Gastroesophageal reflux disease (GERD), commonly with symptoms of heartburn and regurgitation, is a prevalent digestive disorder worldwide [1
]. 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
Several treatment options are available, of which pharmacotherapy, mainly proton pump inhibitors (PPIs), is commonly used [1
]. However, medication only acts to relieve symptoms, which will return if treatment is stopped [1
]. Surgical treatments, on the other hand, aim to target the cause of the reflux [1
]. Laparoscopic Nissen fundoplication (LNF), involving a complete 360° wrap using both anterior and posterior fundic walls, is one of the most used procedures and seen by some as the gold standard [4
]. Alternative approaches commonly used include laparoscopic posterior 270° fundoplication (Toupet fundoplication), laparoscopic anterior 180° fundoplication, and laparoscopic anterior 90° fundoplication [4
Treatment regimens for GERD have been extensively researched [4
], in particular LNF, given the numerous published systematic reviews and randomized controlled trials regarding the procedure [10
]. Reviews have the ability to summarize evidence into knowledge [22
]. However, previous reviews differ markedly in terms of the treatment methods being compared, follow-up, and outcome measurements [10
LNF may cause dysphagia and has mainly been compared with Toupet, intended to reduce dysphagia, without a definite conclusion in the available reviews [14
]. This calls for further comparisons with laparoscopic anterior 90° and 180° fundoplication, with the option to further reduce dysphagia [14
]. Existing reviews have either compared all existing antireflux procedures [8
] or only laparoscopic anterior 180° fundoplication [10
]. To our knowledge, only one study has investigated both degrees in relation to LNF; however, this was not a systematic review [20
LNF and the shorter fundoplication methods (90° and 180°) have been studied in reviews at follow-ups ranging from set timepoints to indefinite or indeterminate periods [8
]. 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
]. 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.
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).
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 I2
interpreted using the thresholds presented 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
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° fundoplication. 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 previous findings, although our focus was on dysphagia for solids [8
]. Unlike the present findings, no differences in medication use were displayed in several studies [9
]. Reflux control in terms of heartburn was reported in previous reviews, where some indicated no differences [9
] and others demonstrated results in favor of LNF [8
]. 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
]. As in the present study, high patient satisfaction, regardless of treatment, was reported in two previous reviews [10
Strengths and limitations of the present study
Bias across studies was not possible to assess and cannot therefore be ruled out [22
]. 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° fundoplication. However, more dysphagia for solids was reported after LNF compared to 90° and 180° fundoplication. 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.
The authors would like to thank Anders Wändahl, Susanne Gustafsson, and Magdalena Svanberg from the Karolinska University Library for their help with the systematic search for relevant records. Further, we would like to thank Jette Möller for her input during the production of the manuscript.
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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.