Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial

doi:10.1016/S0140-6736(11)60410-8

The Lancet

Volume 377, Issue 9777, 7–13 May 2011, Pages 1573-1579

https://doi.org/10.1016/S0140-6736(11)60410-8 Get rights and content

Summary

Background

Researchers have suggested that antibiotics could cure acute appendicitis. We assessed the efficacy of amoxicillin plus clavulanic acid by comparison with emergency appendicectomy for treatment of patients with uncomplicated acute appendicitis.

Methods

In this open-label, non-inferiority, randomised trial, adult patients (aged 18–68 years) with uncomplicated acute appendicitis, as assessed by CT scan, were enrolled at six university hospitals in France. A computer-generated randomisation sequence was used to allocate patients randomly in a 1:1 ratio to receive amoxicillin plus clavulanic acid (3 g per day) for 8–15 days or emergency appendicectomy. The primary endpoint was occurrence of postintervention peritonitis within 30 days of treatment initiation. Non-inferiority was shown if the upper limit of the two-sided 95% CI for the difference in rates was lower than 10 percentage points. Both intention-to-treat and per-protocol analyses were done. This trial is registered with ClinicalTrials.gov, number NCT00135603.

Findings

Of 243 patients randomised, 123 were allocated to the antibiotic group and 120 to the appendicectomy group. Four were excluded from analysis because of early dropout before receiving the intervention, leaving 239 (antibiotic group, 120; appendicectomy group, 119) patients for intention-to-treat analysis. 30-day postintervention peritonitis was significantly more frequent in the antibiotic group (8%, n=9) than in the appendicectomy group (2%, n=2; treatment difference 5·8; 95% CI 0·3–12·1). In the appendicectomy group, despite CT-scan assessment, 21 (18%) of 119 patients were unexpectedly identified at surgery to have complicated appendicitis with peritonitis. In the antibiotic group, 14 (12% [7·1–18·6]) of 120 underwent an appendicectomy during the first 30 days and 30 (29% [21·4–38·9]) of 102 underwent appendicectomy between 1 month and 1 year, 26 of whom had acute appendicitis (recurrence rate 26%; 18·0–34·7).

Interpretation

Amoxicillin plus clavulanic acid was not non-inferior to emergency appendicectomy for treatment of acute appendicitis. Identification of predictive markers on CT scans might enable improved targeting of antibiotic treatment.

Funding

French Ministry of Health, Programme Hospitalier de Recherche Clinique 2002.

Introduction

Acute appendicitis is still the most common indication for surgery in patients admitted to hospital for acute abdominal pain. In about 20% of cases, acute appendicitis is complicated, leading to local or diffuse peritonitis;¹ most, however, are uncomplicated. Although urgent appendicectomy is still the recommended treatment for acute uncomplicated appendicitis, several studies, including four randomised trials,2, 3, 4, 5 have suggested that antibiotic treatment can cure acute appendicitis or can be the first line of treatment. Design limitations of previous studies, however, have decreased the relevance of their results, and consequently the current strategy for treatment of acute appendicitis has not been altered.⁶ Although emergency appendicectomy is well tolerated by most patients, it is nevertheless associated with a risk of postoperative complications in about 2–23% of patients.7, 8 Additionally, over 10 years, 3% of patients undergoing appendicectomy were readmitted for intestinal obstruction directly related to postoperative adhesions.9, 10 Avoidance of emergency appendicectomy in patients with uncomplicated appendicitis, who otherwise would have had surgery, would therefore improve the risk–benefit ratio of acute-appendicitis treatment. We compared the results of treatment with amoxicillin plus clavulanic acid with emergency appendicectomy in a group of patients with uncomplicated acute appendicitis as assessed by CT.

Section snippets

Patients

We undertook an open-label, non-inferiority, randomised controlled trial. The study took place in six academic centres of the Assistance Publique-Hôpitaux de Paris, France, and was approved by the ethics committee of the Hôpital Bicêtre, Le Kremlin-Bicêtre, France. All patients provided signed, informed consent.

All adults examined in the emergency department and suspected to have an acute appendicitis were assessed for possible inclusion in the study. Patients were excluded if one of the

Results

The figure shows the trial profile. 243 patients (aged 18–68 years) were enrolled into the study between March 11, 2004, and January 16, 2007. Four refused to participate in the trial shortly after randomisation, therefore 239 patients constituted the intention-to-treat population. Table 1 shows baseline characteristics of these patients.

Table 2 shows incidence of primary endpoints and incidence of complicated appendicitis with peritonitis and postoperative peritonitis within 30 days after the

Discussion

Incidence of 30-day postintervention peritonitis, which was the main judgment criterion, was significantly higher in the antibiotic-treatment group than in the appendicectomy group. This study showed that antibiotic treatment with amoxicillin plus clavulanic acid was not non-inferior to emergency appendicectomy for treatment of acute uncomplicated appendicitis.

Trials that show that acute appendicitis can be treated successfully with antibiotics2, 3, 4, 5 were weakened by several design

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Cited by (508)

Is non-operative treatment of acute appendicitis possible: A narrative review
2024, African Journal of Emergency Medicine
Acute appendicitis (AA) represents the most frequent surgical emergency. Perforation was long considered the ultimate outcome of AA, prompting appendectomy; which remains the standard treatment. New data have clarified the role of the appendix, justifying conservative treatment. This narrative review aims to summarize the evidence regarding the non-operative treatment (NOT) of AA in adults.
The literature search was performed via the PubMed Medline database. Our criteria-based selection resulted in a total of 48 articles for review.
Recent trials and meta-analyses have assessed NOT, which support primary antibiotic treatment of uncomplicated AA. Although it has a significant recurrence and failure rate, NOT does not appear to increase the risk of appendicular perforation. Moreover, NOT compared with appendectomy, seems to be associated with less morbidity, lower cost of care and preserved quality of life.
First-line NOT seems to be a reasonable approach for the treatment of uncomplicated CT-confirmed AA. Careful patient screening would definitely enhance the success rate.
Acute appendicitis: A block-randomized study on active observation with or without antibiotic treatment
2024, Surgery (United States)
Antibiotic treatment of unselected patients with acute appendicitis is safe and effective. However, it is unknown to what extent early provision of antibiotic treatment may represent overtreatment due to spontaneous healing of appendix inflammation. The aim of the present study was to evaluate the role of antibiotic treatment versus active in-hospital observation on spontaneous regression of acute appendicitis.
Patients who sought acute medical care at Sahlgrenska University Hospital were block-randomized according to age (18–60 years) and systemic inflammation (C-reactive protein <60 mg/L, white blood cell <13,000/μL), in combination with clinical and abdominal characteristics of acute appendicitis. Study patients received antibiotic treatment and active observation, while control patients were allocated to classic active “wait and see observation” for either disease regression or the need for surgical exploration. According to our standard surgical care, certified surgeons in charge decided whether and when appendectomy was necessary. In total, 1,019 patients were screened for eligibility; 203 patients met inclusion criteria, 126 were accepted to participate, 29 declined, and 48 were missed for inclusion.
The antibiotic group (n = 69) and the control group (n = 57) were comparable at inclusion. Appendectomy at first hospital stay was 28% and 53% for study and control patients (χ², P < .004). Life table analysis indicated a time-dependent difference in the need for appendectomy during follow-up (P < .03). Antibiotics prevented surgical exploration and appendectomy by 72% to 50% compared to 47% to 37% in the control group across the time course follow-ups between 5 and 1,200 days.
Early antibiotic treatment is superior to traditional “wait and see observation” to avoid surgical exploration and appendectomy.
Development and Validation of a Deep Learning and Radiomics Combined Model for Differentiating Complicated From Uncomplicated Acute Appendicitis
2024, Academic Radiology
This study aimed to develop and validate a deep learning and radiomics combined model for differentiating complicated from uncomplicated acute appendicitis (AA).
This retrospective multicenter study included 1165 adult AA patients (training cohort, 700 patients; validation cohort, 465 patients) with available abdominal pelvic computed tomography (CT) images. The reference standard for complicated/uncomplicated AA was the surgery and pathology records. We developed our combined model with CatBoost based on the selected clinical characteristics, CT visual features, deep learning features, and radiomics features. We externally validated our combined model and compared its performance with that of the conventional combined model, the deep learning radiomics (DLR) model, and the radiologist’s visual diagnosis using receiver operating characteristic (ROC) curve analysis.
In the training cohort, the area under the ROC curve (AUC) of our combined model in distinguishing complicated from uncomplicated AA was 0.816 (95% confidence interval [CI]: 0.785–0.844). In the validation cohort, our combined model showed robust performance across the data from three centers, with AUCs of 0.836 (95% CI: 0.785–0.879), 0.793 (95% CI: 0.695–0.872), and 0.723 (95% CI: 0.632–0.802). In the total validation cohort, our combined model (AUC = 0.799) performed better than the conventional combined model, DLR model, and radiologist’s visual diagnosis (AUC = 0.723, 0.755, and 0.679, respectively; all P < 0.05). Decision curve analysis showed that our combined model provided greater net benefit in predicting complicated AA than the other three models.
Our combined model allows the accurate differentiation of complicated and uncomplicated AA.
Is nonoperative management of appendicitis safe and effective in multi-morbid patients?
2024, Surgery (United States)
The purpose of this study was to (1) compare post-treatment outcomes of operative and nonoperative management of acute appendicitis in multi-morbid patients and (2) evaluate the generalizability of prior clinical trials by determining whether outcomes differ in multi-morbid patients compared to the young and healthy patients who resemble prior clinical trial participants.
We conducted a retrospective cohort study using the National Inpatient Sample from 2004 to 2017. We included 368,537 patients with acute, uncomplicated appendicitis who were classified as having 0 or 2+ comorbidities. We compared inpatient morbidity, mortality, length of stay, and costs using propensity scores. Unmeasured confounding was addressed with probabilistic sensitivity analysis.
Overall, 5% of patients without comorbidities were treated nonoperatively versus 20% of multi-morbid patients. Compared to surgery, nonoperative management was associated with a 3.5% decrease in complications (95% confidence interval 3%–4%) for multi-morbid patients, but there was no significant difference for patients without comorbidity. However, nonoperative management was associated with a 1.5% increase in mortality for multimorbid patients (95% confidence interval 1.3%–1.7%). Costs and length of stay were lower for all patients treated with surgery. Probabilistic sensitivity analysis showed that results were robust to the effects of unmeasured confounding.
Our results raise concerns about the generalizability of clinical trials that compared nonoperative and operative management of appendicitis because (1) those trials enrolled mostly young and healthy patients, and (2) results in multi-morbid patients differ from outcomes in younger and healthier patients.
The risks of failed nonoperative management of appendicitis in older adults
2024, American Journal of Surgery
The consequences of failed nonoperative management of appendicitis in older patients have not been described.
We used the 2004–2017 National Inpatient Sample to identify acute appendicitis patients managed nonoperatively (<65 years old: 32,469; ≥65 years old: 11,265). Outcomes included morbidity, length of stay (LOS), inpatient costs, and discharge to skilled facilities. Differences were estimated using propensity scores.
For patients <65, nonoperative failure was associated with increased morbidity (7 % [95 % CI 6.9 %–8.1 %]), LOS (3 day [95 % CI 3–4]), costs ($9015 [95 % CI $8216- $9446]), and discharges to skilled facilities (1 % [95 % CI 0.9 %–1.6 %]) compared to successful nonoperative treatment. Patients ≥65 had differences in morbidity (14 % [95 % CI 13.6 %–16.2 %]), LOS (6 days [95 % CI 5–6]), costs ($15,964 [95 % CI $15,181- $17,708]), and discharges to skilled facilities (12 % [95 % CI: 10.0 %-13.3]) compared to nonoperative success.
Nonoperative management of appendicitis should be approached cautiously for older adults.
Development and Feasibility Testing of a Decision Aid for Acute Appendicitis
2023, Journal of Surgical Research
Patients with acute uncomplicated appendicitis will be increasingly asked to choose between surgery and antibiotic management. We developed a novel decision aid for patients in the emergency department (ED) with acute appendicitis who are facing this choice. We describe the development of the decision aid and an initial feasibility study of its implementation in a busy tertiary care ED.
We conducted a prepost survey analysis comparing patients before and after standardized implementation of the decision aid. Patients were surveyed about their experience making treatment decisions after discharge from the hospital. The primary outcome measure was the total score on the decisional conflict scale (; 0-100; lower scores better).
The study included 24 participants (12 in the predecision aid period; 12 in the post period). Only 33% of participants in each group knew antibiotics were a treatment option prior to arriving at the ED. Prior to implementing the use of decision aid, only 75% of patients reported being told antibiotics were a treatment option, while this increased to 100% after implementation of the decision aid. The mean total decisional conflict scalescores were similar in the pre and post periods (mean difference = 0.13, 95% CI: -13 - 13, P > 0.9).
This novel appendicitis decision aid was effectively integrated into clinical practice and helped toinform patients about multiple treatment options. These data support further large-scale testing of the decision aid as part of standardized pathways for the management of patients with acute appendicitis.

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^‡: These authors contributed equally

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ArticlesAmoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Patients

Results

Discussion

J Gastrointest Surg

Cir Esp

Cir Esp

Am J Surg

Lancet Infect Dis

Disconnect between incidence of nonperforated and perforated appendicitis: implications for pathophysiology and management

Ann Surg

Randomized controlled trial of appendicectomy versus antibiotic therapy for acute appendicitis

Br J Surg

Appendectomy versus antibiotic treatment in acute appendicitis: a prospective multicenter randomized controlled trial

World J Surg

Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients