CODA

Clinical Question

In patients with acute appendicitis, does initial therapy with antibiotics or appendectomy result in better outcomes?

Bottom Line

At 90 days after initial treatment, antibiotics alone are non-inferior to appendectomy for the treatment of appendicitis unless the patient had an appendicolith.

Major Points

Appendectomy has been the gold standard for the treatment of acute appendicitis, but recent studies have shown similar efficacy for the use of antibiotics alone, though with many exclusion criteria. The CODA trial broadened their inclusion criteria, specifically including patients with appendicolith, with the aim of making their results more generalizable. In the current paper showing 90-day outcomes, antibiotics alone for the treatment of acute appendicitis were shown to be non-inferior based on the results of a standardized metric of general health status. The antibiotics-only group also had less days of missed work for them and their caregivers. However, this antibiotics-only group did have higher rates of emergency department visits and hospitalizations, as well as a 30% rate of appendectomy after their initial treatment, but this was mostly driven by patients with an appendicolith.

Design

• Multicenter, non-blinded, randomized, controlled trial
• N=1552
  • Antibiotics (n=776)
  • Surgery (n=776)
• Setting: 25 centers in the United States
• Enrollment: May 2016 to March 2020
• Mean follow-up: 90 days (planning to follow for 1 year)
• Analysis: Intention-to-treat and per-protocol
• Primary outcome: 30-day health status, measured using the European Quality of Life-5 Dimensions (EQ-5D) https://euroqol.org/
• Secondary outcomes: Patient-reported resolution of symptoms, serious adverse events, surgical site infections, reactions to antibiotics, Clostridium difficile infections, reoperation, appendiceal perforation at time of operation, appendiceal neoplasm, appendectomy if initially in the antibiotics group.

Population

Inclusion Criteria

• English or Spanish speaking
• Age > 18
• Appendicitis confirmed on imaging in emergency department
• Agree to randomization (those who did not were included in an observational cohort study)

Exclusion Criteria

• Septic shock
• Diffuse peritonitis
• Recurrent appendicitis
• Severe phlegmon on imaging
• Walled-off abscess
• Free air or more than minimal free fluid
• Evidence suggestive of neoplasm

Baseline Characteristics

Antibiotics Appendectomy

• Mean Age: 38.3 + 13.4 37.8 + 13.7
• % Female: 37% 37%
• Race/Ethnicity
  • White: 60% 59%
  • Black: 10% 8%
  • Hispanic: 47% 47%
• Modified CCI Score: 0.24 + 0.53 0.24 + 0.53
• BMI: 29.0 + 6.6 28.6 + 6.1
• Symptom Duration: 1.8 + 3.6 1.6 + 1.6
• Alvarado Score: 6.6 + 1.6 6.7 + 1.7
• Fever: 25% 24%
• Initial WBC: 12,900 + 4000 13,400 + 4100
• Imaging
  • CT alone: 81% 78%
  • Ultrasound alone: 3% 4%
  • >1 imaging test: 16% 18%

Interventions

• Randomized to antibiotics-only or appendectomy
  • Patients in the antibiotics-only group received IV ertapenem, cefoxitin, or metronidazole + ceftriaxone or cefazolin or levofloxacin for either 24 hours or 24 hours of bioavailability
  • Once this IV portion was complete, patients were switched to oral cefdinir or metronidazole + ciprofloxacin for a total 10-day course
  • Appendectomy was recommended if a patient developed diffuse peritonitis or septic shock at anytime, or if their symptoms worsened within 48 hours of initiating antibiotics
  • For the appendectomy group, both open and laparoscopic techniques were allowed and neither were standardized.
• Crossover was allowed based on participant or clinician decision making.

Outcomes

Comparisons are antibiotics alone or appendectomy.

Primary Outcomes

Mean 30-day EQ-5D score

0.92 + .013 vs. 0.91 + 0.13 (difference 0.01 points; 95% CI -0.001 to 0.03)

Secondary Outcomes

All secondary outcomes were reported at 90 days after index treatment:

Any hospitalization after index treatment

24% vs 5%, RR 4.62 (3.21 to 6.65)

Any NSQIP-defined complication per 100 participants

8.1 vs 3.5, RR 2.28 (1.30 to 3.98)

Days in hospital after index treatment

0.68 vs 0.15, RR 4.38 (2.49 to 7.73)

Any visit to emergency department or urgent care clinic after index treatment

9% vs 4%, RR 2.07 (1.32 to 3.25)

Days of missed work for participant

5.26 vs 8.73, RR 0.63 (0.51 to 0.77)

Days of missed work for caregiver

1.33 vs 2.04, RR 0.66 (0.48 to 0.91)

Subgroup Analysis

A subgroup analysis was done for patients with an appendicolith:

Any hospitalization after index treatment

32% vs 5%, RR 6.36 (3.13 to 12.90)

Days in hospital after index treatment

1.15 vs 0.24, RR 4.55 (1.46 to 14.18)

Any visit to emergency department or urgent care clinic after index treatment

8% vs 1%, RR 6.49 (1.50 to 28.09)

Days of missed work for participant

6.14 vs 9.07, RR 0.72 (0.48 to 1.09)

Days of missed work for caregiver

1.77 vs 1.69, RR 1.04 (0.56 to 1.92)

Adverse Events

Cumulative incidence of appendectomy in antibiotics group

48 Hours:

Overall: 0.11 (0.09 to 0.14)

Appendicolith: 0.22 (0.16 to 0.27)

30 Days:

Overall: 0.20 (0.17 to 0.23)

Appendicolith: 0.31 (0.25 to 0.37)

90 Days:

Overall: 0.29 (0.26 to 0.32)

Appendicolith: 0.41 (0.33 to 0.47)

Other Outcomes

96% of appendectomies were performed laparoscopically

Criticisms

• It is not documented whether preoperative or postoperative antibiotics are allowed or were used for the appendectomy group.
  • In the methods section, it states that usual preoperative and postoperative care and discharge criteria was used in the appendectomy group.
• The current paper includes only 90-day follow up data, though the study group is continuing to follow these patients for a total of 1 year.
• Only around 30% of eligible participants agreed to randomization, introducing selection bias.
  • There is an observational cohort of ~500 patients who refused randomization that is currently being studied
• There is potential for significant variability in practice patterns given the lack of protocols regarding hospitalization, the antibiotic regimen, or the operative approach.
• This trial was not blinded, thereby introducing potential confounding with regards to the primary outcome.

Funding

• Funded by a Patient-Centered Outcomes Research Institute Award

Further Reading

• Eriksson S, Granström L. Randomized controlled trial of appendicectomy versus antibiotic therapy for acute appendicitis. Br J Surg 1995;82:166-9.
• Styrud J, Eriksson S, Nilsson I, et al. Appendectomy versus antibiotic treatment in acute appendicitis: a prospective multi-center randomized controlled trial. World J Surg 2006;30:1033-7.
• Turhan AN, Kapan S, Kütükçü E, Yiğitbaş H, Hatipoğlu S, Aygün E. Comparison of operative and non operative management of acute appendicitis. Ulus Travma Acil Cerrahi Derg 2009;15:459-62.
• Hansson J, Körner U, Khorram-Manesh A, Solberg A, Lundholm K. Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients. Br J Surg 2009;96:473-81.
• Vons C, Barry C, Maitre S, et al. Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial. Lancet 2011;377:1573-9.
• Salminen P, Paajanen H, Rautio T, et al.Antibiotic therapy vs appendectomy for treatment of uncomplicated acute appendicitis: the APPAC randomized clinical trial. JAMA 2015;313:2340-8.