Scandinavian Journal of Gastroenterology, 2011; 46: 12511256

ORIGINAL ARTICLE

Long-term follow-up of a randomized controlled trial of observation

versus surgery for acute cholecystitis: Non-operative management is an
option in some patients

MALTE SCHMIDT1,4, KARL SNDENAA1,4, MORTEN VETRHUS2,

TEWELDE BERHANE2 & GEIR EGIL EIDE3
1

Haraldsplass Deaconal Hospital, Bergen, Norway, 2Department of Surgery, Stavanger University Hospital, Stavanger,
Norway, 3Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway, and 4Department of Surgical
Sciences, University of Bergen, Bergen, Norway

Abstract
Background. Cholecystectomy is routinely recommended to prevent recurrent disease after an initial episode of acute
cholecystitis. Therefore, randomized controlled trials have mainly focused on the timing of surgery, but many patients scheduled
for cholecystectomy have deferred surgery with long periods of symptom-free intervals. Our present aim is to examine the longterm feasibility and safety of observation compared with surgery. Methods. Trial of 64 patients with acute cholecystitis previously
randomized to observation or cholecystectomy, which examined outcome in terms of completed randomized treatment and
appearance of further symptoms and the need for surgical treatment. Thirty-three patients were randomized to observation and
31 patients to cholecystectomy. Median follow-up was 14 years. Results. Of the 33 patients randomized to observation, 11 (33%)
experienced a new event of gallstone-related disease (eight (24.2%) had acute cholecystitis) and 11 (33%) were operated. No
signicant difference (p = 0.565) was found between the two randomized groups with regard to recurrent disease or
complications. Virtually no surgery took place after 5 years of follow-up. The difference in completed randomized treatment
between the groups was not signicant (p = 0.077). Long-term mortality was equal in those operated and in those observed.
Conclusions. Twenty-four percent of the patients experienced recurrent cholecystitis, but escalation of disease severity or
increased mortality was not observed. Long-term observation after acute cholecystitis was feasible in two-thirds of the patients as
the risk for recurrent disease was negligible after 5 years.

Key Words: Biliary-clinical, hepatobiliary-clinical, laparoscopy

Introduction
There is consensus in the medical community that
cholecystectomy is the only meaningful treatment for
acute gallstone disease, but the timing has been
debated and prospective, randomized controlled trials
(RCTs) have compared outcome after early and
deferred surgery. Only the length of in-hospital stay
has been found to be different [1]. Studies that
portended to examine quality of life (Q-o-L) in
patients who had delayed surgery found no difference
in the designated Q-o-L parameters even though one

study detected a difference in symptomatic experience [2,3]. We found in a previous follow-up of

patients undergoing cholecystectomy in two RCTs
that 29% of patients with acute cholecystitis (AC) had
some sort of digestive problem after cholecystectomy
even as far out as 5 years [4].
AC lacks clear-cut prospective studies of treatment
options. It is sometimes mixed with uncomplicated
disease as severe disease, and admittedly the clinical
separation may at times seem arbitrary [5,6]. The
opinion has mostly been that the patients should be
operated if serious consequences are to be prevented.

Correspondence: Karl Sndenaa, MD, PhD, Department of Surgery, Haraldsplass Deaconal Hospital, University of Bergen, POB 6165, N-5892 Bergen, Norway.
Tel: +47-91868877. Fax: +47-55978555. E-mail: kasoende@online.no

(Received 9 March 2011; accepted 13 June 2011)

ISSN 0036-5521 print/ISSN 1502-7708 online  2011 Informa Healthcare
DOI: 10.3109/00365521.2011.598548

1258

M. Schmidt et al.

Up to now, retrospective studies have followed segments of patients over several years in an attempt to
clarify the need for surgery [7,8]. It can be derived
from these studies that not all patients with AC need
an operation. In short, can some be safely observed?
Our aim in the present analysis was to examine the
long-term incidence and type of new gallstonerelated events that would lead to hospital contact in
a randomized controlled trial (RCT) with welldened entry criteria [9] and the feasibility and safety
of such an observational policy.
Methods
Enrolment of trial patients was carried out from
October 1991 to May 1994 in two hospitals in
Western Norway [9].
Disease denitions and inclusion criteria
AC was dened as acute abdominal pain, commonly
in the right subcostal or midline epigastric area with a
duration of more than 8 h and tenderness on clinical
examination in the upper right quadrant. This was
conrmed by the presence of gallbladder stones and
inammation signs on ultrasonography and by clinical
biochemistry data.
During the study period, 180 patients with AC
were evaluated. Of these, 71 patients met predened
criteria for exclusion, 6.7% (12/180) with suspected
or obvious peritonitis, and 109 patients were eligible
for randomization. From this group, 45 patients
(41.3%) were excluded for various reasons, and the
remaining 64 patients (58.7%), 36 women (56.3%)
and 28 men, of mean age 55.3 years (range 2677)
who gave consent for participation, were randomized
to observation (n = 33) or cholecystectomy (n = 31)
[9]. Thus, patients who needed urgent treatment with
surgery or percutaneous management were ineligible
for the study [9].
End points and outcome measurements
The main end points were feasibility and safety of
observation according to rate and severity of recurrent
gallstone disease. All gallstone-related events that led
to hospital or outpatient clinic contact after randomization were recorded. In those randomized to operation, outcome was recorded as postoperative events
or major complications. Events that took place before
operation in the group randomized to surgery were
not included in the analysis as they were a consequence of the delay caused by the waiting list policy in
our health-care system and were not in accordance
with the primary intention to examine the effect of

observation, although they were dealt with in the

short-term analysis [4]. A secondary end point was
completion of randomized treatment.
Follow-up and cholecystectomy
Patients who were randomized to surgery had an
operation median 4 months (range 113) after randomization. Patients randomized to observation had
the possibility to terminate their participation (drop
out) in the study and have their gallbladder removed
after discussion with any of the staff doctors in the
respective hospitals, if their problems escalated or
their present situation, although stable, was found
to be intolerable after all. This treatment regime
did not change throughout the whole study period
except for questionnaires up to 5 years [2]. Withdrawals other than change of treatment groups (drop
out) or natural death did not occur.
Follow-up in the study was complete until death or
concluded a mean 14 years (range 1316) after randomization by checking hospital records to register
new events. Information of patients whereabouts was
checked through the National Population Registry.
Ethics
The trial was initially evaluated and approved by the
Regional Committee for Medical and Health Research
Ethics of Western Norway, and the Data Inspectorate for
National Registries. The follow-up was given renewed
approval. Death certicates were collected from Statistics, Norway. The study design was lately registered at
clinicaltrials.gov (NCT11900280).
Statistics
Around 1990 when the structure of the RCT was
designed, we felt that insufcient knowledge was
available to comfortably help compose statistically
valid groups that included observation. However,
for practical purposes, more than 500 patients with
gallstone disease were interviewed during 21/2 years at
two hospitals, and of these, one-third were diagnosed
with AC [9].
The results were analyzed according to a modied
intention to treat with a comparative summary of new
events and postoperative complications as well as
completion of randomization in compliance with
the trials protocol. The AndersenGill model for
multiple failures was used to compare frequency of
gallstone-related events between different subgroups
of patients [10]. A signicance level of 0.05 was
applied. The statistical programs used were SPSS
16.0 for Mac and Intercooled Stata 9.2 for Macintosh.

1259

Observation after acute cholecystitis is an option

In retrospect, a difference in outcome of 25% versus
60% would have been needed to achieve a power of
0.8, alternatively 330 patients in each group to obtain
a 25% versus 35% outcome difference.

treatment between the randomized treatment groups

(p = 0.077, Table III).

Results

At follow-up, 8 and 10 (overall 28.1%) in the respective groups (observation and operation) had died.
Three patients from the observation group and one
in the surgical group were censored as shown in
Figure 1. None of the deaths were caused by gallstone
disease or gallbladder cancer.

Mortality

In the observation group, seven patients had another

incident of cholecystitis and two patients had common bile duct (CBD) stones, while one patient experienced both and one patient had a gallstone pain
attack. This meant that 30.3% (10/33) experienced a
new event of complicated gallstone disease (Table I).
One patient randomized to cholecystectomy dropped
out and was only observed but developed gallstone
ileus and underwent laparotomy without removal of
the gallbladder. There were no differences in occurrence of events between age groups.

Excluded patients
In summary, 50% of excluded patients (58/116) had
had a cholecystectomy.
Discussion
Our randomized controlled study asked two important questions: is observation of AC feasible and is
it dangerous? These questions have not, to our
knowledge, been examined in an RCT with an
extended long-term follow-up, perhaps because there
are several conceptual obstacles to such a trial. The
inclination to remove a diseased gallbladder is deeprooted in the medical community. After all, cholecystectomy for gallstone disease has been common
practice for a century. Besides, AC is generally feared
as a complication, especially in the elderly and frail.
As many as 3943% of patients with AC never have
any warning symptoms [11,12]. Thus, not history
of gallstone disease alone but medical indications for
surgery, elective and emergent, have to be considered
in light of old age, co-morbidity, and complications
like septicemia, threatening perforation, and so on.
Several studies have corroborated our ndings of
the rst 5 years being the time period when new events
usually take place [11,12] although Friedman and

Cholecystectomy
At follow-up, 59.4% (38/64) of all randomized
patients had been operated, one-third (11/33) of
the observation group and 87.1% of the surgical
group (Tables III.) Twenty-seven (71%) were operated laparoscopically. Patients who dropped out from
the observation group underwent cholecystectomy
median 15 months after randomization. Only one
operation took place beyond 5 years (Figure 1):
A patient from the observation group had surgery
without complications. Thus, the ndings regarding
complications are unchanged from Table III in the
earlier report [9]. The difference in rates of adverse
events in the two randomized groups did not reach
statistical signicance (p = 0.565) when analyzed for
multiple failures (events).
Gender did not make any signicant impact on the
cholecystectomy rate (p = 0.456). No signicant difference was found in completion of randomized

Table I. An overview of new gallstone-associated events in all patients, including those who dropped out from their randomized group and
crossed over to the other group. Events that occurred to patients on the waiting list for surgery are excluded.
Observation, n = 33

Operation, n = 31
Operated, n = 27

Operated, n =11
Variables
Pain attacks
Acute cholecystitis
CBD stone
Acute pancreatitis
Gallstone ileus
Patients

Observed, n = 22

Preoperative

Postoperative

Observed, n = 4

Preoperative

Postoperative

2*
4*
1
0
0
5

1
4
2
0
0
6

0
0
0
0
0
0

0
0
0
0
1
1

4
0
1
0
0
5

*Two patients with both AC and pain attacks; one patient with both AC and CBD.
Abbreviations: AC = acute cholecystitis; CBD = common bile duct.

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M. Schmidt et al.

Table II. Gallstone-associated events and postoperative complications analyzed according to completed randomized treatment only. Patients
who dropped out from the RCT were excluded from this analysis. The AndersenGill model for multiple failures was used to compare the
outcome.
No. of
patients
Randomized treatment

After
randomization

All
events

Postoperative

Total

Completed
(%)

Patients
w/events

Patients
w/events

No. of
complications

Patients
w/events (%)

33
31

22 (66)
27 (87)

5
0

5 (23)
10 (37)

Observation
Operation

coworkers found a steady appearance in new events

over a 25-year period [8]. A retrospective study of
waiting list patients found an incidence of 6.7% for
interim emergency admissions, presumably for similar symptoms, when patients were observed up to
1 year [13].
During follow-up, eight patients randomized to
observation had another incident of cholecystitis
and two patients had CBD stones (one of which
had CBD stones both before and after surgery).
One of the 10 patients experienced both. Thus, altogether 30.3% of patients experienced a new event of
complicated gallstone disease and 9% had CBD
stones during observation. New complicated events
have been observed at a cumulative rate of 710% for
cholecystitis [8,14] and about 26% for CBD stones
or acute pancreatitis in studies that observed patients

p-Value
0.565

between 5 and 10 years [8]. One patient who was

randomized to cholecystectomy had postoperative
CBD stones for an incidence of 3.2%. In operated
patients, a 24% incidence of postoperative CBD
stones has been observed in patients between 5 and
10 years after cholecystectomy [2,4,9,11,12]. Removing the gallbladder in order to prevent CBD stones
does not seem to inuence the course profoundly
[12,15,16]. This is in accordance with the present
study although cautious interpretation is warranted
because of the small numbers. It has long been the
practice in our hospitals not to do preoperative cholangiography in connection with cholecystectomy
because this has been time consuming and costly in
our hands and has not been contradicted by our
empirical data. The low gure of CBD stones in
accordance with that in the literature seems to support
Group
Operation
Observation
Operation censored
Observation censored

1.0

Cummulative risk of operation

0.8

0.6

0.4

0.2

0.0
0

10

15

Years from randomization

Figure 1. Cumulative risk of an operation for patients in the two randomized groups of observation (three censored) and operation (one
censored).

Observation after acute cholecystitis is an option

1261

Table III. Feasibility of randomized treatment according to completed treatment group (observation or operation).
Completed treatment
Randomized group

Observed n (%)

Operated n (%)

Chi-square test

Observation, n = 33
Operation, n = 31

22 (66.7)
4 (12.9)

11 (33.3)
27 (87.1)

p = 0.077

this policy as a sensible approach. Gallstone ileus can

be treated without cholecystectomy even if recurrences may occur with such a policy in up to 5% [17].
One-third of those randomized to observation were
operated compared with 87% of those in the opposite
group, in summary nearly 60%. An American survey
of Medicare patients found a readmission rate of 29%
during the rst 3 months after discharge and 10%
planned cholecystectomies, but as many as 37% of
discharged patients had CBD stones causing concern
about the correctness of the diagnosis during the rst
stay [18]. It was reported that 28.5% underwent
cholecystectomy after initial discharge and very few
after the rst 90 days.
According to our ndings, the disease did not seem
to increase in severity as time went by. It may be
argued that the patients interest in having surgery
may have dwindled after so many years, but in principle the follow-up procedure remained unchanged
after randomization except for questionnaires up to
5 years [2]. The chance of having cholecystitis after
randomization to observation was 24%. CBD stones
were rare, and acute pancreatitis was almost nonexistent. In other words, observation did not incur
complications in about two-thirds of patients. In
1991, laparoscopic cholecystectomy was just starting
and complications might have been less today in the
operated patients. However, others have reported
similar gures [19].
A follow-up at 5 years found no difference in the
designated Q-o-L parameters [2]. The time span to
the present study could potentially have created confounding life events as well. A practical use of Q-o-L is
arguable because gallstone disease most often appears
in bouts and these tests were usually designed for
chronic ailments restricting daily activities. It has also
caused difculties to dene Q-o-L tests [3,20].
Mortality caused by cholecystitis is almost nonexistent nowadays, and our gures merely reect the
high average age of this population and the subsequent
comparatively long follow-up. These ndings are in
concordance with previous reports by other authors
[11]. Even more supportive of our assessment after
14 years of follow-up is the fact that patients undergoing surgery had a slight increase in death rate compared with non-operated patients. In a recent report of

patients admitted for cholecystitis, 30.9% of those

who did not undergo cholecystectomy during initial
admission, (explanation: 37% of the 30.9% had CBD
stones), died within 2 years [18]. The cholecystectomy
rate was slightly lower than that in our study with 27%
versus 33%. In-hospital mortality in cholecystectomy
patients was 2.1% and in those not operated 2.7%,
perhaps because of more severe co-morbidities preventing surgery in a population with a mean age as high
as 77 years. This series was comparable with ours for
gender ratio. In a study of severe AC treated with
percutaneous gallbladder drainage, 30% died within
another 6 months because of severe co-morbidity [21].
The concept of the study may have met the criteria of
an equivalence study, but the study was not designed as
such because several issues were partly unforeseen.
Therefore, it would have posed difculties to nd
the difference between equivalence and a statistically
acceptable difference if all such variables should have
been included. Several possible approaches could have
been used for statistical analysis [22]. We analyzed
the outcome for feasibility and safety according to the
aims of the study. Thus, no statistically signicant
differences were found when we analyzed fulllment
of randomized treatment and increased severity of the
condition with regard to new events and postoperative
complications. What constitutes an intention to treat in
our RCT may be a matter of debate [22], but to
include outcome after crossover would clearly have
violated the trials intention of comparing one with
the other.
The study was clearly underpowered, and this
may have caused a type II error when completion
of randomized treatment group was analyzed. A more
appropriate outcome measurement and adequate
trial power might have been foreseen today. This is
reected by the fact that no other RCT with this aim
has been reported during this period. However, for
clinical purposes, we think that the primary aim of the
study was met, namely investigation of feasibility and
safety.
We conclude that conservative management is an
option in the elderly and frail. However, for the
younger patients, for example, below 65 years of
age, cholecystectomy will prevent further unwanted
episodes of AC that may be medically compromising

1262

M. Schmidt et al.

and consequently seems a reasonable choice in these

patients.
Acknowledgments
The initial phase of the studies was supported by a
scholarship from the Centre for Clinical Research,
Haukeland University Hospital. The Research Council
of Norway, the Research Committee of Stavanger
University Hospital, the University of Bergen, Helga
Sembs Foundation, and Karla and Arne Oddmars
Foundation gave nancial support. We acknowledge
the supportive collaboration of the staff at the participating hospitals at the start of the studies. The concluding phase of the studies was given nancial support by
Haraldsplass Deaconal Hospital and Western Norway
Regional Health Authorities through the Centre for
Clinical Research at Haukeland University Hospital.
The authors are grateful for Professor Odd Sreides
contribution to the earlier phase of this study and to the
Department of Surgery at Haukeland University Hospital for allowing us to follow up the patients treated at
their hospital. We express our gratitude to Dr. John A.
Dumot at the Digestive Disease Institute, Cleveland
Clinic Foundation, Ohio, for linguistic advice with the
manuscript.
Declaration of interest: The authors report no
conicts of interest. The authors alone are responsible
for the content and writing of the paper.
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