Author + information
- Received November 5, 2013
- Revision received December 9, 2013
- Accepted December 23, 2013
- Published online May 13, 2014.
- David Erlinge, MD, PhD∗∗ (, )
- Matthias Götberg, MD, PhD∗,
- Irene Lang, MD, PhD†,
- Michael Holzer, MD, PhD†,
- Marko Noc, MD, PhD‡,
- Peter Clemmensen, MD, PhD§,
- Ulf Jensen, MD, PhD‖,
- Bernhard Metzler, MD, PhD¶,
- Stefan James, MD, PhD#∗∗,
- Hans Erik Bötker, MD, PhD††,
- Elmir Omerovic, MD, PhD††,
- Henrik Engblom, MD, PhD‡‡,
- Marcus Carlsson, MD, PhD‡‡,
- Håkan Arheden, MD, PhD‡‡,
- Ollie Östlund, MSc#,
- Lars Wallentin, MD, PhD#∗∗,
- Jan Harnek, MD, PhD∗ and
- Göran K. Olivecrona, MD, PhD∗
- ∗Department of Cardiology, Lund University, Lund, Sweden
- †Department of Cardiology and the Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria
- ‡Center for Intensive Internal Medicine, Ljubljana, Slovenia
- §Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
- ‖Cardiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden
- ¶Department of Cardiology, Medical University of Innsbruck, Innsbruck, Austria
- #Uppsala Clinical Research Center, Uppsala, Sweden
- ∗∗Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- ††Department of Cardiology, Sahlgrenska University, Gothenburg, Sweden
- ‡‡Department of Clinical Physiology, Lund University, Lund, Sweden
- ↵∗Reprint requests and correspondence:
Dr. David Erlinge, Lund University, Department of Cardiology, Skane University Hospital, S-221 85 Lund, Sweden.
Objectives The aim of this study was to confirm the cardioprotective effects of hypothermia using a combination of cold saline and endovascular cooling.
Background Hypothermia has been reported to reduce infarct size (IS) in patients with ST-segment elevation myocardial infarctions.
Methods In a multicenter study, 120 patients with ST-segment elevation myocardial infarctions (<6 h) scheduled to undergo percutaneous coronary intervention were randomized to hypothermia induced by the rapid infusion of 600 to 2,000 ml cold saline and endovascular cooling or standard of care. Hypothermia was initiated before percutaneous coronary intervention and continued for 1 h after reperfusion. The primary end point was IS as a percent of myocardium at risk (MaR), assessed by cardiac magnetic resonance imaging at 4 ± 2 days.
Results Mean times from symptom onset to randomization were 129 ± 56 min in patients receiving hypothermia and 132 ± 64 min in controls. Patients randomized to hypothermia achieved a core body temperature of 34.7°C before reperfusion, with a 9-min longer door-to-balloon time. Median IS/MaR was not significantly reduced (hypothermia: 40.5% [interquartile range: 29.3% to 57.8%; control: 46.6% [interquartile range: 37.8% to 63.4%]; relative reduction 13%; p = 0.15). The incidence of heart failure was lower with hypothermia at 45 ± 15 days (3% vs. 14%, p < 0.05), with no mortality. Exploratory analysis of early anterior infarctions (0 to 4 h) found a reduction in IS/MaR of 33% (p < 0.05) and an absolute reduction of IS/left ventricular volume of 6.2% (p = 0.15).
Conclusions Hypothermia induced by cold saline and endovascular cooling was feasible and safe, and it rapidly reduced core temperature with minor reperfusion delay. The primary end point of IS/MaR was not significantly reduced. Lower incidence of heart failure and a possible effect in patients with early anterior ST-segment elevation myocardial infarctions need confirmation. (Efficacy of Endovascular Catheter Cooling Combined With Cold Saline for the Treatment of Acute Myocardial Infarction [CHILL-MI]; NCT01379261)
Contemporary therapy in patients with ongoing ST-segment elevation myocardial infarctions (STEMIs) is to restore blood flow in the ischemic myocardium as soon as possible to reduce infarct size (IS) and associated complications. IS is one of the main predictors of both short-term and long-term outcomes in patients with acute myocardial infarction (AMI) (1,2). Reducing IS is therefore an important objective of current research to improve outcomes 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). In addition to reperfusion injury, total ischemic time also contributes to greater IS and increased mortality (4,5). Experimental studies have shown that mild hypothermia, induced before reperfusion of acute coronary occlusion, reduces IS and limits microvascular injury (6–11). However, hypothermia has failed to reduce IS if initiated after the onset of reperfusion (10–12). In animal models, hypothermia before the start of ischemia can reduce IS by 100%; during ischemia, IS may be reduced by up to 80%. Immediately at reperfusion, a 20% reduction in IS is achieved, while hypothermia begun after reperfusion does not reduce IS at all (10–12).
The 2 major clinical trials investigating mild hypothermia using endovascular cooling as an adjunct therapy in AMI failed to show a significant reduction in IS (13,14). Post-hoc analysis of those trials showed that only a minority of patients were hypothermic at the onset of reperfusion. The subgroup of patients with anterior STEMIs who were cooled to a temperature of ≤35°C before reperfusion did have significant reductions in IS. Early and more rapidly induced hypothermia, accomplished by a combination of rapid infusion of cold saline together with an endovascular cooling catheter, caused a reduction of IS only if induced before reperfusion, not afterward (10,15). On the basis of these animal studies, the RAPID MI-ICE (Rapid Intravascular Cooling in Myocardial Infarction as Adjunctive to Percutaneous Coronary Intervention) 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 ≤35°C before reperfusion, and cold saline was safely infused to help induce hypothermia as early as possible during the ischemic period before the initiation of endovascular cooling (16). Hypothermia significantly reduced IS normalized to myocardium at risk (MaR) by 38%. A pooled analysis of 2 trials, ICE-IT (Intravascular Cooling Adjunctive to Percutaneous Coronary Intervention and Rapid Intravascular Cooling in Myocardial Infarction as Adjunctive to Percutaneous Coronary Intervention), that used the Accutrol endovascular cooling catheter (Philips Healthcare, San Diego, California) found that IS was reduced in patients achieving temperatures of ≤35°C before reperfusion (13). However, these were post hoc analyses, and a larger efficacy trial was needed to confirm a beneficial effect of hypothermia for patients with STEMIs.
We designed a multicenter, randomized, end point–blinded study using central venous catheter core cooling combined with rapidly infused cold saline as an adjunct to percutaneous coronary intervention (PCI) for the treatment of CHILL-MI (AMI: Rapid Endovascular Catheter Core Cooling Combined With Cold Saline as an Adjunct to Percutaneous Coronary Intervention for the Treatment of Acute Myocardial Infarction).
Ethics and organization
The study was performed in accordance with the Declaration of Helsinki, and the local ethics committees approved the study protocol. All patients gave written informed consent before inclusion in the study. The steering committee designed the trial in collaboration with the sponsor and had responsibility for scientific conduct and the presentation and publication of results. The trial was coordinated and monitored by Uppsala Clinical Research Center (UCR), which also managed the database and performed the statistical analyses. An independent data and safety monitoring board, consisting of physicians independent of the trial sponsor and operational leadership, monitored the safety of the study on the basis of access to unblinded data.
From July 2011 to March 2013, 120 patients from 9 sites in 4 countries (Lund, Uppsala, Stockholm, and Gothenburg, Sweden; Copenhagen and Aarhus, Denmark; Vienna and Innsbruck, Austria; and Ljubljana, Slovenia), were enrolled in this prospective, multicenter, randomized, end point–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) as an adjunct therapy in patients with STEMIs eligible for primary PCI. Men and women ages 18 and 75 years presenting with anterior or inferior STEMIs with ST-segment elevation >0.2 mV in 2 contiguous leads and a duration of symptoms <6 h were included. For inferior STEMI, an additional ST-segment depression in 2 contiguous anterior leads for a total ST-segment deviation (inferior ST-segment elevation plus anterior ST-segment depression) of ≥0.8 mV was required. A second electrocardiogram was obtained in the catheterization laboratory before randomization to ensure persistent ST-segment elevation. Patients with cardiac arrest, previous AMIs, previous PCI or coronary artery bypass grafting, known congestive heart failure, end-stage kidney disease or hepatic failure, recent stroke, coagulopathy, pregnancy, or Killip class II to IV at presentation were excluded.
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 study group assignments 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 1 mg/kg or 0.5 mg/kg if the patient had received morphine before enrollment in the study. Additional 25-mg intravenous bolus doses of meperidine were administered as needed to reduce shivering. Hypothermia was initially induced by forced infusion of 4°C cold saline using pressure bags. Volume administered was 600 to 2,000 ml, according to a weight-adjusted schedule (10 ml/kg for anterior STEMI and 20 ml/kg for inferior STEMI). Before angiography, a 14-F introducer was inserted in the femoral vein. Through the introducer, a 14-F Accutrol catheter was placed into the inferior vena cava with the tip of the catheter at the level of the diaphragm. The target temperature was set to 33°C. 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, and rectum, during rapid core cooling (17). After placement and activation of the cooling catheter, coronary angiography and PCI were performed without delay, except for a brief pause to measure core temperature just before advancing the guidewire through the culprit lesion. Cooling was maintained for 1 h after reperfusion, followed by spontaneous rewarming. If the PCI procedure took longer than 1 h, cooling was continued until the end of the procedure. Loading doses of 500 mg of aspirin and adenosine diphosphate receptor blockers were given to all patients before cardiac catheterization. Heparin, glycoprotein IIb/IIIa inhibitors, and bivalirudin were administered at the discretion of the treating physician.
Cardiac magnetic resonance (CMR) imaging
The analysis of ventricular dimensions, MaR, and IS was performed at a core laboratory (Imacor AB, Lund, Sweden) using postprocessing software (Segment version 1.9 R3084, Medviso, Lund, Sweden) (Online Appendix) (18–21).
Creatine kinase–MB and troponin T were sampled on admission to the catheterization laboratory and at 12 and 24 h after admission. Central core laboratory analysis was performed at UCR. Peak values were defined as the highest measured values within 24 h. The area under the curve was calculated from the measurements. N-terminal pro–brain natriuretic peptide was sampled on day 4 ± 2.
Clinical endpoints were collected using a clinical report form during the index hospital stay, at 45 ± 15 days, and at 6 months. Furthermore, clinical events were collected by adverse event and serious adverse event 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.
On the basis of a mean IS as a percent of MaR in the control group of 48% and a standard deviation in both groups of 18% (10), 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% dropout.
All analyses were performed according to the protocol and the statistical analysis plan, using intention to treat without imputation of missing data. Statistical tests were performed at the 0.05 significance level using 2-sided alternative hypotheses. All statistical analyses were performed by the statistics section at UCR using SAS version 9.3 (SAS Institute Inc., Cary, North Carolina) (Online Appendix).
One hundred twenty 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). Mean times from onset of symptoms to randomization were 132 ± 64 min and 129 ± 56 min in the hypothermia and control groups. All but 3 patients underwent PCI. One patient was reported as having undergone unsuccessful PCI. Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 was established in 93% and 90% of patients, respectively. Thrombus aspiration was performed in 59% and 69% of patients, respectively. The novel, more potent P2Y12 inhibitors ticagrelor or prasugrel were used in 89% and 84% of patients, respectively (Table 1).
Baseline tympanic temperature was similar in the 2 groups (36.0 ± 0.7°C vs. 36.0 ± 0.7°C). After randomization to the hypothermia group, cold saline was started after a mean of 7 min and endovascular cooling after a mean of 30 min. Mean console run time before reperfusion was 13 min. Mean saline volume was 1,325 ± 523 ml, infused during a mean of 28 min before reperfusion. Hypothermia treatment caused an increase in randomization-to-balloon time of 9 min, from 33.3 ± 21.2 min to 42.7 ± 16.6 min. Mean temperature at reperfusion was 34.7 ± 0.6°C (Fig 1). At the time of reperfusion, core body temperatures ≤35°C were achieved in 76% of patients, and core body temperatures ≤35.4°C were achieved in 91% of the patients randomized to hypothermia. Cold saline and endovascular cooling were successfully used in 60 of the 61 patients. Intravenous meperidine was administered in 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 in error. This patient also lacked CMR data.
Assessment of IS and MaR
CMR data were missing for 19% of the patients, equally distributed between the groups. The reasons for missing CMR data were claustrophobia (n = 6), CMR not available or image quality unsatisfactory (n = 6), patient not willing (n = 6), CMR disrupted by patient decision (e.g., chronic back pain) (n = 3), incorrect randomization (n = 1), and rib fracture after cardiopulmonary resuscitation (n = 1). There was no difference between the hypothermia and control groups with regard to the timing of the CMR examination (4.0 ± 1.4 days vs. 3.7 ± 1.5 days, respectively).
The median IS normalized to MaR (the primary end point) was 40.5% (interquartile range [IQR]: 29.3% to 57.8%) in the hypothermia group and 46.6% (IQR: 37.8% to 63.4%) in the control group, with a relative reduction of 13% and an absolute reduction of 5.5% (95% confidence interval: −2.0% to 12.9%; p = 0.15) (Fig. 2, Table 2). Adjustment for investigational site resulted in a p value of 0.27. MaR as a percent of left ventricular mass was similar between treatment groups: 34.6% (IQR: 28.7% to 43.8%) and 34.9% (IQR: 29.1% to 44.8%) in the hypothermia and control groups, respectively.
The relative reduction in IS normalized to MaR in anterior infarcts (predefined subgroup) was 27% (43.7% [IQR: 37.8% to 64.3%] vs. 59.9% [IQR: 46.2% to 67.3%], hypothermia [n = 15] vs. control [n = 21]; p = 0.22) (Fig. 3). The relative reduction in IS normalized to MaR in inferior infarcts was 9% (36.6% [IQR: 9.2% to 75.8%] vs. 40.6% [IQR: 26.6% to 58.8%], hypothermia [n = 34] vs. control [n = 26]; p = 0.74). The p value for interaction by infarct location was 0.48. Exploratory analysis of early anterior infarcts (duration 0 to 4 h) found a relative reduction of 33% (40.9% [IQR: 32.6% to 57.7%] vs. 60.9% [IQR: 46.1% to 68.0%]; p = 0.046) (Fig. 4, Table 2).
When comparing only cooled patients who did achieve the target temperature of ≤35°C, there was still no significant difference IS/MaR, but the importance of temperature was difficult to evaluate, because all patients were in a narrow temperature window, with only 24% at >35°C and only 9% at >35.4°C (Table 2). In an exploratory analysis by sex, women had a numerical absolute increase of 1.4%, whereas men had a numerical absolute reduction of 6.2%. The p value for interaction by sex was 0.45. There was no difference according to full-analysis set or per-protocol set. There was no difference according to TIMI grade 0 or TIMI grades 1 to 3 (Table 2).
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 end point of adjudicated death and heart failure was significantly reduced in the hypothermia group at 45 days (2 vs. 8 events, p = 0.047) (Fig. 5). Heart failure was present only in patients with anterior infarcts. Because there was no mortality in either group, the reduction in events consisted entirely of fewer adjudicated heart failure events.
There were no differences in rates of pneumonia, ventricular arrhythmias, bradycardia, reinfarction, stroke, and major bleeding between the groups (Table 3).
Microvascular obstruction as a percent of the left ventricle was similar between the hypothermia and control groups: 0.24% (IQR: 0% to 9.35%) versus 0.12% (IQR: 0% to 5.25%). Ejection fraction analyzed by CMR at 4 ± 2 days did not differ: 50% (IQR: 42% to 53%) in the hypothermia group and 51% (IQR: 43% to 56%) in the control group (Table 4).
ST-segment resolution at 1.5 h after reperfusion was numerically more pronounced in hypothermia-treated patients (83.0% [IQR: 66.7% to 92.9%] vs. 75.7% [IQR: 57.1% to 88.9%], hypothermia vs. control; p = 0.13). In a post-hoc analysis, ST-segment elevation at 1.5 h was significantly lower in hypothermia-treated patients (2.0 mm [IQR: 0.5 to 5.0 mm] vs. 3.5 mm [IQR: 1.0 to 7.0 mm], hypothermia vs. control; p = 0.047) (Table 4).
The area under the curve or peak concentration for troponin T or creatine kinase-MB did not differ between the groups. N-terminal pro–brain natriuretic peptide at 4 ± 2 days was also similar between the groups (Table 4).
In this prospective, multicenter, randomized trial in patients with STEMIs, hypothermia using intravenous cold saline and an endovascular venous cooling catheter was safe, feasible, and easy to implement and reduced body temperature to 34.7°C before reperfusion, with a delay of reperfusion of 9 min. The primary end point of IS in relation to MaR was not significantly reduced. The key clinical end point of death and heart failure was significantly reduced (driven by heart failure events). In further exploratory analyses, there was a suggestion that anterior STEMI of short duration may be the type of STEMI that benefits from hypothermia therapy, but this needs to be confirmed in a future trial.
The safety of using endovascular cooling alone has previously been demonstrated in awake patients with AMIs (13,14,22). 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. However, an intravenous infusion of cold saline could possibly lead to an increase in acute heart failure and pulmonary congestion in patients with AMIs. 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, reinfarction, stroke, or major bleeding between the groups, and most important, there were no deaths in either group, indicating that the therapy is safe.
In a previous experimental study, it was 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 to 10 min in pigs weighing 40 to 50 kg (10). In the present study, inducing hypothermia with a combination of cold saline infusion and endovascular cooling was clinically feasible and achieved a rapid reduction in core body temperature in patients with STEMIs, without a major delay in time to reperfusion (9 min). In patients randomized to hypothermia, 76% reached ≤35°C and 91% reached ≤35.4°C, with only 14 min of catheter cooling. Lower temperatures at the time of reperfusion reduce IS even further in animal models (11), and efforts to achieve a lower temperature before reperfusion could result in further IS reduction.
Meperidine and buspirone were chosen to suppress shivering because they act synergistically without causing respiratory depression (23). Furthermore, the drugs have been used in previous clinical trials with high tolerance in awake patients with AMIs (13,14). In this study, hypothermia was well tolerated, and treatment was not discontinued in any patients because of shivering.
Using CMR to assess IS in relation to MaR has recently been validated in patients with AMIs (18,19,24) and used to describe the natural course of infarct evolution in humans (25). This method reduces the sample size needed in clinical trials to show significant effects of cardioprotective interventions. Therapeutic hypothermia numerically reduced IS/MaR by 13% but did not reach significance. This is in contrast to a large number of highly reproducible animal experiments in many species (11). To try to understand the effects of hypothermia in humans, we performed predefined analyses of IS/MaR subgroups. TIMI flow grade, temperature, and sex did not significantly influence the results. However, similar to the ICE-IT and COOL-MI (Cooling as an Adjunctive Therapy to Percutaneous Intervention in Patients With Acute Myocardial Infarction) trials, the anterior STEMI subgroup seemed to benefit more, with an IS reduction of 27%. This was further pronounced in early anterior STEMI, with an IS reduction of 33%. In this group, absolute reduction of IS as a percent of the left ventricle was numerically reduced by 6.2%, which seems comparable with the 5.1% absolute reduction in IS in the STOPAMI (Stent Versus Thrombolysis for Occluded Coronary Arteries in Patients With Acute Myocardial Infarction) trial, which is now accepted as a clinically meaningful result for cardioprotection trials (26). It would therefore be logical to further explore the potential cardioprotective effects of hypothermia in a new study focusing only on anterior STEMI of short duration (<4 h from symptom onset to PCI), especially in light of the several cardioprotection studies previously focusing on this subset of patients with STEMIs (27,28).
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, as there were no deaths in either arm. Because all the heart failure events occurred in patients with anterior STEMIs, the reduction in heart failure could be the result of a more pronounced reduction in IS in patients with anterior STEMIs. However, there were also more anterior STEMIs in the control group, which may have influenced the results. There was also a trend toward better ST-segment resolution and reduced ST-segment levels at 1.5 h in the hypothermia group. However, we did not see any difference in cardiac biomarkers, pro–brain natriuretic peptide, microvascular obstruction, or ejection fraction. All of these surrogate parameters are known to have larger variability than IS/MaR and are difficult to evaluate.
The patients were not at high risk, as patients older than 75 years, those in Killip classes II to IV, and those with cardiac arrest were excluded. It cannot be excluded that part of the hyperenhanced myocardium on CMR acquired at 4 ± 2 days may have been due to edema, as it has recently been shown that there is a significant decrease in hyperenhanced myocardium during the first week after infarction (29). There was, however, no difference in the timing of the CMR examination between the hypothermic patients and the controls. Furthermore, area at risk was similar between the treatment groups. CMR data were missing for 19% of the patients, equally distributed between the groups and of similar magnitude as observed in other CMR-based trials (27). The exploratory and secondary analyses should be evaluated with caution because they are at risk for type 1 error.
The results of this study show that although hypothermia induced using a combination of cold saline infusion and endovascular cooling before reperfusion in awake patients with STEMIs was feasible and safe, with only a small delay time to reperfusion, it did not significantly reduce IS. The clinical end point of adjudicated heart failure was significantly reduced in the hypothermia group. Exploratory analyses suggested that anterior STEMI of short duration still might benefit from the treatment, which warrants further evaluation in future trials.
The authors thank Charlotta Elfström and the staff at UCR for excellent project coordination and the Data Safety and Monitoring Board (Dan Atar, chairman; Morten Wang Fagerland; and Simon Dixon) for professional contributions. Bradley Klos and Anthony Mullin of Philips Healthcare contributed expertise and continuous support.
This study was funded by Philips Healthcare (San Diego, California). Dr. Erlinge has received speaker's honoraria from Philips and ZOLL. Dr. Götberg has received consulting honoraria from Medtronic and Volcano. Dr. Lang has received honoraria from Actelion, Bayer, United Therapeutics, AstraZeneca, AOP Orphan, Pfizer, and GlaxoSmithKline; and research support from Actelion, Bayer, and United Therapeutics. Dr. Holzer has received travel grants for scientific conferences and honoraria for lectures from EMCOOLS and ZOLL; and has provided consultancy for Leerink Swann. Dr. Noc has received speaker honoraria from AstraZeneca, Lilly, and Krka. Dr. Clemmensen has research contracts with Philips and UCI; and has received speaker's fees from Philips. Dr. Wallentin has received research grants, consultancy fees, lecture fees, honoraria, and travel support from AstraZeneca, Bristol-Myers Squibb/Pfizer, and GlaxoSmithKline; research grants, consultancy fees, lecture fees, and honoraria from Boehringer-Ingelheim; research grants and consultancy fees from Merck & Company; and consultancy fees from Abbott, Regado Biosciences, and Athera Biotechnologies. Dr. Harnek has received consulting honoraria from Boston Scientific and EPS Vascular. Dr. Olivecrona is a proctor for Edwards Lifesciences; and has received lecture honoraria from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute myocardial infarction
- cardiac magnetic resonance
- interquartile range
- infarct size
- myocardium at risk
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- Thrombolysis In Myocardial Infarction
- Uppsala Clinical Research Center
- Received November 5, 2013.
- Revision received December 9, 2013.
- Accepted December 23, 2013.
- American College of Cardiology Foundation
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