Updates in Surgery (2019) 71:381–387

https://doi.org/10.1007/s13304-018-00614-z

ORIGINAL ARTICLE

Never put equipoise in appendix! Final results of ASAA (antibiotics vs.

surgery for uncomplicated acute appendicitis in adults) randomized
controlled trial
Marco Ceresoli1 · Michele Pisano1 · Niccolò Allievi1 · Elia Poiasina1 · Federico Coccolini1 · Giulia Montori1 ·
Paola Fugazzola1 · Luca Ansaloni1

Received: 20 March 2018 / Accepted: 6 December 2018 / Published online: 17 December 2018
© Italian Society of Surgery (SIC) 2018

Abstract
Acute appendicitis is the most common surgical emergency; however, its etiology and diagnosis are still discussed with a
considerable proportion of wrong diagnosis resulting in appendectomies for non inflamed appendix. Moreover, the biologic
function of the appendix is still unclear. For uncomplicated acute appendicitis the conservative treatment with antibiotics
has been proposed with interesting results. The aim of this study was to compare surgical treatment vs. antibiotics in uncom-
plicated acute appendicitis. This is a monocentric randomized controlled trial comparing surgery with antibiotic therapy in
adults with uncomplicated acute appendicitis. The primary outcome was the success rate (resolution of symptoms within
2 weeks and no need for further treatments); secondary outcomes were complication rate; negative appendectomy rate (only
in surgical arm); and long-term outcomes within a year as recurrence. The study was designed as a non-inferiority trial. From
September 2011 to December 2014, 224 patients fulfilled the eligibility criteria and 45 patients were randomized. Twenty
four patients (53.3%) were randomly assigned to surgery and 21 (46.6%) to antibiotic therapy. In surgical group primary
outcome was reached for all the patients; secondary negative outcomes were recorded in five patients (22.7%): two cases of
negative appendectomies, three wound infections. In antibiotics group treatment fails in 16.8% of cases; secondary negative
outcomes were recorded in one patient who experienced relapse of AA at 30 days No further events or complications were
observed at 1-year follow-up. Due to the poor patients’ accrual the study had no enough statistical power to demonstrate
the non-inferiority of conservative treatment and results were inconclusive. Due to the poor patient’s accrual rate the study
failed to demonstrate the non-inferiority of conservative treatment in uncomplicated acute appendicitis. On the other hand
the study demonstrates the difficulty in performing randomized trials in emergency surgery and focus on the ethical aspects.

Keywords Acute appendicitis · Uncomplicated acute appendicitis · Conservative treatment · Antibiotics · Equipoise ·
Randomized trial

“We’re neither better nor worse than each other, we’re Introduction
an equipoise in difference-but in difference, mind, not
in sameness”. Acute appendicitis is one of the most common surgical
emergencies with an incidence of 90 cases/100,000 inhab-
D. H. Lawrence, “Education of the People”, Reflec-
itants per year [1]. Despite appendectomy was one of the
tions on the Death of a Porcupine and Other Essays,
first emergency surgery intervention described in history,
1925
with the first publication in the late nineteenth century [2,
3], the exact etiology of acute appendicitis remains cur-
rently unclear. With multiple clinical patterns and a very
heterogeneous presentation, the diagnosis of acute appen-
dicitis remains a very difficult “clinical” diagnosis even for
* Marco Ceresoli most experienced surgeons, with a reported rate of nega-
[email protected] tive appendectomy (a histopathological diagnosis of normal
1
General and Emergency Surgery, Papa Giovanni XXIII appendix) ranging from 6 to 20% [4, 5].
Hospital, Piazza OMS 1, 24127 Bergamo, Italy

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382 Updates in Surgery (2019) 71:381–387

Historically the diagnosis of acute appendicitis was based Materials and methods
on right iliac fossa tenderness with the McBurney’s sign, fever,
nausea and vomit. As the accuracy of these signs and symp- ASAA study was conceived as a monocentric prospec-
toms in diagnosing acute appendicitis is weak, several diag- tive randomized non-inferiority trial, comparing anti-
nostic scores have been proposed to improve accuracy. One biotic treatment with surgery in uncomplicated acute
of the most precise and accurate is the appendicitis inflamma- appendicitis.
tory response (AIR) proposed by Andersson [6], developed The trial was reviewed and approved by the ethic com-
modifying the more widely used Alvarado score [7]. The AIR mittee and it has been registered on ClinicaTrial.gov
score, combining sign and symptoms, divides patients into (ClinicalTrials.gov identifier NCT01421901, EUDRA
three groups: low risk, intermediate and high risk of having CT number 2011-002977-44). The study was conducted
acute appendicitis. This score has been validated in several at the Papa Giovanni XXIII Hospital, Bergamo, Italy from
studies with good diagnostic performance and allows to iden- September 2011 and was terminated in December 2014.
tify patients with acute appendicitis who will likely benefit
from surgical intervention and patients with an intermediate
probability, for whom a conservative treatment should be Patients and eligibility criteria
considered.
An increasing number of studies are describing two differ- Patients aged 18–65 years with a first episode of uncom-
ent entities of acute appendicitis, being represented by com- plicated acute appendicitis were considered for inclusion
plicated and uncomplicated appendicitis [8–11]. For compli- in the study. Exclusion criteria were: complicated AA,
cated appendicitis (e.g., peritonitis and perforation), surgery on-going immunodeficiency status, active neoplasm or
is mandatory. On the other hand, several studies, including neoplasm in the last 5 years, assumption of antibiotics in
randomized trials and meta-analysis, have addressed safety, the previous 30 days, pregnancy or delivery in the previ-
effectiveness, therapeutic appropriateness and cost-efficiency ous 6 months, ASA IV and V, allergy to the antibiotics
of antibiotic treatment [12–19]. All these studies (in large established for the study.
part published after the conception of ASAA study) dem- Diagnosis of AA was made according to the appen-
onstrated that conservative treatment is a safe and a valid dicitis inflammatory response (AIR) score [6] with the
option, although associated with a considerable recurrence adjunct of ultrasound in selected patients. According to
rate. Moreover, a recent randomized trial shows that uncom- the AIR score and the ultrasound findings, patients were
plicated appendicitis could resolve spontaneously even without stratified in three classes as follows. Group 1: AIR score
antibiotics [20]. 1–4 (low probability of AA); Group 2: AIR score 5–8
The rationale for conservative treatment in uncomplicated (intermediate probability of AA) and Group 3: AIR score
acute appendicitis is to avoid a surgical intervention in a con- 9–12 (high probability of AA). Patients of group 1 were
siderable high proportion of patients who present with a clini- excluded from the study due to the low probability to have
cal suspicion of acute appendicitis. It is worth mentioning how AA. Patients of Group 2 were examined with abdominal
numerous aspect of appendiceal physiology remain unclear US and were included in the study if the US findings con-
and this elements acquires importance when preservation is firmed the clinical suspect of AA. Patients of Group 3
discussed. Vermiform appendix should not be considered without signs of perforation and with white blood cell
merely as a vestigial organ; in fact its fundamental role in (WBC) count less than 15,000/μl and C reactive protein
immunoregulation of the gastrointestinal tract and mainte- (CRP) less than 5 mg/dl were included in randomization;
nance of the gut microbiota has been demonstrated; moreover, the other were excluded from the study and were operated.
it seems to play a relevant role even in inflammatory bowel
diseases [21].
The aim of this study was to test the equivalence of anti- Randomization and masking
biotics versus appendectomy in a population with an inter-
mediate diagnostic risk of uncomplicated acute appendicitis, Randomization through a computer system was adopted
as per AIR score stratification, to reduce the rate of negative to assign patients in a 1:1 ratio to the two study arms.
appendictomies. The randomization list was prepared by a professional not
directly involved in the study before the first enrolment
and concealed inside opaque envelopes in the surgeon-
on-call room. After the evaluation for eligibility, made by
the on-call surgeon, and the stratification according to the
AIR score and US examination, patients were required to

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Updates in Surgery (2019) 71:381–387 383

sign the informed consent for inclusion in the study; at this after the third dose of Ertapenem was seen, with the subse-
point the on-call surgeon opened the envelope allocating quent need for surgical interventions.
the patient. For obvious reasons, the current study could Secondary negative outcomes were: complication rate;
not be masked and blinded, neither to the participants nor negative appendectomy rate (only in the surgical arm) and
to the surgeons. long-term negative outcomes within a year (surgical re-
operation due to bowel occlusion or intraperitoneal abscess,
bowel occlusion longer than 48 h, intraperitoneal abscess,
Procedures
incisional hernia or wound dehiscence for surgical arm;
recurrence of AA in the antibiotic arm). Length of hospital
Patients who fulfilled the inclusion criteria and gave consent
stay and work absence were also compared.
to participate in the study were randomized to either of the
Drop out occurred in the antibiotic group when a differ-
two study arms: conservative treatment or surgery.
ent disease was diagnosed during the hospital stay or at the
Conservative treatment consisted of intravenous admin-
follow-up colonoscopy or when patient refused the partici-
istration of 1 g of Ertapenem once a day for 3 days during
pation in the trial after randomization. In the surgical arm
hospitalization and further administration of amoxicillin/
drop out occurred when generalized peritonitis and perfora-
clavulanate 1 g per os every 8 h for 5 days. During the hos-
tions or different diseases were detected during surgery or at
pitalization, the daily AIR scoring was repeated to evalu-
the pathological report (except normal appendix) and when
ate a possible failure within the antibiotic arm. A follow-up
patient refused the participation after randomization.
colonoscopy (after 1 month) was always recommended for
all patients older than 40 years, who were managed with
Sample size and statistics
conservative treatment.
The surgical arm consisted of preoperative intravenous
The sample size calculation was based on the outcomes
administration of 1 g of Ertapenem and appendectomy in
of the most recent prospective trial in the Literature at the
the following 12 h. Appendectomy was performed routinely
time of the study design [12]; we considered an estimated
laparoscopically, with the standard 3-port approach; open
failure rate of 15.1% and 15.2% for antibiotics and surgery,
appendectomy was indicated in selected cases, based on the
respectively.
on-call surgeon’s choice. In case of phlegmonous or gan-
To establish the non-inferiority of antibiotic therapy to
grenous acute appendicitis identified at the time of opera-
surgery, we obtained a sample size of 218 patients, 109
tion, Ertapenem 1 g intravenously daily was administered
patients per treatment arm, considering a power (1 − β) of
for 2 further days, followed by Amoxicillin/Clavulanic acid
80% and a type I error risk (α) of 5%, with a non-inferiority
1 g per os three times per day for 5 days.
margin set at 12%. Taking into account a 10% loss at follow-
For all patient, oral intake was resumed after 12 h after
up, a total number of 230 patients (115 per group) was con-
the operation or from the first administration of Ertapenem
sidered as the enrolment goal of the study.
and patients were allowed to have clear fluids and low fluids
Data were prospectively collected and entered in an
diet. Criteria for discharge were ability to tolerate a low fiber
electronic database; continuous variables were expressed
diet, passage of flatus, absence fever, optimal pain control
as mean and standard deviation; categorical data were
with oral medications; and only in the antibiotic group AIR
expressed as proportion and percentages; primary and sec-
score below 5. All patients were re-evaluated as outpatients
ondary outcomes were showed as risk difference with 95%
after 7 and 14 days from the treatment. Telephonic follow-up
confidence intervals and were compared with non-inferiority
was done after 1 year from the acute episode.
test; length of stay and number of sick leave days were com-
pared with the Mann–Whitney test. Data were analyzed with
Outcomes and dropout SPSS 20; alpha was set as 0.05.

The primary outcome of the study was the success rate of

the treatment, defined as the resolution of symptoms (no Results
abdominal pain, no fever) and resolution of inflammatory
markers (WBC < 10,000/μl and CRP < 1 mg/dl) within From September 2011 to December 2014, 366 patients
2 weeks from the appendectomy (in the surgical arm) or with suspected diagnosis of AA were admitted to the
from the third dose of Ertapenem without other treatments XXXXXXXXXXXXXXXXX of these, 224 patients
(in the antibiotic arm). (61.20%) met the inclusion criteria for the randomization.
In the antibiotic arm, primary outcome was considered as All patients were asked to participate in the ASAA study
not reached if clinical conditions had worsened during the and the informed consent was obtained for 45 patients that
antibiotic administration or if no resolution of symptoms were randomized (45/224, 20.08%). Table 1 shows the main

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384 Updates in Surgery (2019) 71:381–387

Table 1  Characteristics of randomized and not randomized patients no resolution of symptoms was appreciated after the third
Eligible not rand- Randomized patients p
Ertapenem administration. Patients’ flow is shown in Fig. 1.
omized patients Table 2 shows the characteristics of randomized patients.
Surgery was performed after a median interval time from
n 224 41
hospital presentation of 22 (8.3) h. All the appendectomies
Age 38 (15.79) 35.12 (13.35) 0.12
were successfully accomplished with standard 3-port lapa-
Sex 0.84
roscopy and no intraoperative complications were recorded.
Male 120 (54%) 23 (56%)
Primary outcome was reached for all the patients, since sur-
Female 104 (46%) 18 (44%)
gical treatment was effective in 100% of cases; secondary
AIR score 6 (1.38) 7.37 (1.15) 0.09
negative outcomes were recorded in five patients (5/22,
Low risk 0 0
22.7%): two cases of negative appendectomies (2/22, 9.1%),
Intermediate risk 206 (92%) 35 (85%)
three cases of wound infections (3/22, 13.6%). No further
High risk 18 (8%) 6 (15%)
complications or events were recorded at 1-year follow-up.
In conservatively treated patients, primary outcome has
been reached in 16 out of 19 patients (84.2%). Primary fail-
characteristics of randomized and non-randomized patients. ure, i.e., no resolution/worsening during antibiotic treat-
Male patients were 23 (51.1%), the mean age was 35.1 years ment, occurred in three cases and surgery was required. One
(± 13.3). Twenty four patients (53.3%) were randomly patient showed worsening of symptoms between the first and
assigned to surgery and 21 (46.6%) to antibiotic therapy. the second Ertapenem administration and was operated on
Four patients, two in each group, dropped out: in the sur- with no complications; one worsened between the second
gical group appendiceal perforation was the cause of the and the third Ertapenem administration and at operation was
dropout in both cases; in the antibiotic group one patient found to have complicated appendicitis (perforation), while
reconsidered his participation during the first day of treat- the third patient worsened after the third dose of antibiotic.
ment and one patient was diagnosed with appendiceal carci- Secondary negative outcomes were recorded in one
noid tumor (well-differentiated pT2), which was detected at patient (1/16, 6.2%), who experienced relapse of acute
histopathology—the appendectomy was performed because appendicitis at 30 days from the third dose of Ertapenem:

Fig. 1  CONSORT flow diagram

Assessed for eligibility (n=366 )

Excluded (n= 321 )

Not meeting inclusion criteria (n=142)
Declined to participate or were not
randomized (n=179)

Randomized (n=45)

Allocation
Allocated to Surgery (n=24) Allocated to Antibiotics (n=21 )
Received allocated intervention (n=24) Received allocated intervention (n=20)
Did not receive allocated intervention (n=0) Did not receive allocated intervention (n=0 )

Follow-Up
Lost to follow-up (n=0 ) Lost to follow-up (n=0)

Discontinued intervention (n=0) Discontinued intervention (reject consent to

partecipate) (n=1)

Analysis
Analysed (n=22) Analysed (n=19)
Excluded from analysis (complicated Excluded from analysis (cancer at the
appendicitis [perforated]) (n=2) pathological examination (n=1)

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Table 2  Characteristics of Clinical characteristic Surgical group Antibiotic group p value

included patients among the two
study groups Number of patients 22 19
Sex 0.12
Male 14 7
Female 8 12
Age 33.6 (± 13.2) 37.1 (± 13.5) 0.11
AIR score 7.5 (± 1.2) 7.2 (± 1) 0.48
Low risk 0 0
Intermediate risk 18 (81%) 17 (89%)
High risk 4 (19%) 2 (11%)
RLQ pain presence 24 (100) 19 (100) 0.99
Vomiting presence (percentage) 8 (36.4) 3 (15.8) 0.13
Rebound tenderness presence (percentage) 22 (100) 18 (94.7) 0.79
Absence 0 1 (5.2)
Blumberg sign 8 (36.4) 7 (36.8)
Defense at the palpation 10 (45.4) 9 (47.3)
Abdominal contraction 4 (18.2) 2 (10.5)
Fever > 38 °C 1 (4.5) 0 0.47
WBC count 14.7 (± 3.1) 12.9 (± 3.1) 0.12
< 10,000 1 (4.5) 4 (21)
> 10,000 11(50) 11(57.9)
> 15,000 10 (45.4) 4 (21)
% Neutrophil 77.4 (± 7.9) 79.3 (± 7.9) 0.42
< 70% 4 (18.2) 3 (15.8)
70.1–84.9% 14 (63.6) 10 (52.6)
> 84.9% 4 (18.2) 6 (31.6)
CRP mg/dl 3.5 (± 4.1) 5.4 (± 5.5) 0.19
< 1.4 7 (31.8) 5 (26.3)
1.4–4.9 10 (45.4) 7 (36.8)
> 4.9 5 (22.7) 7 (36.8)
US 18 (81%) 17 (89%) 0.57

according to the protocol, he underwent surgery and an Discussion

uneventful laparoscopic appendectomy was performed; no
complications were observed. No further events or compli- The present study failed to demonstrate the non-inferiority
cation were observed at 1-year follow-up. Table 2 shows the of conservative treatment of uncomplicated acute appen-
results in detail. dicitis, as compared with surgical treatment. The results
Due to the poor patients’ accrual, the study did not pre- obtained from the randomization of patients revealed that
sent enough statistical power to demonstrate non-inferiority conservative treatment failed in 15.8% of cases imme-
of conservative treatment as shown in Fig. 2 and Table 3; diately and in 5.2% within 1 year; on the other hand,
results are, therefore, to be considered as inconclusive.

Fig. 2  Risk difference among

the two study groups for pri-
mary and secondary outcomes;
Δ indicates the non-inferiority
margin

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386 Updates in Surgery (2019) 71:381–387

Table 3  Study’s outcomes Surgical group Antibiotic group Risk difference

Primary outcome 22/22 (100%) 16/19 (84.2%) 0.157 (− 0.022 to 0.375)

Secondary negative outcome 5/22 (22.7%) 1/16 (6.2%) 0.164 (− 0.08 to 0.378)
Length of hospital stay days, mean (SD) 3.5 (± 1.3) 4.1 (± 2.8)
Sick leave days, mean (SD) 11.4 (± 5.3) 8.5 (± 7.9)

surgical treatment, with 100% of immediate effectiveness, devices) or professional (improving personal surgical skills
was inappropriate in two cases (negative appendectomy, or reluctance to perform a well know surgical operation,
9.1%) and was associated with complication in three cases especially out-of-hours), could influence the equipoise. In
(13.6%). Due to the poor recruitment of patients, data are our study, barring the economic influence, each of the cited
far from the needed sample size to demonstrate the non- problems may have contributed to limit the recruitment. A
inferiority of conservative treatment and no statistically large number of patients, despite being eligible for the study,
valid conclusions can be drawn by the results. It should were excluded for the scarce adherence of the surgeon in
be noticed that these results seems to be comparable with charge to the study protocol. Perhaps the main reason for
data available in the literature [18, 19] and they could be failure of this study is the poor familiarity with RCT among
considered for inclusion in future meta-analysis. surgeons.
Although the poor intrinsic statistical results, some gen- The present study presents the great limitation of a poor
eral considerations can de proposed: the safety of patients patient recruitment rate: an insufficient number of patients
enrolled in the ASAA study was preserved in both arms. was included in the study and the endpoint could not be
No fatal cases have been observed, while the literature reached. Moreover, the results revealed the difficulties in
refers a range between 0.07–0.7 and 0.5–2.4% in patients conducting a randomized trial in emergency surgery dur-
without and with perforation, respectively [11]. The overall ing daily practice. Although the study protocol established
complication rate reached 9.7% and this was comparable a maximum of 12 h from randomization to surgery, patients
with results in literature; in particular: three were wound were operated after a mean time of 22 h, with a very poor
infection (first class Clavien–Dindo classification) in the adherence to study protocol.
surgical group and one was a atrial flutter (second class
Clavien–Dindo classification) in one patient who failed the
antibiotic approach. Patients who failed the antibiotic treat-
Conclusions
ment during the hospital stay (15.8%) were able, in any case,
to reach the resolution of symptoms at 2 weeks.
In conclusion, the dogmatic indication to surgery in case of
The failure of this study allows us to develop some inter-
suspected acute appendicitis allowed saving many lives in
esting considerations regarding ethical and practical issues
pre-antibiotic era. However, this approach has decreased the
when performing RCT in emergency surgery. In 1996 only
stimulus to investigate the role of the vermiform appendix, to
the 7% of original published papers, in a group of major
understand the primum movens of acute inflammation of the
surgical journals, were RCT [22] and only 40% of ques-
appendix, to reach a broad agreement on the diagnosis and
tions regarding surgical treatment could be answered by
on the diagnostic tools, to establish a common histopatho-
RCT [23]; more recently, these figures have considerably
logical classification and to find a worldwide accepted defi-
improved, but the quality of evidence is still below the level
nition of uncomplicated and complicated acute appendicitis.
of RCT comparing medical treatments.
Unfortunately, the present study does not add further evi-
Limiting our analysis to the reasons of insufficient recruit-
dences on this intricated topic; however, it demonstrates the
ment, we ought to underline the matter of equipoise, which
great difficulty in providing evidence-based answers to ques-
“refers to uncertainty among groups of experts who hon-
tions directly arising from daily surgical practice.
estly disagree which treatment is better” [23–26]. The base-
line assumption should be that personal certainty among
Compliance with ethical standards
researchers must be abandoned in favor of evidence-based
medicine before study conception; subsequently the impor- Conflict of interest All authors declare that they have no conflict of
tance of preserving the equipoise from external influences interest.
during the study should be stressed. Factors affecting the
Research involving human participants and/or animals The study was
maintenance of the researcher equipoise may be different:
conducted according to the Helsinki declaration about ethical stand-
patient’s preference could impair the balance between arms; ards; the study protocol was approved by the etical committee of the
conflict of interest, either pecuniary (industry funding for Papa Giovanni XXIII hospital.

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Updates in Surgery (2019) 71:381–387 387

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