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.

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

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

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).

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.