Preserving or Resecting the Normal Appendix in Patients Undergoing Laparoscopy Surgery for Suspected Appendicitis

Normal Diagnostic Laparoscopy Versus Negative Appendectomy in Patients With a Normal Appendix Undergoing Laparoscopic Surgery for Suspected Appendicitis: a Target Trial

When appendicitis is suspected, patients are typically planned for emergency surgery preferably using a laparoscopic approach. Up to 20% of these patients will have a normal appendix, thus not suffering from appendicitis. Surgeons can either perform a normal diagnostic laparoscopy (leave the appendix in situ) or perform a negative appendectomy (resect the normal appendix). International guidelines recommend negative appendectomy based on weak evidence due to the risk of appendix cancer, but some countries and researchers advocate against negative appendectomy as these patients may experience more harm than if the appendix is left in situ. There are limited national guidelines and the decision is often left to the operating surgeon. Surgeons performing negative appendectomies argue that these prevent microappendicitis and the risk of a subsequent episode of appendicitis. As appendix cancers are rare, and a randomised controlled trial including this subgroup of patients with normal appendices undergoing emergency surgery for suspected appendicitis is unfeasible, an emulated target trial is planned.

This target trial aims to evaluate the effect of a normal diagnostic laparoscopy versus negative appendectomy during laparoscopic surgery for suspected appendicitis regarding cancer in the appendix and other complications such as death, reoperation, and readmission.

Study Overview

• Status: Completed
• Conditions: Neoplasms; Acute Appendicitis; Laparoscopic Appendectomy; Abdominal Pain (AP); Diagnostic Laparoscopy
• Intervention / Treatment: Procedure: Normal diagnostic laparoscopy; Procedure: Negative appendectomy

Detailed Description

The target trial emmulates an unfeasible randomised controlled trial by using observational data to investigate the two treatment strategies (two groups) normal diagnostic laparoscopy versus negative appendectomy when a normal appendix is seen during surgery for suspected appendicitis. The assignment to the treatment strategies during surgery for suspected appendicitis is treated as randomised within the levels of the following baseline covariates; sex, age, year of index surgery, and hospital through inverse probability weighting. We will analyse data according to treatment assignment at baseline (intention-to-treat). Because the treatment strategies in this target trial are surgical, all participants will adhere to the surgical treatment strategy: neither a normal diagnostic laparoscopy nor a negative appendectomy at index surgery can be reversed. However, both may be followed by a reoperation, e.g., a new normal diagnostic laparoscopy or a laparoscopic appendectomy (for suspected appendicitis or stump appendicitis). However, this will not influence analyses but be recorded as an outcome.

As inverse probability weighting has been applied, no further adjustment in the pre-specified analyses below is needed.

The continuous outcome, delay of cancer diagnosis for the normal diagnostic laparoscopy group, will be descriptively reported as mean (SD) or median (IQR).

For dichotomous outcomes, the following analyses are planned:

• Kaplan-Meier curves for each group
• Incidence proportion (risk) including 95% CI for each group
• Relative risk
• Risk difference
• Number needed to treat
• Number needed to harm
• Test chi-square

• Study Type: Observational
• Enrollment (Actual): 20000

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients of all ages undergoing laparoscopic surgery for suspected appendicitis, as recorded in the nationwide Danish National Patient Register, are identified via diagnostic and surgical codes. Information on negative appendectomies is retrieved from the nationwide register of the Danish Pathology Data Bank.

We will use inverse probability weighting to adjust for and minimise bias derived from an imbalance in baseline covariates (sex, age, year of surgery, and hospital).

Description

Inclusion Criteria:

• All ages and sexes
• Undergoing laparoscopic surgery for suspected appendicitis from 2005 to 2021
• Resected appendix without inflammation e.g., without appendicitis

Exclusion Criteria:

• Previous resection of the appendix (e.g., previous appendectomy, or resection of the gut including the appendix before January 1, 2005) based on data from surgical codes in the Danish National Patient Register
• Unable to be tracked in the Danish registers, such as a replacement personal identification number, or for those not residing in Denmark based on data from the Civil Registration System
• Diagnostic codes indicating appendix cancer at index surgery (C181), thus, not operated for suspected appendicitis
• Laparoscopic appendectomy converted to open surgery or other surgical procedures conducted contaminated with laparoscopic appendectomy, indicated a need for other surgical interventions because of disease

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Normal diagnostic laparoscopy group; The appendix is left in situ, e.g. not resected and no other surgical procedure is needed to treat other diseases, identified through both the nationwide Danish National Patient Register and Danish Pathology Data Bank	Procedure: Normal diagnostic laparoscopy; The appendix is left in situ e.g., not resected and no other surgical resection is needed to treat other diseases
Negative appendectomy group; The appendix is resected but is without histopathological inflammation and no other surgical resection is needed to treat other diseases, identified through both the nationwide Danish National Patient Register and Danish Pathology Data Bank	Procedure: Negative appendectomy; The appendix is resected but is without histopathological-confirmed inflammation and no other surgical resection is needed to treat other diseases

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cancer in the appendix	Histopathologically verified cancer in the appendix (primary or metastasis) in the nationwide register the Danish Pathology Data Bank e.g., SNOMED morphology codes for cancer (M8**** or M9****) in relation to the topography code of the appendix (T66000)	2 years
Appendix cancer	Histopathologically verified appendix cancer (primary) in the nationwide register the Danish Pathology Data Bank e.g., SNOMED morphology codes for cancer (M8**** or M9****) in relation to the topography code of the appendix (T66000)	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delay in diagnosis of cancer	Time from index normal diagnostic laparoscopy to histopathologically verified cancer in the appendix in the nationwide register Danish Pathology Data Bank, e.g., SNOMED morphology codes for cancer (M8**** or M9****) in relation to the topography code of the appendix (T66000)	2 years
Death	All-cause death registered in the nationwide The Civil Registration System	2 years
Any reoperation	Any reoperations registered in the nationwide Danish National Patient Register	1 year
Abdominal reoperation	Abdominal reoperations registered in the nationwide Danish National Patient Register e.g., with surgical codes KJ*** (gastrointestinal tract), KK*** (urological), or KL***(gynecological)	1 year
Resected appendix	Histopathological record of an appendix in the nationwide register the Danish Pathology Data Bank e.g., record with topography code of the appendix (T66000) after index surgery, including subdivision of morphology codes into appendicitis, negative appendectomy, appendix cancer, and other	2 years
Readmission	Any readmissions registered in the nationwide Danish National Patient Register, including subdivisions into diagnostic codes relating to different diseases	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subgroup analysis for outcomes at 1 year follow-up	Subgroup analyses of all primary and secondary outcomes at the time-point 1 year after index surgery, including 100% of the included participants in the target trial	1 year
Subgroup analysis for outcomes at 2 years follow-up	Subgroup analyses of all primary and secondary outcomes at the time-point 2 years after index surgery, including 75% to <100% of the included participants in the target trial	2 year
Subgroup analysis for outcomes at 5 years follow-up	Subgroup analyses of all primary and secondary outcomes at the time-point 5 years after index surgery, including as few as 75% of the included participants in the target trial	5 year
Sensitivity analysis on comorbidity	For the secondary outcomes (death (2 years), reoperation, and readmission), confounding due to comorbidity will be explored for patients undergoing index surgery from January 1, 2010, and onwards, thus, allowing for calculating Charlson Comorbidity Index based data in the nationwide Danish National Patient Register from 5 years before to index surgery	1 year
Sensitivity analysis on umeasured confounding	For the primary outcomes, unmeasured confounding e.g., due to preoperative imaging or perioperative macroscopic suspicion of cancer, will be addressed by calculating the E value	2 years

Collaborators and Investigators

• Sponsor: Herlev Hospital
• Collaborators: Danish Institute for Public Health
• Investigators: Principal Investigator: Siv Fonnes, MD, PhD, Herlev Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2005
• Primary Completion (Actual): December 31, 2023
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: April 1, 2025
• First Submitted That Met QC Criteria: April 1, 2025
• First Posted (Estimated): April 8, 2025

Study Record Updates

• Last Update Posted (Estimated): April 8, 2025
• Last Update Submitted That Met QC Criteria: April 1, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Signs and Symptoms, Digestive; Intestinal Diseases; Infections; Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Cecal Diseases; Intraabdominal Infections; Abdominal Pain; Appendicitis
• Other Study ID Numbers: HEH-SF-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The researchers have access to pseudonymised data provided by Statistics Denmark, and according to their rules and guidelines on transfer and data security (https://www.dst.dk/en/TilSalg/data-til-forskning/regler-og-datasikkerhed/regler-for-hjemtagelse-af-analyseresultater) information on individual level cannot be transferred outside Statistics Denmark's researcher machines.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No