1
Rapid Endovascular Catheter Core Cooling combined with
cold saline as an Adjunct to Percutaneous Coronary
Intervention For the Treatment of Acute Myocardial
Infarction (The CHILL-MI trial)A Randomized, Controlled Study of the Use of Central Venous Catheter Core Cooling
combined with cold saline as an Adjunct to Percutaneous Coronary Intervention For
the Treatment of Acute Myocardial Infarction
David Erlinge1, Matthias Götberg1, Irene Lang2, Michael Holzer2,
Marco Noc3, Peter Clemmensen4, Ulf Jensen5, Bernhard Metzler6,
Stefan James7, Hans Erik Bötker8, Elmir Omerovic8, Henrik
Engblom9, Marcus Carlsson9, Håkan Arheden9, Ollie Östlund7, Lars
Wallentin7, Jan Harnek1, Göran K Olivecrona1.(1) Department of Cardiology, Lund University, 221 85, Lund, Sweden
(2) Dept of Cardiology & Dept of Emergency Medicine, Medical
University of Vienna, Vienna, Austria
(3) Dept of Cardiology, Ljubliana, Slovenia
(4) Dept of Cardiology, Copenhagen, Denmark
(5) Cardiology Unit, Dept of Medicine, Karolinska University
Hospital, Stockholm, Sweden
(6) Dept of Cardiology, Innsbruck, Austria
(7) Dept of Cardiology, Uppsala University, Uppsala, Sweden
(8) Dept of Cardiology. Sahlgrenska University, Gothenburg, Sweden
(9) Department of Clinical Physiology, Lund University, Lund, Sweden
Short title: Hypothermia for STEMI.
Word count: nn
Journal Subject Codes: Acute myocardial infarction; [118]
Cardiovascular Pharmacology; [130]; Coronary
2
Corresponding author
David Erlinge, MD, PhD, Professor
Department of Cardiology, Lund University
Skane University Hospital,
S-221 85 Lund, Sweden
Phone: +46 46 17 25 97
Fax: +46 46 15 78 57
Abstract (250 w)BACKGROUND: We examined in a prospective, randomized,
multicentre, efficacy trial if rapidly induced hypothermia by
infusion of cold saline and endovascular cooling reduce infarct
size (IS).
METHODS: 120 patients with STEMI with a duration of <6 hours,
planned for primary PCI were randomised to hypothermia induced
by rapid infusion of up to 2000 ml cold saline combined with
endovascular cooling or standard of care. The primary endpoint
was myocardial IS as a percentage of myocardium at risk (MaR),
assessed by cardiac magnetic resonance imaging (CMR) at 4±2
days.
RESULTS: Time from symptom to randomisation was 132±64 vs.
129±56 minutes (mean±SD), control vs. hypothermia. Hypothermia
was initiated before PCI and continued for 1 h after
reperfusion aiming for a temperature of 33°C followed by
spontaneous rewarming. Patients randomised to hypothermia
treatment achieved a mean core body temperature of 34.7°C
3
before reperfusion and had a 9 min longer door-to-balloon time.
IS/MaR was not significantly reduced (control: 46.6 ± 37.8-63.4
vs. hypothermia: 40.5, 29.3-57.8, at 4±2 days, p=0.15). At
45±15 days there was no mortality. The incidence of heart
failure was lower in the hypothermia group (3% vs. 14%,
p<0.05). Exploratory analysis of early anterior infarctions (0-
4h) found a reduction in IS/MaR of 33%, (p<0.05) and an
absolute reduction of infarct size/left ventricular volume of
6.2%. (p<0.15).
Conclusion: Hypothermia induced by intravenous cold saline and
endovascular cooling was safe, feasible, easy to implement and
reduced temperature to 34.7°C before reperfusion with an
acceptable delay of reperfusion and reduced incidence of heart
failure. Although the reduction in IS/MaR did not reach
significance, in the overall population, such an effect was
suggested among early presenters with anterior STEMI.
(ClinicalTrials.gov id NCT01379261).
4
IntroductionContemporary therapy in patients with an ongoing ST-elevation
myocardial infarction (STEMI) is to restore blood flow in the
ischemic myocardium as soon as possible in order to reduce
infarct size and associated complications. Infarct size (IS) is
one of the main predictors of both short and long term outcome
in patients with acute myocardial infarction (AMI).1, 2 Reducing
infarct size is therefore an important objective of current
research in order to improve outcome after AMI. Although
reperfusion therapy is a prerequisite for myocardial salvage,
the process in itself may cause irreversible damage to the
myocardium, referred to as reperfusion injury.3-5 In addition to
reperfusion injury, total ischemic time also contributes to
greater infarct size and increased mortality6, 7. Experimental
studies have shown that mild hypothermia, induced before
reperfusion of acute coronary occlusion, reduces infarct size
and limits microvascular injury.8-14. However, hypothermia has
failed to reduce IS if initiated after the onset of
reperfusion.13-15.
The two major clinical trials investigating mild hypothermia
using endovascular cooling catheters alone as an adjunct
therapy in AMI failed to show a significant reduction in
infarct size.16, 17 Post-hoc analysis of those trials has shown
that only a minority of patients were hypothermic at onset of
reperfusion. The subgroup of patients with anterior STEMI who
were cooled to a temperature of ≤35ºC before reperfusion did
have a significant reduction in infarct size. Early and more
rapidly induced hypothermia, accomplished by a combination of a
5
rapid infusion of cold saline together with an endovascular
cooling catheter, causes a reduction of infarct size only if
induced before reperfusion and not after.13, 18 Based on these
animal studies, the RAPID MI-ICE safety and feasibility study
was performed in which hypothermia was induced by a combination
of infusion of cold saline and an endovascular catheter
cooling. All patients were cooled to a target temperature of
≤35º before reperfusion and cold saline was safely infused to
help induce hypothermia as early as possible during the
ischemic period prior to the initiation of endovascular
cooling19 Hypothermia significantly reduced IS normalized to
myocardium at risk (MaR) by 38%. A pooled analysis of the two
trials ICE-IT and RAPID MI-ICE that employed the Accutrol™
endovascular cooling catheter (Philips Healthcare, San Diego,
CA), found that IS was reduced in patients achieving a
temperature of ≤35°C before reperfusion20. However, these were
post-hoc analyses and a larger efficacy trial was needed to
confirm a beneficial effect of hypothermia for patients with
STEMI.
We designed a multicenter, randomized, endpoint blinded study
using central venous catheter core cooling combined with
rapidly infused cold saline as an adjunct to percutaneous
coronary intervention for the treatment of acute myocardial
infarction. ”Rapid Endovascular Catheter Core Cooling combined
with cold saline as an Adjunct to Percutaneous Coronary
Intervention For the Treatment of Acute Myocardial Infarction”
(CHILL-MI).
6
(CHILL-MI, ClinicalTrials.gov Identifier: NCT01379261).
MethodsEthics and organization
The study was performed in accordance with the Declaration of
Helsinki and the local ethics committees approved the study
protocol. The study protocol was approved by the local ethics
committees. All patients gave written informed consent prior to
inclusion in the study. The Steering Committee designed the
trial in collaboration with the sponsor and had responsibility
for scientific conduct and presentation and publication of
results. An independent Data and Safety Monitoring Board,
consisting of physicians independent of the trial sponsor and
operational leadership, monitored the safety of the study and
had access to un-blinded data.Study population
From July 2011 to March 2013, patients were enrolled in this
prospective, multicenter, randomized, endpoint blinded study to
test the feasibility and safety of an infusion of cold saline
together with endovascular hypothermia, using the Accutrol™
catheter and InnerCool RTx endovascular console (Philips
Healthcare, San Diego, CA, USA) as adjunct therapy in patients
with STEMI eligible for primary PCI. Men and women between 18
and 75 years of age presenting with an anterior or inferior
STEMI with ST-segment elevation of > 0.2mV in two or more
anatomically contiguous leads and a duration of symptoms of <
6h were included. For inferior STEMI an additional ST
depression in 2 contiguous anterior leads for a total ST
7
deviation (inferior ST elevation plus anterior ST depression)
of >0.8mV was required. A 2nd EKG was performed in the cath lab
before randomization to ensure persistent ST-elevation (in
order to avoid inclusion of spontaneously reperfused patients).
Patients with cardiac arrest, previous AMI, previous PCI or
CABG, known congestive heart failure, end stage kidney disease
or hepatic failure, recent stroke, coagulopathy, pregnancy or
Killip class II-IV at presentation were excluded from the
study.
Protocol
Eligible patients were randomized 1:1 to hypothermia or
standard of care after admission and before coronary
angiography. The randomization list was computer-generated
using varying block sizes and stratification by site. Sealed
opaque envelopes containing the study group assignment were
opened after informed consent was obtained. Patients assigned
to hypothermia were administered 30 mg of oral buspirone.
Meperidine was administered as an intravenous loading dose of
1mg/kg. The loading dose was reduced to 0.5mg/kg if the patient
had received morphine prior to enrollment in the study.
Additional 25mg intravenous bolus doses of meperidine were
administered as needed to reduce shivering. Hypothermia was
initially induced by forced infusion of 4ºC cold saline using
pressure bags. Volume administered was 600-2000 ml according to
recommendations from a weight-adjusted schedule (10 ml/kg for
anterior and 20 ml/kg for inferior STEMI patients). Prior to
angiography, a 14 F introducer was inserted in the femoral
vein. Through the introducer, a 14 F Accutrol™ catheter was
8
placed into the inferior vena cava through an introducer with
the tip of the catheter at the level of the diaphragm. The
target temperature was set to 33ºC. Core body temperature was
assessed using an integrated temperature sensor at the tip of
the cooling catheter which helped minimize temperature lag that
occurs in other body compartments such as the bladder, ear or
rectum during rapid core cooling21. Following placement and
activation of the cooling catheter, coronary angiography and
PCI was performed without delay except for a brief pause to
measure core temperature just before advancing the guidewire
through the culprit lesion in the infarct related artery (IRA).
Cooling was maintained for 1h after reperfusion followed by
spontaneous rewarming. If the PCI procedure took longer than 1
hour, cooling was continued until the end of the procedure.
Loading doses of 500mg of Aspirin, and ADP-receptor blockade
were given to all patients before cardiac catheterization.
Heparin, GP IIb/IIIa inhibitors and bivalirudin were
administered at the discretion of the treating physician.
Cardiac Magnetic Resonance (CMR) imaging
After 4±2 days, patients underwent a cardiac Magnetic resonance
imaging (CMR) examination in supine position using a 1.5 tesla
MRI scanner with a five-element cardiac synergy coil. After
initial scout images to locate the heart and the standard
imaging planes, 0.2mmol per kilogram of body weight of an
extracellular gadolinium-based contrast agent were
administered. For visualization of the myocardium at risk (MaR)
and evaluation of left ventricular function, early contrast-
9
enhanced steady state free precession (ssfp) cine images were
obtained approximately 5 minutes after contrast injection22, 23.
For infarct visualisation, late gadolinium enhancement (LGE)
images were acquired 15-20 minutes after administration of the
contrast agent24. Cine and LGE images were acquired in the
short-axis view, from base to apex, and in the three standard
long-axis views (two-chamber, four-chamber and left ventricular
outflow tract views), during breath-hold mage sequence.
Image analysis
The analysis of MaR and infarct size was performed using a
freely available post-processing software (Segment, v.1.9
R3084; http://segment.heiberg.se).25 For assessment of MaR, the
endocardial and epicardial borders were manually traced in end-
diastole and end-systole of the contrast-enhanced ssfp cine
images. The myocardium with increased signal intensity was
manually delineated, as previously described, by an experienced
observer blinded to all other data22, 23. The MaR was expressed
as a percentage of the left ventricular myocardium. The infarct
size was assessed from the short-axis images and quantified
using a previously described and validated semiautomatic
method.26 The assessment of infarct size was performed by an
observer blinded to all other data. The endocardial and
epicardial borders were manually traced in each LGE short-axis
images. Thereafter, the hyper-enhanced myocardium was
automatically quantified using a computer algorithm, taking
partial volume effects in the periphery of the infarction into
account. Regions where the computer algorithm was clearly
10
wrong, manual adjustments were made. IS was expressed as a
percentage of the left ventricular myocardium. Infarct size was
subsequently expressed as percent of MaR. Microvascular
obstruction was defined as hypo-intense regions in the core of
the infarction with signal intensity less than the threshold
for infarction. These regions were manually outlined and
included in the infarct volume. The size of microvascular
obstruction was expressed as percent of the left ventricular
myocardium .
Biochemical markers
CKMB and Troponin T were sampled on admission to the
catheterization laboratory, and at 12h, and 24h after
admission. Peak values were defined as the highest measured
value within 24h. Area under the curve (AUC) was calculated
from the measurements. NT-proBNP was sampled at day 4±2.
Clinical endpoints
Clinical endpoints were collected by a CRF during index
hospitalisation, at 45±15 days and at 6 months. Furthermore,
clinical events were collected by adverse event (AE) and
serious AE (SAE) reporting. Hospital charts were monitored by
independent monitors for all patients. All primary events
(death and heart failure) were evaluated independently by a
blinded clinical events committee (CEC).
Statistics
11
Based on a mean infarct size as percent of myocardium at risk
in the control group of 48% and a standard deviation in both
groups of 17.7 % (based on the pilot study13), 72 evaluable
patients would give 80% power to detect a 25% relative decrease
in the hypothermia group, using a 2-sided test at the 5%
significance level. To account for uncertainty in variability
and dropout rate, a sample size of 120 patients was chosen,
estimated to give 90% power after 20% drop-out.
All analyses were performed according to the protocol and the
statistical analysis plan (SAP), using intention to treat
without imputation of missing data. Statistical tests were
performed at the 0.05 significance level using 2-sided
alternative hypotheses. IS as percentage of MaR was analysed
using linear models with treatment as a factor, and with
treatment and centre as factors. The centre-adjusted model was
pre-defined as primary. Troponin AUC through 48 hours and peak
concentration, and serum NT-proBNP levels at day 4±2, were
analysed using a linear model for log-transformed concentration
with factors treatment and centre. ST-segment resolution in
percent of initial elevation was compared using a Wilcoxon
rank-sum test. IS at 6±1 months, as a percentage of myocardium
at risk as determined at 4±2 days, was analysed in the same way
as the primary variable. The pre-defined subgroup analyses were
anterior or inferior MI, and occluded (TIMI flow 0) or non-
occluded (TIMI flow >0) IRA before PCI. The subgroup analyses
were performed using linear models with factors treatment,
subgroup indicator, and interaction. A supplementary per-
protocol analysis of the primary variable was performed after
12
removing all patients randomized to hypothermia that did not
reach ≤35ºC before reperfusion. All statistical analyses were
performed using SAS v. 9.3 (SAS Institute, SAS Institute Inc.,
Cary, NC, USA).
Results120 patients from 9 sites in 4 countries were enrolled in the
study. There were no significant differences in baseline
characteristics between the groups (Table 1). Clinical and
angiographic data are shown in Table 1. Time from onset of
symptom to randomisation was 129±56 vs. 132±64 minutes
(mean±SD, control vs. hypothermia). Hypothermia was initiated
before PCI and continued for 1 h after reperfusion toward a
target temperature of 33°C followed by spontaneous rewarming.
All but three patients underwent PCI. One patient was reported
as having an unsuccessful PCI. TIMI 3 flow was established in
90% and 93% of the patients, respectively. Thrombus aspiration
was performed in 69% and 59% of the patients respectively. The
novel more potent P2Y12-inhibitors ticagrelor or prasugrel were
used in 84% and 89% of the patients (control vs. hypothermia).
Hypothermia treatment
Baseline tympanic temperature was similar in the two groups
(36.0±0.7°C vs. 36.0±0.7°C, control vs. hypothermia). After
randomization to the hypothermia group, cold saline was started
after 7 min and endovascular cooling was started after 30 min
13
(mean). Mean console run time before reperfusion was 13 min.
Mean saline volume was 1325±523 ml infused during a mean of 28
min before reperfusion. Hypothermia treatment caused a mean
increase in randomisation-to-balloon time of 9 min from
33.3±21.2 to 42.7±16.6 min. Average temperature at reperfusion
was 34.7 ± 0.6°C. At the time of reperfusion, a core body of ≤
35°C was achieved in 76%, and a core body temperature of ≤
35.4°C was achieved in 91% of the patients randomized to
hypothermia that underwent PCI. Cold saline and endovascular
cooling was successfully used in 60 of the 61 patients.
Intravenous Meperidine was administered at the catheterization
laboratory to prevent shivering in all patients in the
hypothermia group with a mean total dose of 114±67 mg.
Buspirone was administered to 71% of the patients. One control
patient received hypothermia by mistake. This patient also
lacks MRI data.
Assessment of Infarct size and Myocardium at risk
CMR data was missing in 19% of the patients, equally
distributed between the groups. The reasons for missing CMR
were claustrophobia (6), CMR not available/image quality
unsatisfactory (6), patient not willing (6), CMR disrupted on
patients decision, e. g. chronic lumbago (3), incorrectly
randomised (1) and costa fracture after CPR (1). There was no
difference between the hypothermia and control groups with
regard to the timing of the CMR examination (3.7±1.5 days vs.
4.0±1.4 days1.4 days, control vs. hypothermia).
14
The primary endpoint of IS normalized to MaR was (46.6 ± 37.8-
63.4% vs. 40.5, 29.3-57.8%, median, Q1-Q3, control vs.
hypothermia, relative reduction 13%, absolute reduction 5.5%,
95% C.I. -2.0% to 12.9%, p=0.15, Figure 1). Adjustment for site
resulted in p=0.27 (Table 4). Myocardium at risk (MaR) as
percentage of left ventricular mass was similar between
treatment groups, (34.9, 29.1-44.8 and 34.6, 28.7-43.8, median,
Q1-Q3, control vs. hypothermia).
The relative reduction in IS normalized to MaR in anterior
infarcts (pre-defined subgroup) was 27% (59.9 ± 46.2-67.3 vs.
43.7, 37.8-64.3%, median, Q1-Q3), control n=21 vs. hypothermia
n=15, (p=0.22). The relative reduction in IS normalized to MaR
in the inferior infarcts was 9% (40.6 ± 26.6-58.8 vs. 36.6,
9.2-75.8%, median, Q1-Q3), control n=26 vs. hypothermia n=34.).
The p-value for interaction was 0.48. Exploratory analysis of
early anterior infarcts (0-4h) found a relative reduction of
33%, (0.046) (60.9 ± 46.1-67.95 vs. 40.9, 32.6-57.7%, median,
Q1-Q3, p=0.046), (Figure 4, Table 4).
When only comparing cooled patients who did achieve target
temperature of ≤35°C, there was no significant difference in
reduction in infarct size (IS) normalized to MaR, but this was
difficult to compare, since all patients were in a narrow
temperature window and only 24% were >35°C and only 9% >35.4°C
(Table 4). In an exploratory analysis by gender, females had a
numerical absolute increase of 1.4% while males had a numerical
absolute reduction of 6.2%. The p-value for interaction was
0.45. There was no difference depending on full analysis set or
15
per protocol set. There was no difference depending on TIMI 0
or TIMI 1-3 (Table 4).
Clinical events and Safety
Combination hypothermia was well tolerated in all patients. PCI
operators and nurses found the protocol easy to implement. The
primary clinical endpoint of adjudicated death and heart
failure was significantly reduced in the hypothermia group at
45 days. (8 vs. 2 events, p=0.047, Figure 5). Heart failure
was only present in patients with anterior infarcts. Since
there was no mortality in either group the reduction in events
consisted entirely of fewer heart failure events.
There was no difference in rates of pneumonia, ventricular
arrhythmias, bradycardia, re-infarction, stroke, or major
bleeding between the groups (Table 2).
Other endpoints
Microvascular obstruction was similar between the control and
hypothermia treated groups: 0.12, 0-5.25 vs. 0.24, 0-9.35,
median, IQR, % of MaR. Ejection fraction analysed by MRI at 4±2
days did not differ; control 50.56, 42.64-55.80 and hypothermia
group 47.99, 41.66-53.07% (Table 3).
ST-segment resolution at 1.5 h after reperfusion was
numerically more pronounced in hypothermia treated patients
(75.7%, 57.1-88.9 vs. 83.0%, 66.7-92.9, p=0.13, control vs.
hypothermia, median, IQR). In a post-hoc analysis ST-segment
elevation at 1.5 h was significantly lower in hypothermia
16
treated patients (3.5 mm, 1.0-7.0 vs. 2.0 mm, 0.5-5.0 p=0.047,
control vs. hypothermia (Table 3).
The area under the curve (AUC) or peak concentration for
Troponin T or CKMB did not differ between the groups. NT-proBNP
at 4±2 days was similar by between the groups (Table 3).
DiscussionIn this prospective, multicentre, randomized trial in STEMI
patients hypothermia using intravenous cold saline and a
endovascular venous cooling catheter was safe, feasible, easy
to implement and reduced temperature to 34.7°C before
reperfusion with a delay of reperfusion of 9 min. IS in
relation to MaR did not reach significance. The key clinical
endpoint of death and heart failure was significantly reduced
(driven by heart failure events). Further analyses indicate
that early anterior STEMI may benefit most from the therapy.
Safety
The safety of using endovascular cooling alone has previously
been demonstrated in awake patients with acute myocardial
infarction.16, 17, 27, 28 The rationale of using a combination of
cold saline together with endovascular cooling was to achieve a
rapid induction of hypothermia as early as possible during the
ischemic period without delaying reperfusion therapy. Previous
data indicate the necessity of reaching a temperature ≤35°C
before reperfusion in order to reduce infarct size.13, 16, 17
17
However, an intravenous infusion of cold saline could possibly
lead to an increase in acute heart failure and pulmonary
congestion in patients with acute myocardial infarction. In
this population without previous congestive heart failure on
presentation, despite large myocardial infarctions, clinical
signs of heart failure were reduced in the hypothermia group.
There was no difference in rates of pneumonia, ventricular
arrhythmias, bradycardia, re-infarction, stroke, or major
bleeding between the groups and most importantly there were no
deaths in either group, indicating that the therapy is safe.
Feasibility
In a previous experimental study, it has been demonstrated that
a combination of cold saline infusion and an endovascular
cooling catheter can accomplish a reduction in core body
temperature to ≤35°C within 5-10 minutes in 40-50kg pigs.13 In
the present study, inducing hypothermia with a combination of
cold saline infusion and endovascular cooling was clinically
feasible and was used to obtain a rapid reduction in core body
temperature in patients with STEMI without a major delay in
time to reperfusion (9 min). In patients randomized to
hypothermia, 76% reached ≤ 35°C and 91% ≤ 35.4°C with only 14
min of catheter cooling. Lower temperatures at the time of
reperfusion reduce infarct size even further in animal
models14, and efforts to achieve lower temperature before
reperfusion could result in further infarct size reduction.
18
Meperidine and buspirone were chosen to suppress shivering
since they act synergistically without causing respiratory
depression.29 Furthermore, the drugs have been utilised in
previous clinical trials with a high tolerance in awake
patients with acute myocardial infarction.16, 17 In this study,
hypothermia was well tolerated, and treatment was not
discontinued in any patients due to shivering.
Infarct size
Using CMR for assessing IS in relation to MaR has recently been
validated in patients with acute myocardial infarction and used
to describe the natural course of infarct evolution in man.30, 31
This methodology reduces the sample size needed in clinical
trials in order to show significant effects of cardio-
protective interventions.
Therapeutic hypothermia numerically reduced IS/AAR by 13% but
did not reach significance. This is in contrast to a large
number of highly reproducible animal experiments in many
species14. In order to try to understand the effects of
hypothermia in man we did predefined analyses of IS/AAR
subgroups. TIMI-flow, temperature and gender did not
significantly influence the results. However, similar as in the
ICE-IT and COOL-MI trials, the anterior STEMI subgroup seemed
to benefit more with an infarction reduction of 27%. This was
further pronounced in early anterior STEMI with an infarction
reduction of 33%. In this group absolute reduction of infarct
size as a percentage of the left ventricle was reduced by 6.2%
19
which can then be compared to the 5.1 % absolute reduction in
IS in the STOP-AMI trial that is now accepted as a clinically
meaningful result for cardioprotection trials32. It would
therefore be logical to further explore the cardioprotective
effects of hypothermia in a study on early anterior STEMI
(symptom onset <4 hours), especially in light of the several
cardioprotective studies already focusing on early anterior
STEMI patients only33-35.
Other endpoints
The main clinical endpoint, a combination of death and heart
failure, was significantly reduced in the therapeutic
hypothermia group, explained solely by a reduction in heart
failure since there were no deaths in either arm. At the same
time we did not see any difference in cardiac biomarkers, pro-
BNP, microvascular obstruction or ejection fraction. We did see
a trend for better ST-resolution, and reduced ST-levels at 1.5
h in the hypothermia group. All of these parameters are known
to have larger variability than IS/AAR and therefore need
larger populations to be powered enough to show differences.
Limitations
The primary aim of this study was to assess the efficacy of
hypothermia to reduce infarct size in patients with STEMI. It
cannot be excluded that part of the hyper-enhanced myocardium
on CMR acquired at 4±2 days can be due to oedema, since it has
recently been shown that there is a significant decrease in
hyper-enhanced myocardium during the first week after
20
infarction.36, 37 There was, however, no difference in the timing
of the MR examination between the hypothermic patients and the
controls, and thus the effect of infarct size reduction in the
hypothermia group cannot be attributed to the changes in
infarct size during the first week after infarction.
Furthermore, area at risk was similar between treatment groups.
CMR data was missing in 19% of the patients, equally
distributed between the groups. 19% missing is of similar
magnitude as observed in other MRI based trials33. The reasons
were usually unrelated to coronary disease, most often due to
claustrophobia.
Conclusions
The results of the study indicate that it is clinically fast,
feasible and safe to induce hypothermia by using a combination
of cold saline infusion and endovascular cooling prior to
reperfusion in awake STEMI patients with only a small delay
time to reperfusion. Clinical endpoints were favourable for
hypothermia treatment, but the lower relative infarct size of
13% compared to controls did not reach statistical
significance. Further analysis indicates that anterior STEMI
could benefit from the treatment but needs validation in future
trials.
AcknowledgementsWe would like to thank Charlotta Elfström for excellent project
management as well as Bradley Klos and Anthony Mullin from
Philips Healthcare for expertise and continuous support.
21
Funding SourcesThe study was funded by Philips Healthcare
DisclosuresDE has received speaker fees from Philips Healthcare
References
1. Miller TD, Christian TF, Hopfenspirger MR, Hodge DO, Gersh
BJ, Gibbons RJ. Infarct size after acute myocardial
infarction measured by quantitative tomographic 99mtc
sestamibi imaging predicts subsequent mortality.
Circulation. 1995;92:334-341
2. Burns RJ, Gibbons RJ, Yi Q, Roberts RS, Miller TD, Schaer
GL, Anderson JL, Yusuf S. The relationships of left
ventricular ejection fraction, end-systolic volume index
and infarct size to six-month mortality after hospital
discharge following myocardial infarction treated by
thrombolysis. Journal of the American College of Cardiology.
2002;39:30-36
3. Kloner RA. Does reperfusion injury exist in humans? Journal
of the American College of Cardiology. 1993;21:537-545
4. Ambrosio G, Tritto II. Lethal myocardial reperfusion
injury: Does it exist, should we treat it? Journal of
thrombosis and thrombolysis. 1997;4:69-70
22
5. Kloner RA, Ganote CE, Jennings RB. The "no-reflow"
phenomenon after temporary coronary occlusion in the dog.
J Clin Invest. 1974;54:1496-1508
6. Denktas AE, Anderson HV, McCarthy J, Smalling RW. Total
ischemic time: The correct focus of attention for optimal
st-segment elevation myocardial infarction care. JACC.
Cardiovascular interventions. 2011;4:599-604
7. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The
wavefront phenomenon of ischemic cell death. 1. Myocardial
infarct size vs duration of coronary occlusion in dogs.
Circulation. 1977;56:786-794
8. Dae MW, Gao DW, Sessler DI, Chair K, Stillson CA. Effect
of endovascular cooling on myocardial temperature, infarct
size, and cardiac output in human-sized pigs. Am J Physiol
Heart Circ Physiol. 2002;282:H1584-1591
9. Duncker DJ, Klassen CL, Ishibashi Y, Herrlinger SH, Pavek
TJ, Bache RJ. Effect of temperature on myocardial
infarction in swine. Am J Physiol. 1996;270:H1189-1199
10. Hale SL, Dave RH, Kloner RA. Regional hypothermia reduces
myocardial necrosis even when instituted after the onset
of ischemia. Basic research in cardiology. 1997;92:351-357
11. Hale SL, Kloner RA. Myocardial temperature in acute
myocardial infarction: Protection with mild regional
hypothermia. Am J Physiol. 1997;273:H220-227
12. Hale SL, Kloner RA. Ischemic preconditioning and
myocardial hypothermia in rabbits with prolonged coronary
artery occlusion. Am J Physiol. 1999;276:H2029-2034
23
13. Gotberg M, Olivecrona GK, Engblom H, Ugander M, van der
Pals J, Heiberg E, Arheden H, Erlinge D. Rapid short-
duration hypothermia with cold saline and endovascular
cooling before reperfusion reduces microvascular
obstruction and myocardial infarct size. BMC cardiovascular
disorders. 2008;8:7
14. Erlinge D. A review of mild hypothermia as an adjunctive
treatment for st-elevation myocardial infarction.
Therapeutic Hypothermia and Temperature Management. 2011;1:129-
141
15. Maeng M, Mortensen UM, Kristensen J, Kristiansen SB,
Andersen HR. Hypothermia during reperfusion does not
reduce myocardial infarct size in pigs. Basic research in
cardiology. 2006;101:61-68
16. Grines CL. Intravascular cooling adjunctive to
percutaneous coronary intervention for acute myocardial
infarction. Presented at Transcatheter Cardiovascular Therapeutics.
Washington DC, USA; 2004.
17. O'Neill WW. Cooling as an adjunct to primary pci for
myocardial infarction. . Presented at Transcatheter Cardiovascular
Therapeutics. Washington DC, USA;2004.
18. Gotberg M, van der Pals J, Gotberg M, Olivecrona GK,
Kanski M, Koul S, Otto A, Engblom H, Ugander M, Arheden H,
Erlinge D. Optimal timing of hypothermia in relation to
myocardial reperfusion. Basic research in cardiology.
2011;106:697-708
19. Gotberg M, Olivecrona GK, Koul S, Carlsson M, Engblom H,
Ugander M, van der Pals J, Algotsson L, Arheden H, Erlinge
24
D. A pilot study of rapid cooling by cold saline and
endovascular cooling before reperfusion in patients with
st-elevation myocardial infarction. Circulation. Cardiovascular
interventions. 2010;3:400-407
20. Erlinge D, Gotberg M, Grines C, Dixon S, Baran K, Kandzari
D, Olivecrona GK. A pooled analysis of the effect of
endovascular cooling on infarct size in patients with st-
elevation myocardial infarction. EuroIntervention : journal of
EuroPCR in collaboration with the Working Group on Interventional
Cardiology of the European Society of Cardiology. 2013;8:1435-1440
21. Bone ME, Feneck RO. Bladder temperature as an estimate of
body temperature during cardiopulmonary bypass. Anaesthesia.
1988;43:181-185
22. Ubachs JF, Sorensson P, Engblom H, Carlsson M, Jovinge S,
Pernow J, Arheden H. Myocardium at risk by magnetic
resonance imaging: Head-to-head comparison of t2-weighted
imaging and contrast-enhanced steady-state free
precession. European heart journal cardiovascular Imaging.
2012;13:1008-1015
23. Gullestad L, Pernow J, Bjuro T, Aaberge L, Skardal R,
Kjekshus E, Hoglund L, Mellgard AJ, Wahlquist I, Ablad B.
Differential effects of metoprolol and atenolol to
neuropeptide y blockade in coronary artery disease.
Scandinavian cardiovascular journal : SCJ. 2012;46:23-31
24. Hedstrom E, Engblom H, Frogner F, Astrom-Olsson K, Ohlin
H, Jovinge S, Arheden H. Infarct evolution in man studied
in patients with first-time coronary occlusion in
comparison to different species - implications for
25
assessment of myocardial salvage. Journal of cardiovascular
magnetic resonance : official journal of the Society for Cardiovascular
Magnetic Resonance. 2009;11:38
25. Heiberg E, Sjogren J, Ugander M, Carlsson M, Engblom H,
Arheden H. Design and validation of segment - freely
available software for cardiovascular image analysis. BMC
Med Imaging.10:1
26. Heiberg E, Ugander M, Engblom H, Gotberg M, Olivecrona GK,
Erlinge D, Arheden H. Automated quantification of
myocardial infarction from mr images by accounting for
partial volume effects: Animal, phantom, and human study.
Radiology. 2008;246:581-588
27. Dixon SR, Whitbourn RJ, Dae MW, Grube E, Sherman W, Schaer
GL, Jenkins JS, Baim DS, Gibbons RJ, Kuntz RE, Popma JJ,
Nguyen TT, O'Neill WW. Induction of mild systemic
hypothermia with endovascular cooling during primary
percutaneous coronary intervention for acute myocardial
infarction. Journal of the American College of Cardiology.
2002;40:1928-1934
28. Kandzari DE, Chu A, Brodie BR, Stuckey TA, Hermiller JB,
Vetrovec GW, Hannan KL, Krucoff MW, Christenson RH,
Gibbons RJ, Sigmon KN, Garg J, Hasselblad V, Collins K,
Harrington RA, Berger PB, Chronos NA, Hochman JS, Califf
RM. Feasibility of endovascular cooling as an adjunct to
primary percutaneous coronary intervention (results of the
lowtemp pilot study). The American journal of cardiology.
2004;93:636-639
26
29. Mokhtarani M, Mahgoub AN, Morioka N, Doufas AG, Dae M,
Shaughnessy TE, Bjorksten AR, Sessler DI. Buspirone and
meperidine synergistically reduce the shivering threshold.
Anesthesia and analgesia. 2001;93:1233-1239
30. Carlsson M, Ubachs JF, Hedstrom E, Heiberg E, Jovinge S,
Arheden H. Myocardium at risk after acute infarction in
humans on cardiac magnetic resonance: Quantitative
assessment during follow-up and validation with single-
photon emission computed tomography. JACC Cardiovasc Imaging.
2009;2:569-576
31. Hedström E. Acute myocardial infarction. The relationship
between duration of ischaemia and infarct size in humans –
assessment by mri and spect. 2005
32. Schomig A, Kastrati A, Dirschinger J, Mehilli J, Schricke
U, Pache J, Martinoff S, Neumann FJ, Schwaiger M. Coronary
stenting plus platelet glycoprotein iib/iiia blockade
compared with tissue plasminogen activator in acute
myocardial infarction. Stent versus thrombolysis for
occluded coronary arteries in patients with acute
myocardial infarction study investigators. N Engl J Med.
2000;343:385-391
33. Stone GW, Maehara A, Witzenbichler B, Godlewski J, Parise
H, Dambrink JH, Ochala A, Carlton TW, Cristea E, Wolff SD,
Brener SJ, Chowdhary S, El-Omar M, Neunteufl T, Metzger
DC, Karwoski T, Dizon JM, Mehran R, Gibson CM.
Intracoronary abciximab and aspiration thrombectomy in
patients with large anterior myocardial infarction: The
27
infuse-ami randomized trial. JAMA : the journal of the American
Medical Association. 2012;307:1817-1826
34. Hausenloy DJ, Baxter G, Bell R, Botker HE, Davidson SM,
Downey J, Heusch G, Kitakaze M, Lecour S, Mentzer R,
Mocanu MM, Ovize M, Schulz R, Shannon R, Walker M,
Walkinshaw G, Yellon DM. Translating novel strategies for
cardioprotection: The hatter workshop recommendations.
Basic research in cardiology. 2010;105:677-686
35. Chakrabarti AK, Feeney K, Abueg C, Brown DA, Czyz E,
Tendera M, Janosi A, Giugliano RP, Kloner RA, Weaver WD,
Bode C, Godlewski J, Merkely B, Gibson CM. Rationale and
design of the embrace stemi study: A phase 2a, randomized,
double-blind, placebo-controlled trial to evaluate the
safety, tolerability and efficacy of intravenous bendavia
on reperfusion injury in patients treated with standard
therapy including primary percutaneous coronary
intervention and stenting for st-segment elevation
myocardial infarction. Am Heart J. 2013;165:509-514 e507
36. Engblom H, Hedstrom E, Heiberg E, Wagner GS, Pahlm O,
Arheden H. Rapid initial reduction of hyperenhanced
myocardium after reperfused first myocardial infarction
suggests recovery of the peri-infarction zone: One-year
follow-up by mri. Circ Cardiovasc Imaging. 2009;2:47-55
37. Ibrahim T, Hackl T, Nekolla SG, Breuer M, Feldmair M,
Schomig A, Schwaiger M. Acute myocardial infarction:
Serial cardiac mr imaging shows a decrease in delayed
enhancement of the myocardium during the 1st week after
reperfusion. Radiology.254:88-97
29
Table 1
Clinical and Angiographic Data. P = NS for all
comparisons. Data are presented as mean ± SD or range.
Variable Hypothermia
(n=61)
Control
(n=59)
Age 57(37-79) 59 (30-75)
Women 13 (21%) 8 (14%)
Hypertension 17 (28%) 7 (12%)
Diabetes 8 (13%) 3 (5%)
Hyperlipidemia 10 (16%) 1 (2%)
Current smoker 28 (46%) 23 (39%)
BMI (kg/m2) 28.4 ± 4.9 27.0 ± 3.3
Anterior STEMI 23 (38%) 28 (48%)
Inferior STEMI 38 (62%) 30 (52%)
Onset of symptoms
to reperfusion
(min)
132 ± 64 129 ± 56
Randomisation-to-
balloon time (min)
42 ± 16 33 ± 21
Initial TIMI flow
0/1
54 (89%) 48 (81%)
Initial TIMI flow
2/3
7 (11%) 11 (19%)
TIMI 3 flow post
PCI
57 (93%) 53 (90%)
Thrombectomy 35 (59%) 41 (69%)
GpIIb/IIIa 14 (23%) 22 (34%)
Bivalirudin 35 (57%) 31 (52%)
Ticagrelor/ 54 (89%) 67 (84%)
30
Prasugrel
Aspirin 61 (100%) 59 (100%)
Buspirone 30 mg 44 (71%) 0
Meperidine/
Pethidine
114 ± 67 mg 0
DES 44 (75%) 50 (86%)
Table 2
Clinical events at day 45±15. P = NS for all
comparisons except heart failure (* = p < 0.05).
Outcome at 45 days Hypothermia (n=61) Control (n=59)
Mortality 0 0
Heart failure 2 (3%)* 8 (14%)
Re-infarction 1 (2%) 0 (0%)
VT/VF 5 (8%) 2 (3%)
Atrial
fibrillation/flutter
4 (6%) 4 (7%)
Stroke 0 0
Pneumonia 3 (5%) 1 (2%)
Pulmonary oedema 1 (2%) 2 (3%)
Major bleeding 0 (0%) 1 (2%)
32
Table 3Cardiac MRI, biomarker, ECG and angiographic endpointsOutcome Hypothermia Control Treatment
contrast (95%
confidence
interval)a
P-
value
Microvascular
obstruction size at
4±2 days (% of
myocardium at risk),
Median (IQR)
0.26 (0; 9.35) 0.12 (0, 5.25) 0.46 (-2.87;
3.79)
0.79
Left ventricular
ejection fraction at
4±2 days (% of end-
diastolic volume),
Median (IQR)
47.99 (41.66;
53.07)
50.56 (42.64;
55.80)
-1.46 (-4.82;
1.91)
0.39
Hs-Troponin-T, 48 hour
AUC (arbitrary unit),
Geometric mean (%CV)
137626 (158) 137468 (123) 0.99 (0.68;
1.43)
0.96
Hs-Troponin-T, peak
concentration (ng/L),
Geometric mean (%CV)
4686 (178) 4787 (135) 0.97 (0.65;
1.43)
0.87
CKMB, 48 hour AUC
(arbitrary unit),
Geometric mean (%CV)
4281 (107) 3877 (99) 1.09 (0.80;
1.47)
0.59
CKMB, peak
concentration (µg/L),
Geometric mean (%CV)
219.1 (136) 191.7 (115) 1.13 (0.80;
1.59)
0.50
NT-proBNP at 4±2 days
(ng/L), Geometric mean
(%CV)
834.2 (115) 637.9 (153) 1.26 (0.88;
1.82)
0.21
ST-segment resolution
1.5h after opening the
IRA (% of initial
elevation), Median
(IQR)
83.0 (66.7;
92.9
75.7 (57.1;
88.9)
5.6 (-0.8; -
13.2)
0.13
ST-segment elevation 2.0 (0.5; 5.0) 3.5 (1.0; 7.0) -1.0 (-2.0; 0.04
33
1.5h after opening the
IRA (mm), Median (IQR)b
0.0)
Patients with at least
50% ST-segment
resolution, N (%)
49 (84%) 50 (86%) 0.87 (0.27;
2.8)
1.00
TIMI flow post-PCI,
N(%)TIMI 2: 2 (3%)
TIMI 3: 57
(93%)
TIMI 2: 5 (8%)
TIMI 3: 53 (90%)
0.27
Percent stenosis post-
PCI, Median (IQR)
0 (0; 0) 0 (0; 0) 0 (0; 0) 0.97
a Infarct size, microvascular obstruction and ejection
fraction: Mean difference and p-value from unadjusted linear
model. Heart failure and 50% ST-segment resolution: Exact odds
ratio and Fisher's test. Biomarkers: Geometric mean ratio and
p-value from log-linear model adjusted for centre. ST-segment
elevation and resolution and percent stenosis: Hodges-Lehmann
estimate of location shift and Wilcoxon's test. TIMI flow:
Exact Wilcoxon's test.b Post-hoc analysis
34
Table 4
Infarct size in relation to area at risk in the total
population and subgroups
Hypothermia Control
N Median (IQR) N Median (IQR)
Full analysis set
49 40.6 (29.3;
57.8)
48 46.6 (37.8;
63.4)Per-protocol seta
49 40.6 (29.3;
57.8)
47 46.8 (37.7;
64.2)≤35ºC seta
38 40.9 (29.3;
57.6)
48 46.6 (37.8;
63.4)TIMI flow before PCIa
TIMI 0 39 48.4 (32.8;
61.3)
35 53.2 (40.4;
64.4)
TIMI 1-3 10 25.0 (16.6;
38.2)
13 33.6 (26.2;
60.9)Infarct locationa
Anterior 15 43.7 (37.8;
64.3)
21 60.0 (46.2;
67.4)Inferior 34 36.7 (28.3;
57.5)
26 40.7 (26.6;
58.8)
Infarct location and time from symptom onset to
reperfusionAnterior
0-4h
12 40.9 (34.3;
57.7)
19 60.9 (46.2;
68.0)Anterior 3 64.3 (64.3; 2 46.8 (33.6;
35
>4h 66.6) 60.0)Inferior
0-4h
30 38.0 (28.3;
57.5)
20 44.6 (27.0;
61.0)Inferior
>4h
4 36.7 (27.7;
49.5)
5 38.0 (26.2;
38.4)Gender
Male 40 42.4 (31.7;
58.4)
41 53.2 (38.4;
64.2)
Female 9 28.3 (23.2;
48.4)
7 26.2 (20.7;
49.9)
a Pre-defined subgroups
38
Figure 3Predefined subgroup analysis of infarct size as percent of
myocardium at risk by treatment and location, full analysis set
(median, quartiles, 5-95%).
A. Inferior STEMI (control n=26, hypothermia n=34, p = 0.76)
B. Anterior STEMI (control n=21, hypothermia n=15, p = 0.22)
InferiorRRR 9%
Control Hypothermia0
20
40
60
80
100
I S% of AAR
Control Hypothermia0
20
40
60
80
100
I S% of AAR
AnteriorRRR 27%
39
Figure 4
Exploratory analysis of early infarctions (symptom to balloon
time 0-4h)
A. All patients 0-4 h (control n=39, hypothermia n=42, p =
0.049) Ollie will calculate to confirm
B. All patients with inferior STEMI 0-4h (control n=20,
hypothermia n=30, p = n.s.)
C. All patients with anterior STEMI 0-4h (control n=19,
hypothermia n=12, p = 0.046)
Top Related