Randomized Clinical Trial Of Antibiotic Therapy Versus Appendicectomy As Primary Treatment Of Acute Appendicitis In Unselected Patients

Dissections

INTERVENTIONAL 25 August 2009

Evidence-based Medicine for Surgeons

Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients Authors: Hansson J, Korner U, Khorram-Manesh A, et al Journal: British Journal of Surgery 2009; 96: 473–481 Centre: Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden BACKGROUND

Early appendicectomy is the standard treatment for acute appendicitis. Some studies have indicated significant long-term risks following surgical exploration for appendicitis. In recent years, antibiotic therapy has been proposed as a safe, primary treatment for acute appendicitis.

IN

SUMMARY

RESEARCH QUESTION

Antibiotic treatment vs surgery in acute appendicitis

Population

Antibiotic group (202)

Patients older than suspected appendicitis.

18

with

Indicator variable Antibiotic therapy. Outcome variable Primary: treatment efficacy and major complications (reoperation, abscess formation, bowel obstruction, wound rupture or hernia, or serious anaesthesiarelated or cardiac problems). Secondary: minor complications, length of antibiotic therapy, abdominal pain after discharge from hospital, Comparison Surgical treatment.

Surgery (167)

Stayed in allocated group

Crossed over into other group

Stayed in allocated group

Crossed over into other group

106

96

154

13

102

89

130

13

59

50

71

7

Analyzed at 1 month Analyzed at 1 year Primary outcomes Recurrences

14

1

48%

85%

11

18 (p < 0.05)

Minor complications

40

37

Abdominal pain in 1 yr

39

30

Days of antibiotic use

10

4.8 (p < 0.001)

Days of hospital stay

3

3

Treatment efficacy Major complications Secondary outcomes

Authors' claim(s): “...Antibiotic treatment appears to be a safe first-line therapy in unselected patients with acute appendicitis.”

THE TISSUE REPORT Contrary to accepted conventions regarding "intention to treat analysis", the authors pull a sleight of the wrist and introduce what they call a "per protocol" classification of results: analysis based on the actual treatment received and not on the randomization arm that the patient was allocated to. Foul! They use an unacceptable randomization technique - allocation based on odd and even birthdays - that results in two widely different numbers in each of the groups, something that should not occur in true random allocation. One recurrent issue in these studies is the fact that it is not possible to know with certainty how many in the antibiotic group really had appendicitis. (continued at the bottom of the next page) ...

EBM-O-METER Evidence level

Overall rating

Bias levels

Double blind RCT

Sampling

Randomized controlled trial (RCT) Prospective cohort study - not randomized Case controlled study Case series - retrospective

Trash Life's too short for this

Swiss cheese Full of holes

Safe Holds water



Newsworthy “Just do it”

Comparison Measurement

l | Novel l | Feasible l Ethical l | Resource saving l

Interesting

The devil is in the details (more on the paper) ...

© Dr Arjun Rajagopalan



SAMPLING Sample type Simple random

Inclusion criteria Patients > 18 yrs with suspected apendictis 

Exclusion criteria

Final score card

Not stated

Antibiotics

Surgery

Target

?

?

Cluster

Accessible

?

?

Consecutive

Intended

202

167

Convenience

Drop outs

Judgmental

Study

Stratified random

See table on previous page for details

= Reasonable | ? = Arguable |  = Questionable Duration of the study: May 2006 and September 2007 To confirm a 10–15% difference in outcome measures at 80% power with a 5% significance level - 200 in each arm



Sampling bias: The a priori sample size of 200 was not met in the surgery arm. (See comparison bias below).

COMPARISON Randomized

Case-control

Non-random

Historical

None

Controls - details Allocation details

Those with an uneven date of birth were allocated to antibiotics (study group), and those with an even date of birth to appendicectomy (control group). Study patients received intravenous antibiotics (cefotaxime 1 g twice and metronidazole 1·5 g once) for at least 24 h. During this time patients received intravenous fluids with no oral intake. Patients whose clinical status had improved the following morning were discharged to continue with oral antibiotics (ciprofloxacin 500 mg twice a day and metronidazole 400 mg three times a day) for a total of 10 days. Appendicectomy was always performed according to the authors’ usual practice: single-dose antibiotic prophylaxis, open or laparoscopic technique and postoperative antibiotic treatment when the appendix was gangrenous or perforated.

Comparability

-

Disparity

A higher white cell count and a higher proportion of local peritonitis in the surgery group.

Comparison bias: The method of randomization used is flawed. The two groups are markedly different in final numbers (202 vs 167): clearly pointing to the lack of proper randomization where the numbers should match up.

MEASUREMENT Measurement error

1.Treatment efficacy: a. antibiotic group: definite improvement without surgery within a median follow-up of 1 year; b. surgery group: confirmed appendicitis at operation or another appropriate surgical indication for operation)

? Y

Blinding

Scoring

N

Protocols

?

Training

Y

Observer error Gold std.

Device error Device suited to task

Repetition

Device used

N

N

-

N

N

N

-

Y

-

N

N

-

Other outcomes measured - major complications, minor complications, length of antibiotic therapy, abdominal pain after discharge from hospital, length of hospital stay - are standard data that can be measured objectively. Measurement bias: Response to antibiotic therapy is not an iron clad marker of underlying appendictis, given the well known difficulty with diagnosing appendictis clinically. In contrast, surgical removal of the appendix allows definitive confirmation of the disease.

Resolution of the symptoms is not an acceptable surrogate marker. This paper does not offer a satisfactory argument for primary antibiotic treatment of acute appendictis; early appendicectomy remains the standard of care. © Dr Arjun Rajagopalan