Five-Year Follow-up of Antibiotic Therapy for Uncomplicated Acute Appendicitis in the APPAC Randomized Clinical Trial

Abstract

Importance: Short-term results support antibiotics as an alternative to surgery for treating uncomplicated acute appendicitis, but long-term outcomes are not known.

Objective: To determine the late recurrence rate of appendicitis after antibiotic therapy for the treatment of uncomplicated acute appendicitis.

Design, setting, and participants: Five-year observational follow-up of patients in the Appendicitis Acuta (APPAC) multicenter randomized clinical trial comparing appendectomy with antibiotic therapy, in which 530 patients aged 18 to 60 years with computed tomography-confirmed uncomplicated acute appendicitis were randomized to undergo an appendectomy (n = 273) or receive antibiotic therapy (n = 257). The initial trial was conducted from November 2009 to June 2012 in Finland; last follow-up was September 6, 2017. This current analysis focused on assessing the 5-year outcomes for the group of patients treated with antibiotics alone.

Interventions: Open appendectomy vs antibiotic therapy with intravenous ertapenem for 3 days followed by 7 days of oral levofloxacin and metronidazole.

Main outcomes and measures: In this analysis, prespecified secondary end points reported at 5-year follow-up included late (after 1 year) appendicitis recurrence after antibiotic treatment, complications, length of hospital stay, and sick leave.

Results: Of the 530 patients (201 women; 329 men) enrolled in the trial, 273 patients (median age, 35 years [IQR, 27-46]) were randomized to undergo appendectomy, and 257 (median age, 33 years, [IQR, 26-47]) were randomized to receive antibiotic therapy. In addition to 70 patients who initially received antibiotics but underwent appendectomy within the first year (27.3% [95% CI, 22.0%-33.2%]; 70/256), 30 additional antibiotic-treated patients (16.1% [95% CI, 11.2%-22.2%]; 30/186) underwent appendectomy between 1 and 5 years. The cumulative incidence of appendicitis recurrence was 34.0% (95% CI, 28.2%-40.1%; 87/256) at 2 years, 35.2% (95% CI, 29.3%-41.4%; 90/256) at 3 years, 37.1% (95% CI, 31.2%-43.3%; 95/256) at 4 years, and 39.1% (95% CI, 33.1%-45.3%; 100/256) at 5 years. Of the 85 patients in the antibiotic group who subsequently underwent appendectomy for recurrent appendicitis, 76 had uncomplicated appendicitis, 2 had complicated appendicitis, and 7 did not have appendicitis. At 5 years, the overall complication rate (surgical site infections, incisional hernias, abdominal pain, and obstructive symptoms) was 24.4% (95% CI, 19.2%-30.3%) (n = 60/246) in the appendectomy group and 6.5% (95% CI, 3.8%-10.4%) (n = 16/246) in antibiotic group (P < .001), which calculates to 17.9 percentage points (95% CI, 11.7-24.1) higher after surgery. There was no difference between groups for length of hospital stay, but there was a significant difference in sick leave (11 days more for the appendectomy group).

Conclusions and relevance: Among patients who were initially treated with antibiotics for uncomplicated acute appendicitis, the likelihood of late recurrence within 5 years was 39.1%. This long-term follow-up supports the feasibility of antibiotic treatment alone as an alternative to surgery for uncomplicated acute appendicitis.

Trial registration: ClinicalTrials.gov Identifier: NCT01022567.

Figure 1.. Patient Flow in the Appendicitia Acuta (APPAC) Trial at 5-Year Follow-up

^aIncludes appendicolith, perforation, abscess, or suspicion of tumor. ^bSee Salminen et al. ^cIncludes all adverse events during the entire follow-up period (variable yes/no for complications), ie, patients with a possible complication at previous follow-up are included in the 5-year analysis even if they were not reached by phone (1 patient in the appendectomy group and 10 patients in the antibiotic group).

Figure 2.. Kaplan-Meier Graph for Time to Recurrence After Antibiotic Therapy at 5-Year Follow-up

There were 256 antibiotic group patients available (one death excluded) for assessment of appendicitis recurrence. Of these, 15 underwent appendectomy during the primary hospitalization (ie, nonresponders to antibiotic therapy: 7/15 had complicated acute appendicitis, and 8/15 had uncomplicated acute appendicitis at surgery and histopathology). Of the 85 patients who underwent appendectomy for suspected appendicitis recurrence, 78 had a true recurrence (76 with uncomplicated and 2 with complicated acute appendicitis) and 7 patients did not have appendicitis at histopathology.

Figure 3.. Kaplan-Meier Graph for Time to Recurrence Associated With Visual Analog Scale (VAS) Pain Score at 5-Year Follow-up

The red ticks represent the patients with false-positive surgery after 2-month follow-up (n = 4) (ie, no appendicitis at surgery or histology). Shading around lines indicates 95% CI; n = 212 at 0 months. There were 226 patients in the antibiotic group who had not undergone appendectomy, and VAS at 2 months was available for 212 of these patients (log-rank P < .001).