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Multicentre observational cohort
study of NSAIDs as risk factors
for postoperative adverse events
in gastrointestinal surgery
Dmitri Nepogodiev,
1
Stephen J Chapman,
2
James C D Glasbey,
3
Michael Kelly,
4
Chetan Khatri,
5
J Edward Fitzgerald,
6
Aneel Bhangu
7
To cite: Nepogodiev D,
Chapman SJ, Glasbey JCD,
et al. Multicentre
observational cohort study of
NSAIDs as risk factors
for postoperative adverse
events in gastrointestinal
surgery. BMJ Open 2014;4:
e005164. doi:10.1136/
bmjopen-2014-005164
▸Prepublication history for
this paper is available online.
To view these files please
visit the journal online
(http://dx.doi.org/10.1136/
bmjopen-2014-005164).
Received 28 February 2014
Revised 9 June 2014
Accepted 10 June 2014
For numbered affiliations see
end of article.
Correspondence to
Aneel Bhangu;
aneelbhangu@doctors.org.uk
ABSTRACT
Introduction: Non-steroidal anti-inflammatory drugs
(NSAIDs) are recommended as postoperative analgesia
by the Enhanced Recovery After Surgery Society.
Recent studies have raised concerns that NSAID
administration following colorectal anastomosis may be
associated with increased risk of anastomotic leak.
This multicentre study aims to determine NSAIDs’
safety profile following gastrointestinal resection.
Methods and analysis: This prospective, multicentre
cohort study will be performed over a 2-week period
utilising a collaborative methodology. Consecutive
adults undergoing open or laparoscopic, elective or
emergency gastrointestinal resection will be included.
The primary end point will be the 30-day morbidity,
assessed using the Clavien-Dindo classification. This
study will be disseminated through medical student
networks, with an anticipated recruitment of at least
900 patients. The study will be powered to detect a
10% increase in complication rates with NSAID use.
Ethics and dissemination: Following the Research
Ethics Committee Chairperson’s review, a formal waiver
was received. This study will be registered as a clinical
audit or service evaluation at each participating
hospital. Dissemination will take place through
previously described novel research collaborative
networks.
BACKGROUND
The Enhanced Recovery After Surgery Society
recommends the use of non-steroidal anti-
inflammatory drugs (NSAIDs) as part of post-
operative analgesia protocols.
1
The routine use
of NSAIDs is also endorsed by the WHO’sPain
Relief Ladder. NSAIDs have been shown to be
generally effective and safe as postoperative
analgesia, with an opioid-sparing effect.
23
Recent evidence has questioned the safety
of NSAIDs following major gastrointestinal
(GI) surgery. Two retrospective analyses of
different prospective databases of patients
undergoing primary colorectal anastomosis
found that specific NSAIDs may increase the
risk of anastomotic leak. The first showed
that among 2800 patients postoperative diclo-
fenac use was independently associated with
increased risk.
4
The second studied 500
patients, finding that the introduction of pro-
tocolised use of celecoxib brought a signifi-
cant increase in the anastomotic leak rate
from around 3% to 15%.
5
A further retro-
spective study of 800 patients also suggested
that non-selective NSAIDs may increase anas-
tomotic leak rates.
6
These clinical findings are supported by
animal studies that have demonstrated that
NSAID use following bowel anastomosis may
be associated with decreased anastomotic
strength and increased leak rates.
78
NSAIDs
are implicated in reducing collagen synthesis
and hydroxyproline deposition during the
healing process. Downregulation of prostaglan-
din expression may also increase microthrom-
bus and microembolus formation, further
contributing to postoperative adverse effects.
The need for further evidence
Concerns have been raised about the safety
of NSAIDs following bowel anastomosis;
however, the majority of the evidence until
now is reliant on secondary analyses or retro-
spective series. Most studies concern colorec-
tal surgery, with very little evidence available
for oesophageal and gastric surgery.
Furthermore, most studies focus on anasto-
motic leaks, providing no evidence on the
broader side effect profiles of NSAIDs, which
may include increased risk of GI bleeding,
cardiac ischaemia and renal failure.
Primary aim
The primary aim of this study was to determine
the safety profile of postoperative NSAIDs after
GI resection in current practice across the UK.
Nepogodiev D, Chapman SJ, Glasbey JCD, et al.BMJ Open 2014;4:e005164. doi:10.1136/bmjopen-2014-005164 1
Open Access Protocol
Hypothesis
The 30-day adverse event rate, following risk adjustment,
should be equivalent in patients taking and not taking
NSAIDs.
METHODS
Study design
We plan to undertake a national multicentre prospective
audit which will be disseminated through university
medical school and student networks (figure 1). The
generic collaborative methodology has been described
previously.
9
Study setting
This study will take place in general surgical units in
National Health Service (NHS) hospitals. Any of the
NHS hospitals performing elective or emergency GI
resection may participate. Each centre will contribute
2 weeks of consecutive patient data from up to two study
periods.
Inclusion criteria
▸Consecutive adult patients undergoing upper or
lower GI bowel resection.
▸Patients undergoing either elective or emergency,
and open, laparoscopic, laparoscopic-assisted or
laparoscopic-converted procedures may be included.
▸Bowel resection is defined as complete transection
and removal of a segment of the rectum, colon, small
bowel, stomach or oesophagus.
Exclusion criteria
▸Patients under 18 years of age.
▸Appendicectomy for acute appendicitis. Patients who
undergo incidental appendicectomy as part of
another procedure may be included.
▸Any procedure with bowel repair, but without
resection.
▸Wedge resection without complete bowel transaction.
▸Trauma indication.
▸Gynaecological primary indication.
▸Urological primary indication.
Primary outcome measure
The primary outcome measure will be the 30-day
adverse event rate, measured by the Clavien-Dindo classi-
fication. This is an internationally standardised and vali-
dated scoring system for postoperative complications
(table 1).
10
Secondary outcomes
Secondary outcome measures will be anastomotic leak,
wound infection and cardiovascular events (table 2).
Explanatory variables
Administration of NSAIDs from day 1 (day of surgery)
through to the third postoperative day is the main
explanatory variable. Patients will be stratified into high
(recommended daily dose or above) or low (below the
recommended daily dose, including once only) NSAID
dose groups. Data will be collected on the specific
NSAID administered in order to allow analysis by NSAID
type. Aspirin will not be considered as an NSAID for this
analysis, although data on its administration will be col-
lected. The Revised Cardiac Risk Index will be calcu-
lated for each patient to adjust for pre-existing
cardiovascular risk (box 1).
12
Data will be collected on
the operation type (colorectal or upper GI/hepatobili-
ary) to facilitate analysis of homogeneous operative
groups.
Quality assurance
Although many collaborators participating in the study
will be medical students, each local team must include
at least one qualified doctor to closely supervise the stu-
dents. The study will additionally be registered with a
sponsoring consultant surgeon at each site.
Figure 1 Flowchart of study design. GI, gastrointestinal; LOS, length of stay; SSI, surgical site infection.
2Nepogodiev D, Chapman SJ, Glasbey JCD, et al.BMJ Open 2014;4:e005164. doi:10.1136/bmjopen-2014-005164
Open Access
A detailed protocol describing how to register the
study and an in-depth description of data fields and how
to collect them will be made available to collaborators.
This protocol will be interactively presented and
explained in detail at a national collaborators meeting.
Regional leads for the study will also be encouraged to
hold meetings with local collaborating teams to debrief
them on the protocol. Feedback from these meetings
will be used to clarify any ambiguities in the protocol.
To ensure that collaborators understand the inclusion
criteria and application of the Clavien-Dindo classifica-
tion, they will be asked to complete a case-based online
e-learning module prior to starting data collection.
In order to overcome a learning curve in identifying
patients and relevant data, all participating centres will
be asked to pilot completing patient identification and
the initial stages of the data collection form for 1 day in
the week leading up to the main study starting date.
Throughout the data collection period, the trial man-
agement group will hold weekly Twitter question and
answer sessions (http://www.twitter.com/STARSurgUK),
giving an opportunity for collaborators to clarify any
uncertainties regarding the protocol. A summary of fre-
quently asked questions will be distributed to all colla-
borators following each Twitter session, providing real-
time feedback to collaborators.
Validation
Following data collection, only data sets with >95% data
completeness will be accepted for pooled national
Table 1 The Clavien-Dindo classification of postoperative
complications
Grade Definition (examples listed in italics)
I Any deviation from the normal postoperative
course without the need for pharmacological
treatment other than the “allowed therapeutic
regimens”, or surgical, endoscopic and
radiological interventions
Allowed therapeutic regimens are: drugs as
antiemetics, antipyretics, analgesics, diuretics and
electrolytes. This grade also includes
physiotherapy and wound infections opened at
the bedside but not treated with antibiotics
Examples: Ileus, thrombophlebitis
II Requiring pharmacological treatment with drugs
beyond those allowed for grade I complications.
Blood transfusions and total parenteral nutrition
are also included
Examples: Surgical site infection treated with
antibiotics, myocardial infarction treated medically,
deep venous thrombosis treated with
low-molecular weight heparin, pneumonia or
urinary tract infection treated with antibiotics
III Requiring surgical, endoscopic or radiological
intervention
Examples: return to theatre for any reason,
endoscopic therapy, interventional radiology
IV Life-threatening complication requiring critical care
management; CNS complications including brain
haemorrhage and ischaemic stroke (excluding
TIA), subarachnoidal bleeding
Examples: Single or multiorgan dysfunction
requiring critical care management, for example,
pneumonia with ventilator support, renal failure
with filtration
V Death of a patient
CNS, central nervous system; TIA, transient ischaemic attack.
Table 2 Secondary outcome measures
Outcome measure Definition
Length of stay Day of admission counts as day
1, and the day of discharge as a
whole day
Anastomotic leak Anastomotic leak detected
clinically/symptomatically,
radiologically and/or
intraoperatively
Intra-abdominal/
intrapelvic collection
Abscess/collection leak detected
clinically/symptomatically,
radiologically and/or
intraoperatively
Wound infection Based on the Centre for Disease
Control’s definition of surgical
site infection,
11
which is any one
of:
(1) Purulent drainage from the
incision
(2) At least two of: pain or
tenderness; localised swelling;
redness; heat; fever; AND the
incision is opened deliberately to
manage infection or the clinician
diagnoses a surgical site
infection
(3) Wound organisms AND pus
cells from the aspirate/swab
Cardiac event Includes myocardial infarction,
unstable angina, sudden death
from cardiac causes, ischaemic
and haemorrhagic stroke,
transient ischaemic attack,
peripheral arterial thrombosis,
peripheral venous thrombosis
and pulmonary embolus
Box 1 The Revised Cardiac Risk Index
Revised Cardiac Risk Index
1. History of ischaemic heart disease
2. History of congestive heart failure
3. History of cerebrovascular disease (stroke or transient ischae-
mic attack)
4. History of diabetes requiring preoperative insulin use
5. Chronic kidney disease (creatinine >177 mmol/L)
6. Undergoing suprainguinal vascular, intraperitoneal or
intrathoracic surgery
Nepogodiev D, Chapman SJ, Glasbey JCD, et al.BMJ Open 2014;4:e005164. doi:10.1136/bmjopen-2014-005164 3
Open Access
analysis. An independent assessor will validate 5% of all
data points, with a target of >98% accuracy.
Data management
A standardised Microsoft Excel spreadsheet (Excel 2010;
Microsoft, Redmond, Washington, USA) with preset
fields will be used to collect data at each centre. Data
protection regulations at each centre will be complied
with. Patient identifiable data will not be transmitted to
the trial management group. The required anonymous
data fields are shown in table 3.
Anticipated minimum recruitment
It is estimated that an average centre performs approxi-
mately 15 GI resections in a 14-day period. A minimum
of 60 centres will be recruited, with at least two centres
participating at each of the 30 medical schools. Overall,
we anticipate recruiting at least 900 patients.
Power calculation
The study will have at least 80% power to detect an
increase in the 30-day adverse event rate from 15% to
25% with NSAID use. It is anticipated that a third of the
Table 3 Required data fields
1 Patient age (whole years) Years
2 Patient gender Male, female
3 ASA score I, II, III, IV, V
4 History of ischaemic heart disease Yes, no
5 History of congestive heart failure Yes, no
6 History of cerebrovascular disease (stroke or transient
ischaemic attack)
Yes, no
7 History of diabetes No, diet, controlled, tablet controlled, insulin controlled
8 Chronic kidney disease (creatinine >177 μmol/L) Yes, no
9 Was the patient taking regular aspirin? Yes, and restarted in the first 7 postoperative days; yes, but
did not restart in the first 7 postoperative days; no
10 Was the patient taking a perioperative statin? Yes, high dose (40 mg OD simvastatin or equivalent),
Yes, low dose (5–20 mg OD simvastatin or equivalent),
No
11 Date of operation DD/MM/YY
12 Time of operation 24 h clock
13 Operative approach Laparoscopy, laparoscopy converted to open, open
14 Primary operation performed Hartmann’s, left hemicolectomy, right hemicolectomy,
subtotal colectomy, panproctocolectomy, anterior resection,
abdominoperineal resection, small bowel resection, complete
gastrectomy, partial gastrectomy, oesophagectomy,
Whipple’s, other (free text)
15 Elective or emergency Elective, emergency
16 Anastomosis performed Handsewn, stapled, stoma
17 Stoma formation Planned temporary, permanent, none
18 Underlying pathology/indication Diverticular disease, hernia, malignancy, polyp, ischaemic
bowel, adhesional obstruction, faecal perforation, ulcerative
colitis, Crohn’s disease, postoperative complication, other
19 Highest postoperative glycaemic reading within 72 h of
surgery using finger prick, blood gas or laboratory value
(mmol/L)
Value (mmol/L)
20 Postoperative critical care admission? Planned from the theatre, unplanned from the theatre,
unplanned from the ward, none
21 Postoperative ERAS pathway used? Yes, no
22 Was an NSAID used postoperatively? Yes—ibuprofen, yes—diclofenac, yes—naproxen, yes—
celecoxib, yes—rofecoxib, yes—other, no
23 What day was the first dose of NSAID given? Day 1–7 (day 1 is day of surgery), none given
24 What dose of NSAID was given? Low, high, none given
25 Total length of stay (days) Days
26 30-day readmission? Yes, no
27 Surgical complication grade (Clavien-Dindo
classification, list most severe grades I–V)
None, I, II, III, IV, V
28 Anastomotic leak Yes, no
29 Wound infection Yes, no
30 Intra-abdominal/pelvic abscess Yes, no
31 Cardiovascular event Yes, no
ASA, American society of anesthesiologists; ERAS, enhanced recovery after surgery; NSAID, non-steroidal anti-inflammatory drug.
4Nepogodiev D, Chapman SJ, Glasbey JCD, et al.BMJ Open 2014;4:e005164. doi:10.1136/bmjopen-2014-005164
Open Access
patients will receive NSAIDS.
4
A baseline complication
rate of 15% was used to determine the sample size,
acting as a midpoint between high and low rates from
various subgroups undergoing bowel resection. This rate
was based on a recent audit of emergency appendicec-
tomy in the UK, a combination of elective and emer-
gency surgery, and known morbidity profiling.
10 13
By
recruiting 300 patients receiving NSAIDs and 600
control patients, this study will have 93.5% power to
detect an increase in the complication rate from 15% to
25% (α=0.05).
Statistical analysis
Differences between demographic groups will be tested
with the χ
2
test. Multivariable binary logistic regression
will be used to test the influence of clinically plausible
variables on the outcome measures, to produce adjusted
OR and bootstrapped 95% CI. These tests will be per-
formed firstly on the whole dataset and then on a
matched group of 2:1 control : experimental (NSAID
administration), using propensity scoring. Data handling
will be performed in SPSS V.21.0 and statistical model-
ling in the R Foundation Statistical Programme 3.0.0.
ETHICS AND DISSEMINATION
Research ethics approval
Following the Research Ethics Committee Chairperson’s
review, a formal waiver was received. The study will be
undertaken as a clinical audit. This was further sup-
ported by written advice from a University NHS Trust
Research & Development Office Director and the
National Research Ethics Service (NRES). This study will
be registered as a clinical audit or service evaluation at
each participating hospital.
Protocol dissemination
The generic collaborative methodology underlying
protocol dissemination and collaborator recruitment has
been described previously.
9
The protocol will be dissemi-
nated primarily through medical student networks,
including student surgical and medical societies. The
Association of Surgeons in Training (http://www.asit.
org) will also disseminate the protocol to its members. A
student local lead will be designated at each medical
school to facilitate local dissemination. The protocol
document will be made available online and will also be
disseminated through social media, including Twitter
(https://twitter.com/STARSurgUK) and Facebook
(https://www.facebook.com/STARSurgUK).
DISCUSSION
This paper describes the protocol for a novel study,
addressing an important clinical question using rapid-
delivery, snapshot methodology. The development of the
national network, formed by the natural geographical
locations of medical schools within the UK, is also novel.
The observational nature of this study means it is
classified as an audit. Within the confines of this, a
detailed and protocolised approach is warranted to
ensure maximum quality.
The multicentre nature of this study means that the
approaches taken for its design are pragmatic. In par-
ticular, the definitions used and the number of data
points are designed to aid local investigators to ensure
simplicity of delivery, while containing enough detail to
answer the relevant clinical question.
A randomised controlled trial would provide the
highest level of evidence to guide patients and clinicians
towards optimal postoperative analgesic regimes. In
order to power these trials, and to justify funding appli-
cations, a multicentre observational study is required.
Author affiliations
1
Norwich Academic Foundation Programme, Norwich, UK
2
University of Leeds Medical School, Leeds, UK
3
Cardiff University Medical School, Cardiff, UK
4
University of Liverpool Medical School, Liverpool, UK
5
Imperial College London Medical School, London, UK
6
University College London, London, UK
7
West Midlands Deanery General Surgery Rotation, Birmingham, UK
Acknowledgements The Royal College of Surgeons of England (http://www.
rcseng.ac.uk) is providing complimentary meeting facilities for the training
day.
Collaborators STARSurg Collaborative. The STARSurg Steering Committee
prepared this protocol manuscript: DN, SJC, JCDG, MK, CK, JEF, AB.
Contributors DN and JEF participated in the conception, design, writing and
editing of the protocol. SJC, JCDG, MK and CK participated in the design and
writing of the protocol. AB participated in the statistical analysis and is the
guarantor. All authors read and approved the final manuscript.
Funding A regional meeting grant has been received from the Association of
Surgeons in Training (http://www.asit.org) towards the costs of the national
collaborator training day.
Competing interests DN, MBChB, is an academic foundation trainee (year 2)
at the Norfolk & Norwich University Hospital. SJC, BSc, is a final year medical
student at the University of Leeds Medical School. JCDG, BSc, is a final year
medical student at the Cardiff University Medical School. MK, BSc, is a final
year medical student at the University of Liverpool Medical School. CK, BSc,
is a fifth year medical student at the Imperial College London Medical School.
JEF, BA MBChB MRCS, is a general surgery registrar at Barnet Hospital and
studying at University College London. AB, MBChB MRCS, is an academic
general surgery registrar in the West Midlands Deanery General Surgery
Rotation.
Provenance and peer review Not commissioned; externally peer reviewed.
Open Access This is an Open Access article distributed in accordance with
the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license,
which permits others to distribute, remix, adapt, build upon this work non-
commercially, and license their derivative works on different terms, provided
the original work is properly cited and the use is non-commercial. See: http://
creativecommons.org/licenses/by-nc/3.0/
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