Antibiotics versus placebo in adults with CT-confirmed uncomplicated acute appendicitis (APPAC III): randomized double-blind superiority trial.

BACKGROUND: Non-operative management of uncomplicated acute appendicitis is an option, but omission of antibiotics from the regimen has not been tested. METHODS: A double-blind, placebo-controlled, superiority RCT in adults with CT-confirmed uncomplicated acute appendicitis was designed to compare placebo with antibiotics (intravenous ertapenem followed by oral levofloxacin and metronidazole). The primary endpoint was treatment success (resolution resulting in discharge without appendicectomy within 10 days); secondary outcomes included pain scores, complications, hospital stay, and return to work. RESULTS: From May 2017 to September 2020, 72 patients with a mean(s.d.) age of 37.5 (11.1) years were recruited at five hospitals. Six were excluded after randomization (5 early consent withdrawals, 1 randomization protocol violation), 35 were assigned to receive antibiotics, and 31 to receive placebo. Enrolment challenges (including hospital pharmacy resources in an acute-care surgery setting) meant that only the lowest sample size of three predefined scenarios was achieved. The 10-day treatment success rate was 87 (95 per cent c.i. 75 to 99) per cent for placebo and 97 (92 to 100) per cent for antibiotics. This clinical difference of 10 (90 per cent c.i. -0.9 to 21) per cent was not statistically different for the primary outcome (1-sided P = 0.142), and secondary outcomes were similar. CONCLUSION: The lack of antibiotic superiority statistically suggests that a non-inferiority trial against placebo is warranted in adults with CT-confirmed mild appendicitis. Registration number: EudraCT 2015-003634-26 (https://eudract.ema.europa.eu/eudract-web/index.faces), NCT03234296 (http://www.clinicaltrials.gov).

Appendicitis was the most common reason for emergency surgery, but we now know that mild and severe acute appendicitis are two different diseases. Severe appendicitis still necessitates removal of the appendix but antibiotics alone are an option for mild disease. This small study found that most cases of mild appendicitis to resolve even without antibiotics. Larger studies (more patients) would be needed to show that omitting antibiotics is safe and no worse than antibiotic therapy for milder acute appendicitis.

Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin for Treatment of Uncomplicated Acute Appendicitis: The APPAC II Randomized Clinical Trial.

Importance: Antibiotics are an effective and safe alternative to appendectomy for managing uncomplicated acute appendicitis, but the optimal antibiotic regimen is not known. Objective: To compare oral antibiotics with combined intravenous followed by oral antibiotics in the management of computed tomography-confirmed uncomplicated acute appendicitis. Design, Setting, and Participants: The Appendicitis Acuta (APPAC) II multicenter, open-label, noninferiority randomized clinical trial was conducted from April 2017 until November 2018 in 9 Finnish hospitals. A total of 599 patients aged 18 to 60 years with computed tomography-confirmed uncomplicated acute appendicitis were enrolled in the trial. The last date of follow-up was November 29, 2019. Interventions: Patients randomized to receive oral monotherapy (n = 295) received oral moxifloxacin (400 mg/d) for 7 days. Patients randomized to receive intravenous antibiotics followed by oral antibiotics (n = 288) received intravenous ertapenem (1 g/d) for 2 days followed by oral levofloxacin (500 mg/d) and metronidazole (500 mg 3 times/d) for 5 days. Main Outcomes and Measures: The primary end point was treatment success (≥65%) for both groups, defined as discharge from hospital without surgery and no recurrent appendicitis during 1-year follow-up, and to determine whether oral antibiotics alone were noninferior to intravenous and oral antibiotics, with a margin of 6% for difference. Results: Among 599 patients who were randomized (mean [SD] age, 36 [12] years; 263 [44%] women), 581 (99.7%) were available for the 1-year follow-up. The treatment success rate at 1 year was 70.2% (1-sided 95% CI, 65.8% to ∞) for patients treated with oral antibiotics and 73.8% (1-sided 95% CI, 69.5% to ∞) for patients treated with intravenous followed by oral antibiotics. The difference was -3.6% ([1-sided 95% CI, -9.7% to ∞]; P = .26 for noninferiority), with the confidence limit exceeding the noninferiority margin. Conclusion and Relevance: Among adults with uncomplicated acute appendicitis, treatment with 7 days of oral moxifloxacin compared with 2 days of intravenous ertapenem followed by 5 days of levofloxacin and metronidazole resulted in treatment success rates greater than 65% in both groups, but failed to demonstrate noninferiority for treatment success of oral antibiotics compared with intravenous followed by oral antibiotics. Trial Registration: ClinicalTrials.gov Identifier: NCT03236961; EudraCT Identifier: 2015-003633-10.

Risk of Appendiceal Neoplasm in Periappendicular Abscess in Patients Treated With Interval Appendectomy vs Follow-up With Magnetic Resonance Imaging: 1-Year Outcomes of the Peri-Appendicitis Acuta Randomized Clinical Trial.

Importance: The step after conservative treatment of periappendicular abscess arouses controversy, ranging from recommendations to abandon interval appendectomy based on low recurrence rates of the precipitating diagnosis to performing routine interval appendectomy owing to novel findings of increased neoplasm risk at interval appendectomy. To our knowledge, there are no randomized clinical trials with sufficient patient numbers comparing these treatments. Objective: To compare interval appendectomy and follow-up with magnetic resonance imaging after initial successful nonoperative treatment of periappendicular abscess. Design, Setting, and Participants: The Peri-Appendicitis Acuta randomized clinical trial was a multicenter, noninferiority trial conducted in 5 hospitals in Finland. All patients between age 18 and 60 years with periappendicular abscess diagnosed by computed tomography and successful initial nonoperative treatment from January 2013 to April 2016 were included. Data analysis occurred from April 2016 to September 2017. Interventions: Patients were randomized either to interval appendectomy or follow-up with magnetic resonance imaging; all patients underwent colonoscopy. Main Outcomes and Measures: The primary end point was treatment success, defined as an absence of postoperative morbidity in the appendectomy group and appendicitis recurrence in the follow-up group. Secondary predefined end points included neoplasm incidence, inflammatory bowel disease, length of hospital stay, and days of sick leave. Results: A total of 60 patients were included (36 men [60%]; median [interquartile range] age: interval appendectomy group, 49 [18-60] years; follow-up group, 47 [22-61] years). An interim analysis in April 2016 showed a high rate of neoplasm (10 of 60 [17%]), with all neoplasms in patients older than 40 years. The trial was prematurely terminated owing to ethical concerns. Two more neoplasms were diagnosed after study termination, resulting in an overall neoplasm incidence of 20% (12 of 60). On study termination, the overall morbidity rate of interval appendectomy was 10% (3 of 30), and 10 of the patients in the follow-up group (33%) had undergone appendectomy. Conclusions and Relevance: The neoplasm rate after periappendicular abscess in this small study population was high, especially in patients older than 40 years. If this considerable rate of neoplasms after periappendicular abscess is validated by future studies, it would argue for routine interval appendectomy in this setting. Trial Registration: ClinicalTrials.gov identifier: NCT03013686.

A randomised placebo-controlled double-blind multicentre trial comparing antibiotic therapy with placebo in the treatment of uncomplicated acute appendicitis: APPAC III trial study protocol.

INTRODUCTION: Recent studies show that antibiotic therapy is safe and feasible for CT-confirmed uncomplicated acute appendicitis. Spontaneous resolution of acute appendicitis has already been observed over a hundred years ago. In CT-confirmed uncomplicated acute diverticulitis (left-sided appendicitis), studies have shown no benefit from antibiotics compared with symptomatic treatment, but this shift from antibiotics to symptomatic treatment has not yet been widely implemented in clinical practice. Recently, symptomatic treatment of uncomplicated acute appendicitis has been demonstrated in a Korean open-label study. However, a double-blinded placebo-controlled study to illustrate the role of antibiotics and spontaneous resolution of uncomplicated acute appendicitis is still lacking. METHODS AND ANALYSIS: The APPAC III (APPendicitis ACuta III) trial is a multicentre, double-blind, placebo-controlled, superiority randomised study comparing antibiotic therapy with placebo in the treatment CT scan-confirmed uncomplicated acute appendicitis aiming to evaluate the role of antibiotics in the resolution of uncomplicated acute appendicitis. Adult patients (18-60 years) with CT scan-confirmed uncomplicated acute appendicitis (the absence of appendicolith, abscess, perforation and tumour) will be enrolled in five Finnish university hospitals.Primary endpoint is success of the randomised treatment, defined as resolution of acute appendicitis resulting in discharge from the hospital without surgical intervention within 10 days after initiating randomised treatment (treatment efficacy). Secondary endpoints include postintervention complications, recurrent symptoms after treatment up to 1 year, late recurrence of acute appendicitis after 1 year, duration of hospital stay, sick leave, treatment costs and quality of life. A decrease of 15 percentage points in success rate is considered clinically important difference. The superiority of antibiotic treatment compared with placebo will be analysed using Fisher's one-sided test and CI will be calculated for proportion difference. ETHICS AND DISSEMINATION: This protocol has been approved by the Ethics Committee of Turku University Hospital and the Finnish Medicines Agency (FIMEA). The findings will be disseminated in peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: NCT03234296; Pre-results.