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.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Salminen reports receipt of personal fees for lectures from Merck, Lilly, and Orion Pharma. No other disclosures were reported.

Figures

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-rankP < .001).