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Background The role of routine supplemental oxygen for patients with uncomplicated acute myocardial infarction (AMI)
has recently been questioned. There is conflicting data on the possible effects of hyperoxia on ischemic myocardium. The few
clinical trials examining the role of oxygen in AMI were performed prior to the modern approach of emergent reperfusion and
advanced medical management.
Methods
Air Verses Oxygen In myocarDial infarction study (AVOID Study) is a prospective, multi-centre, randomized,
controlled trial conducted by Ambulance Victoria and participating metropolitan Melbourne hospitals with primary
percutaneous coronary intervention capabilities. The purpose of the study is to determine whether withholding routine
supplemental oxygen therapy in patients with acute ST-elevation myocardial infarction but without hypoxia prior to reperfusion
decreases myocardial infarct size. AVOID will enroll 490 patients, N18 years of age with acute ST-elevation myocardial
infarction of less than 12 hours duration.
Conclusions There is an urgent need for clinical trials examining the role of oxygen in AMI. AVOID will seek to clarify
this important issue. Results from this study may have widespread implications on the treatment of AMI and the use of oxygen in
both the pre-hospital and hospital settings. (Am Heart J 2012;163:339-345.e1.)
Background
Coronary artery disease (CAD) is a leading cause of
morbidity and mortality worldwide. 1 In particular, many
patients with CAD present with ST-elevation myocardial
infarction (STEMI) as a result of acute thrombotic
coronary artery occlusion. The optimal treatment for
patients presenting with STEMI is reperfusion therapy
either with primary percutaneous coronary intervention
(PCI) or administration of a thrombolytic drug. 2,3
Current guidelines recommend additional treatments
for patients with STEMI prior to reperfusion therapy,
such as oxygen, aspirin, and nitrates. 4 While there is
supportive evidence from clinical trials for the administration of aspirin 5 and nitrates, 6 there is no data from
prospective, randomised, controlled clinical trials to
support the use of routine supplemental oxygen.
For many years, the administration of supplemental
oxygen has been considered beneficial for the treatment of patients with acute myocardial infarction
largely based on experimental laboratory data. For
example, in a laboratory study, anaesthetized dogs
underwent coronary artery occlusion and were then
administered either 21% oxygen, 40% oxygen or 100%
oxygen. In the 40% oxygen group, there was decreased
myocardial injury and infarct size compared with the
air or 100% oxygen groups. 7 In another experimental
study, two groups of dogs underwent 90 minutes of
coronary occlusion followed by 72 hours of reperfusion. 8 One group received 100% inspired oxygen from
20 minutes before reperfusion and 3 hours after
reperfusion whereas the air group received room air.
The infarct size in the oxygen group was reduced by
38% and left ventricular ejection fraction was improved
compared with the dogs receiving room air. Together,
these data have been interpreted as suggesting that
high concentrations of inspired oxygen may be of
benefit in acute myocardial infarction followed by
reperfusion therapy.
340 Stub et al
Methods
Study sites
This study will be conducted by Ambulance Victoria in
partnership with 12 major metropolitan hospitals in Melbourne,
Australia. The Mobile Intensive Care Ambulances (MICA) of
Ambulance Victoria are equipped with 12 lead electrocardiogram (ECG) capability and pulse-oximetry monitors and have
significant experience in successfully conducting pre-hospital
clinical trials in critically ill patients. 21,22 Ambulance Victoria,
also has a Melbourne wide field triage 12-lead ECG program to
Stub et al 341
Figure 1
Inclusion/exclusion criteria
Randomization
342 Stub et al
been used successfully in previous pre-hospital trials performed by the authors. 21,22
Consent/ethics
All eligible patients will be experiencing pain and many will
be treated with morphine. Also, the study must be undertaken
immediately on arrival of paramedics to ensure validity.
Therefore, fully informed consent prior to enrolment is not
possible. In Victoria, Australia, the medical treatment act allows
for enrolment in clinical trials in the pre-hospital setting with
subsequent formal consent being obtained by the patient or
person responsible at a later stage. A person responsible is
defined in the Victorian Medical treatment act, 24 usually
this person will be a guardian or the nearest relative (ie, next
of kin) of the patient. The ethical issues associated with delayed
consent and randomization of acute cardiac patients has been
carefully considered by ethics committees in Victoria with
formal approval obtained for the AVOID study in July 2011.
Our approach of delayed consent is similar to that which has
been accepted in previous trials by the authors. 21,22 There is the
possibility of a patient's clinical deterioration after enrolment
and prior to formal consent. This has been considered as part of
the ethics application and will be dealt with by consent of the
person responsible for the patient. The AVOID study has been
registered with clinicaltrials.gov (NCT01272713) and conforms
to the National Health and Medical Research Council of
Australia's framework for the conduct of pre-hospital clinical
emergent trials.
Intervention/study treatment
Patients allocated to the no oxygen arm will receive standard
acute coronary syndrome treatment as per pre-hospital and inhospital protocols, except that no oxygen will be administered
pre-hospital or in-hospital for normoxic patients. If the oxygen
saturation falls below 94% post-randomization, oxygen will
be administered via nasal cannulae (4 L/min) or Hudson mask
(8 L/min) and titrated to achieve oxygen saturation of 94%.
Patients randomised to oxygen therapy will receive standard
acute coronary syndrome treatment as per pre-hospital and
hospital protocols, with pre-hospital supplemental oxygen
administered via Hudson mask at 8 L/min and in-hospital
oxygen as per hospital policy.
End-points
The primary end-point for the study will be infarct size
ascertained by mean peak troponin. Peak and area under the
curve of creatine kinase (CK) release will also been measured.
These two routinely collected cardiac biomarkers have been
shown to reliably predict infarct size in STEMI patients. 25-27
Infarct size will be evaluated via a blood test on admission and
then 6 hourly tests for 48 hours and 12 hourly measurements
between 48 hours and 72 hours. Infarct size will be measured
by, mean and peak cTnI, mean and peak CK and the area under
the curve of CK and cTnI release over the first 72 hours of
inpatient stay. 28
Secondary end-points
survival to hospital discharge/or day seven (whichever
sooner)
TIMI score,
ECG ST-segment resolution
Major Adverse Cardiac Events including death, MI, and rehospitalization measured at 6 months
Myocardial salvage determined by cardiac magnetic resonance imaging (CMRI) (subset of patients n = 40)
Coronary angiography. Coronary angiography and
intervention will be performed according to standard techniques. Adjunctive anti-platelet, anticoagulation therapies and
use of thrombus aspiration will be at the discretion of the
treating interventional cardiologist. Angiographic lesion characteristics will be classified according to the modified AHA/ACC
classification from 2 orthogonal planes. 29 Pre-procedural and
post-procedural assessments of epicardial TIMI flow grade will
be performed by two investigators blinded to treatment
assignment. 30 Procedural factors including symptom-and doorto-balloon inflation, glycoprotein IIb/IIIa inhibitors, thromboaspiration, and type of implanted stent will be recorded.
Electrocardiographic analysis. A blinded observer
will perform all analysis of ST-segment resolution from a preprocedural 12-lead ECG compared with the first post-procedural
ECG, which will be performed within 30-90 minutes after PCI on
the coronary care ward according to established guidelines. 31,32
Cardiac MRI. A key secondary end-point will be the
measurement of infarct size as percent of area at risk
determined with T2-weighted CMRI. 33 Because CMRI expertise are only currently available at one of the study centers,
this estimation of myocardial salvage will be performed on
only a subgroup of patients (n = 40). All CMRI will be
performed on a clinical 1.5-T CMRI scanner (Signa HDx 1.5-T;
GE Healthcare, Waukesha, WI) on day 4 to 5 of hospital stay
and repeated at 6 months.
Left ventricular (LV) function will be assessed by a standard
steady state free precession technique called FIESTA [Fast
Imaging Employing Steady State Acquisition] (repetition time
[TR] 3.8 ms, echo time [TE] 1.6 ms, 30 phases, and slice thickness
of 8 mm). LV ejection fraction will be calculated by volumetric
analysis from a contiguous short axis FIESTA stack (8 mm slice
thickness) covering the LV and right ventricle from the apex to a
level well above the atrio-ventricular groove using the summation of disc method 34 by two blinded cardiologists. For area-atrisk determination, LV short-axis slices covering the whole
ventricle using a T2-weighted triple inversion recovery breathhold fast spin echo pulse sequence will be obtained using a body
coil. 35 Area-at-risk will be quantified by manual delineation of
myocardium with bright signal intensity 2 SD above the mean
signal obtained in the remote, non-infarcted myocardium and
multiplying the slice thickness and the myocardial density of
1.05 g/mL, expressed as a percentage of LV mass. Late enhancement images covering the whole ventricle will be acquired
approximately 15 minutes after intravenous administration of a
bolus of gadolinium-diethylene triamine penta-acetic acid to
identify regional necrosis/fibrosis for infarct size quantification
using an inversion recovery gradient echo technique. The area of
hyperenhanced myocardium (bounded by endocardial and epicardial contours) on each of the short axis slices will be manually
traced then multiplied by the slice thickness and the myocardial
density of 1.05 g/mL to obtain the infarct mass, and expressed as
a percentage of LV mass (infarct size). 36 Myocardial salvage
index will be calculated as the area-at-risk minus percentage
infarct size divided by area-at-risk. 37 All analyses will be
Data collection
A study coordinator will extract all relevant study data
to a secure stand alone study database.
Pre-hospital data
Pre-hospital data will be collected via the paramedic
electronic patient care record, which is recorded and stored
in the Victorian Ambulance Clinical Information System
(VACIS) and downloaded to a secure data warehouse at
Ambulance Victoria. All pre-hospital data relevant to the
study is currently recorded by paramedics immediately after
the case in VACIS. Pre-hospital data will include demographic, medical history, clinical presentation, treatment
and adverse events (Table I).
There is a randomization field recorded in the VACIS
to identify patients in the AVOID study. The ambulance
data warehouse will be routinely searched to identify if
any eligible patients were not randomised to the study.
This will be feedback to participating MICA teams on a
monthly basis.
In-hospital data
In-hospital data will be obtained from the medical
records at each participating hospital. In-hospital data will
include demographic, medical history, clinical, procedural details, outcome data and adverse events (Table I).
Several tests including the ECG, cardiac catheterization
reports and MRI will be reviewed by 2 independent
assessors to ensure validity. Six-month follow up will be
via phone call enquiring as to health status and events or
hospital admissions since discharge (Table I).
Data analysis
All patients will be analysed according to intention-to
treat population for all primary and secondary outcomes.
Infarct size will be assessed by cardiac biomarkers.
Calculations and statistics will be performed using the
statistical package STATA version 11 (Stata Corporation,
College Station, TX). Variables that approximated a
normal distribution will be summarized as mean SD,
and groups compared using t tests. Non-normal variables
will be summarized as median and first and third quartiles
(Q1, Q3), and groups compared using Mann-Whitney
Rank sum tests with exact inference. Binomial variables
will be expressed as proportions and 95% confidence
intervals (exact binomial) and groups compared by 2
tests. Between group comparisons of area under the
curves for cTnI and CK release, the time of ischemia, the
Stub et al 343
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Sample size
To calculate the target sample size for the trial a mean
peak cTnI level within the first 72 hours post symptoms
344 Stub et al
Summary
Despite inhaled oxygen therapy being a routine
component of pre-hospital and in-hospital care for AMI,
there is concern that rendering patients hyperoxic may
increase myocardial infarct size and possibly lead to
worse outcomes. This has led to international guidelines cautioning against the use of routine oxygen in
normoxic patients with uncomplicated AMI. The AVOID
study will be one of the first clinical trials in the modern
era of pre-hospital ECG field triage and PPCI to investigate
the role of routine oxygen in patients with acute STEMI.
Together with other trials such as the High Concentration
vs Titrated Oxygen therapy in ST-elevation myocardial
infarction (Optimise trial: ANZCTRN 12607000500459)
and the Swedish study, Supplemental Oxygen in Catheterized Coronary Emergency Reperfusion (Soccer trial
NCT01423929), the AVOID study will provide invaluable
information for both pre-hospital and in-hospital care of
patients with AMI.
Disclosures
Data safety management
An independent Data Safety Monitoring Group will be
established. The Chair of the Data Safety Monitoring
Group will undertake an interim analysis after 100
patients have been enrolled in each arm of the study.
Consideration to stopping the study will be made if there
are key differences in safety endpoints at hospital
discharge including, death, recurrent myocardial infarction and intubation post enrolment.
Limitations
The AVOID study has several limitations. First it is a
non-blinded randomised study of oxygen therapy using
surrogate primary end points. However, infarct size
measured by biomarkers have been closely associated
with the rates of death and major adverse cardiac events
and thus support the validity of using such end points in
studies of patients with STEMI.
Second, to prevent selection bias, we performed
randomization in the pre-hospital setting, and therefore
before coronary angiography. It is possible, therefore
that some patients may not go on to reperfusion
therapy. This may have an impact on study outcomes,
but importantly makes our findings applicable to a
general population with STEMI who experience both
pre-hospital and in-hospital interventions. Other important infarct trials have significantly changed clinical
practice despite utilizing surrogate outcome measures. 41,42 The AVOID study has the potential to
significantly impact on both pre-hospital and in-hospital
care of patients with STEMI.
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