November 12, 2020

REBEL Cast Ep 89: The CODA Trial – Antibiotics vs Appendectomy for Appendicitis

Background: The well-established, standard treatment for acute appendicitis is surgical appendectomy.  However, recent research has challenged the dominance of the surgical approach in looking at antibiotics alone. The available literature on non-operative treatment of appendicitis (NOTA) has important limitations: exclusion of patients with appendicoliths, small sample size and predominance of open appendectomy over laparoscopic appendectomy. While data on NOTA is intriguing, it is clear that additional studies are needed.

REBEL Cast Ep89 – The CODA Trial – Antibiotics vs Appendectomy for Appendicitis

Paper: The CODA Collaborative. A Randomized Trial Comparing Antibiotics with Appendectomy for Appendicitis. NEJM 2020. PMID: 33017106

Clinical Question: In adult patients, are antibiotics noninferior to surgery for the treatment of acute appendicitis?

What They Did:

  • Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA)
  • Pragmatic, nonblinded, noninferiority, randomized trial at 25 US centers
  • Patients randomized to:
    • Antibiotics: At least 24 hours of IV antibiotics followed by a 10-day course
    • Surgery: Laparoscopic and conventional (open) appendectomy allowed

Outcomes:

  • Primary: 30d health status (Assessed with the European Quality of Life-5 Dimensions – EQ-5D questionnaire)
    • Focuses on mobility, self-care, usual activities, pain/discomfort, and anxiety/depression
    • Scores range from 0 to 1 with higher scores indicating better health status
    • Noninferiority margin = 0.05 points
  • Secondary:
    • Patient-reported resolution of symptoms (Defined as absence of pain, tenderness and fever)
    • Appendectomy in the antibiotics group
    • National Surgical Quality Improvement Program (NSQIP) – defined complications at the time of the index treatment or during follow up
      • Site related infectious complications (incisional infections or abscesses); Specifically, those requiring percutaneous drainage
      • Reactions to antibiotics
      • Diff infections
      • More extensive procedures (i.e. bowel resection, reoperation, laparotomy, colostomy, or ileostomy)
      • Appendiceal perforation found during an operation
      • Appendiceal neoplasm
    • Complications through 90d
    • Serious adverse events

Inclusion:

  • English- or Spanish-speaking adults (≥18 years of age)
  • Presenting to the ED
  • Acute appendicitis confirmed on imaging
  • In the absence of exclusion criteria, perforation on imaging was not an exclusion criterion

Exclusion:

  • Septic shock
  • Diffuse peritonitis
  • Recurrent appendicitis
  • Evidence of severe phlegmon on imaging (Determined by surgeon that extensive operation such as ileocolectomy likely to be performed)
  • Walled-off abscess
  • Free air or more than minimal free fluid
  • Evidence suggestive of neoplasm
  • Prisoners
  • Immunodeficiency
  • Uncompensated liver failure
  • Taking medication to treat IBD
  • Active treatment for malignancy, not in remission
  • Pregnancy
  • Recent (within 90d) placement of a surgical implant)
  • LVAD
  • Image findings of any of the following
    • Appendiceal soft-tissue mass
    • Imaging features of mucocele or tumor concerning for malignancy
    • Concern for any carcinomatosis on imaging
  • Severe allergy to proposed antibiotics
  • Abdominal/pelvic surgery in past month

 Results:

  • 1552 adults underwent randomization
    • 414 with an appendicolith
  • 30d EQ-5D Questionnaire:
    • Antibiotics: 0.92 +/- 0.13
    • Surgery: 0.91 +/- 0.13
    • Mean difference 0.01 points; 95% CI -0.001 to 0.03
    • Results were similar in the per-protocol analysis (Mean difference 0.01 points; 95% CI -0.002 to 0.03)
  • In the antibiotics group:
    • 11% underwent surgery by 48hrs
    • 20% underwent surgery by 30d
    • 29% underwent surgery by 90 days
    • 41% underwent surgery by 90 days if appendicolith present
    • 25% underwent surgery by 90days if no appendicolith was present
  • NSQIP-Defined Complications:
    • Antibiotics: 8.1 per 100 participants
    • Surgery: 3.5 per 100 participants
    • Rate Ratio 2.28; 95% CI 1.30 to 3.98
  • Complications in Pts with Appendicolith:
    • Antibiotics: 20.2 per 100 participants
    • Surgery: 3.6 per 100 participants
    • Rate Ratio: 5.69; 95% CI 2.11 to 15.38
  • Complications in Pts without Appendicolith:
    • Antibiotics: 3.7 per 100 participants
    • Surgery: 3.5 per 100 participants
    • Rate Ratio: 1.05; 95% CI 0.45 to 2.43
  • No difference in resolution of symptoms by day 7, 14, or 30 between groups
  • The mean number of missed workdays for patients was 5.26d in the antibiotics group and 8.73 in the appendectomy group
  • No deaths in either group 

Strengths:

  • Largest randomized controlled trial investigating NOTA
  • Patients were consecutively enrolled which helps to avoid selection bias
  • Trial was designed to identify outcomes that patients considered to be most important
  • Analyses were prespecified in subgroups according to the presence or absence of an appendicolith
  • Independent data and safety monitoring board reviewed three formal interim analyses were performed annually and did not recommend stopping the trial
  • To address potential selection bias a secondary per-protocol analysis of EQ-5D scores and serious adverse events at 30 days was done
  • Patients that did not undergo randomization were enrolled in an observational cohort or an EMR-only cohort for follow up
  • 90% completion rate of survey at 30d follow up and 86% completion rate of survey at 90d
  • Sociodemographic and clinical characteristics were similar between groups
  • Adherence to antibiotics was 90% among participants in the antibiotics group
  • Broad inclusion criteria reducing chance of selection bias 

Limitations:

  • Unblinded trial with subjective primary outcome may influence the results of the trial
  • Amount of analgesic agents or pain-control medications provided was not standardized or monitored in either treatment group
  • ≈14% lost to follow-up with no additional information
  • 90d follow data may be too short a time to see recurrence rate and long-term complications in the antibiotic group
  • All patients with appendicitis were approached for participation but only 30% of eligible patients agreed to undergo randomization
  • There was no protocol to specify requirements for hospitalization or for a given antibiotic regimen

Discussion:

  • Most common antibiotics in the trial:
    • Initial IV use (at least 24hrs): ertapenem, cefoxitin OR metronidazole plus one of the following…ceftriaxone, cefazolin, levofloxacin
    • For oral use (remainder of 10 total days): metronidazole plus one of the following…ciprofloxacin, cefdinir
  • Authors initially planned to report the results after all participants had at least 1 year of follow up however given the COVID-19 pandemic the results are based on the first 90 days after randomization
  • Although surgeons had the option to perform appendectomy either laparoscopically or open, 96% were performed laparoscopically. In prior studies, open appendectomy was more common, and this procedure is associated with more complications. The predominance of laparoscopic appendectomy is a better reflection of current practice
  • Time to discharge from either the ED or the hospital for index treatment was 1.33d in the antibiotics group and 1.3d in the appendectomy group (i.e. no difference)
  • Percutaneous drainage procedures were more common in the antibiotics group vs appendectomy group overall (2.5 vs 0.5 per 100 participants; rate ratio 5.36; 95% CI 1.55 to 18.50) particularly those with an appendicolith
  • When the analysis was limited to participants in either group who had undergone appendectomy the percentage with a perforation was higher in the antibiotics group vs appendectomy group (32% vs 16%). This higher rate was attributable to those with an appendicolith (61% vs 24%) and not to those without an appendicolith (14% vs 13%)

Author Conclusion: “For the treatment of appendicitis, antibiotics were noninferior to appendectomy on the basis of results of a standard health-status measure.  In the antibiotics group, nearly 3 in 10 participants had undergone appendectomy by 90 days.  Participants with an appendicolith were at a higher risk for appendectomy and for complications than those without an appendicolith.”

Clinical Take Home Point: Although an antibiotic 1st strategy was non-inferior in this trial compared to appendectomy, nearly 3 in 10 patients had undergone appendectomy by 90 days, there were 3x more ED visits, and 2x more complications (This could be balanced with less days of missed work). Patients with an appendicolith are at a much higher risk of complications and need for surgery and in these patients an antibiotic 1st strategy should not be recommended.

References:

  1. The CODA Collaborative. A Randomized Trial Comparing Antibiotics with Appendectomy for Appendicitis. NEJM 2020. PMID: 33017106
  2. Jacobs D. Antibitoics for Appendicitis – Proceed with Caution. NEJM 2020. PMID: 33017105

For More Thoughts on This Topic Checkout:

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)

Cite this article as: Salim Rezaie, "REBEL Cast Ep 89: The CODA Trial – Antibiotics vs Appendectomy for Appendicitis", REBEL EM blog, November 12, 2020. Available at: https://rebelem.com/rebel-cast-ep-89-the-coda-trial-antibiotics-vs-appendectomy-for-appendicitis/.
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Salim Rezaie

Emergency Physician at Greater San Antonio Emergency Physicians (GSEP)
Creator & Founder of REBEL EM
3 Comments
  • Joe Colucci
    Posted at 08:25h, 12 November Reply

    Hi guys – thanks for discussing this trial! Wanted to point out something you may have missed, and that maybe changes your interpretation of the trial. The requirement that folks in the abx arm get 24h of IV abx included single doses of antibiotics with 24h of bioavailability – i.e. a single dose of IV ertapenem. Many sites participating in the trial did this routinely, so 47% of patients in the abx arm were able to go home from the ED, rather than being admitted to the hospital at all.

    If the choice were between going home immediately (after a single dose of IV abx) vs staying in hospital for surgery, 1) would you be more likely to choose antibiotics for yourself, and 2) do you think it changes how you would counsel patients about the options?

    • Salim Rezaie
      Posted at 08:32h, 12 November Reply

      Hey Joe,
      Yes we were aware that 47% of pts got IV abx with 24hr bioavailability. It still doesn’t change my interpretation of the study…

      1. I would still choose laparoscopic appendectomy, even if I could go home the same day
      2. I would still give patients the choice of what they want to do with a shared decision making strategy

      In the end…1/3rd of patients ended up with appendectomy by 90d, 3x more ED visits, and 2x more complications with abx 1st vs laparoscopic appendectomy. Bioavailability aside, these are not very impressive numbers for an illness that has a definitive treatment which is minimally invasive, done all the time, and has very few complications.

      Salim

  • Quiz 91, November 20th, 2020 – The FOAMed Quiz
    Posted at 02:05h, 20 November Reply

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