Thursday, June 9, 2016

Antibiotics vs. surgery for appendicitis: Critique of a meta-analysis

A meta-analysis can be useful when looking at a topic that has been studied by several different groups of investigators. The pooling of data from different published papers can sometimes bolster a conclusion about the effectiveness of a treatment.

However, a meta-analysis is only as good as the studies it includes, and the biases of those performing the meta-analysis can color the results.

Last month, a meta-analysis concerning antibiotics vs. surgery for the treatment of uncomplicated acute appendicitis by investigators from Nottingham University Hospitals was published in the World Journal of Surgery.

The authors concluded that “antibiotic therapy represents a safe, efficacious and viable treatment option for the treatment of uncomplicated acute appendicitis.” I disagree.

Five randomized trials involving 1430 subjects were included in the meta-analysis. After one year of follow-up, the efficacy of treatment for those receiving antibiotics was 62.2% compared with those undergoing appendectomy whose treatment efficacy was 88%. Depending on the inclusion or exclusion of a particularly weak study there was said to be a 39-52% risk reduction for complications in the antibiotic group.

This meta-analysis has so many problems that it is hard to know where to start.

All five studies compared antibiotics to open rather than laparoscopic appendectomy, which has fewer complications, a one-day hospital length for simple appendicitis, and is now the standard of care in the US.

One of the studies from Sweden was published in 1995 [Eriksson] and included only 40 patients. The method of randomization was not described. The 20 appendectomy patients all presumably underwent open surgery which is irrelevant in 2016 when more than 80% of appendectomies in the US are done laparoscopically. After a mean follow-up of 17 months, 7/20 (35%) of those who were treated initially with antibiotics required appendectomy for recurrent appendicitis.

Another Swedish study [Hansson 2009] comprised 202 patients who were given antibiotics and 167 patients who had appendectomies. The randomization scheme was by odd or even date of birth, a notoriously poor method. Since the investigators could easily know what group the patients were to be “randomized” to, manipulation of enrollment by the treating physicians may have confounded the results.

The diagnosis of appendicitis was made on clinical grounds for more than 70% of the patients. It is possible that some patients who were treated with antibiotics never had appendicitis at all. The results of this study are difficult to interpret because patients were allowed to cross over from one group to the other based on their preference, the clinical judgment of the surgeon, or for “unspecified clinical judgment.” Since 47.5% of those assigned to antibiotic treatment crossed over and had surgery, the efficacy of antibiotics is difficult to ascertain.

This paper claimed that major complications were three times higher in patients who initially had appendectomies. Two of these major complications involved patients who underwent hemicolectomies because a malignancy of the appendix or colon was found during the appendectomy. I would hardly call those complications.

A third Swedish study [Styrud 2006] involved only male patients; 124 underwent appendectomy and 128 were given antibiotics only. The diagnosis of acute appendicitis was based on clinical findings and laboratory studies. Despite being published in 2006, only 8 patients (6%) underwent laparoscopic appendectomy. This was probably because the study was conducted from 1996 to 1999. One wonders why it took seven years to be published. 15 of the 128 patients in the antibiotic group had appendectomies within 24 hours because they failed to improve on antibiotics, and seven of them had perforations.

Of those treated with antibiotics successfully during the initial hospitalization, another 16 required appendectomy during the one year of follow-up. The total failure rate for antibiotics was 24%. Hospital stays, sick leave days, and time off from work were similar in both groups. It is not clear whether the second hospitalization for the 16 patients in the antibiotic group requiring subsequent appendectomy was counted in the hospital stay and time off from work data.

The fourth study was from France [Vons 2011]. Antibiotics were given to 120 patients compared to 119 who underwent appendectomy. Diagnosis of uncomplicated acute appendicitis was made by CT scan in all patients. Of note was that 18% of those who underwent appendectomy as the initial treatment had complicated appendicitis found at surgery despite their CT scan interpretations.

Combining those who failed antibiotic therapy during the index hospitalization and those who required appendectomy later within the year of follow-up, the failure rate for antibiotics was 36.6%.

The fifth study was the recent randomized trial from Finland which I dissected soon after it was published [here and here]. Briefly, 27% of patients treated with antibiotics required appendectomy within one year, only 5.5% of appendectomies were done laparoscopically, the antibiotic used was not a first line drug in the US, and the length of follow-up was only one year.

All of the randomized trials in the meta-analysis above have serious methodological flaws. Comparing antibiotics to open appendectomy is not valid in the 21st century. Their follow-ups were too short, and they had failure rates that were, in my opinion, unacceptably high.

I remain thoroughly unconvinced about the efficacy of antibiotics for the treatment of appendicitis.


George Gasman said...

What would be an appropriate length of time for followup after a laparoscopic appy?

artiger said...

George, in my practice, F/U after lap appy is one week, and then I am done with them unless problems occur. Some might say that with such an early dismissal, I don't know about the long term complications; to the contrary, if you practice in a rural area like I do, you have absolutely no way of escaping your postop problems. There aren't many after lap appy, and I've tried the antibiotic route several times, most all of which have been failures.

Korhomme said...

Many years ago I read a paper about this; I don't remember the source or all the details, but the gist was this. A hundred or thereabouts American nuclear submariners were at work when they developed lower abdominal or right iliac fossa pain. Some, of course, might not have had antibiotics. They all recovered – at least in the short term.

One problem with the use of antibiotics is 'philosophical'; antibiotic resistance is a major problem, and treating appendicitis with them rather than a simple operation is, I think. problematic.

I don't know how many cases are treated laparoscopically in the UK or elsewhere, but I'd expect it's less than the US.

Skeptical Scalpel said...

I agree that most uncomplicated laparoscopic appendectomy patients need to be seen only once for a postoperative office visit. If a complication occurs later, the patient will generally come back.

Kor, the paper I've heard about concerned only a few submarine sailors. There is supposedly a paper from Russia about something like 247 soldiers treated for appendicitis without surgery during World War II. Of course, with all these cases the diagnosis was made on clinical grounds only. Whether these people had appendicitis or not is unknown.

I agree with you about treating appendicitis with antibiotics and possibly promoting more resistant organisms. When patients with simple appendicitis undergo surgery, they receive one dose of preoperative antibiotics and maybe a second dose postop. A full course of antibiotic treatment for patients with appendicitis who don't undergo surgery is a minimum of one week.

Anonymous said...

The issue is as SS has stated but larger. We as a profession lack the ability to analyze the published studies we read and critically determine the BS meter level of each. It was only in my later parts of my Residency that I learned anything at all about reviewing the published articles. Typical functional docs have no training. Even to this day I tend to look at each article with great concern until it moves me the other way. A guilty until proven innocent approach. This is great issue for my wife who is a pet professional and how tends to believe what is written until proven otherwise as she was taught to. Too bad more of us aren't trained to do the same review and evaluation. Better yet isn't that what peer review is "supposed" to do?
Isn't the whole concept of peer review supposed to be the jury as to whether or not eyes are dotted and tees crossed so that average readers don't have to? If we are supposed to analyze every article to determine it's merits why not have non-reviewed articles and let the reader beware?
Instead of listing the authors credentials and then praise them as to their experiences and financial ties to industry why not instead list the reviewer's credentials and their unbias and their experience in evaluating statistics and scientific publishings?
I would much prefer to not have to read every article with question but since the peer review process fails more times then not I have no choice. Lets revamp the peer review to require them to add in addition to every article the reviewer's comments as to the errors and details of the process used to support the conclusions. We can then start reading there and if there aren't too many flags we can continue on to the actual research
Dr D

Skeptical Scalpel said...

Dr D, many have called for a change in the way papers are peer reviewed. It's not so simple. Manuscripts are reviewed by volunteers. Some are good, some are bad, some are awful. As long as peer-reviewed was done without compensation, it is unlikely to improve. I don't see any publisher changing the way papers are reviewed especially because the future of journals is uncertain. The enormous profits that journals have made for decades may soon be coming to an end because of initiatives like Sci-Hub which provides free access to articles in paid journals.

Anonymous said...

Thanks for your insightful posts, SS. I'd like to provide a patient's perspective on this. I recently found myself in the ER, diagnosed with acute appendicitis. I had the classic symptom of abdominal pain that migrates to LRQ plus rebound tenderness. I also felt cold.

I went in to rule out appendicitis, and was shocked when ultrasound confirmed appendix inflamed, distended to 10mm, no free fluid. WBC was over 14. Diagnosis: uncomplicated AA. The surgical resident was called and gave me the consent form to sign.

It all happened very fast, to go from completely healthy to facing surgery in a matter of hours was for me extremely stressful. I think with other surgeries one has time to process, research, make a decision. And in other emergencies you'd probably be unconscious or screaming. With this, all I had was a little bit of a tummy ache and next thing I'm staring down the barrel at the OR, a place I've never been.

Then they gave me the option of antibiotics and I agonized over it. I really didn't know what to do. They gave me the odds of recurrence, said it was my choice.

In the end I thought antibiotics seemed more conservative, why not try it and see? So that's the route I went. It's been a week since then. Three days in hospital took a toll and taking antibiotics has its problems. Now I'm coming to the end of the course and there is still pain on palpation, I'm constantly checking myself is it getting worse? Better? Could it perforate and cause more problems? Follow up is till two weeks away. I have to decide if I should go back to the ER or not. Then again, I might be doing the same with post op pain, worrying about complications.

Options are good I suppose but they also add immensely to patient stress. Sometimes I think I made the wrong choice, other times I'm glad to have saved the appendix, so far.

Skeptical Scalpel said...

Anonymous, thank you for sharing your story. I think we will be hearing more of this sort of thing as antibiotics catch on.

Of all your questions, the only one I can answer is "Could it perforate and cause more problems?" Yes. What are the chances that it would perforate? I don't know. We are in uncharted waters. We do know that about 27% of the time, appendicitis will recur within one year. We do not know how many of these recurrences will be perforations. There have not been enough patients treated with antibiotics who later had perforations to give a meaningful answer.

I have two questions for you. Will you please let me know how this turns out? If you had it to do over again, would you still choose antibiotics?

Anonymous said...

Had a bit of a technical glitch trying to respond here the first time . . . I think it published before I was ready to send, please disregard if so . . . anyway:

Thanks, SS. for your response.

To answer your questions,

1. I will post here and let you know what happens, happy to.

2. I think I would choose surgery and get it over and done with. Of course if I was sitting here with surgical complications I might say the opposite.

I've come to learn a lot about the problems that antibiotics can cause and those were not really explained to me as well as they could have been, I feel.

In my case I really struggled with deciding, to the point that they said well let's admit you and start you on the IV antis, which is the same step for both choices, and then you can decide later.

Having done that, the next day I think I was ready to commit to surgery. However my WBC count was way down by then and the pain was much less, so at that point the surgeon dropped by and said he was happy to keep on with the antis. It was still my choice but I felt they were backing away from surgery. The following day when I was starting to hate being in hospital I was 95% for surgery, but by then with my WBC count still normal they said I was no longer an acute case. Thus my indecision led me into a decision.

My internal vacillation between the options was very stressful. I tormented myself going back and forth, asking myself what's the worst case scenario on each side.

Skeptical Scalpel said...

Thank you for the information. Everyone assumes antibiotics don't cause problems like bad old fashioned surgery does. I don't think anyone has mentioned the anxiety associated with the decision-making process and the second guessing you have been going through. Maybe it's not as easy a decision as many have led us to believe. Good luck.

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