Abstract Background Due to the increase of cardiovascular diseases acetylsalicylic acid (ASA) has become one of the most frequently prescribed drugs these days. Despite the rising number of patients with ASA medication presenting for elective general and abdominal surgery and the potentially increased risk of hemorrhage in these patients, there are no clear, evidence-based guidelines for the perioperative use of antiplatelet agents. The present randomised controlled trial was designed to evaluate the safety and optimize the use of ASA in the perioperative management of patients undergoing general and abdominal surgery. Methods/Design This is a two-arm, monocenter randomised controlled trial. Patients scheduled for elective surgical treatment (i.e. inguinal hernia repair, cholecystectomy and colorectal resections) with ASA as a permanent medication are randomised equally to perioperative continuation or discontinuation of ASA. Patients who are randomised in the discontinuation group stop the administration of ASA five days prior to surgical treatment and start intake of ASA on postoperative day 5. Fifty-two patients will be enrolled in this trial. The primary outcome is the incidence of postoperative bleeding and cardiovascular events at 30 days after surgery. In addition a set of general as well as surgical variables are analysed. Discussion This is a randomised controlled two-group parallel trial designed to assess the safety and optimize the use of ASA in the perioperative management of patients undergoing general and abdominal surgery. The results of this pilot study build the basis for a confirmative randomised controlled trial that may help to clarify the use and potential risk/benefits of perioperative ASA medication in patients undergoing elective surgery. Trial registration The trial is registered with Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN45810007">ISRCTN45810007</a>.</p

A Tiede

Anastasia Rakow

Antithrombotic Trialists' Collaboration

Christoph Reissfelder

Dalibor Antolovic

F Servin

HJ Rupprecht

ISIS 2 (Second International Study of Infarct Survival) Collaborative Group

J O'Riordan

J Thachil

JM Gaspoz

Jürgen Weitz

M Di Minno

Markus W Büchler

Moritz Koch

Nuh N Rahbari

PC Elwood

Pietro Contin

T Lecompte

W Burger

W Lepper

English

PubMed

Abstract Background Due to the increase of cardiovascular diseases acetylsalicylic acid (ASA) has become one of the most frequently prescribed drugs these days. Despite the rising number of patients with ASA medication presenting for elective general and abdominal surgery and the potentially increased risk of hemorrhage in these patients, there are no clear, evidence-based guidelines for the perioperative use of antiplatelet agents. The present randomised controlled trial was designed to evaluate the safety and optimize the use of ASA in the perioperative management of patients undergoing general and abdominal surgery. Methods/Design This is a two-arm, monocenter randomised controlled trial. Patients scheduled for elective surgical treatment (i.e. inguinal hernia repair, cholecystectomy and colorectal resections) with ASA as a permanent medication are randomised equally to perioperative continuation or discontinuation of ASA. Patients who are randomised in the discontinuation group stop the administration of ASA five days prior to surgical treatment and start intake of ASA on postoperative day 5. Fifty-two patients will be enrolled in this trial. The primary outcome is the incidence of postoperative bleeding and cardiovascular events at 30 days after surgery. In addition a set of general as well as surgical variables are analysed. Discussion This is a randomised controlled two-group parallel trial designed to assess the safety and optimize the use of ASA in the perioperative management of patients undergoing general and abdominal surgery. The results of this pilot study build the basis for a confirmative randomised controlled trial that may help to clarify the use and potential risk/benefits of perioperative ASA medication in patients undergoing elective surgery. Trial registration The trial is registered with Current Controlled Trials ISRCTN45810007.</p

Rahbari Nuh N

Contin Pietro

Rakow Anastasia

Reissfelder Christoph

Antolovic Dalibor

Büchler Markus W

Weitz Jürgen

Koch Moritz

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BMC Surgery

A randomised controlled trial to evaluate and optimize the use of antiplatelet agents in the perioperative management in patients undergoing general and abdominal surgery- the APAP trial (ISRCTN45810007)

Springer - Publisher Connector

STUDY PROTOCOL Open Access
A randomised controlled trial to evaluate and
optimize the use of antiplatelet agents in the
perioperative management in patients
undergoing general and abdominal surgery-
the APAP trial (ISRCTN45810007)
Dalibor Antolovic*†, Christoph Reissfelder†, Anastasia Rakow, Pietro Contin, Nuh N Rahbari, Markus W Büchler,
Jürgen Weitz, Moritz Koch
Abstract
Background: Due to the increase of cardiovascular diseases acetylsalicylic acid (ASA) has become one of the most
frequently prescribed drugs these days. Despite the rising number of patients with ASA medication presenting for
elective general and abdominal surgery and the potentially increased risk of hemorrhage in these patients, there
are no clear, evidence-based guidelines for the perioperative use of antiplatelet agents. The present randomised
controlled trial was designed to evaluate the safety and optimize the use of ASA in the perioperative management
of patients undergoing general and abdominal surgery.
Methods/Design: This is a two-arm, monocenter randomised controlled trial. Patients scheduled for elective
surgical treatment (i.e. inguinal hernia repair, cholecystectomy and colorectal resections) with ASA as a permanent
medication are randomised equally to perioperative continuation or discontinuation of ASA. Patients who are
randomised in the discontinuation group stop the administration of ASA five days prior to surgical treatment and
start intake of ASA on postoperative day 5. Fifty-two patients will be enrolled in this trial. The primary outcome is
the incidence of postoperative bleeding and cardiovascular events at 30 days after surgery. In addition a set of
general as well as surgical variables are analysed.
Discussion: This is a randomised controlled two-group parallel trial designed to assess the safety and optimize the
use of ASA in the perioperative management of patients undergoing general and abdominal surgery. The results of
this pilot study build the basis for a confirmative randomised controlled trial that may help to clarify the use and
potential risk/benefits of perioperative ASA medication in patients undergoing elective surgery.
Trial registration: The trial is registered with Current Controlled Trials ISRCTN45810007.
Background
The individual risk for perioperative bleeding in abdom-
inal and general surgery is influenced by multiple factors.
Such factors include extent and type of surgery as well as
patient-related features such as age, co-morbidities and
perioperative medication. Considering the current demo-
graphic development surgeons are being confronted with
older patients presenting with multiple co-morbidities
and medications. Antiplatelet agents and in particular
acetylsalicylic acid (ASA) were shown to be beneficial in
a variety of atherothrombotic diseases [1-4] and are
therefore among the most frequently prescribed drugs
these days. However, due to the increased risk of hemor-
rhage the perioperative use of ASA has remained an
issue of ongoing discussion [5-13].
Randomised controlled trials (RCT) that allow evidence-
based recommendations regarding the perioperative use
* Correspondence: dalibor.antolovic@kssg.ch
† Contributed equally
From the Department of Surgery, University of Heidelberg, Germany
Antolovic et al. BMC Surgery 2011, 11:7
http://www.biomedcentral.com/1471-2482/11/7
© 2011 Antolovic et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
and risk of ASA in general and visceral surgery are still
lacking. Therefore, the decision to balance possible
thromboembolic risks after withdrawal of ASA versus
bleeding risks after continuation of ASA during the peri-
operative period is rather based on the individual experi-
ence and personal opinion of the treating physician and/
or surgeon.
Apart from severe bleeding episodes complicating the
clinical course after an operation, thromboembolic
events also account for serious consequences for the
individual patient. Presumably, the routinely performed
discontinuation of the regular ASA medication in the
perioperative setting entails to an increased incidence of
thromboembolic events. Retrospective analyses have
shown that acute cardiovascular events occur in 2-10%
of patients after perioperative discontinuation of ASA,
mostly within the first eight days after stopping the
long-term anticoagulation regimen.
This is a randomised controlled two-group parallel
trial designed to assess the safety and optimize the use
of ASA in the perioperative management of patients
undergoing general and abdominal surgery. The results
of this trial will be used to perform a valid power calcu-
lation and to design a confirmative RCT with a higher
number of enrolled patients. This may help to clarify
the use and potential risk/benefits of perioperative ASA
medication in patients undergoing elective surgery.
Methods and Design
This study has been designed as a prospective rando-
mised controlled, single centre trial with two study
arms.
After the study has been approved by the ethics
committee of the University of Heidelberg and regis-
tration of the protocol at an international registry
(ISRCTN45810007) patients on continuous medication
with ASA undergoing elective general or abdominal
surgery at the Department of General, Visceral and
Transplant Surgery, University of Heidelberg, Germany
are being screened for participation in this study. Ran-
domisation is conducted using opaque, serially num-
bered envelopes. The envelopes are being supplied by
the Clinical Trial Centre of the Department of Surgery,
University of Heidelberg, Germany.
Participants and Trial population
This study includes patients over 18 years of age who
require long-term ASA therapy and are scheduled for
the following procedures:
1.) Inguinal Hernia Repair (e.g. Shouldice repair, Lich-
tenstein’s repair, laparoscopic hernia repair)
2.) Cholecystectomy (open and laparoscopic approach)
3.) Elective Colorectal Surgery (right or left hemico-
lectomy, sigmoid resection, low anterior resection)
Written informed consent is obtained prior to inclu-
sion into the trial.
Patients with ASA medication who were advised to con-
tinue antiplatelet therapy throughout the perioperaive per-
iod due to medical indication (e.g. shortly after coronary
stent implantation, bleeding disorders, etc.) or who were
cardiologically evaluated as being a high-risk patient were
excluded from this trial. Moreover, emergency procedures,
simultaneous participation in another clinical trial, with-
drawn or missing written consent and/or a mental condi-
tion rendering the subject incapable of understanding the
nature, scope, and consequences of the trial lead to exclu-
sion from this study. The eligibility criteria are:
Inclusion Criteria
- Age equal or greater than 18 years
-Patient has given written informed consent
-Patient is scheduled for elective surgery based on an
indication for either inguinal hernia repair, cholecystect-
omy or colorectal surgery procedures
-Patient treated with ASA on a long-term-medication
basis
-Low- or intermediate-risk patient according to cardi-
ological evaluation
Exclusion Criteria
-High-risk patient according to cardiological evaluation
(e.g. necessary perioperative continuation of the ASA
application shortly after coronary stent implantation,
interfering bleeding disorders etc.)
-Emergency procedure
-Withdrawn or missing written consent
-Simultaneous participation in another clinical trial
with interference of intervention and outcome
-Severe psychiatric or neurologic diseases or a mental
condition rendering the patient incapable of understand-
ing the nature, scope, and consequences of the trial.
-Concomitant treatment with coumarin-type-anticoa-
gulation or clopidogrel
Trial interventions
Patients are randomized into one the following two
study arms:
Arm 1: Continuation of ASA during the perioperative
period
Arm 2: Discontinuation of ASA five days prior to sur-
gery and resumption of ASA intake on postoperative
day 5.
Primary outcomes/secondary outcomes (Table 1)
The primary objective of the present randomised con-
trolled trial is to evaluate the safety of continuous use of
ASA during the perioperative period of patients under-
going elective general and abdomina surgery with the
Antolovic et al. BMC Surgery 2011, 11:7
http://www.biomedcentral.com/1471-2482/11/7
Page 2 of 4
ultimate aim to generate high-quality data for the devel-
opment of evidence-based guidelines on the periopera-
tive use of ASA.
The primary outcome is the incidence of perioperative
bleeding episodes and clinically apparent thromboem-
bolic events within 30 days after surgery. Secondary
endpoints are the duration of the surgical intervention,
intraoperative blood loss, transfusion requirements,
length of hospital stay (d), medical and surgical morbid-
ity, and the necessity of readmission.
Sample size
Owing to the lack of data that would allow a valid sam-
ple size calculation, the present trial was designed as a
randomised controlled pilot trial. A total of fifty-two
consecutive patients with continous low-dose medica-
tion of ASA, who are scheduled for elective general and
abdominal surgery, are enrolled in the present study and
randomly allocated to either study arm. This pilot trial
generates data for the power calculation of a subsequent
RCT with a confirmative design. For the pilot phase of
this trial the number of patients to be enrolled was arbi-
trary defined by the investigators.
Statistical analysis
The statistical analysis will be performed on the basis of
baseline data such as age, gender, type of surgery, compli-
cations/adverse effects and duration of hospital stay.
There will be a report of the mean and standard devia-
tion for variables with continuous measures, whereas we
will report numbers and percent for categorical data. Sta-
tistical computations will be performed with JMP (SAS
Institute, Cary, NC) and SPSS (SPSS Inc., Chicago, IL).
Ethical approval and registration
The ethics committee of the University of Heidelberg
approved this clinical study (Reference number S003-
2008). The trial is registered at an international study reg-
istry http://www.controlled-trials.com ISRCTN45810007).
Acknowledgements
The investigators thank participants and staff of the Central Patient
Management (ZPM) of our hospital for screening patients, especially Mrs.
Silke Auer and Mrs. Heike Siebert and Professor Christoph Seiler for his
assistance in the design of this study. Additional thanks are offered to PD Dr.
Moritz von Frankenberg for help in recruitment and running of the trial.
Authors’ contributions
DA, CR, AR and MK designed the study and wrote the original protocol, PC
and NNR help in enrolling patients in this study and MWB and JW are
scientifically responsible for the study. All authors read and approved the
final manuscript.
Competing interests
The authors declare that they have no competing interests with this study.
Received: 26 September 2010 Accepted: 3 March 2011
Published: 3 March 2011
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Table 1 Primary and secondary outcomes
Primary endpoints Definition and assessment of outcomes
Perioperative thromboembolic event
Perioperative bleeding complication Occurrence of critical blood-loss requiring surgical intervention or the application of coagulation products (FFP,
coagulation factors) to normalize the INR
Secondary endpoints Definition and assessment of outcomes
Operation time [min]: Time from skin incision to placement of last skin staple/suture.
Intraoperative blood loss [ml]: Blood loss observed from skin incision to placement of last staple/suture.
Duration of postoperative hospital stay
[days]:
Time from day of surgery to day of discharge.
Morbidity/
Surgical complications
Medical complications
Peri-/postoperative need for blood/
coagulation products
Re-laparotomy/laparoscopy Re-operation within the time of index hospitalization respectively within the time of follow-up after the
index operation.
In-hospital mortality: Death due to any reason within the patient’s initial hospital stay.
Readmisson
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Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1471-2482/11/7/prepub
doi:10.1186/1471-2482-11-7
Cite this article as: Antolovic et al.: A randomised controlled trial to
evaluate and optimize the use of antiplatelet agents in the
perioperative management in patients undergoing general and
abdominal surgery- the APAP trial (ISRCTN45810007). BMC Surgery 2011
11:7.
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Crossref

(Second International Study of Infarct Survival) Collaborative Group: Randomised trial of intravenous streptokinase, oral aspirin, or both, or neither among 17,187cases suspected acute myocardial infarction:ISIS-2. Lancet

A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infraction. Br Med J

al: Cost effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary artery disease.

Antithrombotic Trialists’ Collaboration: Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ

Di Minno G: Perioperative handling of patients on antiplatelet therapy with need for surgery. Intern Emerg Med

R: Antiplatelet Agents in the Perioperative Period. Arch Surg

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A randomised controlled trial to evaluate and optimize the use of antiplatelet agents in the perioperative management in patients undergoing general and abdominal surgery- the APAP trial (ISRCTN45810007)

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