Utilization of Anti-reflux Treatment and Course of Illness Leading to Reoperation After Anti-reflux Surgery in a National Population-based Cohort
Conditions: GERD, Fundoplication
Sponsor: University of Southern Denmark

07-05-2018 
 
1 
 
Title 
Utilization of anti-reflux treatment and course of illness leading to reoperation after anti-reflux surgery in a 
national population-based cohort.  
Aim 
The purpose of this study is to investigate course of illness leading to reoperation after primary anti-reflux 
surgery and investigate the utilization of anti-reflux treatment, both medical and surgical, in the period 
2000-2017 
Background 
Episodic reflux of gastric contests to the esophagus is physiological but is considered gastroesophageal 
reflux disease (GERD) when accompanied by bothersome symptoms, typically heartburn, regurgitation or 
retrosternal pain. Extra-esophageal symptoms such as asthma, laryngitis and chronic cough may also occur 
(1). GERD is a complex and multifaceted disease (2, 3), affecting 10-20% of the Western population (4) and 
has been shown to significantly reduce the quality of life (5). Worldwide, the prevalence of GERD has been 
increasing (6–8). Treatment of GERD consists of anti-secretory drugs, mainly proton pump inhibitors (PPI), 
or anti-reflux surgery. Laparoscopic anti-reflux surgery is considered standard of care in surgical treatment 
of gastro-esophageal reflux disease (9) and with careful patient selection based on thorough preoperative 
workup (10), symptom control and patient satisfaction are high compared to medical therapy. This has 
previously been demonstrated in meta-analysis (11, 12). 
From 1990-2000 the utilization of anti-reflux surgery in the USA rose to 16.7 procedures per 100.000 
inhabitants with a concomitant rise in the use of the transabdominal laparoscopic approach. This resulted 
in a decline of perioperative mortality and morbidity (13, 14). The rate of anti-reflux surgery dropped to 6.1 
procedures per 100.000 inhabitants in 2010, men the patients were now older with significantly higher 
levels of comorbidity. Despite this, length of stay, morbidity and mortality was reduced even further. The 
laparoscopic approach is used in 80% of American procedures and the rate has not changed during the last 
ten years. It is unknown whether Denmark follows the same trends, as the popularity of anti-reflux surgery 
has been somewhat limited and the surgical setup is different with significantly fewer centers.  
Despite the high success rate of anti-reflux surgery, reoperation does occur. The indication for reoperation 
is most often recurrence of reflux symptoms or dysphagia, and reoperation should be preceded by 
thorough investigation and possible endoscopic balloon-dilation (15). Laparoscopic reoperation is both 
feasible and safe, but has been linked to higher morbidity, higher risk of conversion to open surgery and 
longer length of stay. The final result seem to result in less patient satisfaction than primary surgery, but 
the available evidence is limited by a high risk of bias due to small sample size and a possible 
underreporting of complications (16, 17).  
An American study reported a cumulative five- and ten year incidence of reoperation of 5.2% and 6.9% 
respectively. The rate of reoperation was highest in the first year after primary anti-reflux surgery. 30% of 
reoperations were performed in a different center than the primary procedure. In a Danish study, Funch-
Jensen et al (18), investigated rate of reoperation in Denmark 1997-2005 and calculated a rate of 5% 
without significant differences in length of stay, rate of complications or mortality compared to primary 

07-05-2018 
 
2 
 
surgery. Reoperation was however associated with a higher rate of conversion to open surgery with a 
tendency towards higher rates of conversion in low-volume centers. As in the American study, reoperation 
was often performed at different centers than the primary procedure. Whether this was the result of 
centralization or patient’s wishes is unknown.  
It is our hypothesis, that from 2000-2017, reoperative anti-reflux surgery was performed primarily with a 
laparoscopic approach without increased length of stay or rate of complications compared to primary 
surgery. Due to increased surgical experience the rate of complications is decreasing despite increased 
comorbidity. Endoscopic balloon-dilatation delays reoperation but does not prevent it.  
Methods 
The study is a two-part register-based cohort study based on data from The National Patient Registry, The 
Civic Registry and Danish Anaesthesia Database in the period 1996-2017. The two individual parts of the 
study concerns the same population. 
The population is defined as all adult Danish patients undergoing anti-reflux surgery (Nomesco:  KJBC00, 
KJBC01, KJBC02, KJBW96, KJBW97) from 2000-2017 identified from The National Patient Register.   
Age, sex, Charlson Comorbidity Index at date of surgery and length of stay in relation to any surgery and 
any surgical or endoscopic procedure performed after anti-reflux surgery (including diagnosis 30 days 
postoperatively to establish possible morbidity) are derived from the National Patient Registry.  
ASA-score, weight, height, use of alcohol or tobacco and priority of any surgery (emergency or planned) 
during the study period are retrieved from The Danish Anaesthesia Database. From the Civic Register, data 
on mortality in the study period are retrieved. 
Information on the use of pharmacological treatment for gastroesophageal reflux disease on population 
level is retrieved from MEDSTAT and data on population size on population level are retrieved from 
Statistics Denmark.  
Statistical analysis 
1)  Course of illness leading to reoperative anti-reflux surgery 
Data will be analyzed using STATA15. Descriptive analysis of age, sex, comorbidity (Charlson Comorbidity 
Index, ASA-score, BMI, alcohol/tobacco use), complications to surgery, rate of endoscopic dilation and 
mortality comparing patients with only primary anti-reflux surgery and patients with reoperation during the 
study period, will be performed using Student’s t-test, Chi2-test and Mann-Whitney-U test. 
Logistic regression will be performed with reoperation (laparoscopic, open or other) as primary outcome 
and age, sex, comorbidity (Charlson Comorbidity Index, ASA-score, BMI, alcohol/tobacco use), 
complications to surgery and endoscopic or surgical procedure during study period as independent 
variables. If the number of patients is sufficient, subanalysis will be performed with emergency reoperation 
as dependent variable/outcome.  

07-05-2018 
 
3 
 
Secondary analysis will be performed using Cox-regression investigating time to reoperation with age, sex, 
comorbidity (Charlson Comorbidity Index, ASA-score, BMI, alcohol/tobacco use), complications to surgery 
and endoscopic or surgical procedure during study period as independent variables.  
2) Utilization of treatment of gastroesophageal reflux disease. 
The rate of anti-reflux surgery per 100.000 inhabitants for each year during the study period will be 
calculated using census data from Statistics Denmark. From MEDSAT the rate of use of pharmacological 
anti-reflux treatment per 100.000 inhabitants will be calculated using abovementioned census-data. Trends 
in the utilization of surgery are investigated with trend-analysis in the form of Poisson-regression 
alternatively negative binominal regression.   
Funding and ethical considerations 
The study is part of a ph.d. thesis and is funded by The Region of Southern Denmark, The University of 
Southern Denmark, The Department of Surgery, Kolding Hospital  and The Research Council at Little Belt 
Hospital.  
The study requires no informed consent in Danish law as the study is register-based. However, permission 
from The Danish Data Protection Agency and The Danish Health Data Agency will be obtained before the 
study is commenced.  
None of the involved parties have financial interests or conflicts of interest pertaining to this study.  
References 
1. 
Madanick RD. Extraesophageal presentations of GERD: where is the science? Gastroenterol Clin 
North Am. 2014;43:105-120. 
2. 
Boeckxstaens GE, Rohof WO. Pathophysiology of gastroesophageal reflux disease. Gastroenterol Clin 
North Am. 2014;43:15-25. 
3. 
Herregods TV, Bredenoord AJ, Smout AJ. Pathophysiology of gastroesophageal reflux disease: new 
understanding in a new era. Neurogastroenterol Motil. 2015;27:1202-1213. 
4. 
Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastro-oesophageal reflux disease: 
a systematic review. Gut. 2005;54:710-717. 
5. 
Hansen JM, Wildner-Christensen M, de Muckadell OBS. Gastroesophageal reflux symptoms in a 
Danish population: a prospective follow-up analysis of symptoms, quality of life, and health-care use. 
The American journal of gastroenterology. 2009;104:2394-2403. 
6. 
Friedenberg FK, Hanlon A, Vanar V et al. Trends in gastroesophageal reflux disease as measured by 
the National Ambulatory Medical Care Survey. Dig Dis Sci. 2010;55:1911-1917. 
7. 
El-Serag HB. Time trends of gastroesophageal reflux disease: a systematic review. Clin Gastroenterol 
Hepatol. 2007;5:17-26. 
8. 
Rubenstein JH, Chen JW. Epidemiology of gastroesophageal reflux disease. Gastroenterol Clin North 
Am. 2014;43:1-14. 
9. 
Fuchs KH, Babic B, Breithaupt W et al. EAES recommendations for the management of 
gastroesophageal reflux disease. Surg Endosc. 2014;28:1753-1773. 
10. 
Jobe BA, Richter JE, Hoppo T et al. Preoperative diagnostic workup before antireflux surgery: an 
evidence and experience-based consensus of the Esophageal Diagnostic Advisory Panel. J Am Coll 
Surg. 2013;217:586-597. 
11. 
Rickenbacher N, Kotter T, Kochen MM, Scherer M, Blozik E. Fundoplication versus medical 

07-05-2018 
 
4 
 
management of gastroesophageal reflux disease: systematic review and meta-analysis. Surg Endosc. 
2014;28:143-155. 
12. 
Wileman SM, McCann S, Grant AM, Krukowski ZH, Bruce J. Medical versus surgical management for 
gastro-oesophageal reflux disease (GORD) in adults. Cochrane Database Syst Rev. 2010CD003243. 
13. 
Finlayson SR, Laycock WS, Birkmeyer JD. National trends in utilization and outcomes of antireflux 
surgery. Surg Endosc. 2003;17:864-867. 
14. 
Finks JF, Wei Y, Birkmeyer JD. The rise and fall of antireflux surgery in the United States. Surg Endosc. 
2006;20:1698-1701. 
15. 
Patti MG, Allaix ME, Fisichella PM. Analysis of the Causes of Failed Antireflux Surgery and the 
Principles of Treatment: A Review. JAMA Surg. 2015 
16. 
Furnee EJ, Draaisma WA, Broeders IA, Gooszen HG. Surgical reintervention after failed antireflux 
surgery: a systematic review of the literature. J Gastrointest Surg. 2009;13:1539-1549. 
17. 
Symons NR, Purkayastha S, Dillemans B et al. Laparoscopic revision of failed antireflux surgery: a 
systematic review. Am J Surg. 2011;202:336-343. 
18. 
Funch-Jensen P, Bendixen A, Iversen MG, Kehlet H. Complications and frequency of redo antireflux 
surgery in Denmark: a nationwide study, 1997-2005. Surg Endosc. 2008;22:627-630.