In the largest study of surgery versus antibiotics for appendicitis, almost half of patients who received a single course of antibiotics did not require an appendectomy by four years.
Investigators said the results illustrate a need for surgeons and emergency physicians to change the way they talk to patients about treatment options for appendicitis.
They want patients to be given a choice between surgery and antibiotics, following an individualized discussion of the risks and benefits, and patients’ goals and concerns.
“Surgeons have strong opinions about what is the right amount of risk and have not been too open about asking questions about how patients conceptualize the risk of ‘failure,’” said lead investigator David Flum, MD, MPH, a professor and the associate chair of surgery at the University of Washington School of Medicine, in Seattle, referring to the risk that a patient will need surgery after antibiotics.
“But there’s the other side of it, which is to ask patients, ‘What else is going on in your life right now?’” he said. “And it’s remarkable how little, or not, that was part of our training as surgeons to ask these questions.”
Dr. Flum and his co-investigators presented the results, which are the latest data from the CODA (Comparison of Outcomes of antibiotic Drugs and Appendectomy) trial at the American College of Surgeons virtual Clinical Congress 2021. The study was published simultaneously in The New England Journal of Medicine (2020;383[20]:1907-1919).
Researchers randomized 1,552 patients with appendicitis to surgery or antibiotics, which were delivered intravenously for 24 hours and then orally for 10 days. The noninferiority trial included patients with perforation and those with appendicoliths, groups historically considered too at risk to be part of a randomized trial of antibiotics.
Analysis showed that 31% of patients who had antibiotics as a first-line treatment underwent an appendectomy by 90 days, 40% by one year and 49% by four years.
Although most patients underwent an appendectomy for recurrence, 4.5% had surgery for nonclinical reasons such as travel; 14% did not have a known reason.
There were no deaths related to appendicitis or its treatment in the study.
Based partly on the early CODA results and other studies, the ACS changed its guidance for appendicitis treatment in triage guidelines issued for the COVID-19 pandemic last December, calling antibiotics “an acceptable first-line treatment” for most patients with appendicitis.
The investigators said the evidence supports antibiotics as a first-line option for patients, even after the pandemic has ended.
“While some clinicians may find these rates of appendectomy unacceptable, there are conditions where it’s common for patients to select less invasive treatments, even if there’s a probability that surgery may ultimately be needed,” said co-investigator Giana H. Davidson, MD, MPH, an associate professor of surgery at the University of Washington School of Medicine.
“We believe patients with appendicitis, including those with an appendicolith, should be appropriately informed about both treatment options as part of a shared decision-making process.”
Tool Available to Help Patients and Physicians
CODA investigators have developed an online decision-making tool, available at www.appyornot.org.
Available in English and Spanish, the video provides information about treatment risks and benefits, and asks users questions about personal preferences, priorities and resources to help them choose a treatment based on their individual situation.
“Our hope is that a standardized tool that can be easily disseminated across health systems can help patients effectively get information about their diagnosis and clinical outcomes and help facilitate treatment discussions between patients and their surgeons,” Dr. Davidson said.
The online tool is the first stage of part of a planned national program, led partly by the ACS, which will include training support for clinicians and a protocol to standardize appendicitis treatment.
Patients and Surgeons Differ Over Acceptable Failure Rate
At least one study suggests that many patients are interested in trying antibiotics first, even if they are likely to require an appendectomy at some point.
In a report published in the British Journal of Surgery, over 70% of people surveyed said they were willing to try antibiotics if it gave them a 60% chance of avoiding surgery. The study came from a survey of 1,257 American adults who were asked about their willingness to accept the risk for treatment failure (Br J Surg 2021 Aug 17. doi:10.1093/bjs/znab280). Dr. Flum was a co-author of the study.
Some surgeons have said a recurrence rate of even 25% is difficult to justify.
In August, Irish surgeons reported results of a randomized controlled trial, known as COMMA, of 186 patients who received antibiotics or surgery as a first-line approach to appendicitis (Ann Surg 2021;274[2]:240-247).
Within a year, one-fourth of patients in the antibiotic arm experienced a recurrence. Patients treated with antibiotics also had a reduced quality of life compared with those treated with surgery, the investigators reported.
They concluded: “Without a test to exclude patients at high risk of recurrence, it is difficult to justify how antibiotic-only treatment can be routinely recommended for patients with acute uncomplicated appendicitis.”
But CODA investigators said surgeons need to consider that patients may be reluctant to undergo surgery.
Patients’ decisions about treatment are influenced by factors other than long-term surgery risk, they said.
“When we have patients that come in and say, ‘I have kids at home. I don’t have any other caretaker to take care of them,’ or ‘I have a test on Friday and I have to be able to get to that test,’ they’re not thinking just in terms of ‘Will I need an eventual appendectomy?’” Dr. Davidson said. “They’re thinking about what goes into having to cope with needing an urgent or emergent operation at this moment in their life.”
Patients also are concerned about finances related to surgery or time off work. Many patients would prefer to avoid surgery if they don’t have insurance coverage or have a high deductible, Dr. Flum said.
Appendicolith and Appendiceal Diameter Associated With Appendectomy
Patients with an appendicolith who received antibiotics were more likely to require an appendectomy within 48 hours of diagnosis, but this heightened risk did not extend over weeks and months. The hazard ratio for appendectomy among patients with an appendicolith compared with those without was 2.9 within 48 hours (95% CI, 1.9-4.4), but fell to 1.4 from 48 hours to 30 days (95% CI, 0.8-2.4) and 1.1 from 31 days to two years (95% CI, 0.8-1.6).
When asked whether they would still offer antibiotics to patients with an appendicolith, panelists said they would outline the risks but would not rule out antibiotics.
“I don’t think it’s completely off the table to offer these folks a trial of antibiotics if they are well aware of their risks being higher with that appendicolith,” said co-investigator Callie Thompson, MD, an assistant professor of surgery at University of Utah Health, in Salt Lake City.
In an unexpected finding, patients with an appendiceal diameter of at least 10 mm were also more likely to have required surgery after receiving antibiotics. This is the first study to report that wider appendiceal diameter may be a factor contributing to recurrence.
Lillian Kao, MD, MS, a professor and the division chief of acute care surgery at McGovern Medical School at The University of Texas Health Science Center at Houston, called the finding “hypothesis-generating.” It will be explored in further analyses, she said.
Patients in Both Arms Reported Positive Perceptions
Feelings of dissatisfaction and regret were rare, but more common among patients in the antibiotic arm, particularly those who eventually required surgery.
Patients who had surgery initially or those who eventually needed surgery after antibiotics were more likely to experience prolonged time off work. Overall, most patients returned to usual activities within 30 days and missed less than two weeks of work.
Patients reported their health status as measured by the EQ-5D. The EQ-5D survey asks questions in five dimensions related to mobility, self-care, usual activities, pain/discomfort and anxiety/depression. However, outcomes data from the CODA trial are mostly short term: Surveys were available for 97% of patients after one year, 10% at three years and only 5% at four years.
Dr. Thompson said no single factor can predict the success or failure of either antibiotic or surgical treatment for all patients. “It means tailoring treatment recommendations and plans based on an individual patient’s goals and values, which change over time,” she said.
Barriers to Implementation
Dr. Davidson pointed out that the current payment system disincentivizes surgeons to engage in-depth discussions with patients about the risks and benefits of the two approaches. These conversations might take longer than the operation itself, she said.
The investigators also addressed concerns about missed neoplasms in patients who receive antibiotics rather than surgery. In the study, appendiceal neoplasms were identified in nine participants: seven in the appendectomy group and four in the antibiotics group who underwent appendectomy, including two that were discovered since the first report was published in 2020.
Dr. Kao said surgeons need to tell patients that there’s a potential risk for a missed neoplasm when they don’t have surgery.
“You have to arm patients with the best available information, which is what CODA is supplying, and let them judge for themselves,” she said. “But I think it’s a very low rate, and that should not be the primary driver of decision making unless there’s some family history or other concern.”
She said surgeons should consider whether patients have timely access to return to the ER if antibiotic therapy fails. Hospitals will need to put policies in place so patients can receive appropriate care if they return to the hospital in need of surgery, she said.
If a patient has to “sit in the emergency room for six hours again, that’s not improving access,” Dr. Kao said.
Study’s Limitations and Strengths
Many elements of care were not standardized. Surgeons could choose laparoscopic or open surgery, and imaging in the emergency department could be ultrasound or CT. The study did not include patients who had sepsis, recurrent appendicitis, evidence of severe phlegmon on imaging, had free air or abscesses, or were pregnant or immunocompromised. Women were under-recruited in the study.
However, CODA was a pragmatic trial, taking advantage of the way care is delivered in the United States and the effects on normal treatment patterns. It’s the only major trial of surgery versus antibiotics for appendicitis in adults that reflects real-world practice in the United States, Dr. Flum said.
The second-largest trial to date of surgery versus appendectomy, known as the APPAC trial, took place in Europe and did not include high-risk patients. The failure rate for antibiotic therapy among 257 patients was 39.1% over five years, or 100 patients (JAMA 2018;320[12]:1259-1265).