Download A randomized controlled trial of oxygen therapy in acute myocardial

A randomized controlled trial of oxygen therapy in
acute myocardial infarction Air Verses Oxygen In
myocarDial infarction study (AVOID Study)
Dion Stub, MBBS, a,b,c,f,g Karen Smith, BSc(Hons) PhD, b,d,f,g Stephen Bernard, MBBS MD, a,b,g
Janet E. Bray, RN, PhD, b,d,g Michael Stephenson, RN, BHlthSc, Grad, Dip (MICA), d,g Peter Cameron, MBBS, MD, a,b,g
Ian Meredith, BSc, MBBS, PhD, b,d,e,g and David M. Kaye, MBBS, PhD a,b,c,g Melbourne, Australia
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
From the aAlfred Hospital, Melbourne, Australia, bMonash University, Melbourne,
Australia, cBaker IDI Heart Diabetes Institute, Melbourne, Australia, dAmbulance Victoria,
Melbourne, Australia, and eMonash Hospital, Clayton, Melbourne, Australia.
f
Dr Stub and Dr Smith contributed equally to this manuscript.
g
On behalf of AVOID Investigators. See online Appendix for complete listing.
Clinical Trial Registration: The AVOID study has been registered with clinicaltrials.gov
(NCT01272713).
Submitted August 30, 2011; accepted November 17, 2011.
Reprint request: Dion Stub, MBBS, Alfred Hospital, Cardiology, Commercial Rd,
Melbourne, Melbourne, Vic 3004, Australia.
E-mail: [email protected]
0002-8703/$ - see front matter
© 2012, Mosby, Inc. All rights reserved.
doi:10.1016/j.ahj.2011.11.011
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.
American Heart Journal
March 2012
340 Stub et al
In contrast to the experimental data, emerging clinical
data have recently challenged the notion that supplemental oxygen should be used in all patients. In
particular, there is some evidence that oxygen administration before and during reperfusion in patients with
STEMI may be harmful. For example, the hemodynamic
effects of inhalation of oxygen in high concentration has
been investigated in 50 patients with acute myocardial
infarction. 9 In this study, high-dose oxygen resulted in
adverse effects including a fall in cardiac output, a rise in
blood pressure and an increase systemic vascular
resistance. The latter would be expected to increase
myocardial work and increase myocardial ischemia.
To date, there have been three prospective, controlled
trials of supplemental oxygen compared with no
supplemental oxygen in patients with myocardial infarction. In a double-blind, randomised in-hospital study, 200
patients with myocardial infarction were allocated to
receive supplemental oxygen or air administered by face
mask for the initial 24 hours in hospital. 10 The 2 groups
were comparable at baseline. There was no significant
difference in mortality, incidence of arrhythmias or use of
analgesics between the groups and the investigators
concluded that there was no benefit from the routine
administration of oxygen in uncomplicated myocardial
infarction. In a second study, 50 patients were allocated
to either supplemental oxygen or room air. 11 The main
outcome measure was the requirement for analgesia,
which did not differ with oxygen use. This study did not
report mortality rate. Finally, in a Russian study, 137
patients were allocated to either supplemental oxygen
(4-6L/Min) or air. 12 Complications including heart failure,
pericarditis and rhythm disorders occurred less frequently in the oxygen group (risk ratio 0.45; 95% CI
0.22-0.94). One patient out of 58 died in the oxygen
group and none out of 79 participants in the air group.
A meta-analysis analysed the outcomes in the 387
patients included in these three studies. 13 The pooled risk
ratio of death for patients allocated to oxygen administration was 2.88 (95% CI 0.88-9.39) in an intention-to-treat
analysis and 3.03 (95% CI 0.93-9.83) in patients with
confirmed myocardial infarction. While suggestive of
harm, the small number of deaths recorded meant that
this finding did not reach statistical significance. Pain was
measured by analgesic use and the pooled risk ratio for
decreased use of analgesics in the oxygen group was 0.97
(95% CI 0.78-1.20).
In addition to the above studies, other clinical studies
have examined the use of novel techniques for additional
oxygen delivery to the ischemic myocardium during
reperfusion. In a clinical trial testing the role of
hyperbaric oxygen in myocardial infarction, 112 patients
with STEMI were allocated to either hyperbaric oxygen
or usual supplemental oxygen (40% by mask or 6 L/min
by nasal prongs) during thrombolysis. 14 There was no
significant difference between the groups in creatinine
kinase levels at 24 hours or left ventricular ejection
fraction on discharge. Overall, there was no overall
benefit with this approach found in this study. In a
clinical trial testing coronary artery reperfusion with
hyperoxic blood during reperfusion, 269 patients with
acute AMI undergoing PCI were randomly assigned to
receive hyperoxemic blood reperfusion or normoxemic
blood reperfusion by catheter into the area of reperfused
myocardium. 15 At 30 days, there was no significant
difference in the infarct size, ST-segment resolution, or
regional wall motion score. Although improvement in
cardiac function was seen in patients with anterior MI
who were reperfused within 6 hours, this finding was a
post hoc analysis. A meta-analysis of all studies of
hyperoxic myocardial reperfusion found that this treatment caused a significant reduction in coronary blood
flow, an increase in coronary vascular resistance, and a
significant reduction in myocardial oxygen consumption. 16 These data appears to suggest that supplemental
oxygen may be harmful.
On the basis of the apparently contradictory experimental and clinical data, uncertainty over the utility of
routine supplemental oxygen for uncomplicated acute
coronary syndrome patients now exists. As a reflection of
this, European guidelines for the management of acute
coronary syndromes do not now include a recommendation for supplemental oxygen. 17 Additionally, the recent
American Heart Association guideline for the management of acute coronary syndromes does recommend
oxygen, they note that there is no clinical trial evidence to
support this recommendation. 4 The most recent addendum to the 2006 Australian National Heart Foundation
Guidelines does not recommend the routine use of
supplemental oxygen. 18 Accordingly, prospective clinical trials comparing supplemental oxygen with no
supplemental oxygen in this condition are required. 19,20
We therefore propose to undertake a randomised,
controlled trial comparing supplemental oxygen therapy
with air in patients without hypoxia who present with
acute STEMI to determine the effect on the size of the
myocardial infarct at hospital discharge. The primary
hypothesis for the study is that the current practice of
routine supplemental oxygen therapy in patients with
STEMI, prior to reperfusion impacts on myocardial infarct
size compared with no supplemental oxygen therapy.
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
American Heart Journal
Volume 163, Number 3
Stub et al 341
Figure 1
Summary of AVOID trial.
detect STEMI and emergently transport to the nearest primary
PCI (PPCI) capable hospital. 23 All 12 metropolitan PPCI capable
hospitals in Melbourne will be participating in the AVOID study.
oxygen prior to randomization, or have any condition associated
with altered conscious state.
Inclusion/exclusion criteria
Randomization
MICA paramedics will screen suspected STEMI patients and
determine the eligibility for enrolment (Figure 1). Inclusion
criteria include, adults ≥18 years of age, who describe chest
pain commencing less than 12 hours prior to assessment, STelevation Myocardial Infarction on pre-hospital 12-lead ECG
(characterized by, ST-segment elevation of ≥1 mm in two
contiguous limb lead or ST-segment elevation of ≥2 mm in two
contiguous chest leads or new left bundle branch block
pattern). Patients will be excluded if they are hypoxic with
oxygen saturation measured on pulse oximeter b94% with the
patient breathing air, have bronchospasm on examination
requiring nebulised salbutamol therapy using oxygen, receive
The MICA ambulances will be provided with randomization
envelopes. Half in each pack will contain instructions for
withholding supplemental oxygen therapy and half with
instructions for standard treatment. The envelopes will be
randomised by computer- generated code into blocks of ten,
numbered externally, and then sealed within an opaque
envelope that conceals the treatment designation. MICA
ambulances will carry sequential three envelopes at any time
and these will be replaced with envelopes from the remainder
of the block which will be kept by the team's manager. When
a team completes a block, another block of 10 will be
allocated by the study coordinator. This randomization has
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)
American Heart Journal
March 2012
• 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
American Heart Journal
Volume 163, Number 3
performed offline on dedicated workstations by fully blinded
observers with excellent reproducibility (r = 0.98) for infarct
size assessment.
The AVOID study is supported by a FALCK Foundation research
grant, a non profit organization supporting research into prehospital care (www.falckfoundation.com), an Alfred Hospital
Foundation Grant, as well as a Paramedics Australasia grant.
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 χ 2
tests. Between group comparisons of area under the
curves for cTnI and CK release, the time of ischemia, the
Stub et al 343
Table I. AVOID data points
Domain
Demographics
Medical history
Diabetes
Hypertension
Hypercholesterolemia
Smoking history
Body mass index
Family history of
coronary disease
History of CAD/
PCI /CABG
History of heart failure
NYHA class
Medications
Infarct Details
Time of symptom onset
Total pre hospital time
Door to reperfusion time
Symptom to
reperfusion time
ECG
Vital Signs
Heart rate
Blood Pressure
Oxygen saturation
Respiratory rate
Glasgow Coma Scale
Pain Score
Cardiac Rhythm
Cardiogenic Shock
Killip Class
Procedural Details
PCI or thrombolysis
Extent of coronary disease
Lesion Type (A,B,C)
Degree of stenosis
(pre and post)
TIMI flow (pre and post)
IABP
Thrombectomy catheter
Adverse Events
Cardiac Markers
Discharge Disposition
NYHA
CABG
CVA
AMI
Stent thrombosis
Arrhythmia
Deceased
Re-hospitalization
Pre-Hospital In-hospital 6 months
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
area at risk and the infarct size as assessed by MRI will be
performed using the Wilcoxon rank-sum test. A comparison of the incidence of cumulative adverse clinical
events between the two groups will be performed by
means of Fisher's exact test.
Sample size
To calculate the target sample size for the trial a mean
peak cTnI level within the first 72 hours post symptoms
American Heart Journal
March 2012
344 Stub et al
was ascertained from the literature for uncomplicated
STEMI patients. 25-28 , 38 The mean peak cTnI level in the
oxygen group was estimated to be 75 ± 35 ng/mL. 26
Based on the previous clinical trials of oxygen in
STEMI, 10,12 we hypothesize that withholding oxygen
would change the mean peak cTnI levels by 20%. For a
statistical power of 90% and a probability of a type I error
of 0.01 using a 2-sided test requires, the sample size be
326 (163 in each group). This sample has been increased
by 50% to allow for the positive predictive value of prehospital diagnosis of STEMI to be b100% 39 and for some
loss to follow-up. The final sample is 490 (245 patients in
each arm).
Data will be analysed on an intention to treat basis,
including all enrolled patients. Secondary end points will
include a per-protocol analysis of those patients with
confirmed myocardial infarction. 40 The trial begun
enrolment on the October 21, 2011, and based on the
current rate of recruitment and number of STEMI
patients transported to participating hospitals it is
expected that the study will take 24-30 months to
enroll 490 patients.
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.
Conflicts of Interest: None to declare.
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American Heart Journal
Volume 163, Number 3
Appendix. Investigators for
AVOID study
Chief Investigators: Stephen Bernard, MBBS, MD; Karen
Smith, BSc, PhD. Steering Committee: Michael Stephenson, RN, BHlthSc Grad Dip (MICA); Janet Bray, RN, PhD;
Bill Barger, MACAP; Ian Jarvie, MACAP; Ian Meredith,
BSc, MBBS, PhD; Dion Stub, MBBS; Peter Cameron, MBBS,
MD; David Kaye, MBBS, PhD. Primary Site Investigators:
Professor Ian Meredith, BSc, MBBS, PhD, Monash Medical
Centre, Clayton, Australia; Anthony Dart, BA, BM, BCh,
D Phil, Alfred Hospital, Melbourne, Australia; Gishel New,
MBBS, PhD, Box Hill Hospital, Box Hill, Australia; Robert
Stub et al 345.e1
Whitbourn, MBBS, BMedSc, MD; St Vincent's Hospital,
Fitzroy, Australia; Omar Farouque, MBBS, PhD, Austin
Hospital, Heidelberg, Australia; Leeanne Grigg, MBBS,
Royal Melbourne Hospital, Carlton, Australia; Jeffrey
Lefkovits, MBBS, Cabrini Hospital, Malvern, Australia;
Michael Rowe, MBBS Knox Hospital, Knox, Australia; Ron
Dick, MBBS, Epworth Hospital, Richmond, Australia;
Geoff Toogoood, MBBS, Frankston Hospital, Frankston,
Australia. William Van Gaal, MBBS, MSc, Northern
Hospital, Epping, Australia; Yean L. Lim, MBBS, PhD,
Western Hospital, Footscray, Australia. Cardiac MRI:
Andrew J. Taylor, MBBS, PhD, James Hare, MBBS, PhD,
Leah Iles, MBChB, Andris H. Ellims, MBBS.