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

david.erlinge@med.lu.se

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

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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%)

31

Bradycardia 2 (3%) 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

36

Figure 1

   

37

Figure 2Infarct size as percent of myocardium at risk by treatment

(median, quartiles, 5-95%).

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)

40

Figure 5