Applying Long-term Follow-up to Improve Patient Selection in Laparoscopic Anti-reflux Surgery
Conditions: GERD, Reflux, Gastroesophageal, Surgery
Sponsor: University of Southern Denmark

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Title 
Applying Long-term Follow-up to Improve Patient Selection in Laparoscopic Anti-reflux Surgery 
Aim 
The aim of this study is to use patient-reported and register-based long-term follow-up after anti-reflux 
surgery, to investigate treatment effect and use the results to establish a clinically applicable scoring 
system to ensure optimal selection of patients for surgical treatment of gastroesophageal reflux disease. 
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, 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 (11,12).  
Despite a tailored approach, laparoscopic anti-reflux surgery is not without risks of adverse effects, most 
notably disruption of the fundoplication, post-fundoplication dysphagia and gas-bloat-syndrome, in some 
cases leading to reoperation (13–18). Furthermore non-surgical factors such as pre-existing anxiety or 
depression disorders can influence postoperative satisfaction and symptom relief when compared to 
patients without concomitant psychological disorders (19).    
Although few studies conclude that medical and surgical treatment of GERD have similar effectiveness, 
disease-specific quality of life generally improves after anti-reflux surgery and patient satisfaction is high. 
Depending on surgical procedure, the postoperative quality of life, ranges from significantly increased 
compared to preoperative measurements, to “normal” values as found in subjects devoid of GERD (20–33). 
73-98% are satisfied with their condition after surgery and would choose surgery again (22,32–38).  
Laparoscopic anti-reflux surgery is more effective than medical management with regard to short to 
medium length follow-up (12,34,35). Few studies provide long-term follow-up. After ten years, the benefits 
of surgery seem to decrease, but there is still a significant improvement in quality of life compared to 
preoperative measurements (36,39). Known causes of dissatisfaction are postoperative complication, redo-
fundoplication and developing new bothersome symptoms such as gas-bloat and dysphagia combined with 
inadequate symptom relief (37,40).   
Follow-up of randomized clinical trials have demonstrated, that anti-reflux surgery patients use acid 
suppressing drugs, primarily proton pump inhibitor (PPI) therapy at postoperative follow-up. Use have been 
considered minimal with <20% using PPI-therapy (35) and 27-44% using PPI at five-year follow-up (38). A 
recent register-based study (41), demonstrated a greater number of redeemed prescriptions of proton 

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pump inhibitor after primary anti-reflux surgery, than previously known. Five-, 10- and 15-year risks of long-
term PPI use were 29.4%, 41.1% and 56.6%. However, this register-based study could not examine whether 
patients had objective recurrence of reflux disease and also did not examine indication for treatment as 
well as prescribing physician. From 2001 to 2011, 94,4% of PPI where prescribed in primary care (42) and it 
is unknown why post-fundoplication patients are prescribed PPI. It has previously been demonstrated, that 
the use of acid suppressing drugs after anti-reflux surgery does not necessarily correlate with abnormal acid 
exposure to the esophagus (43,44). In general, the use of PPI has increased rapidly in Denmark, rising 243% 
from 2001 to 2011 despite more restrictive guidelines and changes in reimbursement (42). As the majority 
of proton pump inhibitors are prescribed by general practitioners and not by the surgical centers, surgeons 
have very little knowledge of this aspect of life following anti-reflux surgery.  
This study is part of the PhD project entitled: ”Utilization, outcome and development of laparoscopic anti-
reflux surgery” originating from the University of Southern Denmark (Protokol #: SDUSF-2016-115-(682)). 
Methods and analysis 
The study is a retrospective cohort study utilizing data from patient records and follow-up with patient-
reported quality of life as well as registry-based data. 
Study population 
The study population consists of all adult patients (age 18) having undergone laparoscopic anti-reflux 
surgery (Nomesco Classification of Surgical Procedures (NCSP) (45): KJBC01) from January 1, 2002 to 
December 31, 2013 in The Department of Surgery, Kolding Hospital, a part of Lillebaelt Hospital Denmmark 
(n=557). Patients will be identified through Lillebaelt Hospital’s Patient Administrative System. Day of 
surgery will be considered index date.  
Date of follow-up will be the date, patient filled out quality of life questionnaires as described below. For 
patients deceased since index date, permission to include data from electronic patient records and registry-
based data will be applied for from The Danish Patient Safety Authority.  
All patients will be contacted by the existing Danish national digital communication system (e-Boks) and 
asked to participate in the study. Patients exempt from using the system, will be contacted by letter. Only 
patients providing informed consent will be included in the study. 
Data sources 
Data for the study will consist of electronic patient records, follow-up with patient-reported quality of life 
measurements and registry-based data. 
Electronic patient records 
From the electronic patient records, the following data will be identified: age (years), sex (male/female), 
body mass index (kg/m2), alcohol consumption (drinks of 12g ethanol per week), tobacco use (current, 
former or never-smoker), ASA-score, Charlson Comorbidity Index (CCI) (46) and previous abdominal surgery 
(yes/no).  

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Preoperative endoscopically verified occurrence of hiatal hernia (yes/no), esophagitis (yes/no) will be 
included as well as, from 24-hour pH-measurement and esophageal manometry, reflux-index (%), symptom 
correlation (%) and presence of esophageal motility disorder (hypomotility, normal motility or 
hypermotility). Patients preoperative reflux symptoms defined as typical symptoms (yes/no), atypical 
symptoms (yes/no) and dysphagia (yes/no) are included as are surgical data included duration of surgery 
(minutes), type of fundoplication (270 Toupet/360 Nissen), Length of hospital stay (days), per- and 
postoperative complications registered within 30 days as defined by Clavien-Dindo (47). 
Quality of life follow-up 
Patients will be contacted as described above and asked to answer validated questionnaires regarding 
disease-specific quality of life (GERD-HRQL) (48) and dysphagia (Dysphagia Handicap Index) (49). Patients 
will also be asked if they are currently taking PPI (yes/no), in what dosage (never/when needed/once 
daily/twice daily), which symptoms have warranted PPI-use (reflux 
symptoms/dysphagia/gastritis/preemptive against peptic ulcer disease/other) and which physician 
prescribed the drug (general practitioner/surgeon/other doctor at hospital/other specialist in private 
practice) 
Registries 
All Danish inhabitant are issued with a civil registry number at birth or at date of moving to Denmark. The 
civil registry number are a unique personal identifier and is used across a variety of nationwide databases 
with regards to health, financial and educational data. Data from the following nationwide Danish registries 
will be included in the study:   
The National Patient Registry (NPR) on re-operative surgery (NCSP: KJBC00-02, KJBW96-98, KJBB00-01, 
KJBB96-97) and endoscopy (NCSP: KUJD02-05, KJCA55) during follow-up). NPR contains records of all 
discharge diagnosis since 1977 and all outpatient diagnosis since 1994 (50,51). All performed procedures, 
including endoscopies and surgeries are also registered using NCSP.  
The National Patient Registry of Psychiatry (NPR-PSYK) on psychiatric diagnoses (ICD-10: F01-F99) in a 
two-year period before primary surgery. NPR-PSYK is a sub-registry of NPR and specifically contains records 
of all psychiatric discharge and outpatient diagnosis from psychiatric departments since 1995  (50,51). 
The Civil Registry on marital status, 90-day mortality after primary surgery and all-cause mortality during 
follow-up. The Danish Civil Registry maintains complete records of births, deaths, civic status and 
emigration status of the entire Danish population based on civil registration number (52). 
The Danish National Prescription Registry on use of anti-reflux medication (ATC: A02BA, A02BC, A02BX), 
anti-thrombotic treatment (ATC: B01A), non-steroid anti-inflammatory drugs (NSAID) (ATC: M01A) and 
selective serotonin reuptake inhibitors (SSRI) (ATC: N06AB) in a time period beginning two years before 
surgery and ending at end of follow-up. The Danish National Prescription Registry contains information on 
all sale of prescription drugs including date of sale, Anatomical Therapeutic Chemical Classification (ATC) 
code, civil registration number of buyer and package volume since 1994 (53).  

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Statistics Denmark on educational level at time of primary surgery (54) defined by ISCED (55), occupation 
status (employed/unemployed/retired) (56) and equivalent annual income in the year preceding primary 
surgery (57).  
Primary outcome 
Primary outcome of the study is treatment success or failure, with failure defined for each patient as at 
least one of the following statements being fulfilled: 
1. Having undergone reoperation (NSCP: KJBC00-02, KJBW96-98, KJBB00-01, KJBB96-97) between 
index date and end of follow-up. 
2. Having filled prescription of >60 DDD/year of PPI in any year between index date and end of follow-
up. 
3. Having no measure 3 on GERD-HRQL indicating symptoms being bothersome every day. 
4. Having no measure  4 on Dysphagia Handicap index indicating symptoms being a moderate 
problem. 
Date of failure will be defined as follows: In case of 1), date of failure will be date of reoperation. In case of 
2), date of failure will be date of first prescription filled in the year, where >60 DDD of PPI are filled. In case 
of 3) or 4), date of failure will be end of follow-up.  
Secondary outcomes 
Secondary outcome will be 90-day mortality after primary surgery, rate of reoperation, use of PPI in 
DDD/year, use of PPI at follow-up (including indication and prescribing physician) and Quality of life defined 
by GERD_HRQL, Dysphagia Handicap Index.  
 
Statistical analysis 
Contingency tables 
Contingency tables will be created listing:  
1) Patient characteristics: Age (median), sex (male/female), body mass index (kg/m2), alcohol 
consumption (drinks of 12g ethanol per week), tobacco use (current, former or never-smoker), 
ASA-score, CCI, preoperative psychiatric diagnoses, use of anti-reflux medication (yes/no), NSAID 
(yes/no) and SSRI before surgery (yes/no) and previous abdominal surgery (yes/no), educational 
level at time of primary surgery (ISCED), occupation status (employed/unemployed/retired) and 
equivalent annual income in the year preceding primary surgery. 
2) GERD characteristics: Symptom profile: typical symptoms (yes/no), atypical symptoms (yes/no) and 
dysphagia (yes/no), endoscopically verified occurrence of hiatal hernia (yes/no), esophagitis 
(yes/no), measures from 24-hour pH-measurement and esophageal manometry: reflux-index (%), 
symptom correlation (%) and presence of esophageal motility disorder (hypomotility, normal 
motility or hypermotility). 

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3) Operative characteristics: Duration of surgery (minutes), type of fundoplication (270 Toupet/360 
Nissen), length of hospital stay (days), per- and postoperative complications registered within 30 
days as defined by Clavien-Dindo and 90-day mortality. 
4) Follow-up: Rate of reoperation (%), use of PPI in DDD/year, use of PPI at follow-up (including 
indication and prescribing physician), GERD-HRQL and Dysphagia Handicap Index.  
 
Categorical and continuous variables will be compared using Chi2, Fisher’s Exact Test and Kruskal-Wallis-test 
where appropriate. 
Cox regression 
Cox regression will be performed with treatment success as dependent variable, time to end of follow-up 
(as defined above) and the following variables will be tested and included as independent variables where 
appropriate: Age (median), sex (male/female), body mass index (kg/m2), alcohol consumption (drinks of 
12g ethanol per week), tobacco use (current, former or never-smoker), ASA-score, CCI, preoperative 
psychiatric diagnoses, use of anti-reflux medication (yes/no), NSAID (yes/no) and SSRI before surgery 
(yes/no) and previous abdominal surgery (yes/no), educational level at time of primary surgery (ISCED), 
occupation status (employed/unemployed/retired) and equivalent annual income in the year preceding 
primary surgery, typical symptoms (yes/no), atypical symptoms (yes/no) and dysphagia (yes/no), 
endoscopically verified occurrence of hiatal hernia (yes/no), esophagitis (yes/no), measures from 24-hour 
pH-measurement and esophageal manometry: reflux-index (%), symptom correlation (%) and presence of 
esophageal motility disorder (hypomotility, normal motility or hypermotility), type of fundoplication (270 
Toupet/360 Nissen). 
Clinical scoring system 
Using results from the Cox regression and using the methods for validation described by Steyerberg et al 
(58), a clinical scoring system will be developed with the purpose of identifying probability of treatment 
success based on preoperative known variables. 
Dataflow 
Data collected from electronic patient records and patient-reported quality of life follow-up will be stored 
using RedCAP (REDCap 7.4.23, Vanderbilt University, Nashville, TN, USA) hosted by OPEN - Odense Patient 
Data Explorative Network, Department of Clinical Research, University of Southern Denmark and Odense 
University Hospital, Denmark. Data will be transferred to Statistics Denmark and merged with registry-data. 
All analysis will be performed using STATA15 (StataCorp, College Station, TX, USA) on the servers of 
Statistics Denmark.  
 
Ethics and dissemination 
The study has been approved and registered at Lillebaelt Hospital according to current Danish Law and has 
previously been approved by The Danish Data Protection Agency (Permission #17/1942). Generated 
datasets will be stored on the servers of Statistics Denmark in compliance with Danish and EU-regulations 

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on personal health data and will be anonymized after merging, so that the unique personal identifier is 
removed.  
Permission to contact patient for the project will be obtained from The Danish Patient Safety Agency. Each 
patient must consent to inclusion in the study, including the use of electronic patient records and registry-
based data as described above. For deceased patients, permission for use of electronic patient records and 
registry-based data will be obtained from The Danish Patient Safety Agency. Specific permission for use of 
registry-based data will be obtained from The Danish Health Data Authority and Statistics Denmark. 
The results of the study will be published in peer-reviewed medical journals regardless of whether these 
are positive, negative or inconclusive. Two peer-reviewed articles are expected to come from this study: 
one including the primary results, and one calculating a clinical scoring system based on the results.  

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