Appendectomy or Antibiotics for Acute Appendicitis? Latest on the CODA Trial

This transcript has been edited for clarity.

Robert D. Glatter, MD: Hi and welcome. I'm Dr Robert Glatter, medical advisor for Medscape Emergency Medicine.

The well-established standard treatment for acute appendicitis is surgical appendectomy. I think we can all agree on that. It's pretty clear. However, there's been a large amount of research in the past decade that's challenged the dominance of the surgical approach, looking at using antibiotics alone. Many of us are well aware of this.

The literature is really limited by important things. We should talk about these, such as exclusion of patients with appendicolith, a very small sample size, and also the predominance of using an open approach vs a laparoscopic approach. Certainly, the data and the studies are interesting, but we really need more data on this.

This is what the CODA (Comparison of Outcomes of antibiotic Drugs and Appendectomy) trial did. The New England Journal of Medicine study was published in November 2020 and compared antibiotics with appendectomy. The question they were asking was, in adult patients, are antibiotics not inferior to surgery for treatment of acute appendicitis?

Here to join me in this really important discussion is Dr Joseph Sakran, an acute care and trauma surgeon at Johns Hopkins Hospital, and Dr Ali Raja, executive vice chair of emergency medicine at Massachusetts General Hospital, Harvard Medical School.

Welcome, gentlemen.

Joseph V. Sakran, MD, MPH, MPA: Thanks so much for having us.

Ali S. Raja, MD, MBA, MPH: Hi, Rob.

Glatter: It's great to have you. This is such an important discussion to have, obviously, for all emergency physicians, general surgeons, internists — you name it. We're all interested in this, especially with the pandemic hitting. So how do we manage these patients that are rolling in in the midst of COVID?

Ali, I was hoping to start with you. If you could describe what CODA was — the study design and what it was looking at, the outcomes — we'll start off with that.

Raja: Sounds great. Then I'll hand it off to Joe to talk about the rest of it. First of all, sometimes these studies have horrible acronyms and names, but this one actually makes sense. With CODA, it's the Comparison of Outcomes of antibiotic Drugs and Appendectomy. It actually is a perfect title because that's exactly what they did. It was a pragmatic, nonblinded, noninferiority randomized trial. What that means is, it's hard to blind somebody to getting an appendectomy vs getting antibiotics, but obviously this needed to be nonblinded. Robert, you mentioned that the standard really has been getting appendectomies.

This study was not designed to show that one was necessarily better than the other; the goal was to show that antibiotics were noninferior. Then the randomized bit — obviously, they just randomized. It was done at 25 different centers across the US. The two treatment options were either surgery, laparoscopic or conventional — I think in their study, 96% of the surgeries were done laparoscopically, which is different from many of the prior studies — vs antibiotics. There was at least 24 hours of IV antibiotics followed by 10 days of oral antibiotics after that.

In terms of outcomes, they looked at a couple of things. They focused on a 30-day health assessment using the European Quality of Life (EQ-5D), which has five dimensions (I wrote them down): mobility, self-care, usual activities (whatever those usual activities are), pain and discomfort, and anxiety and depression. The scores range from 0 to 1 overall.

Secondarily, they looked at all the stuff we would want them to look at. Did the patients who got the antibiotics end up needing appendectomies later on? Did the patients' symptoms actually get better and any complications and serious adverse events? That's what the trial was about and those are the outcomes they were looking at.

Glatter: Obviously, this is a pretty subjective measure, wouldn't you say?

Raja: It certainly is. How well you're doing your daily activities, how anxious you are. There's a lot of subjectivity built into this.

Glatter: Certainly, it's an unblinded study for that reason. Trying to look at that factor subjectively, someone who's had their appendix out vs not is quite difficult to do. There are some issues as a surgeon assesses them. I think the study was admirable in that sense. I understand why they picked this factor to analyze patients.

Sakran: If I can just build off of what Dr Raja said, because he gave such a nice overview. We've heard a lot over the past decade of these noninferiority trials. To make it very simple, these trials are essentially an attempt to show that the new treatment, which in this case is the antibiotics, is not an unacceptably worse alternative to the standard, which is typically still operative intervention.

When you look at this primary outcome, this 30-day assessment using EQ-5D, which Dr Raja just described, it's very interesting because there is a lot of work right now trying to look at what happens when patients are discharged out of the hospital.

In general, as a system, we don't do a really good job of understanding the long-term or the post-discharge outcomes. Looking at this in a patient-reported outcome measure is actually very interesting. I will say that part of me wondered whether that was the right primary outcome to be evaluated. When you look at some of the secondary outcomes they included in the study — appendectomy in the antibiotic group and complications through 90 days — we don't have anything past 90 days, but it was up until 90 days.

Glatter: No, absolutely. One thing that struck me is that if you're going to stay in the hospital for one day and get IV antibiotics, wouldn't you just want your appendix out? I know the surgeons want to see if you become peritoneal. Certainly, that was a reason in terms of their study design. In my standpoint, I would just like to get the antibiotics, even oral ones, be watched for a few hours, and go home. What is your take on this?

Raja: Dr Glatter, before Dr Sakran talks about the outcomes of the study and everything else, it was fascinating to me that although this was a well-designed study, only 30% of eligible patients agreed to undergo randomization. If they heard, "Oh, well, I'm consenting to this trial. The two arms are: I get my appendix taken out tonight or tomorrow, or I stay in the hospital for IV antibiotics for a night. Well, I wasn't planning to have appendicitis. My schedule is ruined. I don't want to be in the hospital. If one of the options is going home right now on oral antibiotics, maybe I'll do that."

"If both options require me to stay in the hospital for a day or two anyway, why do I want to do this study? Just take my appendix out."

Overall, 70% of patients didn't want to undergo randomization and go into the study. That's probably because of exactly what you just said.

Glatter: Right. I think people expect to have their appendix out. This is something that the community and the world knows — that if you have appendicitis, traditionally this is what we do. Convincing people, that public perception, that shared decision-making, is so important as our studies go forward.

Sakran: I think that's right. Just to build a little bit off what both you and Dr Raja have been articulating around this 1-day admission, what happens next — the self-selection that occurs, and only those 30% actually agreeing to undergo randomization.

If you look at the careful wording in regard to the initial antibiotic course, which was IV antibiotics for 24 hours or "bioavailability," 47% of the antibiotic group were not hospitalized for the index treatment. What that means to me is that even they got something like ertapenem during the initial ED visit, which lasts 24 hours, or they maintained their time in the ED and then were sent out of the ED.

I'm sure Dr Raja has a lot of thoughts about this, but I can just say, as we focus on continuing to rapidly move patients out of the ED as a metric in many institutes, it would be interesting to hear about the feasibility of that if folks were not going to use something that had a 24-hour bioavailability.

I also think that when you look at this study, it is very different in the sense that this was really the first time that we had a study, unlike the European studies, where the predominant intervention was a laparoscopic appendectomy. I think Dr Raja said in 96% of the cases, and that's important for a variety of reasons.

I can just give you my own personal example. For many of my patients with uncomplicated appendicitis, say they come in in the morning; I get them to the operating room, I take out their appendix, and they're discharged that same day. Now, that's not everyone, but that happens quite often. Then that gets us down the road of thinking about hospital stay, costs, further complications, and so forth.

Glatter: Right. I think that's an important thing, if your length of stay is going to be 8-12 hours and you're looking at a day of IV antibiotics, it's a no-brainer. Many patients have life issues and they can't stay in the hospital. That's the other thing. Giving them antibiotics for 24 hours is not reasonable, but then again, an oral antibiotic is something they could put up with. Quality of life and life issues are really important in this choice.

Raja: We have a home hospital program where we send patients home and later on, that day, they're seen by a PA or an NP, or even a hospitalist for some cases. If you really do want them to be hospitalized for 24 hours and if your antibiotic regimen requires that, you can have somebody go to the house and poke on their belly a little bit later that day, just to make sure that they're not getting worse. That's definitely an option, given the hospital overcrowding that we're all dealing with right now.

Glatter: We can agree that if you see an appendicolith, you're less likely to give someone that option of antibiotics, certainly looking at the recurrence rates and the need for operative intervention. We can see that. Plus, there's another issue: older patients who are obese and have a family history of appendiceal cancer. It's a consideration to use a nonoperative or antibiotic approach? Would you agree?

Sakran: When you look at the nonoperative approach, we know that, in general, cancers and tumors of the appendix are extremely rare. The incidence is anywhere from 0.15 to 0.9 per 100,000. We typically see this in individuals between the ages of 50 and 55. They affect men and women equally and they most typically present as appendicitis or sometimes a hernia filled with mucin.

The idea here is that even in the CODA study, nine patients underwent appendectomy who had a neoplasm. The question is, are you willing to potentially miss those cancers? I'm not sure I necessarily have the right answer to that right now, but I would just say that if it was my family member, the answer would probably be no, especially considering the low complications in the majority of patients who undergo a laparoscopic appendectomy. This kind of gets us back to the results of the study; maybe we can take a second to go over those.

The antibiotics in the CODA trial were found to be not inferior to the appendectomy group on the basis of the 30-day EQ-5D. We know that complications were more common in the antibiotic group: 8 vs around 3.5 per 100, for an odds ratio of nearly 2.3. This appears to be coming primarily from the group with an appendicolith, as Dr Glatter mentioned.

The other thing to keep in the back of your mind is that when you look at the antibiotic group, 29% underwent appendectomy by 90 days. When you look at that specifically for those with an appendicolith, that's about 41%. It's very interesting and very different from those who didn't have an appendicolith.

As in everything that we do in medicine, you need to look at the patient that you're taking care of. You have to analyze that patient: Look at their risk factors for surgery, whether they're presenting signs and symptoms, their radiologic imaging, and make the best decision that you can make based on the evidence that you have for the patient.

Glatter: That's a very important point you're making. I'll let Ali chime in in a second on that.

I'd like to also get each of your experience at your institutions. Has there been buy-in to this approach?

Raja: There is not the level of buy-in that you might expect if these data were widely accepted. I'll tell you why. I had a patient a couple of weeks ago where it was a very questionable early appendicitis. He had some tenderness, the CT showed a little bit of stranding, but nothing was enlarged. It was very questionable.

We gave him antibiotics and watched him for a day, and he got better and went home. I don't actually know that he had appendicitis, but we consulted with our surgeons, who were fantastic, and that was the plan we came up with. I'll tell you, the vast majority of these patients are still going to the operating room, at least here.

I'll give you an anecdote. Six months ago, my 8-year-old had appendicitis and it was not a horrible case. His belly just started getting tender and the pain just started localizing. He was in the ED and was seen by one of the surgical residents.

My friend, who is the pediatric surgery attendant who took him to the ER, said, "Look, your son got the appendectomy that a doctor's kid gets, which is very early. This may or may not have been appendicitis, but we're going to go ahead and take the appendix out so that mom or dad feels better about it."

It is not standard practice to just treat patients with real honest-to-goodness appendicitis — even without an appendicolith — with antibiotics rather than surgery, at least in my shop.

Sakran: I would totally agree with Dr Raja. I think he's spot-on. The majority of these patients are going to the operating room and getting their appendix taken out.

Now, there are certain situations or scenarios where we may decide not to do that and attempt a course of antibiotics. But in general, I think Dr Raja nicely described that and that's what is typically done as well at our shop.

Glatter: Certainly someone who is at a high operative risk, an older patient who just can't withstand an operation, that would be something to me that's just antibiotics and observation at that point. Would you agree, Joe?

Sakran: That's exactly how I used to think as well, saying, "Listen, an older patient, a number of different risk factors." I think there is some rule for that. There are some data that are starting to come out. It's not very clear and it's not level 1 evidence yet, but saying that in those patients, maybe you need to be more aggressive because they really can't tolerate a perforation, a drain, back and forth of antibiotics.

The short answer is, we don't know exactly how we should be approaching those. I think you're right, Dr Glatter, that you really have to look at those factors. If their surgical risk is just beyond what you think is the benefit of taking out their appendix, then antibiotics would seem like a reasonable option.

Glatter: Right. Many patients that I've seen say, "What if I get abdominal pain 2 months from now? What if I'm traveling, on a vacation, I'm somewhere in a remote part of the world — what do I do?" I think that fear and anxiety that the pain could come back and they could have appendicitis is a lifestyle issue.

Many of the patients I see who've been offered antibiotics choose no, especially the younger ones and people who are very mobile and really travel quite a bit. Obviously not as much now, but that's my experience. How would you guys react to that?

Sakran: Well, I think you're right. I've had patients that are either executives or students that are going to spend 6 months abroad, and they come in and say, "What do you think? Should I get the antibiotics, or should I just get my appendix taken out? I'm getting ready to travel."

Like we said, most patients go to the operating room. In those cases especially, my recommendation is operative intervention, because the last thing that you want is to be in the middle of a resource-poor setting and you don't have access to high-quality surgical care. It becomes a lot more complicated at that point.

Glatter: In all the studies that I've seen, no one has died, no one has had a ruptured appendix who hasn't had a fecalith. In other words, in stable, nonruptured acute appendicitis, no one's perforated and no one's died, from my experience in reading this literature. That's reassuring that if you're somewhere where you can't have your appendix out, it's safe to get antibiotics and then maybe have an interval appendectomy.

Raja: I think that's right. I think that the important thing to remember is that at least in the CODA trial, they excluded patients who came in late and were really sick. If you were in septic shock, if you had diffuse peritonitis, if you had a walled-off abscess, you weren't even in the study. You're right; if you started off with your general run-of-the-mill appendicitis, you didn't go bad one way or the other after randomization. That's absolutely true.

Glatter: Right. Going forward, I think it's an option. Certainly as practice changes, as people move to different practice settings, there are going to be differences in what becomes "standard of care." It will be interesting over the next few decades how this evolves.

Raja: There are some equity issues here. Dr Sakran, you were just talking about the fact that you might have these students or these folks who are concerned about a delayed appendectomy and not being in a setting with enough resources. They say, "Hey, doc, what do you think I should do? Tell me about this."

The way that we sell this one way or the other, we can talk about the benefits of not having to deal with a surgery right now — getting some antibiotics and going home — or we can talk about the fact that there are going to be these potential delayed appendectomies as a surprise.

When we're having that shared decision-making conversation that's depended so much on the subjective way with which we sell one or the other proposition, it inherently leads to at least the concern of inequity, because the way that we sell it to one person may be very different from the way that we sell it to another person.

Obviously you're all thinking about this as well, but we need to be especially cautious about the way that we speak about the various options to patients who might look different or act different and give them the real, raw data without too much editorialization by ourselves, which I'm definitely prone to at times.

Sakran: That's absolutely correct. I think that's such an important point, Dr Raja. We know health inequity exists all across our country and all through our different healthcare systems, regardless of whether you're in Baltimore or Boston. Being cognizant of this and ensuring that there is a lens on everything that we approach, in order to achieve a more equitable delivery of healthcare, is so critical. Thank you for reemphasizing that.

The other point I was going to make is that we don't have long-term data from this CODA trial. When you look at the 5-year follow-up that was done from APPAC (Appendicitis Acuta trial), essentially 40% ended up needing an appendectomy over a 5-year period. It's almost like a coin toss.

Dr Glatter, the way you started off the conversation was really nice in the sense that we probably still need more data. I think we're starting to hone down that maybe a certain portion of these patients could be managed nonoperatively, safely, with minimal recurrence. Maybe there's a subsegment of that population that still requires operative intervention. I think time will tell.

Glatter: Well, it's almost like biliary colic. It's not exactly the same, but it kind of occurred to me: They come in, they're noninfective, we manage their pain. Sometimes they get a dose of antibiotics, they go home, and they get followed up for operations. But in the same vein, this is almost how I think this is evolving. Would you tend to agree or do you see any parallels?

Sakran: We see a ton of patients with biliary colic. When you look at biliary disease in general, the people are coming in with acute cholecystitis. They're inflamed and they clearly have an acute gallbladder. Those patients are being admitted and it's being taken out during that hospital stay.

The second group that I think of includes those with gallstone pancreatitis. In general, those patients should be admitted and have their gallbladder taken out, because we know that 50% of those patients will come back in 4-6 weeks with another bout of pancreatitis that's probably even worse.

Now, biliary colic is a very good example. These are patients with a noninflamed gallbladder. If their pain is controlled, they can be sent out with minimal pain control and then return and follow up in the general surgeon's office or set up for evaluation and potential removal. About 10% of the population has cholelithiasis. Some patients go through their entire life without any issues and some have significant pain that is debilitating. That's how I manage those groups of biliary disease. I think there are some similarities, as you're alluding to.

Glatter: Yes, it just kind of struck me. I think we're kind of a ways from that; it's just a thought. I want to wrap up and maybe get a few pearls from each of you. Ali, if you want to start.

Raja: Absolutely. There are two main takeaways for my practice in the ED. The first is that we routinely used to tell patients, "You've been diagnosed with appendicitis. Let me tell you about what the plan is. The plan is going to be that the surgical team will come down and see you, and your surgeon will talk to you about the operation. We'll get your operation done first thing in the morning if you come in the middle of the night, or maybe later today if you come in early this morning."

Leaving the door open for shared decision-making with the surgical team about antibiotics is going to be key for those of us who practice emergency medicine, simply because of the fact that if we bias our own patients toward surgery, we make it even less likely that even in those patients for whom antibiotics are very appropriate, that they'd be willing to accept that. First of all, we need to not bias our patients one way or the other.

The other thing is that we need to be ready for that 20%-40% of patients who got treated with antibiotics some time ago — not 5 years in all cases, but within 90 days as it was in the CODA trial — who come back in and say, "You know that pain that I had about 2 months ago when I got the antibiotics? I'm really worried that it might be appendicitis." There's a good chance that it might be again. We just need to be aware that those patients, many of them, will come back with a repeat appendicitis.

Glatter: Great. Joe?

Sakran: Those are such great points. We do sometimes tend to have a certain way that we think this should be managed. I think presenting the evidence in an objective way and tailoring it to the patient that you have, and giving them the pros and cons, is so critical.

Also, be considerate of the fact that if you do end up managing patients with nonoperative appendicitis, especially if they're older, if they're above the age of 50, they probably need a colonoscopy to ensure that there is no obvious cecal neoplasm.

Again, those data are still playing out as to how we're specifically going to approach those individuals. That's critical because there are, even if it's a small majority, a proportion of patients that will have a neoplasm and the presenting piece with the appendicitis.

Glatter: Absolutely. These are great pearls. I want to thank both of you. This is such an informative discussion that really helps us go forward, because this is one of the most common things all of us see in our everyday practice. Thank you again.

Raja: Thanks.

Sakran: Thanks so much for having us.

Robert D. Glatter, MD, is an attending physician at Lenox Hill Hospital in New York City and assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is an editorial advisor and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes.

Joseph V. Sakran, MD, MPH, MPA, is a director of emergency general surgery and assistant professor of surgery at Johns Hopkins University in Baltimore, Maryland. Sakran's interest in medicine stems partly from having nearly lost his life after a gunshot wound to the throat during his senior year of high school, and he has subsequently dedicated his life to making a social impact to curb gun deaths.

Ali S. Raja, MD, MBA, MPH, is associate professor of emergency medicine and executive vice chair at Massachusetts General Hospital in Boston, Massachusetts. A practicing emergency physician and author of over 200 publications, his federally funded research focuses on improving the appropriateness of resource utilization in emergency medicine.

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Cite this: Robert D. Glatter, Joseph V. Sakran, Ali S. Raja. Appendectomy or Antibiotics for Acute Appendicitis? Latest on the CODA Trial - Medscape - Mar 09, 2021.