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Clinical Study Protocol
ASINC
Principal investigator:
Dr Anna Oscarsson Tibblin
Department of Anaesthesia
University Hospital
SE-58185 Linköping
On-site investigator:
Dr Anil Gupta
Department of Anaesthesia
University Hospital
SE-70182 Örebro
Sponsor:
Professor Christina Eintrei
Department of Anaesthesia
University Hospital
SE-58185 Linköping
On site investigator:
Professor Johannes Järhult
Department of Surgery
Ryhov Hospital
SE-55185 Jönköping
Study Coordinator:
Susanne Öster
Department of Anaesthesia
University Hospital
SE-58185 Linköping
On-site investigator:
Professor Robert Hahn
Department of Anaesthesia
Södertälje Hospital
SE-15286 Södertälje
On-site investigator:
Dr Helena Krook
Department of Anaesthesia
Vrinnevi Hospital
SE-60182 Norrköping
On-site investigator:
Dr Eva Pettersson
Department of Anaesthesia
Motala Hospital/University Hospital
SE-58185 Linköping
Co-investigator:
Dr Matti Nyström
Department of Anaesthesia
University Hospital
SE-58185 Linköping
Co-investigator:
Dr Anders Bolling
Department of Anaesthesia
Vrinnevi Hospital
SE-60182 Norrköping
Co-investigator:
Dr Eva-Lena Zetterlund
Department of Anaesthesia
University Hospital
SE-581 85 Linköping
Consultant Statistics:
Mats Fredricson PhD
Department of Medical Statistics
University Hospital
SE-581 85 Linköping
Consultant Cardiology:
Professor Eva Swahn
Department of Cardiology
University Hospital
SE-58185 Linköping
Consultant Cardiology:
Dr Tim Tödt
Department of Cardiology
University Hospital
SE-58185 Linköping
2
Table of contents
Page no:
4.
5.
6.
7.
8.
Introduction
1.1
Background
1.2
Earlier data
1.3
Long-term outcome
1.4
Relevance of this study
1.5
Aim of this study (study objectives)
2
Methods
2.1
Study design
2.2
Study population
2.3
Inclusion criteria
2.4
Exclusion criteria
9.
11.
13.
Definitions
2.5
Pharmaceutical considerations
2.6
Blinding procedures
2.7
Recruitment & Randomization
2.8
Statistics & Power
2.9
Study Flow Chart
15.
Comments
16.
Myocardial Damage Flow Chart
17.
2.10
Perioperative Adverse Events
18.
3.
Follow-up
4.
Study Outcome
4.4
Definitions of Study Outcomes
5.
Organization
6.
Data management
7.
Monitoring
8.
Ethical considerations
19.
20.
21.
References
3
The ASINC study
(Aspirin in non-cardiac surgery)
1.
Introduction
1:1
Background
Approximately 12 % of the Swedish population suffers from cardiovascular disease and it
causes about 50% of all deaths. Therefore, myocardial ischemia and infarction continue to be
a major cause of perioperative morbidity and mortality in patients undergoing non-cardiac
surgery. The incidence of perioperative myocardial infarction varies from 1,6-38%, depending
on the study population and the type of surgery. The prognosis after perioperative myocardial
infarction remains poor, with a mortality rate of 36-70%.
Numerous studies have shown the efficacy of aspirin in reducing major cardiovascular events
in a nonsurgical setting. As a growing number of patients on aspirin therapy are undergoing
non-cardiac surgery, the risk and benefit of this drug in a perioperative setting will become
increasingly important. Despite potential reduction in thrombotic complications, aspirin has
traditionally been discontinued 7-10 days before elective surgery because of concern of
perioperative hemorrhagic complications.
Due to the increasing data on the efficacy aspirin in reducing any vascular event,
a medical survey has shown that a majority of vascular surgeons continue aspirin therapy in
high risk patients in the perioperative period.
However, evidence from large trials evaluating the perioperative risks and benefits of aspirin
therapy is scarce and there are no prospective, randomised trials evaluating aspirin in the
perioperative period in non-cardiac surgery.
4
1:2 Earlier data
Prior to this investigation, we have studied the incidence of Troponin T
elevation and long-term prognosis in elderly (> 70 years) undergoing noncardiac surgery.
546 patients undergoing non-cardiac surgery were included over an 18 months period. The
patients underwent a range of surgical procedures, including gynaecology, orthopaedics,
urology, general and vascular surgery. Patients admitted for diagnostic procedures were
excluded.
9,7% of the patients developed elevated TnT levels on the 5th to 7th
postoperative day. 11% of the patients with abnormal TnT levels had clinical and/or
electrocardiographic signs of myocardial injury. One year after surgery 32% of the patients
with TnT levels above the diagnostic threshold had died. This compared with a one-year
mortality rate of 5,6% in the patients with normal TnT in the postoperative period.
Consistent with earlier studies, we also demonstrated that the presence of
chronic cardiovascular disease, including known coronary artery disease, previous myocardial
infarction, congestive heart failure, peripheral vascular disease and hypertension, significantly
contributed to the development of abnormal TnT values and myocardial injury . In addition
we confirmed that perioperative anesthetic complications, including hypotension (40% of
baseline systolic pressure), hypoxemia (<90% SpO2 for > 5 minutes), tachyarythmias, as well
as large perioperative bleeding, significantly increased the risk of myocardial cell injury in the
perioperative period. After adjusting for confounding factors, independent predictors of an
elevated postoperative TnT value were medication with diuretics (OR, 3.2 95% CI 1.4-7.2 ),
anticoagulants (OR, 2.6 95% CI 1.1-6.1) and insulin (OR, 5.69 95% CI 1.3-25.2 ).
Peroperative tachycardia remained a strong predictor of elevated TnT levels (OR, 11.5, 95%
CI 1.8-73.7).
1.3 Long-term outcome
Elevated TnT levels in the postoperative period were also
associated with death one year after surgery both in univariate and multivariate analysis. After
adjusting for covariates, a TnT value above the diagnostic threshold was associated with 15fold increase in mortality compared to control, HR (hazard ratio) 14.9 (95% CI 3.7-60.3).
Other predictors of death included tachycardia (HR, 14.9 95% CI 3.45-64.8), ASA 4 (HR, 8.1
95% CI 1.3-50.0), reoperation (HR, 6.4 95% CI 1.1-36.9), as well as the use of diuretics (HR,
4.2 95% CI 1.3-13.8). Our study showed that TnT is a powerful, independent predictor for
one year mortality in elderly patients undergoing noncardiac surgery. In addition we extended
these findings while showing that even mild increases in TnT postoperatively, without clinical
5
or electrocardiographic signs of myocardial ischemia were of strong prognostic value for
long-term outcome.
In this study aspirin was discontinued 7-10 days before the surgical procedure in
all patients on chronic aspirin therapy.
Numerous studies have shown the efficacy of aspirin in reducing major
cardiovascular events. A metaanalysis by He et al have shown that aspirin decreases the risk
of myocardial infarction by 31% and the risk of thrombotic CVA by 18%. In addition, the
2002 Antithrombotic Trialists´ Collaboration has reported that antiplatelet therapy, primarily
with aspirin, reduces the outcome of any serious vascular event by approximately 25%, nonfatal myocardial infarction by one third, non-fatal stroke by one fourth and vascular mortality
by one sixth. In patients undergoing coronary artery by pass surgery studies have
demonstrated an increased postoperative bleeding in patients on aspirin treatment. Despite the
fact that preoperative aspirin may contribute to increased postoperative bleeding, substantial
data exist regarding aspirin´s protective effect following CABG. Therefore, the Sixth
American College of Chest Physicians (ACCP) Consencus Conference on Antithrombotic
Therapy recommends life-long aspirin therapy in patients undergoing CABG.
Little data exist regarding risks and benefits with low dose aspirin in a
noncardiac surgical setting and there is no concensus with regards to the use of aspirin in high
risk patients undergoing noncardiac surgery.
1.4
Relevance of this study
Due to the fact that there are no large prospective randomised multi-centre studies
evaluating the risk and benefit of aspirin in the perioperative period, the clinical relevance of
this study must be considered as significant. The possibility of reducing the incidence of
cardiovascular complications in the perioperative period will be of great importance both in a
medical and a health-economical perspective.
1.5
Aim of this study
The aim of this study is to assess the risks and benefits of continued aspirin therapy in the
perioperative period in a non-cardiac setting.
Two main questions are to be addressed:
1.
What effect do aspirin have in reducing perioperative cardiovascular
complications?
2.
Does low dose aspirin increase postoperative bleeding complications?
6
Study objectives
To study the effect of aspirin therapy in a high risk study population regarding:
1.
Myocardial cell injury, detected by Troponin T. (Primary endpoint)
2.
Myocardial infarction, diagnosed in accordance to the European Society of
Cardiology`s and American College of Cardiology`s published guidelines.
( Secondary endpoint)
3.
Haemorrhagic complications (Secondary endpoint), including:
a. Incisional hemorrhagic complications
b. Gastrointestinal bleeding
c. Hemorrhagic cerebrovascular accident
d. Spinal/Epidural hematoma
4.
Long-term outcome, i.e. mortality one year after surgery. (Secondary endpoint)
5.
Prediction of perioperative myocardial injury and/or poor long-term prognosis
by BNP (brain natriuretic peptide), CRP and albumin.
6.
Thrombotic cerebrovascular accident
7.
Health economical evaluation regarding the effect of low-dose ASA on life
expectancy and postoperative quality of life.
Methods
2.1 Study design
High-risk patient
undergoing noncardiac surgery
Randomised
Aspirin

Randomised
Placebo
A prospective, randomised, double-blinded placebo-controlled multicenter study on
high risk patients undergoing non-cardiac surgery.
7

Randomisation to Aspirin (75mg) Treatment or Placebo Treatment in cardiovascular
high risk patients undergoing non-cardiac surgery of high or intermediate risk

Follow-up: 30 days and 12 months after surgery.
2.2 Study population
540 patients, 270 patients in the Aspirin Treatment group and 270 patients in the Placebo
group. Patients will be randomised independently to each treatment group. The consideration
that led to the sample size are described in section 3.6.
Patients will be recruited from the Departments of Anesthesiology and Intensive Care,
Linkoping University Hospital, Orebro University Hospital, Motala Hospital, Västervik
Hospital, Department of Surgery Ryhov Hospital Jönköping, Departments of Anesthesiology
and Intensive Care, Södersjukuset, Stockholm, Södertälje Hospital and Vrinnevihospital ,
Norrköping.
2.3 Inclusion criteria
Patients undergoing elective high or intermediate risk1 non-cardiac surgery & with one of the
following cardiac risk factors will be included:

Patients with known or suspected ischemic heart disease2

Medical history of congestive heart failure3

Renal impairment (S-creatinine > 170 µmol·ml-1).

History of cerebrovascular accident4

Insulin-treated Diabetes Mellitus5
2.4 Exclusion criteria

Patients undergoing diagnostic procedures

Patients with unstable coronary artery disease6

Patients with incompensated congestive heart failure7

Patients in shock8.

Patients with pacemaker.

Patients under 18 years.

Patients with an allergy to aspirin

Patients with a known history of gastrointestinal bleeding
8

Patients with a known history of intra-cerebral haemorrhage

Patients on Warfarin or Clopidogrel

Patients on Metotrexate 8
Definitions:
1. High risk surgery: Surgery with a known cardiac risk of > 5%. Defined as: aortic
surgery, large peripheral vascular surgery. Surgery with large fluid shifts such as
esophagus, liver, pancreatic surgery. Large bowel surgery on patients that have
undergone intraabdominal surgery prior to the study.
Intermediate risk surgery: Surgery with a cardiac risk of 1-5%, including carotid
endarterectomy, head & neck surgery, intraperitoneal and intrathoracic surgery,
orthopedic surgery and prostate surgery. In our study patients undergoing general,
urological, gynaecological and orthopedic surgery will be included. Therefore in
addition to be a patient with cardiac risk factors, the patient must undergo one of the
following procedures to be included:

Intraperitoneal surgery (laparotomy) of at least one hour duration,
including:

Oesophageal surgery

Pancreatic surgery

Gastric surgery

Liver surgery

Surgery of the biliary tract except uncomplicated
cholecystectomy.


Endocrinal surgery

Bowel surgery

Fundoplication
Urological procedures including:

Prostate surgery, both open and transurethral

Nefrectomy

Cystectomy
9


Orthopedic prosthesis surgery including:

Hip arthroplasty

Knee arthroplasty

Shoulder arthroplasty
Gynecological procedures including:

Abdominal hysterectomies

Intraabdominal and pelvic cancer surgery
2. Ischemic heart disease: An imbalance between oxygen delivery and oxygen demand
in the myocardium. Here defined as an absolute reduction of coronary blood flow
caused by atherosclerosis in the coronary arteries, leading to angina pectoris and/or
myocardial infarction.
3. Congestive heart failure: Decreased myocardial function, leading to a reduction of
ejection fraction. This decreases oxygen delivery to peripheral tissues. In the study
defined as heart failure diagnosed prior to the inclusion with symptoms such as
orthopnea, peripheral edema. The patients shall be on medication including diuretics
and/or ACEinhibitors.
4. Cerebrovascular accident= Stroke or TIA. Patients with intracerebral haemorrhage
prior to the study will not be included.
5. Unstable coronary artery disease: Atherosclerosis in the coronary arteries, resulting in
a reduced coronary blood flow. In case of transient ischemia- symptoms of angina
pectoris. Persistent ischemia-resulting in myocardial infarction. Unstable CAD:
Increasing symptoms of myocardial ischemia-even in rest.
6. See under 3. Incompensated CHF: Patients with no or inadequate treatment, resulting
in symptomatology s described above and/or signs of incompensation on chest X-ray.
7. Shock: Circulatory failure resulting in an inadequate tissue perfusion and oxygen
delivery to peripheral tissues. This leads to metabolic acidosis and increasing lactate in
plasma due to anaerobic metabolism.
8. Patients on metothrexate will not be included due to this drug interaction with
acetylsalicylic acid.
10
2.5 Pharmaceutical considerations
Study product:

Acetylsalicylic acid-Trombyl®
Reference product:

Placebo
2.6 Blinding procedures
The study product as well as the reference product will be produced by APL, Stockholm.
After product control the drugs will be packed in plastic cans and labelled. Packaging will be
made in accordance to a randomisation list. Coding will occur through coded envelopes. The
drugs are in the form of capsules and are identical in appearance and weight. The study drugs
will be delivered to the Pharmacy JJ Berzelius SA by Tamro. The study product will be stored
in room temperature for < 24 months. The pharmacy will store the drugs until randomisation.
Drugs non-used will be returned to the pharmacy. The capsules will be saved for two years.
Destruction will be provided by the pharmacy.
2.7 Recruitment & Randomization procedures
The patient is randomised to either aspirin treatment or treatment with placebo. An algorithm
will be used to assign patients randomly in a one-to-one ratio, to one of the two study groups.
The randomisation takes place as soon as the patient has given informed consent to be
included in the investigation. Information and informed consent will take place on the
preoperative visit in the surgical department prior to surgery. The therapy will be started 7
days prior to surgery and terminated on the 3rd postoperative day.
2.8 Statistics and Power analysis:
The calculation of sample size has been made from our earlier study. From the total study
population of 546 patients, we selected patients with one of our planned inclusion criterias,
i.e. patients with ischemic heart disease, medical history of congestive heart failure, renal
impairment creatinine > 170 molml-1 , history of cerebrovascular accident, insulindependent diabetes mellitus. 14% of these patients developed pathological TnT levels in the
perioperative period. In this prospective randomised, double blinded study we calculate that
an inclusion of 540 patients would allow us to detect a reduction of TnT elevation from 14%
11
to 7%, with an  level of 0.05 and a statistical power of 80%. A reduction of incidence with
50% may seem as a large reduction. However, earlier studies in a non-surgical patient
population have shown that low-dose ASA reduces the incidence of myocardial infarction up
to 50% 13. An independent, multidisciplinary Data Managing Safety Board will ensure the
safety of the study patients.
‘Normal Troponin T’ stands for a TnT level < 0,01 g/l . (The Joint European Society of
Cardiology/American College of Cardiology Committee. Myocardial infarction redefined: a
consensus document of joint ESC/ACC committee for redefinition of myocardial infarction. J
Am Coll Cardiol 200; 36: 959-6). All increases in TnT above 0,01 g/l are signs of
myocardial cell injury. In Sweden, there is only one method of analysis for TnT, which is well
studied and validated.
Calculation of patient population is performed on primary endpoint, that is myocardial injury.
The incidence of per and postoperative bleeding is difficult to evaluate due to the fact that the
patient population will undergo a wide variety of different surgical procedures. We do not
believe that the incidence of bleeding complications will increase on the basis of low-dose
aspirin treatment. However, The DSMB ( data safety monitoring board) will focus on security
aspects and exclude an increased incidence of spinal/epidural hematomas, increased
frequency of perioperative bleeding complications, increased transfusion requirement. This
analysis will lead to a termination of the study if:
1. The proportion of pathological TnT levels as a sign of myocardial injury, is
significantly increased in one of the study groups.
2. If serious bleeding complication significantly differs between the groups.
At this statistical analysis chi2 test will be used for primary and secondary variables, except
for bleeding which will be analysed using t-test or corresponding non-parametric test (MannWhitney).
The main analysis will be begin with a two-group comparison as described above, but the
main analysis will be concentrated on multivariable methods, including logistic- and linear
regression analysis in analogy with methods described above to evaluate confounding and
interaction.
Methods for analysis of survival, Kaplan-Meier and Cox-regression analysis will be used for
studying 30 days and one-year survival.
12
The definition of a positive outcome of this study is: A significantly reduced incidence of
myocardial injury without increased incidence of bleeding complications.
The primary time of analysis is 48 hours postoperatively. We know that myocardial
ischemia debutes normally 6-12 hours after surgery, with the highest incidence of myocardial
infarction 24- 48 hours postoperatively. Troponin T increases early (6 t) after myocardial
injury and remains elevated up to 12 days after the cell damage. Therefore we believe that
with a primary time of analysis at 48 hours we will detect most myocardial cell injuries in the
perioperative period.
All the patients included in this study are cardiovascular risk patients and should therefore be
the object of preventive medication. Patients included, not on chronic ASA medication, will
be referred to their General Practitioner for evaluation and decision on ASA medication. We
believe that > 95% of the included patient will be on chronic ASA medication prior to
inclusion.
2.9 Study flow diagram
Cardiac risk patient accepted for non-cardiac surgery of high or
intermediate risk.
After written and oral information, the patients gives informed
consent to participate in ASINC.
Randomization.
The patient is randomised to Aspirin Treatment or Placebo
Treatment. Oral treatment with placebo or aspirin 75mg starts 7
days prior to surgery1.
The patient that has accepted to be included in the study will be
referred to the operating theatre 2 hours prior to surgery
13
ECG & preoperative laboratory testing will be collected in all
study patients.2
Preoperative preparations, preoperative management as well as
immediate postoperative care will be undertaken according to the
discretion of the attending anesthetist.
Postoperative laboratory testing& investigations: See under
comment 3.
ECG: will be taken directly postoperatively and daily the two first
postoperative days4.
Troponin T levels above the diagnostic threshold:
Patients will be referred to a specialist at the Department of
Cardiology for evaluation and treatment according to a
standardized flow chart, see 5.
Complications will be registered and diagnosed 6.
The amount of blood transfusion will be registered.
Treatment with the study drug will be discontinued on the 3rd
postoperative day 7.
Follow-up: At 30 days and 12 months after surgery. Mortality,
myocardial infarction, CVA and coronary interventions (PCI and
CABG) will be registered 8,9.
14
Comments:
1 If the included patient is on chronic low dose aspirin treatment, this medication will be
discontinued 7 days prior to surgery, according to standard procedures. The patient
will be randomised to either aspirin 75mg or placebo. The study drug will be
discontinued on the 3rd postoperative day. On day three after surgery, the patients will
restart their chronic medical treatment.
2 Standard laboratory testing as well as TnT will be analysed at each centre. Samples for
pro-BNP will be transported to and analysed in Linkoping. All blood samples will be
coded with the inclusion number of the patient.
Preoperative testing & investigations:
TnT
Pro-BNP
CRP (high-sensitive)
Hb
B-glucose
Leucocytes
Albumin
ECG
In case of elevated TnT levels in the preoperative period further evaluation,
according to the ‘Myocardial damage’ flow chart (see under 5 ) will be made, and
surgery rescheduled.
3 Postoperative laboratory testing:
Directly after surgery:
ECG
12 hrs postop:
TnT, B-glucose
24 hrs postop:
ECG, TnT, albumin, weight
48 hrs postop:
ECG, TnT
4 ECGs will be analysed by cardiologists and clinical physiologists unaware of the
patients symptomatology and Troponin T values.
15
5 ‘The Myocardial Damage Flow Chart’:
ASINC patient
Trop T pos
Ja
Nej
Hemodynamisk instabilitet pga CAD
och/eller ST förändringar
Ja
Sannolik CAD
EKG
Riskfaktorer för arterioskleros
Ja
E
C
H
O
ASA
BB
LMWH (inneliggande)
ev Statin
Ja
God prognos
Biologiskt vital
Ja
Möjligt att vårda pat på
kardiologisk vårdavdelning
Ja
God prognos
Biologiskt vital
Ja
God
kirur
gisk
vård
P
r
i
m
ä
r
v
å
r
d
A-EKG 4-6v
Kardiolog bedömning
Ja
Ischemi på A-EKG
Uttalad angina
Ja
Coronar angiografi
PCI/CABG
Patients with signs of myocardial infarction will discontinue the study medication in
order to receive ASA therapy. However, the patient will not be excluded from the
study itself.
6 In the perioperative period different types of bleeding complications will be
documented. Gastrointestinal bleeding, spinal/epidural hematomas, cerebrovascular
lesions, postoperative bleeding resulting in erythocyte transfusions and/or reoperation.
Per- and postoperative requirements of erythrocyte transfusions, plasma, thrombocyte
transfusions as well as the need of fibrinolysis inhibitors and/or desmopressin will be
documented. Gastrointestinal bleeding is defined as bleeding from the gastrointestinal
tract, resulting in symptoms such as melena or hematemesis and/or positive F-Hb.
Diagnostic procedures will be performed according to symptomatology. ( gastro-,
colo-, sigmoido-scopi, ultrasound and/or angiography or bleeding scintigraphy).
Diagnostic procedures will be made if the patient has a verified hematemesis/melena
or a decrease in Hemoglobin resulting in transfusion. A subjective assessment of
perioperative bleeding problems will be made by the surgeon,(see amendment 1 in the
CRF).
7 Patients on chronic low-dose aspirin treatment will continue this medication after
completing the study period, ie on the 3rd postoperative day. Patients with risk factors
16
for cardiovascular disease, but not on chronic ASA therapy will be referred th their GP
for assessment and decision on low-dose ASA medication.
8 Telephone interviews will be undertaken 30 days and 1 year after surgery. This will
include EQ-5D.
9 If the patient does not survive the follow-up period, death certificates, medical records
and autopsy reports will be studied to obtain the cause of death. The cause of death
will be classified as cardiovascular, malignancy or other.
2.10 Perioperative Adverse Events:
AE and SAE will be documented during the study period.
All SAE will be reported immediately to the sponsor and the principal investigator. The
immediate report will be followed by a written report. In the case of a serious bleeding
complication a report will be sent to the Medical Product Agency according to guidelines. All
serious adverse events will be followed until the event is resolved (with or without sequelae).
The following categories of adverse event severity will be used:
Mild:
Awareness of a sign or symptom that does not interfere with the
patients´s usual activity or is transient, resolved without treatment
and with no sequelae.
Moderate:
Interferes with patient´s usual activity and/or requires symptomatic
treatment.
Severe:
Symptoms causing severe discomfort and significant impact of the
patient´s usual activity and requires treatment.
An adverse event is considered serious if the event:

Leads to death

Leads to serious deterioration in the health of the subject
17
3.Follow-up
Patients will be followed with telephone interview 30 days and one year after surgery. If new
cardiovascular events are reported, further information will be acquired from the patient´s
medical records. EQ-5D will be included in the telephone interview. If the patient has died
during the follow-up years, information on the cause of death will be collected from medical
charts, death certificates and if present autopsy reports. The follow-up will be made by the
Department of Anaesthesia, University Hospital Linkoping.
4. Study outcome
4.1 Primary outcome
A.
Perioperative myocardial injury
4.2 Secondary outcome
A.
Perioperative myocardial infarction
B.
Incidence of haemorrhagic complications.
4.3 Other outcomes
A.
One year mortality
Cardiac events (myocardial infarction, PCI and/or CABG,) and thrombotic
cerebrovascular events within one year after surgery.
Correlation between perioperative myocardial injury and preoperative albumin,
CRP, BNP and TnT.
B.
Correlation between postoperative TnT and long-term prognosis.
Risk of perioperative myocardial injury related to aspirin treatment compared to
placebo.
C.
Risk of death one year after surgery related to aspirin treatment compared to placebo.
D.
Cost-effect analysis regarding the effect of low-dose ASA in the perioperative period.
18
4.4 Definitions of study outcomes.
Perioperative myocardial injury: Troponin T above the diagnostic threshold on at least one
occasion during the study period. With or without electrocardiographic or clinical signs
suggestive of myocardial ischemia.
Acute myocardial infarction is defined as typical increase and gradually degrease in
Troponin T together with one of the following criterias:
-ischemic symptoms
-development of pathological Q-wave
electrocardiographic signs suggestive of ischemia (ST-segment depression or
elevation).
Perioperative myocardial infarction within 72 hours of surgery.
Perioperative bleeding complications will be defined as follows:
Incisional haemorrhagic complication:
Wound hematoma requiring
reoperation.
Gastrointestinal bleeding:
Gastrointestinal bleeding is defined as
bleeding from the gastrointestinal tract, resulting in symptoms such as melena or hematemesis
and/or positive F-Hb. Diagnostic procedures will be performed according to symptomatology.
( gastr-, colo-, sigmoido-scopi and/or angiography, ultrasound or bleeding scintigraphy).
Diagnostic procedures will be made if the patient has a verified hematemesis/melena or
decrease in Hemoglobin which results in transfusion.
Hemorrhagic cerebrovascular accident:
Leading to permanent or transient
neurological deficit. Diagnosed by computer tomography.
Spinal/epidural hematoma:
Leading to severe backpain and/or
neurological deficit including sensibility or motoric deficit in the lower extremities.
Diagnosed by MRI.
Cardiac events includes myocardial infarction, percutaneous intervention and coronary artery
by-pass grafting.
Death separated into cardiac, malignancy and other.
5. Organization
The 540 patients that will be included in this study will be divided between the centres as
follows:
19
Örebro US
gynecology, urology, general surgery
120 pat
Motala Hospital
orthopedic surgery
50 pat
Ryhov Hospital
general, vascular surgery
70 pat
Linköping US
general, orthopedic, gynaecological surgery and urology 120 pat
Västervik hospital
general, orthopedic, gynaecological surgery and urology 30 pat
Södersjukhuset
general, orthopedic, gynaecological surgery and urology 50 pat
Södertälje Hospital
general, orthopedic, gynaecological surgery and urology 50 pat
Vrinnevi, Norrköping
general, orthopedic, gynaecological surgery and urology 50 pat
Each centre has its own specialist involved in the study which is responsible for inclusion and
data collection.
Estimated time-frame including follow-up: 2-3 years.
6. Data management
All Clinical Report Files and other data from the included patients will be kept during the
study period in a specific locked cabinet at each centre.
All protocols, copies of perioperative journals, ECG´s and test results will thereafter be
transferred to Linköping. The main data register will be held in Linköping.
Each week the centres will be contacted by a central coordinator ( research nurse) in
Linköping for update. The principal investigator, Anna Oscarsson Tibblin, will be responsible
for the data archives. The study protocols will remain in Linkoping for 10 years.
7. Monitoring
On-site monitoring will be performed before, during and after the trial,by the TEKLA group,
to assure that the trial is conducted in accordance to ICH GCP. The TEKLA group are
independent personnel trained in Good Clinical Practice and monitoring.
8. Ethical considerations and Risk/Benefit
As described under 1.3, studies have suggested that low-dose aspirin may cause
increased per/postoperative bleeding complications. Therefore an independent DSMB (data
safety managing board) will supervise data for safety reasons during the study period, see
under 3.8. The DSMB will focus on haemorrhagic complications. Due to the fact that all
included patients are cardiovascular high risk patients, with increased risk of cardiovascular
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complications in association to pain and other stress responses, we have not planned to change
our policy of epidurals for postoperative analgesia after large intraabdominal surgery. Studies
have shown that aspirin per se does not increase the risk of spinal hematoma associated with
regional anesthesia. However, since included patient will receive low molecular weight
heparin the day before surgery according to standard procedure, there is a theoretical
possibility of increased risk of spinal/epidural hematomas. A large metaanalysis by Tryba et
al showed an incidence of epidural hematomas of 1:150000 epidural catheters. We therefore
assess the risk of cardiovascular complications due to inadequate analgesia as clinically more
significant and frequent than the risk of spinal/epidural hematomas in this particular high risk
study population. We have also discussed this ‘dilemma’ with the reference group for regional
anesthesia in the Swedish Society of Anestesiology. This reference group has no objection to
the study, but refers to the ethical committee. The study is now accepted by the regional
ethical committee in the South-East of Sweden.
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