COMMENTARY

Antibiotics Versus Surgery in Appendicitis: New Research Underway

David R. Flum, MD, MPH; Giana H. Davidson, MD, MPH

Disclosures

July 27, 2017

Unresolved Questions Remain on Antibiotic Therapy

In his June 2 commentary on Medscape, Dr Albert Lowenfels reviewed a meta-analysis[1] of appendectomy and antibiotics for appendicitis and concluded that "Antibiotics may have a role to play...but there are still many unresolved questions, indicating that for now surgery will continue to be a dominant treatment strategy."

As surgeon leaders of the Patient-Centered Outcomes Research Institute–funded randomized trial "Comparing Outcomes of Drugs and Appendectomy (CODA),"[2] we appreciate Dr Lowenfels's questions about the current state of the evidence. We also agree that there are significant gaps in knowledge related to the use of antibiotics that need to be addressed before this becomes a part of usual care.[3]

The meta-analysis by Harnoss and colleagues[4] combined eight studies (including randomized, quazi-randomized, and nonrandomized prospective cohorts) involving 2551 patients. They found that while approximately 3 out of 4 patients were successfully treated with antibiotics, there was considerable heterogeneity in rates of antibiotic treatment failure and recurrence between studies (ranging from 0% to 53% for initial failure and 11% to 60% for recurrence by one year). These European studies demonstrate the efficacy and safety of antibiotic therapy, but design flaws, unusual practice patterns (such as prolonged in-hospital convalescence and mandatory open procedures), and missing outcome domains mean that the effectiveness of antibiotics needs to be established in usual clinical practice in the United States.

One finding of the meta-analysis worth highlighting addresses a question that surgeons and the public often pose: whether antibiotic treatment will result in the appendix "bursting" and causing more harm. The meta-analysis did not find this, noting that complication rates at 1 year are similar among the surgical group and the antibiotic group requiring an eventual operation (RR 0.95; 95% CI, 0.35-2.58). Beyond this finding, the evidence gaps remaining are substantial and cannot be addressed without a new clinical trial to determine whether antibiotics are "as good" as appendectomy.

The CODA Trial Focuses on Identifying the Best Approach

CODA is a noninferiority trial with a goal of randomly assigning 1552 patients at up to 16 sites of practice across the United States to either antibiotics or appendectomy for the treatment of most cases of acute appendicitis (including a 500-person observational cohort for comparison). CODA includes adult English- and/or Spanish-speaking patients with the most common type of appendicitis, excluding only those with an abscess or a phlegmon on preoperative imaging that is considered so severe that a simple appendectomy would not be recommended. Of note, patients with suspicion of perforation on preoperative imaging are being included (due to questions about the reliability of imaging in predicting perforation),[5] as are patients with signs of appendicolith, despite their exclusion from some previous studies.

Exclusions for uncommon life-threatening illness, pregnancy, and clinical contraindications such as immunocompromised status and inability to undergo anesthesia means that the CODA trial should be highly generalizable. CODA includes all types of approaches to appendectomy as well as all guideline-concordant[6] antibiotic administration, including the totally outpatient use of antibiotics[7] (similar to the treatment for diverticulitis).

This is considered a pragmatic trial, hopefully offering enough heterogeneity in patient type and practice setting to inform common practice. CODA focuses on both clinical outcomes and patient-reported outcomes including healthcare-related quality of life, work productivity, missed school, future healthcare burden, and decisional regret. The follow-up period is at least 2 years (and as many as 4), but we hope to evaluate patients for a longer period pending future funding.

For Now, Appendectomy Should Be Considered Over Antibiotics

Beyond the existing evidence gaps, there are compelling reasons to hesitate before offering antibiotics to your next patient with appendicitis. Perhaps the best reason is that appendectomy is a safe and effective procedure that is curative of the illness, with advancements in the field of anesthesia and surgery turning a disease that killed so many patients into an hour-long, often outpatient procedure. Until noninferiority (similar to equivalence) is addressed, the clinical community should hesitate to change its approach.

There is also a problematic aspect of nonoperative management that CODA needs to address before antibiotics should be considered for usual care. Evaluations of appendectomy specimens reveal an approximately 1% rate of incidental neoplasm, representing tumors that may be left behind in patients treated with antibiotics. A recent review of 7970 specimens suggests that actual risk may be a bit lower than previously estimated.[8] Among 74 neoplasms (0.9%), 12 were benign tumors and 11 were metastases. Of the remaining 51, only eight were adenocarcinomas (one was lymphoma) and the remainder (n = 42) were carcinoids, putting the rate of new malignancy at 0.6%. The rate of incidental neoplasm may be even lower if, as in the CODA trial, those with evidence of a neoplasm on imaging are excluded from treatment with antibiotics.

What remains to be determined, and is a focus area of CODA, is whether lingering symptoms combined with imaging findings will help identify emerging neoplasms in those who do not undergo appendectomy at the index episode of appendicitis. This is a critical area to consider before antibiotics are offered as part of usual care because, among the 300,000 patients treated for appendicitis each year, a rate of 0.6% unremoved neoplasm would affect close to 2000 people.

Given the existing evidence gaps and real questions about the role of antibiotics in appendicitis, we agree with Dr Lowenfels that appendectomy remain the approach, unless antibiotics are being offered in the context of a research trial. While CODA is in progress (in year 2 of a 5-year study), we encourage patients and clinicians in the United States to remain open-minded about the potential value of antibiotics while at the same time not offering antibiotics for appendicitis as part of usual practice. This brings to mind the observation of Martin Buxton, emeritus professor of health economics at Brunel University, London, that "It is always too early to evaluate a technology until suddenly, it's too late." We hope that the CODA trial can evaluate the important question of noninferiority for antibiotics before this becomes the case.

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