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Hello, everyone. Today we will have a journal club on the paper called and under mice. Trial comparing antibiotics was are conducted before appendicitis by the code a collaborative. Why did we choose this paper? It is because it's a current nice guidelines. Um, the removal of the appendix is the gold standard treatment for the uncomplicated appendicitis, and these have been based on multiple research for multiple societies worldwide. So the ground of this paper appendectomy has been a golden standard for a very long time. There have been several studies looking at the antibiotics. However, those studies excluded important subgroups such as appendical lease, and it's been proven that appendical ease. They have a more complicated appendicitis, and those studies have also had small sample sizes. So what the quarter collaborative did? They conducted a randomized trial to compare antibiotic therapy with appendectomy in adults with appendicitis, and they've included those who have appendical iss. Initially, the plan was to report results after one year follow up, but the covid pandemic started, and the covid interest has grown. So they reported the outcomes only after the 1st 90 days of the follow up, which can raise some questions the methods. Um, the hypotheses was that the antibiotics are non inferior to the appendectomy for the patient related outcomes, and that there are subgroups with better outcomes. For example, uh, appendicolith or non appendicolith subgroups. So they've, uh, used one university and 25 clinical sites. They designed the methodology according to the engagement of the patient stakeholders, so the patient's have been involved in the design of the trial. It was pragmatic, non blinded noninferiority under mice trial inclusion criteria. They've included everyone above the age of 18, including 18 English and Spanish speaking, who presented emergency department with appendicitis that has been confirmed by the imaging CT, or ultrasound, or MRI. And they also took an appendical is as a separate subgroup. They've excluded those who have had a septic shock, diffuse peritonitis, recurrent appendicitis, severe flagman, meaning the extended surgery may be needed. World of abscesses, free air of fluid or neoplasms random ization. So the participants were randomly assigned to the treatment group by the Data Coordinated Center. How it happened. It was performed in the blocks the random blocks of 46 or eight people, and it was certified according to the recruitment side and a particular status, so overall it has been pretty random. However, this random ization has been controlled. Um, and it's been determined by the treatment center and by the presence of appendical ISS or absence. But overall pretty random. The two treatment groups Antibiotics Group and Appendectomy Group in Antibiotics Group people received IV antibiotics for at least 24 hours that were followed up by the oral antibiotics for a total of 10 days. The guidelines on antibiotic use were published in surgical infection society infectious disease. So knowing that, for example, in the UK each trust had its own antibiotic policy, I would think that there have been some differences in the way of which antibiotic were used because the study haven't reported it at all. That can give us some variability. And the discharge criteria they used for antibiotic group is the people should have intake of liquids without difficulty, adequate pain control and improving clinical condition. So appendectomy was performed that there was the diffused peritonitis, septic shock, worsening signs and symptoms. However, this criteria we're not required to be met, so there were no standardization of either discharge or proceeding to appendectomy in a project in my group, either laproscopic or open was used again. The technique was not standardized and usual, preoperative and postoperative care and discharge criteria were used again. Nothing has been mentioned. What, exactly is the usual preoperative and postoperative care, and how the discharge has been decided upon analgesic to was not standardized or monitored. And the protocol, most importantly, this one. The protocol allowed for cross over on the basis of participant and clinical decision making so people could enter each other groups based on their wish. The outcomes. I looked at the protocol published and compare the outcomes from the protocol with the outcomes reported by the study. In the primary outcomes, they looked at the quality of life. Five dimension to it's called E Q five GM at the 30 days I'll later show you these two and what these two involves. Secondary outcomes. They looked at major complications or resolution of symptoms by four weeks. Eventual appendectomy pain or narcotic use, which, by the way, has not been standardized. Recurrent episode of appendicitis. Emergency department visits for abdominal pain or repeat imaging. Need for more complicated surgical procedure. Uh, there are so the one outcome that they haven't reported is the rate of preparation or rate of futures, mobile obstructions and hernia development. And this is purely because the study have been stopped at 90 days follow up, and they haven't follow up for one year. So they didn't have the data to report. Statistics used the used power calculation, which is really good. They use the sufficient power above 82% and they determined that 1505 52 patient's are needed. The estimated treatment effect had a 97.5% of confidence interval. They used independent data analysis and reviewers who reviewed the study throughout which is good and to address potential selection bias. They performed several types of analysis, like I T T or per Protocol and another type that I will tell you about later. From May 16 2002 February 2020 a total of 8168 patient's were screened, and out of those, 1589 were eligible and out of those 1552 under Ventolin organizations. So the power calculation has been met, and it's pretty much was equal. For both groups, the dropout rates were low in antibiotics, the dropout rate was 13% in that conducted me 15% reasons for dropout were stated, like were lost to follow up or withdrew. But why exactly? Not sure they haven't been very specific. And another thing to draw your attention Is that the dates for the recruitment 2016 to 2020. So this is before the covid pandemic. So the total recruitment has happened before the covid pandemic started, and I know that in the background, the study has reported that the covid pandemic effective their decision to earlier terminated study to publish the results. Looking at the baseline demographics, the age was pretty similar gender pretty similar ethnicity to I had no major concerns here. Um, again the imaging used similar. Everything has been balanced, so we can now, with information we already have. We can now assess the risk of bias about the random ization. And I think it's a low risk because they have had an allocation sequence concealed and it has been random, and there are no background, um, imbalances. So I think it's a low risk for them. deviation from intended intervention. However, I think is a high risk because they have deviated from the intended follow up period which could potentially affect the results. Yeah, so now back to results. In antibiotic group, 51% of the participants were admitted to the hospital for the index treatment. It means 51% had IV antibiotics in the hospital and the rest were discharged after 24 hours with the oral. In the appendectomy group, 95% of the participants were admitted to 96%. You had appendectomy laparoscopically. Um, The meantime from random ization to discharge was 1.3 days in both groups, so it's pretty magical. At least one additional course of antibiotics was prescribed within 90 days for the antibiotic group in 11% and that here instituting it was pretty good in both groups and 90% an antibiotic group above 99%. An appendectomy group, Primary Outcomes reported. So they reported the quality of life at a 30 day interval, and it's been pretty equal between the groups. So 0.92 in antibiotic and 0.91 an epidemic to me. So it was consistent with the noninferiority of antibiotics to appendectomy, and they performed three different analysis. So intention to treat the per protocol analysis. And they also performed the analysis with the use of multiple imputation for the missing primary outcome data. And they all show the noninferiority of antibiotics in the antibiotic group. Appendectomy was eventually performed in 11% of participants by 48 hours in 20% by 30 days in 29% by 90 days. So we we see that there is an increase in people requiring appendectomy by 90 days, so it would be really useful for us to see the data of what happened after one year. So those who had appendical ease their incidents of appendectomy was 41%. So it has been higher. So meaning it's just more proven that appendical is carry a more complex appendix. Appendicitis. So now risk a bass for missing out cam data. I put that they have some concerns because although they did report they've been a drop out and the dropout rate was low. They haven't reported the reasons for the drop out. And so we don't know. We can't accurately assess, um, the missing outcome data or when. Why I've put no high risk is because they performed three types of the analysis, which I'll give them some concerns. And this is the quality of life to that they've been using. So if you look at it, it's pretty subjective. They look at the mobility, selfcare, usual activities, pain, discomfort, anxiety, depression and the score can differ from person to person, even though their condition had maybe similar secondary outcomes. Oh, and also talking about this box. They haven't had any standardization of the pain relief analgesia discharge criteria. So this all adds to the subjectivity of this quality of life assessment. Someone could have been having paracetamol and ibuprofen as a pain relief. Someone could be having the morphine. Hence their pain and discomfort can levels can be different, and the outcome of the pain discomfort can be different different, so this has not been regulated secondary outcomes. The resolution of symptoms were similar in two groups. Buy 90 days visit to the emergency department. After the index treatment, 9% of people visited Edie, an antibiotic group, versus 4% in the appendectomy. It pretty similar hospitalization. 24% of antibiotic group required what versus 5% in appendectomy group, and the important bit is in new plasma identified the nine participants. Seven of those were in a project in the group, and two of those were antibiotics Group. But in those who later on underwent appendectomy, so adverse events there were no deaths. Um, regarding cities adverse events, four per 100 participants in antibiotic group and three per 100 participants in appendectomy. Group rates are pretty similar. Complication rates are eight per 100 an antibiotic group, 3.5 per 100. And in appendectomy group, um, the higher rate antibiotic group over over at you to build to those who have a ridiculous and reactions to antibiotics were more common in the antibiotic group. Understandably rate of, uh, Contributories difficile infection is similar in both groups, 0.6% 0.6 per 100. And the use of more extensive procedures like small bowel or colon resection was pretty low in both groups. So this is a risk of bias based on the measurement of the outcome is really complex, um, diagram. But overall, why I put high risk is because yes, for the primary outcome, they had a standardized protocol to be used. They had a standardized perform, a which was quite subjective. But those non regulated secondary outcomes, like analgesic paying discharge criteria they haven't been any standard they had allowed for cross over, and it all can affect the primary outcomes. So I put a high risk. Um, so now this is the risk of bias in selection of the reported results. I think it was no, because they did do everything that has been published in the protocol. No discussion. So overall antibiotics did show noninferiority to predict, Um, it's 30 days. Um, uh, it would be useful to see what happens after one year after two years after five years, how many people will represent with appendicitis and we'll develop so called recurring the appendicitis. So by 90 days, 29% of participants so about one story, bit less in debt in antibiotic group had undergone appendectomy by one week resolution of symptoms of appendicitis was similar in two groups. Participants in their caregiver in the antibiotic group missed less time from work than those in the appendectomy group, But emergency department visits and hospitalization after the index treatment were more common in the antibiotic group, so it all comes back to the preference of the person. So it's really hard to take time of work and, if it is preferred by the patient to receive antibiotics in order to control the pain of appendicitis, this study has proven that you can use antibiotics, and it just allows you to give more information to the patient, and this allows them to make a better decision. The important bit is about missing new plasma. Could appendicitis be the first sign of the new plasma? It could be a particular new plasma, Unfortunately, carry a poor prognosis. So I think, um, identifying it on histology means you pretty much caught appendicitis at an earlier stages. And I think this is important because not everything is seen on the imaging. And there have been nine people. Yes, it's a very, very small number less than 1%. But still you've identified nine you plus by performing appendectomy really non invasive procedure and a pedicular. These have been linked to a higher rate of complicated appendicitis coming back to appendectomy. It's a non non invasive procedure. It's a, uh, minimally invasive because you standards lap laparoscopic appendectomy next limitations of the study, so only 30% agreed to be randomized of those eligible. The child was not blinded by either aunts. It could have been blinded by the assessor ends. But it wasn't, um, some patient's declined appendectomy and some patient declined antibiotics. And there have been a crossover which could lead to some bias. There have been no adjustment for multiple testing of secondary outcomes. No standard, no protocol. Another thing. So for the discussion, I've already talked about that. It would have been useful to have a one year follow up because the rate of appendectomy after antibiotics has been increasing. Um, the study was done before the pandemic started. Another important discussion point to have is a female patient population, although it was balanced between the groups. The more complicated appendicitis. For example, appendicitis perforation in female population, you would want to treat it so because, if not a serious information of appendix, if it laying next to the ovaries next to development, ship it in cost cutting, which increases the rate of ectopic pregnancies, and so in females you would be more inclined towards performing. Object to me and also the subjectivity of the primary outcomes. It was affected by non regulated, um, non regulated pain, relieve, use or not regulated, dispatched criteria. So this is something to think about.
