Comparing Antibiotics versus Surgery for Treating Appendicitis—The CODA Study [Internet]

Excerpt

Note: The material presented in this abstract previously appeared in the following peer-reviewed publication: CODA Collaborative; Flum DR, Davidson GH, Monsell SE, et al. .. A randomized trial comparing antibiotics with appendectomy for appendicitis. N Engl J Med. 2020;383(20):1907-1919. doi:10.1056/NEJMoa2014320 . Copyright © (2020) Massachusetts Medical Society. Reprinted with permission. 2020 Massachusetts Medical Society

Background: Antibiotics are considered a feasible treatment for appendicitis, yet appendectomy remains the standard in the United States. Previous randomized trials comparing these treatments excluded important subgroups and recruited small sample sizes. As a result, questions remain about the applicability of these previous findings.

Objectives: We conducted the Comparison of Outcomes of antibiotic Drugs and Appendectomy (CODA) randomized clinical trial to compare antibiotics with appendectomy among adults with appendicitis, including those with appendicolith. We recruited a diverse population; compared an overall measure of health status as the primary outcome; and included several secondary clinical and patient-reported outcomes, complications, and measures of health care utilization.

Methods: The CODA trial was a pragmatic, nonblinded, noninferiority, randomized trial comparing antibiotic therapy (10-day course) with appendectomy in patients with appendicitis at 25 US centers. Patients, clinicians, professional societies, and others participated in trial design; IRBs at each site approved the study; participants gave written informed consent. Participants were enrolled from May 3, 2016, to February 5, 2020. Consecutive English- and Spanish-speaking adults (aged ≥18 years) with imaging-confirmed appendicitis in emergency departments (EDs) were approached, including patients with radiographic findings of appendicolith. The consent process included a standardized informational video or pamphlet in English or Spanish. Consenting participants were randomized to treatment stratified by recruitment site and appendicolith status. Those declining randomization were offered participation in an observational study. Antibiotics consisted of intravenous (IV) formulations for at least 24 hours, followed by pills (10-day total). For appendectomy, laparoscopic and conventional (open) surgical approaches were allowed; technique was not standardized. For both arms, the protocol allowed crossover based on participant and clinician decision-making. The primary outcome—30-day health status—was assessed using the EuroQol 5-domain (EQ-5D), a generic health status measure. Secondary outcomes included clinical and safety outcomes and serious adverse events (SAEs—ie, death, life-threatening event, or inpatient hospitalization [excluding for treatment of appendicitis]) were monitored, as were ED and urgent care (UC) visits for related symptoms, ED and hospitalization days related to appendicitis or treatment for appendicitis, and days of missed work (for patients and caregivers). Enrollment of 1552 participants was planned to ensure sufficient power overall (>82%). Using an intention-to-treat framework, we assessed 30-day EQ-5D responses using a linear regression model. To address potential selection bias, we performed a secondary treatment per-protocol analysis of EQ-5D scores and SAEs.

Results: Of 8168 patients screened, 1552 participants (31% of those eligible) were randomized to antibiotics (n = 776) or appendectomy (n = 776). Sociodemographic and clinical characteristics were similar between groups. The mean (SD) 30-day EQ-5D score was 0.92 (0.13) in the antibiotics group vs 0.91 (0.13) in the surgical group (difference, 0.01 [95% CI, −0.001 to 0.03]), consistent with noninferiority. Results were similar in the per-protocol analysis (difference, 0.01 [95% CI, −0.002 to 0.03]). The results for subgroups with and without appendicolith likewise showed noninferiority for primary outcomes. Among antibiotics-assigned patients, appendectomy was performed in 11% by 48 hours, 20% at 30 days, and 29% at 90 days. The 90-day rate of appendectomy was 41% among those with appendicolith and 25% in those without. The percentage with an ED or urgent care visit after initial treatment was 8.9% in the antibiotics group vs 4.3% in the appendectomy group; the percentage with hospitalization after initial treatment (including for eventual appendectomy) was 24% vs 5.2%, respectively. The mean numbers of missed workdays in the antibiotics and appendectomy groups were 5.26 and 8.73, respectively, for participants and 1.33 and 2.04, respectively, for caregivers. There were no deaths, and rates of SAEs per 100 participants were 4.0 (27/676) in the antibiotics group and 3.0 (20/656) in the appendectomy group (rate ratio, 1.29 [95% CI, 0.67-2.50]). Rates of National Surgical Quality Improvement Program morbidity events were 8.1 (antibiotics) and 3.5 (appendectomy) per 100 participants (rate ratio, 2.28 [95% CI, 1.30-3.98]); at least 1 such event occurred in 5.5% and 3.2% of participants, respectively. The higher overall rate per 100 participants with antibiotics was attributable to those with appendicolith (20.2 vs 3.6), not those without (3.7 vs 3.5).

Conclusions: In the short term, antibiotics were not inferior to appendectomy for appendicitis, as assessed by general health status. Among antibiotics-assigned participants, nearly 3 in 10 underwent appendectomy within 90 days, with more subsequent ED visits and hospitalizations. Conversely, more than 7 in 10 participants avoided surgery, many were managed as outpatients, and antibiotics-assigned patients and their caregivers missed less work than did those assigned to appendectomy. Participants with appendicolith treated with antibiotics were at higher risk for both appendectomy and serious morbidity.

Limitations: Only approximately 30% of eligible patients agreed to randomization; the percentage varied by site, which may have introduced selection bias. As a pragmatic trial, the protocol did not specify criteria for hospitalization or a given antibiotic regimen. The study was not blinded, which may have influenced several outcomes. Some surgery-assigned patients declined surgery (n = 49), and some antibiotics-assigned patients underwent appendectomy without meeting protocol criteria for surgery (n = 4) or following recovery (n = 240).

Note: Findings reported in this report have appeared in the following articles. Use has been noted throughout:

1. CODA Collaborative; Flum DR, Davidson GH, Monsell SE, et al. .. A randomized trial comparing antibiotics with appendectomy for appendicitis. N Engl J Med. 2020;383(20):1907-1919. doi:10.1056/NEJMoa2014320

2. CODA Collaborative; Davidson GH, Flum DR, Monsell SE, et al. .. Antibiotics versus appendectomy for acute appendicitis—longer-term outcomes. N Engl J Med. 2021;385(25):2395-2397. doi:10.1056/NEJMc2116018

3. Writing Group for the CODA Collaborative; Monsell SE, Voldal EC, Davidson GH, et al. .. Patient factors associated with appendectomy within 30 days of initiating antibiotic treatment for appendicitis. JAMA Surg. 2022;157(3):e216900. doi:10.1001/jamasurg.2021.6900

4. Writing Group for the CODA Collaborative . Self-selection versus randomized assignment of treatment for appendicitis. JAMA Surg. 2022;157(7):598-608. doi:10.1001/jamasurg.2022.1554

5. Thompson CM, Voldal EC, Davidson GH; Writing Group for the CODA Collaborative . Perception of treatment success and impact on function with antibiotics or appendectomy for appendicitis: a randomized clinical trial with an observational cohort. Ann Surg. Accepted manuscript. Published online July 11, 2022. doi:10.1097/SLA.0000000000005458

6. Davidson GH, Flum DR, Talan DA, et al. .. Comparison of Outcomes of antibiotic Drugs and Appendectomy (CODA) trial: a protocol for the pragmatic randomised study of appendicitis treatment. BMJ Open. 2017;7(11):e016117. doi:10.1136/bmjopen-2017-016117

7. Ehlers AP, Davidson GH, Bizzell BJ, et al. .. Engaging stakeholders in surgical research: the design of a pragmatic clinical trial to study management of acute appendicitis. JAMA Surg. 2016;151(6):580-582. doi:10.1001/jamasurg.2015.5531

8. Ehlers AP, Davidson GH, Deeney K, Talan DA, Flum DR, Lavallee DC. Methods for incorporating stakeholder engagement into clinical trial design. EGEMS (Wash DC). 2017;5(1):4. doi:10.13063/2327-9214.1274