is important to study the long-term outcomes of surgical methods and see whether they stand the test of time.
Performance and safety as well as patient perception of a procedure are important aspects to study. However, previous systematic reviews often included numerous outcomes and, therefore, several statistical analyses [8-10, 12, 19]. A multiple comparisons problem is therefore deemed possible. Methodological choices and inconclusive results from previous research demonstrate the need for a systematic review and meta-analysis that seeks to answer the question about LNF's effectiveness in relation to shorter fundoplication methods for GERD using a few key outcomes measured at a definitive long-term timepoint.

Objective
To assess the effect of LNF for adults with GERD compared to laparoscopic anterior 90°and 180°fundoplication with focus upon reflux control, complications, and satisfaction 5 years after surgery.

Materials and methods
This study adheres to the Cochrane handbook on systematic reviews 5.1.0 [22], with the preregistered protocol PROSPERO (2017 CRD42017075895).

Eligibility criteria
Randomized clinical trial with at least one arm being LNF. Adults (≥ 18 years old) with clinically diagnosed GERD, irrespective of manifestations and medication use, not chronically ill. Intervention and comparison: LNF and 90°and/or 180°laparoscopic anterior fundoplication. 5 years follow-up. Outcome data: reflux control (heartburn and/or PPIs), complications (dysphagia for solids and/or reoperation), and satisfaction being dichotomous or able to convert. Satisfaction was defined as choosing surgery again or believed right to undergo. Full-text article published in English or Swedish in a peer-reviewed journal.

Search methods and selection of studies
Medline (Ovid), Embase, CINAHL, Cochrane Library, and Web of Science were systematically searched by medical information experts at the Karolinska Institutet library to identify relevant studies up to April 2020 (for keywords, see supplementary material). Reference lists of the included studies as well as relevant reviews were scanned for additional references. After removal of duplicates, the authors first independently screened and assessed the eligibility of titles/ abstracts and then of the full-text articles. Excluded studies were stored for future reference, together with reasons for excluding. The study was considered the unit of interest. Disagreement was resolved through discussions.

Data extraction and analysis
The following data were extracted: methods (aim, study period, setting, recruitment, eligibility criteria), participants (number assessed for eligibility and randomized, age, gender), intervention, comparator, outcomes (assessments, timepoint/s, events, sample size). Each study was assessed for bias by both authors using the Cochrane Collaboration's assessment tool [22]. Dichotomous outcome data were collated, and percentages recalculated as numbers. Meta-analyses were performed in Review Manager [23], using risk ratio (RR) as the effect measure in a random-effects model with an inverse variance statistical method, and significance level 0.05. Analyses were performed for each outcome separately, using the available case analysis with no imputation. In case of missing data, or for clarification, study authors were contacted. Subgroup analyses were performed for each outcome measure (dysphagia, mediation use, heartburn, reoperation, satisfaction) to compare laparoscopic anterior 90°fundoplication and laparoscopic anterior 180°fundoplication separately with LNF. This was done to see if an association was found between LNF and both fundoplication methods or LNF and one of the methods. To quantify the effect of heterogeneity, we used I 2 interpreted using the thresholds presented 68 Laparoscopic Nissen fundoplication versus 90°and 180°fundoplication for gastroesophageal reflux disease in the Cochrane handbook [22]. If considerable heterogeneity was identified, subgroup analyses were performed. Bias in meta-analyses was not assessed due to the low number of studies [22,24].

Results
The database search identified 2137 records, an additional 10 were identified through review of references, and 1359 remained after removal of duplicates. After scanning titles and/or abstracts, 120 full-text articles were assessed for eligibility. In total, four studies met the eligibility criteria and were included in this review [25][26][27][28]. Scanning the reference lists of the included studies did not provide any additional studies of interest. The selection process is presented as a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram in Fig. 1.

Included studies
Included studies were published between 2005 and 2012 and the intervention groups included 194 participants and the comparator groups 204 participants (Table 1). Ludemann et al. reported that the fundus during the laparoscopic anterior 180°fundoplication was sutured to the right crus muscle [26]. This was not reported in Cao et al. [25].
The risks of biases are summarized in Fig. 2 and were mostly low except for selective reporting. The assessment of each study was based on the discrepancy between the reported information in the methods and the results sections. Some studies failed to report on outcomes mentioned in the methods section, while others presented results for outcomes which were omitted from the methods. None of the studies were assigned to have a high risk of bias in more than one domain.

Heterogeneity
Most meta-analyses showed an I 2 value 0-25%, indicating that heterogeneity was unlikely to be important 70 Laparoscopic Nissen fundoplication versus 90°and 180°fundoplication for gastroesophageal reflux disease K review Fig. 7 Satisfaction 5 years after treatment. LNF Laparoscopic Nissen fundoplication, IV Inverse variance, CI Confidence interval [22]. An exception was the meta-analysis for medication use, with an I 2 value of 66%, which may represent substantial heterogeneity. However, the two subgroup analyses presented I 2 values of 0%, meaning that the heterogeneity in the overall analysis was most likely explained by the subgroup analyses.

Summary of main results
We found no statistically significant difference in reflux control between LNF and laparoscopic anterior 90°or 180°fundoplication measured by heartburn and PPI use, albeit results in favor of LNF. However, subgroup analysis indicated a significantly lower use of medication after LNF than laparoscopic anterior 90°f undoplication. Furthermore, there was significantly higher risk of dysphagia for solids after LNF than in patients who underwent laparoscopic anterior 90°or 180°fundoplication. Subgroup analysis of LNF versus laparoscopic anterior 90°fundoplication regarding dysphagia showed borderline significant results due to low numbers. Reoperation and satisfaction rates were equivalent between procedures. In summary most differences were between LNF and laparoscopic anterior 90°fundoplication, highly likely related to the evident differences in fundoplication degree.

Quality of evidence
The risk of bias was assessed as unclear in several instances, mostly in the random sequence generation and in outcomes of interest. Included studies provided inadequate information about some important contextual and cultural factors, affecting the generalizability.

Comparison with findings from other studies
To our knowledge, no previous systematic review and meta-analysis has investigated reflux control, complications, and satisfaction at the five-year follow-up in GERD patients who underwent LNF or laparoscopic anterior 90°/180°fundoplication. Our results regarding higher rates of dysphagia are consistent with pre-vious findings, although our focus was on dysphagia for solids [8-10, 12, 19]. Unlike the present findings, no differences in medication use were displayed in several studies [9,10,19]. Reflux control in terms of heartburn was reported in previous reviews, where some indicated no differences [9,10,19] and others demonstrated results in favor of LNF [8,12]. However, these reviews compared LNF to more treatment options than the ones used in the present study. Two reviews reported no differences in reoperation rates, as seen in our results [9,10]. As in the present study, high patient satisfaction, regardless of treatment, was reported in two previous reviews [10,19].

Strengths and limitations of the present study
Bias across studies was not possible to assess and cannot therefore be ruled out [22,24]. A potential major risk of bias is related to selective outcome reporting, since presented results often differed from stated methods.

Implications and conclusion
Ideally, a surgical procedure would have high reflux control and few complications among satisfied patients. When considering the different outcomes of a procedure, the review findings indicate a trade-off between reflux control and complications. At 5-year follow-up, patients who received LNF reported significantly less medication use than those who had 90°f undoplication. However, more dysphagia for solids was reported after LNF compared to 90°and 180°f undoplication. There was not enough evidence to detect significant differences in terms of heartburn, reoperation, and satisfaction after 5 years. The limited evidence fails to provide an unequivocal method of choice for GERD patients, but rather indicates what would be expected, namely a tradeoff between reflux control and complications. The results of the present review suggest that more trials need to be done to provide consistent evidence. review tematic search for relevant records. Further, we would like to thank Jette Möller for her input during the production of the manuscript.
Funding The project was sponsored by Implantica, Zug, Switzerland according to research grant K952211103, providing full data ownership for Karolinska Institutet, Stockholm, Sweden, regarding the content, including data analysis, and the right to publish at any time regardless of the results.

Author Contribution
All authors contributed to the study conception and design as well as the eligibility criteria. The literaturesearchwas performedby experienced, independent, medical information experts from the Karolinska Institutet library, based on a search strategy designed by the information experts in collaboration with the authors. The selection of studies and assessment of risks of bias was performed by both authors. Data extraction and data analysis was performed by Johanna Hoffsten and critically reviewed by Yvonne Forsell. The first draft was written by Johanna Hoffsten and all authors critically revised the work. All authors read and approved the final manuscript.
Funding Open access funding provided by Karolinska Institute.
Conflict of interest J. Hoffsten is a consultant for Implantica, however, Karolinska Institutet has full data ownership as specified in the funding contract. Y. Forsell declares that she has no competing interests.
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