Effect of Pericardial Effusion Complicating ST-Elevation Myocardial Infarction as Predictor of Extensive Myocardial Damage and Prognosis

Accepted Manuscript Effect of Pericardial Effusion Complicating ST-Elevation Myocardial Infarction as Predictor of Extensive Myocardial Damage and Prognosis Alexander Jobs, MD, Charlotte Eitel, MD, Janine Pöss, MD, Steffen Desch, MD, Holger Thiele, MD, Ingo Eitel, MD PII:

S0002-9149(15)01610-0

DOI:

10.1016/j.amjcard.2015.07.007

Reference:

AJC 21269

To appear in:

The American Journal of Cardiology

Received Date: 12 April 2015 Revised Date:

24 June 2015

Accepted Date: 3 July 2015

Please cite this article as: Jobs A, Eitel C, Pöss J, Desch S, Thiele H, Eitel I, Effect of Pericardial Effusion Complicating ST-Elevation Myocardial Infarction as Predictor of Extensive Myocardial Damage and Prognosis, The American Journal of Cardiology (2015), doi: 10.1016/j.amjcard.2015.07.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Effect of Pericardial Effusion Complicating ST-Elevation Myocardial Infarction as Predictor of Extensive Myocardial Damage and Prognosis

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Alexander Jobs, MD; 1,2Charlotte Eitel, MD; 1,2Janine Pöss, MD; 1,2Steffen Desch, MD; Holger Thiele*, MD; 1,2Ingo Eitel*, MD

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1,2

1

University Heart Center Lübeck, Medical Clinic II, Department of Cardiology, Angiology and Intensive Care Medicine, Lübeck, Germany 2

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German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck,

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Ratzeburger Allee 160, 23538 Lübeck, Germany

*both authors should be considered as shared senior authors

NCT00712101

Running title:

Pericardial effusion complicating STEMI

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ClinicalTrials.gov:

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Address for correspondence:

Ingo Eitel, MD University Heart Center Lübeck Medical Clinic II University Hospital Schleswig-Holstein Ratzeburger Allee 160 23538 Lübeck Germany Tel. +49 451 500 2501 Fax. +49 451 500 6437 E-Mail: [email protected]

1

ACCEPTED MANUSCRIPT Abstract Pericardial effusion (PE) is a common complication following ST-elevation myocardial infarction (STEMI). However, the frequency and prognostic relevance of PE complicating STEMI is unknown. Aim of this study was to investigate the exact incidence, infarct

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characteristics, and the prognostic impact of moderate to large PEs detected by cardiac magnetic resonance (CMR) in acute reperfused STEMI patients. In total 780 STEMI patients reperfused by angioplasty (<12 h after symptom onset) were enrolled in this CMR study at 8 centers. CMR was completed in median 3 days after infarction using a standardized protocol.

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Central core laboratory-masked analysis for the presence of moderate to large PE was

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performed. The primary clinical endpoint was the occurrence of major adverse cardiac events (MACE) defined as composite of all-cause death, reinfarction, and new congestive heart failure within 12 months after the index event. A moderate to large PE was detected in 183 (24%) patients. Patients with moderate to large PEs had significantly larger infarcts, less myocardial salvage, a larger extent of microvascular obstruction, higher incidence of

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intramyocardial hemorrhage and more pronounced left ventricular dysfunction (P<0.001 for all). Significant predictors of a moderate to large PE were age, TIMI flow before PCI and infarct size. MACE rates were significantly higher in the PE group (P=0.003) and a moderate

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to large PE was identified as a significant independent predictor for MACE (hazard ratio, 3.12 [confidence interval, 1.49-6.81]; P=0.003) together with TIMI risk score and left ventricular

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ejection fraction. In conclusion, a moderate to large PE complicating STEMI is a common finding (almost 25%) and related to more severe infarcts with subsequent significantly increased MACE rates during 1-year follow-up. Consequently, a moderate to large PE is a marker of poor outcome in STEMI patients.

Key words pericardial effusion, ST-elevation myocardial infarction, cardiac magnetic resonance imaging

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ACCEPTED MANUSCRIPT Introduction Pericardial effusion (PE) without tamponade is a common complication following myocardial infarction (MI) with reported incidences between 6-43% depending on the definition used1-12. Most PEs complicating ST-elevation MI (STEMI) develop within the first

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week after MI and are mild to moderate in size11,12. Moreover, accumulating evidence indicates that the presence of PE after STEMI is associated with poor prognosis2,6,7,9,13. However, since most previous studies were performed before primary percutaneous coronary intervention (PCI) became clinical routine, the prevalence and prognostic

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significance of PE complicating STEMI in a contemporary population is unknown.

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Echocardiography is the first-line modality for evaluation of PE. However, echocardiography is user-dependent, often hampered by poor acoustic window, and is limited in its ability to detect

focal

PEs.

Cardiac

magnetic

resonance

(CMR)

imaging

is

superior

to

echocardiography for the detection of PE and has emerged as the reference standard for the assessment of presence, severity, and extent of PEs14. To the best of our knowledge, no

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study investigated the frequency and prognostic relevance of CMR-detected PEs in patients with STEMI treated by primary PCI. Aim of our study was therefore to investigate the exact incidence, infarct characteristics, and the prognostic impact of CMR-detected PE in acute

Methods

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reperfused STEMI patients.

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This prospective CMR study was a predefined substudy of the Abciximab Intracoronary versus intravenously Drug Application in STEMI (AIDA STEMI) trial, which compared intravenous versus intracoronary abciximab application in STEMI patients and did not show a difference in infarct size, reperfusion injury and clinical outcome between the treatment groups15,16. The detailed design and main results of the trial have previously been published15-17. The study was approved by national regulatory authorities and ethics committees of participating centers. All patients provided written informed consent. 3

ACCEPTED MANUSCRIPT Consecutive patients enrolled in the AIDA STEMI trial at 8 sites were included in the CMR substudy15. The sites were chosen based on proven expertise in performing CMR examinations in patients with MI. By protocol CMR was performed on days 1 to 10 after the index event. Exclusion criteria were the typical contraindications for CMR as described

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previously together with the detailed scan protocol15. CMR images were sent to the CMR core laboratory for blinded assessment. Certified CMR evaluation software was used (cmr42 Circle Cardiovascular Imaging Inc, Calgary, Alberta, Canada) and all analyses were done according to standard definitions as previously described15.

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A moderate to large PE was defined as a collection of fluid of 5 mm or more in the enddiastolic phase in the short-axis and corresponding 2- and 4-chamber views of the cine

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steady state free precision sequences (Figure 1)18,19. The CMR core laboratory is highly experienced in CMR postinfarction acquisition and post-processing with excellent reproducibility and low inter- and intraobserver variability20,21.

The primary clinical endpoint major adverse cardiovascular event (MACE) was a

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composite of all-cause death, re-infarction, and new congestive heart failure within one year after infarction, using outcome definitions described previously15-17. All components of the combined clinical endpoint were adjudicated by a clinical endpoint committee, blinded to the

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patient's assigned treatment, based on data provided by the clinical trial sites. To avoid double counting of patients with more than one event, every patient could be counted only

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once for the primary clinical endpoint. Consequently, for those subjects who had more than one type of event at the same time, the more severe event was counted according to a hierarchical order (death > re-infarction > congestive heart failure). Baseline patient characteristics, procedural details, and CMR findings are described according to the presence or absence of a moderate to large PE. Data for continuous variables are presented as medians with interquartile range (IQR). Categorical variables are presented as frequencies and percentages. Differences between groups were assessed by Fisher’s exact and by Wilcoxon rank-sum test for categorical and continuous data, 4

ACCEPTED MANUSCRIPT respectively. To identify predictors for a moderate to large PE and MACE, stepwise multivariable logistic and Cox regression analyses were performed, respectively, after univariable pre-selection of candidate predictors. The inclusion criterion for stepwise multivariable analysis was a P<0.05 in univariable analysis. For univariable pre-selection, all

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variables of Table 1 and Table 2 were considered. To improve the ratio of events per variable the TIMI risk score and not its single variables were considered for Cox regression analysis. Because the myocardial salvage index accounts for infarct size by its inclusion in the formula for calculation of myocardial salvage, we also discarded the myocardial salvage index.

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Hazard ratios (HR) and odds ratios (OR) with 95% confidence intervals were calculated for uni- and multivariable analyses as appropriate. Rates for MACE and all-cause mortality were

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plotted and compared by means of Kaplan-Meier curves and log-rank test, respectively. A two-tailed p-value <0.05 was defined as statistically significant. SPSS version 20.0 was used for statistical analyses.

Results

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From July 2008 to April 2011, 795 patients were enrolled in the AIDA STEMI CMR substudy (Figure 2). Of these, 15 patients were excluded because of inadequate image quality. Thus, the final study population consisted of 780 patients (Figure 2). Demographic

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and clinical characteristics are presented in Table 1. A moderate to large PE was detected in 183 (24%) patients with a median size of 7.0 mm (IQR: 5.8-8.8 mm). Of these, 103 (56%)

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moderate to large PEs were circumferential. The highest PE dimension was predominantly located laterally (45%) or next to the right ventricle (34%). Localization of a moderate to large PE (i.e. septal, apical, lateral, or next to the right ventricle) was not associated with site of infarction (P=0.301). No PE required pericardiocentesis due to hemodynamic compromise and we did not identify any patient during follow-up with constrictive pericarditis following myocardial infarction. Patients with a moderate to large PE were significantly older and less often smokers. Moreover, patients in the PE group had significantly more often anterior 5

ACCEPTED MANUSCRIPT infarctions (P=0.025) with a corresponding left anterior descending culprit lesion (P<0.001). Other cardiovascular risk factors, reperfusion times, prescribed drugs and study procedures were similar between groups. Of the 597 patients with a PE size <5 mm, 273 (46%) patients had no detectable PE. The median PE size of the PE size <5 mm group was 3.4 mm (IQR:

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2.8-4.1 mm). The median time between the index event and CMR was 3 days (IQR: 2-4 days) for both groups (P=0.80). The presence of a moderate to large PE was associated with more severe myocardial infarctions as shown by several CMR parameters (Table 2).

Regression analysis was performed to assess predictive factors associated with the

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occurrence of a moderate to large PE complicating STEMI. Predictors with a significant effect in univariable analysis are listed in Table 3. After stepwise multivariable analysis only age,

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TIMI-flow before PCI, and infarct size remained as independent predictors of a moderate to large PE (Table 3).

Clinical 12-month follow-up was completed for all patients. The primary endpoint of MACE occurred in 52 patients (7%). MACE occurred more often in patients with a moderate to large

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PE than without (21 events [12%] versus 31 events [5%], P=0.003 by log-rank test, Figure 3). The event rate for death (8 events [4%] versus 12 events [2%], P=0.066) and reinfarction (8 events [4%] versus 13 events [2%], P=0.095) were only numerically higher, whereas there

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were significantly more events of congestive heart failure in the moderate to large PE group (11 events [6%] versus 12 events [2%], P=0.005). In univariable regression analysis, 8

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variables had a significant effect on MACE. However, after stepwise backward selection only TIMI risk score, LVEF, and a moderate to large PE remained as predictors with significant effect on MACE in the model (Table 4).

Discussion

To our best knowledge this is the first multicenter study investigating the incidence, predictors and clinical significance of CMR-detected moderate to large PE in STEMI patients treated by primary PCI. The main findings of our study can be summarized as follows: First, 6

ACCEPTED MANUSCRIPT a moderate to large PE is a common complication with an incidence of 24%. Second, main predictors for the occurrence of a moderate to large PE are age, TIMI-flow before PCI, and infarct size. Third, the presence of a moderate to large PE is an independent predictor of MACE 1 year after STEMI.

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Although echocardiography is the most often used modality for the detection of PE, CMR allows for a more comprehensive and sensitive evaluation of the amount and distribution of pericardial fluid accumulation. Previous echocardiographic studies reported heterogeneous results regarding the incidence of PE in patients with MI based on the definition of PE (6-

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43%)1-12. In our large multicenter study using the reference standard (i.e. CMR) for detection of PE, the incidence of a moderate to large PE was 24%. These data are in line with a small

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single-center CMR study reporting an incidence of post-infarction PE of 23%22. In agreement with earlier reports3,5,6,10,22 patients with a moderate to large PE had more often anterior infarction and more extensive myocardial damage, i.e. greater infarct size, less myocardial salvage and more reperfusion injury. In accordance with these results, surrogate

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variables for an increased infarct size were predictive for echocardiography-detected PE in a recently published retrospective study1. Thus, as confirmed by our multicenter data, the presence of a moderate to large PE in the early post-infarction period seems to be a marker

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of MI severity which may explain its prognostic significance. The majority of PE does not cause hemodynamic compromise and a PE may often be

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viewed as a benign reaction to the MI. Classically, PE complicating STEMI is thought to be caused by increased local microvascular permeability together with a poor hemodynamic status leading to congestion without pericardial irritation8. The fact that infarct size was predictive for a moderate to large PE and the occurrence of a moderate to large PE was rarely restricted to the infarct region supports these pathophysiological considerations. However, in a recent single-center CMR study, STEMI patients with PE had the highest peak C-reactive protein levels, which were significantly related to the extent of pericardial late gadolinium enhancement22. The contribution of a reduced oncotic pressure to development 7

ACCEPTED MANUSCRIPT of PE complicating STEMI, as in cirrhosis or nephrotic syndrome, was not observed in a previous study investigating the etiology of post-infarct PE8. Taken together, in light of all available evidence, post-infarction PE seems to be caused by a combination of pericardial inflammation, poor hemodynamic status, and increased microvascular permeability inside the

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necrotic myocardial tissue. However, the PE related pericardial inflammation seems to be distinct from that of classic infarct pericarditis, which is accompanied by friction rub and pleuritic pain23. The postcardiac injury syndrome, which is putatively caused by immune

time course and clinical findings are different23.

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complexes, needs also to be clearly distinguished from early post-infarct PE, since both the

Our study is the first to assess the prognostic impact of a moderate to large PE on hard

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clinical endpoints. Our data clearly demonstrate that the presence of a moderate to large PE is associated with increased MACE rates. In the multivariable regression analysis, a moderate to large PE remained significantly associated with MACE together with the TIMI risk score and LVEF, two well-known and validated prognostic markers in this population24,25.

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This is congruent with the fact that patients with a moderate to large PE complicating STEMI have more severe infarcts as determined by CMR leading to a more appreciable reduction in LV function with subsequent increased risk for future cardiovascular events. Our results that

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a moderate to large PE complicating STEMI is associated with higher MACE rates are in line with several earlier echocardiographic studies2,6,7,9,13. However, our study expands the

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prognostic value of PE complicating STEMI to patients treated by primary PCI as such data were not available in a prospective manner so far. The available evidence suggests that clinicians should be aware of PE after STEMI. Since most PEs complicating STEMI develop within the first days3,11 such PEs will be detectable early in the course of the index hospital stay. Retrospective data indicate that small PEs may evolve to moderate to large PEs2. In addition, two studies reported that patients with initially moderate to large PE without cardiac tamponade developed electromechanical dissociation and/or free-wall rupture with consecutive death in 8% and 46%, respectively2,26. We therefore 8

ACCEPTED MANUSCRIPT suggest that such patients should be observed in a cardiac intensive care unit with close hemodynamic and echocardiographic surveillance including an early screening for PE especially in older patients with extensive anterior myocardial infarctions. Retrospective studies have shown that the incidence of PE complicating STEMI decreases with early

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revascularization especially primary PCI and this is accompanied by a concomitant decrease of mortality1,5.

The results of our and other studies suggest that the presence of PE after STEMI can be taken as a surrogate marker for a severe infarct leading to a worse prognosis. This indicates

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an intensive monitoring of these high risk patients not only in-hospital, but also after hospital discharge. Interestingly, the difference in MACE rates between patients with and without a

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moderate to large PE was predominantly driven by new congestive heart failure and most patients with a moderate to large PE had an ejection fraction greater than 40%. Therefore, one might speculate that patients with a moderate to large PE complicating STEMI could benefit from a more aggressive medical heart failure therapy (i.e. aldosterone antagonist) as

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currently recommended27,28.

Our study has several limitations worth emphasizing. First, the detection of PE by CMR is limited to centers with CMR capability. However, thoroughly performed echocardiography

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should also be able to detect a moderate to large PE after STEMI. Furthermore, patients with cardiogenic shock and acute heart failure, as well as patients with pacemakers and other

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metallic implants cannot undergo CMR (~5-10% of patients with STEMI). Second, the evaluation of moderate to large PE as prognostic marker is based on a relative small number of clinical events, despite being the largest study assessing the prognostic relevance of PE. Third, no systematic echocardiographic assessment of PE was performed; therefore, no direct comparison between echocardiographic- and CMR-detected PE is possible. However, CMR is the reference standard for PE detection and quantification14,19 and it offers the acquisition of other emerging high-potential risk markers29. Moreover, in a single-center study of post-infarct PE, PE detection by CMR and echocardiography agreed in 80% of cases22. 9

ACCEPTED MANUSCRIPT Disclosures

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None

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ACCEPTED MANUSCRIPT 9. Sugiura T, Nakamura S, Kudo Y, Okumiya T, Yamasaki F, Iwasaka T. Clinical factors associated with persistent pericardial effusion after successful primary coronary angioplasty. Chest 2005;128:798-803. 10. Sugiura T, Takehana K, Hatada K, Takahashi N, Yuasa F, Iwasaka T. Pericardial

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14. Mulvagh SL, Rokey R, Vick GW, 3rd, Johnston DL. Usefulness of nuclear

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magnetic resonance imaging for evaluation of pericardial effusions, and comparison with two-dimensional echocardiography. Am J Cardiol 1989;64:1002-1009. 15. Eitel I, Wohrle J, Suenkel H, Meissner J, Kerber S, Lauer B, Pauschinger M,

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Birkemeyer R, Axthelm C, Zimmermann R, Neuhaus P, Brosteanu O, de Waha S, Desch S, Gutberlet M, Schuler G, Thiele H. Intracoronary compared with intravenous

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bolus abciximab application during primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: cardiac magnetic resonance substudy of the AIDA STEMI trial. J Am Coll Cardiol 2013;61:1447-1454. 16. Thiele H, Wohrle J, Hambrecht R, Rittger H, Birkemeyer R, Lauer B, Neuhaus P, Brosteanu O, Sick P, Wiemer M, Kerber S, Kleinertz K, Eitel I, Desch S, Schuler G. Intracoronary versus intravenous bolus abciximab during primary percutaneous coronary intervention in patients with acute ST-elevation myocardial infarction: a randomised trial. Lancet 2012;379:923-931. 12

ACCEPTED MANUSCRIPT 17. Thiele H, Wohrle J, Neuhaus P, Brosteanu O, Sick P, Prondzinsky R, Birkemeyer R, Wiemer M, Kerber S, Schuehlen H, Kleinertz K, Axthelm C, Zimmermann R, Rittger H, Braun-Dullaeus RC, Lauer B, Burckhardt W, Ferrari M, Bergmann MW, Hambrecht R, Schuler G, Abciximab Intracoronary versus intravenously Drug

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Application in STEMII. Intracoronary compared with intravenous bolus abciximab application during primary percutaneous coronary intervention: design and rationale of the Abciximab Intracoronary versus intravenously Drug Application in ST-Elevation Myocardial Infarction (AIDA STEMI) trial. Am Heart J 2010;159:547-554.

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18. Bogaert J, Francone M. Pericardial disease: value of CT and MR imaging. Radiology 2013;267:340-356.

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multimodality cardiovascular imaging of patients with pericardial disease: endorsed by

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Grothoff M, Gutberlet M, Schuler G, Thiele H. Reliability of myocardial salvage assessment by cardiac magnetic resonance imaging in acute reperfused myocardial

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infarction. Int J Cardiovasc Imaging 2012;28:263-272. 21. Eitel I, Desch S, Fuernau G, Hildebrand L, Gutberlet M, Schuler G, Thiele H. Prognostic significance and determinants of myocardial salvage assessed by cardiovascular magnetic resonance in acute reperfused myocardial infarction. J Am Coll Cardiol 2010;55:2470-2479. 22. Doulaptsis C, Goetschalckx K, Masci PG, Florian A, Janssens S, Bogaert J. Assessment of early post-infarction pericardial injury by CMR. JACC Cardiovasc Imaging 2013;6:411-413. 13

ACCEPTED MANUSCRIPT 23. Mehrzad R, Spodick DH. Pericardial involvement in diseases of the heart and other contiguous structures: part I: pericardial involvement in infarct pericarditis and pericardial involvement following myocardial infarction. Cardiology 2012;121:164176.

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27. Task Force on the management of STseamiotESoC, Steg PG, James SK, Atar D, Badano LP, Blomstrom-Lundqvist C, Borger MA, Di Mario C, Dickstein K, Ducrocq G, Fernandez-Aviles F, Gershlick AH, Giannuzzi P, Halvorsen S, Huber K, Juni P,

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Kastrati A, Knuuti J, Lenzen MJ, Mahaffey KW, Valgimigli M, van 't Hof A, Widimsky P, Zahger D. ESC Guidelines for the management of acute myocardial infarction in

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patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569-2619. 28. American College of Emergency P, Society for Cardiovascular A, Interventions, O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Jr., Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, TamisHolland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG, Yancy CW. 2013 14

ACCEPTED MANUSCRIPT ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78-140. 29. Eitel I, de Waha S, Wohrle J, Fuernau G, Lurz P, Pauschinger M, Desch S,

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Schuler G, Thiele H. Comprehensive Prognosis Assessment by CMR Imaging After

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ST-Segment Elevation Myocardial Infarction. J Am Coll Cardiol 2014;64:1217-1226.

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ACCEPTED MANUSCRIPT Figure Legends Figure 1

Patient example. Patient with transmural anterior myocardial infarction with

circumferential pericardial effusion with a maximal diameter of 14.7 mm next to the right ventricle. A: Steady state free precision (SSFP) 4-chamber view, B: SSFP 4-chamber view

Figure 2

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with measurements, C: SSFP 2-chamber view, D: SSFP short axis view.

AIDA STEMI indicates Abciximab Intracoronary versus intravenously Drug

Application in ST-elevation myocardial infarction; and CMR, cardiac magnetic resonance

Prognostic impact of CMR-detected moderate to large PE. Kaplan-Meier

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Figure 3

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imaging.

curves for cumulative MACE rate (A) and cumulative mortality rate (B) during 1 year after

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infarction. PE indicates pericardial effusion.

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ACCEPTED MANUSCRIPT Table 1 Patient Characteristics Total study

N=780

Pericardial effusion <5 mm

≥5 mm

n=597

n=183

62 (51-71)

61 (51-70)

Men

594/780 (76%)

Current smoker

P

64 (53-74)

0.005

455/597 (76%)

139/183 (76%)

>0.99

336/713 (47%)

280/555 (50%)

56/158 (35%)

<0.001

Hypertension*

530/778 (68%)

398/595 (67%)

132/183 (72%)

0.20

Hypercholesterolemia**

297/772 (38%)

218/590 (37%)

79/182 (43%)

0.14

Diabetes mellitus

156/777 (20%)

110/594 (19%)

46/183 (25%)

0.06

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2

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Age (years)

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Variable

Body mass index (kg/m )

27.4 (24.9-30.3)

27.4 (24.8-30.3)

27.1 (24.9-30.7)

0.96

Previous infarction

47/780 (6%)

41/597 (7%)

6/183 (3%)

0.08

Anterior infarction

358/745 (48%)

259/567 (46%)

99/178 (56%)

0.03

180 (109-310)

180 (105-310)

184 (114-309)

0.71

Door-to-balloon-time (minutes)

30 (22-42)

30 (22-43)

29 (22-40)

0.40

Reperfusion >3h

6/777 (1%)

5/594 (1%)

1/183 (1%)

>0.99

Times

admission (minutes)

II III IV

AC C

I

EP

Killip-class on admission

TE D

Symptom-onset to PCI hospital

0.08

686/780 (88%)

533/597 (89%)

153/183 (84%)

59/780 (8%)

40/597 (7%)

19/183 (10%)

19/780 (2%)

11/597 (2%)

8/183 (4%)

16/780 (2%)

13/597 (2%)

3/183 (2%)

Number narrowed coronary artery 0.88

vessels 1

413/780 (53%)

318/597 (53%)

95/183 (52%)

2

222/780 (28%)

170/597 (29%)

52/183 (28%)

1

ACCEPTED MANUSCRIPT 3

144/780 (18%)

108/597 (18%)

36/183 (20%)

Infarct related artery

<0.001 342/780 (44%)

246/597 (41%)

96/183 (52%)

Left circumflex

92/780 (12%)

62/597 (10%)

30/183 (16%)

Right

339/780 (43%)

282/597 (47%)

57/183 (31%)

Left main

5/780 (1%)

5/597 (1%)

0/183 (0%)

Bypass graft

2/780 (0%)

2/597 (0%)

TIMI-flow before PCI

RI PT

Left anterior descending

0/183 (0%)

0.09

435/780 (56%)

321/597 (54%)

TIMI-flow I

103/780 (13%)

77/597 (13%)

26/183 (14%)

TIMI-flow II

127/780 (16%)

103/597 (17%)

24/183 (13%)

TIMI-flow III

115/780 (15%)

96/597 (16%)

19/183 (10%)

Stent implanted

763/778 (98%)

583/595 (98%)

180/183 (98%)

>0.99

Thrombectomy

187/780 (24%)

148/597 (25%)

39/183 (21%)

0.37

Intraaortic balloon pump

34/780 (4%)

21/597 (4%)

13/183 (7%)

0.06

M AN U

TIMI-flow after PCI

0.09

12/780 (2%)

9/597 (2%)

3/183 (2%)

19/780 (2%)

12/597 (2%)

7/183 (4%)

59/780 (8%)

39/597 (7%)

20/183 (11%)

689/780 (88%)

537/597 (90%)

152/183 (84%)

3 (2-5)

3 (2-5)

4 (2-5)

0.02

26 (12-45)

25 (11-43)

31 (17-55)

0.001

54 (21-77)

57 (21-78)

48 (25-76)

0.57

ß-blockers

745/778 (96%)

566/596 (95%)

179/182 (98%)

0.06

ACE-inhibitors/AT-1-antagonist

739/778 (95%)

564/596 (95%)

175/182 (96%)

0.56

Aspirin

780/780 (100%)

597/597 (100%)

183/183 (100%)

>0.99

Clopidogrel, prasugrel or both

760/760 (100%)

584/584 (100%)

176/176 (100%)

>0.99

TE D

TIMI-flow 0

114/183 (62%)

SC

TIMI-flow 0

TIMI-flow I TIMI-flow II

TIMI risk score

AC C

Peak CK (µmol/l×s)

EP

TIMI-flow III

ST-segment resolution after 90 min (%)

Concomitant medications

2

ACCEPTED MANUSCRIPT Statins

740/778 (95%)

562/596 (94%)

178/182 (98%)

0.07

Aldosterone antagonist

91/778 (12%)

67/596 (11%)

24/182 (13%)

0.51

Completion of abciximab

739/780 (95%)

567/597 (95%)

172/183 (94%)

>0.99

AC C

EP

TE D

M AN U

SC

RI PT

Continuous and categorical data are presented as median (interquartile range) and frequency (percentage), respectively. ACE indicates angiotensin-converting enzyme; AT-1, angiotensin 1; PCI, percutaneous coronary intervention; and TIMI, Thrombolysis in Myocardial Infarction. * Hypertension was diagnosed if patients were on antihypertensive treatment or had ≥3 systolic blood pressure values >140 mmHg on at least two different days; ** Hypercholesterolemia was diagnosed if patients were on cholesterol lowering medication or their serum total cholesterol was ≥200 mg/dl.

3

ACCEPTED MANUSCRIPT Table 2 Cardiovascular Magnetic Resonance Results Characteristic

Total study

Pericardial effusion

P

≥5 mm

(n=780)

(n=597)

(n=183)

Area at risk (%LV)

35 (25-48)

34 (24-47)

Infarct size (%LV)

17 (8-25)

15 (7-24)

Myocardial salvage index

51 (33-69)

54 (35-75)

Late MO (%LV)

0.0 (0.0-1.7)

0.0 (0.0-1.4)

Hypointense core (%LV)

0.0 (0.0-1.7)

0.0 (0.0-1.2)

0.0 (0.0-3.4)

<0.001

Hypointense core present

238/689 (35%)

167/528 (32%)

71/161 (44%)

0.004

RI PT

<5 mm

0.01

21 (15-29)

<0.001

44 (23-59)

<0.001

0.9 (0.0-2.9)

<0.001

SC

M AN U

LV ejection fraction (%)

39 (28-49)

50 (43-58)

51 (44-58)

48 (41-55)

<0.001

LV enddiastolic volume (ml)

146 (120-173)

146 (120-173)

146 (123-172)

0.79

LV endsystolic volume (ml)

72 (54-91)

72 (54-89)

75 (56-99)

0.03

AC C

EP

TE D

Continuous and categorical data are presented as median (interquartile range) and frequency (percentage), respectively. LV indicates left ventricular; and MO, microvascular obstruction.

1

ACCEPTED MANUSCRIPT Table 3 Univariable and Multivariable Logistic Regression Analysis for the Prediction of the Presence of Pericardial Effusion ≥5 mm Presence of Pericardial Effusion ≥5 mm Univariable

OR (95% CI)

P

Age (per year)

1.02 (1.01-1.03)

0.004

1.03 (1.02-1.06)

0.004

Current smoker (no vs. yes)

0.54 (0.37-0.78)

0.001

-

-

Anterior infarction (no vs. yes)

1.49 (1.06-2.09)

0.021

-

-

TIMI-flow before PCI (per grade)

0.82 (0.71-0.96)

0.013

0.71 (0.56-0.91)

0.006

Peak CK (per µmol/l×s)

1.01 (1.01-1.02)

0.001

-

-

LV ejection fraction (per %)

0.98 (0.96-0.99)

0.001

-

-

Area at risk (per %LV)

1.01 (1.00-1.03)

0.009

-

-

Infarct size (per %LV)

1.04 (1.02-1.05)

<0.001

1.03 (1.01-1.05)

0.001

Late MO (per %LV)

1.10 (1.04-1.16)

0.001

-

-

Hypointense core (no vs. yes)

1.71 (1.19-2.45)

0.004

-

-

RI PT

P

SC

OR (95% CI)

M AN U

Variable

Multivariable

AC C

EP

TE D

CI indicates confidence interval; CK, creatine kinase; LV, left ventricular; MO, microvascular obstruction; OR, odds ratio; PCI, percutaneous coronary intervention; and TIMI, Thrombolysis in Myocardial Infarction.

1

ACCEPTED MANUSCRIPT Table 4 Predictors of MACE in Univariable and Multivariable Cox Regression Analysis MACE within 1 year Univariable P

HR (95% CI)

P

TIMI risk score

1.43 (1.28-1.60)

<0.001

1.27 (1.07-1.51)

0.006

Current smoker (no vs. yes) Number of narrowed coronary artery vessels Peak CK (per µmol/l×s)

0.46 (0.24-0.88)

0.02

1.35 (1.01-1.79)

0.04

1.01 (1.00-1.02)

0.03

LV ejection fraction (per %)

0.93 (0.92-0.95)

<0.001

Infarct size (per %LV)

1.04 (1.02-1.06)

<0.001

Late MO (per %LV)

1.09 (1.02-1.16)

0.008

Pericardial effusion ≥5mm (no vs. yes)

2.29 (1.31-3.98)

0.003

RI PT

HR (95% CI)

-

-

-

-

-

-

0.94 (0.91-0.97)

<0.001

SC

Variable

Multivariable

3.12 (1.49-6.81)

0.003

AC C

EP

TE D

M AN U

CI indicates confidence interval; CK, creatine kinase; HR, hazard ratio; LV, left ventricular; MO, microvascular obstruction; and TIMI, Thrombolysis in Myocardial Infarction.

1

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

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