Surgery for Appendicitis: Moving Away From a Simple ‘Yes’ or ‘No’?

Originally published by our sister publication General Surgery News

BOSTON—Appendicitis patients in the United States commonly undergo appendectomy, but European studies have shown that many patients can be successfully treated with antibiotics. At the 2023 Clinical Congress of the American College of Surgeons, experts weighed in on the merits of both, as well as the role of interval appendectomy.

The principal investigator on multiple trials over the last 15 years evaluating nonoperative therapy for acute appendicitis, Paulina Salminen, MD, PhD, FACS (Hon.), a professor of surgery at the University of Turku in Finland, is strongly pro-antibiotics.

“But I’m also pro-surgery. We’re not discussing appendicitis in the context of yes or no—we have two different diseases. I may also be pro-symptomatic therapy, too, because we do have some data, and I’m really for evidence-based medicine,” she said.

The treatment algorithm leading to appendectomy follows the thought that acute appendicitis always leads to perforation, Dr. Salminen said. “But we know that’s not true. We have two different diseases and a lot of gray area, and we need to move from yes and no into differential diagnosis for appendicitis severity.”

Given their assessment that nonoperative therapy is appropriate only for uncomplicated acute appendicitis, Finland’s APPAC trials investigating antibiotics versus appendectomy and varieties of antibiotic approaches exclude patients with perforation, abscess, tumor and appendicoliths.

APPAC I, comparing appendectomy and antibiotic therapy, concluded that surgery was not needed for most patients, as 73% were treated successfully without surgery at one year (JAMA 2015;313[23]:2340-2348). “Also, of the patients initially treated with antibiotics who later had surgery, none had major complications, so antibiotics are a safe first-line treatment,” Dr. Salminen said.

APPAC II, which compared oral antibiotics with IV antibiotics plus oral antibiotics, found no difference between the two groups, also potentially allowing outpatient treatment in the future (JAMA 2021;325[4]:353-362).

In a secondary analysis of prognostic factors of initial nonreponsiveness to antibiotics, the group identified patient temperature greater than 38° C or an appendiceal diameter exceeding 15 mm (JAMA 2024 Apr 17. doi:10.1001/jamasurg.2023.5947). “In our opinion, nonoperative treatment is not for all patients with acute appendicitis, but it seems to be optimal for a selected patient population after ruling out complicated appendicitis,” Dr. Salminen said.

On the topic of symptomatic therapy, Dr. Salminen gave a quick update of APPAC III, a pilot feasibility randomized controlled trial (RCT) comparing placebo and antibiotics in patients with uncomplicated acute appendicitis. Participants achieved the primary end point of treatment success at 10 days in 34 of 35 (97%) of patients in the antibiotic group and 27 of 31 (87%) in the placebo arm (Br J Surg 2022;109[6]:503-509).

“This is a very small number of patients, but throughout other studies and large RCTs the results are consistent, with approximately 70% of patients doing fine without surgery; the key is to rule out complicated acute appendicitis,” she said.

The next trial, APPAC IV, will assess whether antibiotics can be omitted for uncomplicated acute appendicitis, similar to how diverticulitis is now being handled.

“This is the question that needs to be answered before we can have a paradigm shift. I am currently pro-antibiotics and possibly pro-nonoperative therapy for symptomatic treatment, but also pro-surgical treatment for those assessed to have a more complicated course of the disease.”

Surgical Management

A case series published in the 1950s of 471 patients treated conservatively found a recurrence rate of 20%, of whom 16% required an interval appendectomy. The author advocated for conservative treatment to avoid complications associated with surgery, and suggested few patients needed interval appendectomy and that the latter was safe for those who did (Br J Surg 1956;2[5007]:1458-1461). For Benjamin H. Stone, MD, MBA, the study generates three main questions.

“Is it effective therapy for the disease process? Does the long-term data hold up to the gold standard? Would I recommend this for my family? If we practice in that light, we often make the best decisions possible,” said Dr. Stone, an assistant professor at the University of Kansas, in Kansas City.

He noted that some contemporary RCTs have been criticized for how they enrolled patients—that RCT criteria may not reflect real-world decision making. “The NOTA [nonoperative treatment for acute appendicitis] trial used clinical parameters much like we use,” Dr. Stone said. The study, which was not an RCT, found that at seven days, 12% of patients in the antibiotic arm required surgery; at two years, this proportion grew to 17% (Ann Surg 2014;260[1]:109-117).

The CODA trial, a noninferiority RCT looking at general state of health as measured by the EQ-5D (EuroQol 5 Dimension) instrument, found about a 1% difference between patients managed nonoperatively and those who underwent surgery, so it met its primary end point (N Engl J Med 2020;383[20]:1907-1919). But looking at secondary outcomes, 29% failed medical therapy at 90 days. (The failure rate was 41% in those with appendicoliths.)“When this study was published, the ACS posted on their website that antibiotics are equivalent to surgery. But when we do further follow-up, we find approximately 50% of the patients in the antibiotic group eventually required appendectomy,” Dr. Stone said.

In a summary of five RCTs published since 1995 showing one-year recurrence rates of 10% to 25%, Dr. Stone said, “we’re not trying to come up with a new or novel therapy for appendicitis; we’re asking how it compares to our gold standard, and I believe the evidence tells us the gold standard for acute appendicitis remains appendectomy.”

Interval Appendectomy

While the first two talks examined the management of acute uncomplicated appendicitis, Drew Gunnells, MD, a colorectal surgeon and an assistant professor at the University of Alabama at Birmingham, focused mainly on complicated appendicitis and the role of interval appendectomy.

In unstable patients with complicated appendicitis—those who present in extremis with some degree of sepsis—urgent surgery is needed. But about 80% of patients who are stable can forgo an appendectomy during the initial admission.

“Afterward, you see these patients in clinic; they’ve had acute complicated appendicitis, had an appendicolith, had a drain. Who needs the interval appendectomy, and is it necessary? The reason we ask is because the morbidity is not insignificant, with complication rates ranging 12% to 23%, similar to patients operated on immediately. Why wait if the complication rates are similar?” Dr. Gunnells said.

But there are benefits to waiting. After four to eight weeks, the inflammation improves, “and that is a much different operation. It also, obviously, eliminates the recurrence of appendicitis and gives us a more definitive diagnosis ruling out underlying malignancy,” he said.

The recurrence rate of appendicitis after an uncomplicated episode ranges from approximately 20% to 40% when evaluating the five-year follow-up data of the CODA and APPAC trials. The data are not as clear for complicated episodes, as most of these patients received surgical management at some point and many of the studies are small case series. However, the main purpose for interval appendectomy in complicated appendicitis is the risk for malignancy, which can be as high as 29% and increases with patient age, Dr. Gunnells said.

“In our opinion, interval appendectomy should be offered to patients with complicated appendicitis, especially in patients over 65 due the risk of malignancy. In patients with uncomplicated appendicitis, there has to be a more individualized approach. Patients need to understand the recurrence risk, so counseling these patients is paramount.”