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Aborted myocardial infarction in intracoronary compared with standard intravenous abciximab administration in patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction
International Journal of Cardiology 153 (2011) 21–25
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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Aborted myocardial infarction in intracoronary compared with standard intravenous abciximab administration in patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction Ingo Eitel a,⁎, Steffen Desch a, Kathrin Schindler b, Georg Fuernau a, Gerhard Schuler a, Holger Thiele a a b
University of Leipzig, Heart Center, Department of Internal Medicine, Cardiology, Leipzig Germany University of Leipzig, Heart Center, Department of Diagnostic and Interventional Radiology, Leipzig Germany
a r t i c l e
i n f o
Article history: Received 22 February 2010 Received in revised form 5 July 2010 Accepted 7 August 2010 Available online 6 September 2010 Keywords: Myocardial infarction Aborted myocardial infarction Abciximab Glycoprotein IIb/IIIa inhibitor Magnetic resonance imaging
a b s t r a c t Backgound: Abciximab reduces major adverse cardiac events (MACEs) in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Intracoronary (IC) abciximab bolus application might be more effective than a standard intravenous (IV) bolus. So far the occurrence of aborted MI, a new therapeutic target of effective treatment in STEMI, has not been evaluated in IC versus IV abciximab administration in STEMI patients undergoing primary PCI. Methods: To investigate the extent of aborted MI, 154 patients undergoing primary PCI were randomized to either IC (n = 77) or IV (n = 77) bolus abciximab administration with subsequent 12-hour intravenous infusion. For assessment of infarct size and extent of microvascular obstruction, all patients underwent late enhancement magnetic resonance imaging (MRI). Aborted MI was defined by major (≥ 50%) ST-segment resolution and a lack of subsequent cardiac enzyme rise ≥ 2 the upper normal limit. We also assessed the occurrence of true aborted MI defined as the absence of myocardial necrosis in MRI. Results: The incidence of aborted MI was significantly higher in the IC group (p = 0.04); true aborted MI was only observed in the IC abciximab group (p = 0.01). At multivariable logistic regression analysis, IC abciximab application was a significant independent predictor of true aborted MI (p = 0.03). Aborted MI patients had an excellent prognosis at 6-month follow-up with no MACE as compared to 24 events in patients with non-aborted MI. Conclusions: IC bolus application of abciximab in STEMI patients undergoing primary PCI results in a higher incidence of aborted MI and subsequent improved clinical outcome. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Randomized clinical trials have collectively shown that adjunctive intravenous (IV) abciximab administration can improve coronary microcirculation and therefore reduces major adverse cardiac events (MACEs) after primary percutaneous coronary intervention (PCI) [1–6]. However, abciximab is rapidly bound with a high affinity to exposed glycoprotein IIb/IIIa receptors on the surface of circulating platelets, limiting the number of antibodies entering the culprit vessel via the IV application route. The intracoronary (IC) bolus administration provides high abciximab concentrations at the culprit lesion, facilitating dosedependent anti-platelet effects, which could translate in further MACE reduction [7,8]. We have previously shown that IC bolus administration of abciximab is superior to standard IV treatment with respect to reduction in infarct size, extent of microvascular obstruction (MO), and
improvement of perfusion in primary PCI [9]. However, data of this mode of drug delivery are limited and mainly based on retrospective registries and small randomized trials [7,10–12]. Recently, aborted MI has emerged as a new therapeutic target in reperfusion trials [13]. Owing to the prognostic relevance and preservation of myocardium, aborted MI represents the ultimate goal in reperfusion therapy in patients with ST-elevation myocardial infarction (STEMI) [13,14]. We hypothesized that IC abciximab administration results in a higher incidence of aborted MI as compared with standard IV abciximab administration. Therefore, we performed a subanalysis of the randomized Leipzig Immediate PercutaneouS coronary Intervention Abciximab IV versus IC in ST-Elevation Myocardial Infarction Trial (LIPSIA-STEMI) to comprehensively analyze aborted MI in patients undergoing primary PCI for STEMI. 2. Methods
⁎ Corresponding author. Department of Internal Medicine/Cardiology, University of Leipzig, Heart Center, Strümpellstr. 39, 04289 Leipzig, Germany. Tel.: + 49 341 865 1428; fax: + 49 341 865 1461. E-mail address: [email protected] (I. Eitel). 0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.08.027
The present study is a subanalysis of the LIPSIA-STEMI trial, which compared IC versus IV abciximab administration in STEMI patients. In this randomized, controlled trial, IC abciximab bolus application with subsequent 12 h continuous intravenous infusion showed reduced no-reflow and infarct size as assessed by contrast-enhanced
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magnetic resonance imaging (MRI). The detailed design and main results of the trial have been previously published [9]. In brief, patients with STEMI undergoing primary PCI were eligible for this trial, if symptoms lasted b12 h and if ST-segment elevation of at least 0.1 mV in ≥ 2 extremity leads or at least 0.2 mV in ≥2 precordial leads were present. 2.1. Primary percutaneous coronary intervention Per protocol, the abciximab bolus administration was to be performed before PCI. In the IC group, bolus administration was recommended after infarct-related artery recanalization by the PCI wire before balloon dilatation to allow high abciximab concentration in the target region. The bolus was administered directly within 1 min through the PCI guiding catheter. All patients were treated with aspirin, unfractionated heparin and clopidogrel. The use of angiotensin-converting-enzyme inhibitors, beta-blockers and statins was strongly recommended according to guidelines [15]. 2.2. Angiographic, electrocardiographic and enzymatic analysis Coronary angiography of the target lesion was performed, as described previously [9]. In brief, angiographic analysis included initial (before abciximab administration) and final flow of the culprit vessel. Collateral circulation to the infarct-related artery was graded using the scoring scheme proposed by Rentrop [16]. Visual assessments were performed offline in the angiographic core laboratory by 2 blinded observers. For electrocardiographic interpretation cumulative ST-segment resolution approximately 90 min after PCI expressed as percentage was calculated by 2 blinded observers as defined previously [9]. The infarct size was measured indirectly by the area under the curve of the creatine kinase release derived from measurements every 6 h over 2 days. 2.3. Cardiac magnetic resonance imaging Infarct size and MO were determined by a 1.5-T MRI scanner (Philips Intera CV, Best, The Netherlands) at days 1–4 after the index event, as described previously [9]. In brief, left ventricular (LV) function was assessed by a standard steady-state free precession technique. For acute infarct determination, short-axis slices covering the whole ventricle using a T2-weighted turbo spin echo sequence were obtained. Enhancement images covering the whole ventricle were acquired approximately 1 (for early MO assessment) and 15 min (for late MO and infarct size assessment) after intravenous administration of 0.2 mmol/kg bodyweight of gadobutrol (Gadovist, Schering, Germany). A 3D inversion-recovery turbo gradient echo sequence was used for image acquisition. All measurements were performed by fully blinded operators at the MRI core laboratory, as previously described [9]. 2.4. Definition of aborted myocardial infarction The diagnosis of aborted MI was made according to previous definitions: 1) if creatine kinase (CK) and CK-MB fraction concentrations did not increase by ≥2 the normal concentration; and 2) the ST-segment resolution was ≥ 50% within 2 h after treatment [13,17,18]. We also examined the incidence of a so called true aborted MI which we recently defined as the absence of myocardial necrosis in late enhancement MRI [14].
Table 1 Patient characteristics. Variable
Intracoronary abciximab (n = 77)
Age (years); median (IQR) Male sex; no. (%) Cardiovascular risk factors; no. (%) Current smoking Hypertension Hypercholesterolemia Diabetes mellitus Prior myocardial infarction; no. (%) Anterior myocardial infarction; no. (%) Number of diseased vessels; no. (%) 1 2 3 Killip-class on admission; no. (%) 1 2 3 4 Reperfusion times (minutes) Symptom-onset-to-reperfusion Door-to-balloon time Concomitant medications; no. (%) Beta-blockers ACE-inhibitors/AT-1 antagonist Aspirin Clopidogrel Statins Aldosterone antagonist Completion of abciximab infusion
Intravenous abciximab (n = 77)
P
64 (54–70) 63 (82)
66 (54–73) 59 (77)
0.33 0.73
38 54 27 24 8 44
(49) (70) (35) (31) (10) (57)
39 (51) 57 (74) 31 (40) 22 (29) 7 (9) 40 (52)
0.98 0.72 0.62 0.86 1.00 0.63 0.89
40 (52) 24 (31) 13 (17)
37 (48) 26 (34) 14 (18)
53 17 5 2
51 (66) 21 (27) 5 (7) 0
0.66 (68) (22) (7) (3)
244 (163–433) 31 (22–40) 76 76 77 77 76 10 73
(99) (99) (100) (100) (99) (13) (95)
218 (159–323) 29 (21–40) 76 77 77 77 77 10 72
(99) (100) (100) (100) (100) (13) (94)
0.47 0.77 1.00 0.97 1.00 1.00 0.97 1.00 0.97
Data are presented as median and interquartile range. TIMI = Thrombolysis in Myocardial Infarction; ACE = angiotensin-converting-enzyme; AT-1 = angiotensin-1.
3. Results Of the 154 patients enrolled, 77 were randomly assigned to IC and 77 to IV abciximab administration (Fig. 1). This was an all-comers study, and no eligible patients were excluded during the study period. Demographic and clinical characteristics are shown in Table 1. There were no significant differences between groups regarding baseline characteristics (age, gender), medications and reperfusion times. Discontinuation of glycoprotein IIb/IIIa inhibitor administration was necessary in 4 IC (n = 2 groin bleeding, n = 1 hematemesis, n = 1 pericardial effusion) and 5 IV group patients (n = 3 groin bleeding, n = 1 pericardial effusion, n = 1 diffuse bleeding caused by thrombocytopenia) (p = 0.93). 3.1. Magnetic resonance imaging
2.5. Clinical endpoints The clinical endpoint evaluated in this study was the occurrence of MACE defined as a composite of death, reinfarction, urgent target vessel revascularization and new congestive heart failure within 30 days and 6 months after the index event. The diagnosis of reinfarction and new congestive heart failure were defined as previously described [9]. To avoid double counting of patients with N 1 event, each patient contributed only once to the composite MACE endpoint (death N re-MI N urgent target vessel revascularization N congestive heart failure).
Results of MRI were available in 67 (87%) of the IC and in 71 (92%) of the IV abciximab group patients (Fig. 1). The median time between randomization and MRI
2.6. Statistical analysis Each categorical variable is expressed as number and percentage of patients. Most continuous variables had non-normal distribution (as evaluated by Kolmogorov– Smirnov tests) and are therefore presented as medians together with interquartile range. Differences between groups were assessed by Fisher's exact or the Chi-square test for categorical variables and by the student t-test for continuous data with normal distribution. Otherwise the nonparametric Wilcoxon rank-sum test was used. Multivariable logistic regression analysis was applied to identify predictors of aborted MI. At this scope, all variables showing a significant or borderline association (p ≤ 0.1) with aborted MI at univariable analysis were included in the model. For univariable analyses, all variables of Table 1 as well as TIMI-flow before and after PCI and collateral circulation grade were tested. For the combined clinical end point, the Kaplan–Meier method was applied, and differences were assessed by the log-rank test. All statistical tests were performed with SPSS software, version 17.0 (SPSS Inc. Illinois, MS). A 2-tailed p-value b 0.05 was considered statistically significant.
Fig. 1. Study flow diagram.
I. Eitel et al. / International Journal of Cardiology 153 (2011) 21–25 was 2 days (interquartile range, 2 to 3 days) for both groups (p = 0.94). The significant differences in infarct size and extent of MO between the groups have been reported previously (Table 2) [9].
3.2. Angiographic, electrocardiographic and enzymatic analysis TIMI-flow grades before and after PCI as well as the ST-segment resolution data have been reported previously (Table 2) [9]. In brief, TIMI-flow grades before and after PCI were similar between groups, but ST-segment resolution as a continuous variable was significantly better in the IC abciximab group (p = 0.006). The enzymatic infarct size assessed by the area under the curve of creatine kinase release was also significantly smaller in the IC group as compared with the IV abciximab group (Table 2).
3.3. Clinical outcome In line with our previously published 30-day clinical outcome data [9], there was a reduction of the composite MACE rate at 6-month follow-up (10% versus 21%) in the IC abciximab administration group (p = 0.07). There were 4 cardiac deaths (5%) in the IC and 4 (5%) in the IV abciximab group. Nonfatal reinfarctions occurred in 0 patients after IC and in 2 (3%) after IV abciximab application. The need for target vessel revascularization was 2 (3%) versus 4 (4%) and new congestive heart failure occurred in 2 (3%) and 6 (8%) patients, respectively.
3.4. Incidence and predictors of aborted myocardial infarction Characteristics of patients with aborted MI compared to patients with non-aborted MI are shown in Table 3. An aborted MI according to the established criteria was observed in 18 patients (12%) (Fig. 2). Of these, 6 patients (4%) showed no detectable myocardial necrosis in late enhancement MRI consistent with a true aborted MI (Fig. 3). Patients in the IC group had a significantly higher incidence of aborted MI as compared to the standard IV abciximab group (13 [16%] versus 5 [6%]; p = 0.04). True aborted MI was observed in 6 patients (8%) of the IC group and in 0 subjects of the IV group (p = 0.01) (Fig. 2). Patients with an aborted MI had a significantly smaller infarct size, extent of MO and better LV function (p b 0.001, respectively), as well as a trend to a shorter pain-toballoon time (p = 0.07) as compared with patients with non-aborted MI (Table 4). In a multivariable regression model adjusted for significant variables in univariable analysis using aborted MI as the dependent variable, the only significant predictor of aborted MI was TIMI-flow before PCI (p b 0.001) (Table 5). Using true aborted MI as the dependent variable in multivariable regression analysis adjusted for significant or borderline predictors in univariable analysis TIMIflow before PCI (p b 0.001), abciximab IC group (p = 0.02) and pain-to-balloon time (p = 0.04) emerged as significant predictors of true aborted MI without detectable myocardial necrosis in MRI (Table 6). Patients with aborted MI had no MACE at 6-month follow-up as compared to 24 events in patients with non-aborted MI (p = 0.07).
Table 2 Angiographic, electrocardiographic, enzymatic and cardiac magnetic resonance results. Variable
TIMI-flow grade pre PCI; no. (%) 0 1 2 3 TIMI-flow grade after PCI; no. (%) ≤2 3 Collateral circulation grade; no (%) ≤1 (absent or weak collateral flow) N1 (significant collateral flow) ST-segment resolution (%) AUC of CK release (μmol l− 1 h− 1) Early MO (%LV) Late MO (%LV) Infarct size (%LV) Ejection fraction (%)
Intracoronary abciximab (n = 77)
Intravenous abciximab (n = 77)
P
0.51 44 (57) 9 (12) 6 (8) 18 (23)
52 (67) 5 (7) 4 (5) 16 (21)
12 (16) 65 (84)
11 (14) 66 (86)
54 (71)
52 (68)
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Table 3 Characteristics of patients with aborted MI compared to patients with non-aborted MI. Variable
Non-aborted MI (n = 136)
Age (years); median (IQR) Male sex; no. (%) Cardiovascular risk factors; no. (%) Current Smoking Hypertension Hypercholesterolemia Diabetes mellitus Prior myocardial infarction; no. (%) Anterior myocardial infarction; no. (%) Number of diseased vessels; no. (%) 1 2 3 Killip-class on admission; no. (%) 1 2 3 4 Reperfusion times (minutes) Symptom-onset-to-reperfusion Door-to-balloon time Concomitant medications; no. (%) Beta-blockers ACE-inhibitors/AT-1 antagonist Aspirin Clopidogrel Statins Aldosterone antagonist Completion of abciximab infusion
64 (53–72) 109 (80)
Aborted MI (n = 18)
P
66 (57–73) 13 (72)
0.47 0.44
(50) (71) (40) (27) (10) (57)
9 (50) 15 (83) 4 (22) 8 (44) 2 (11) 7 (39)
1.00 0.26 0.15 0.13 0.52 0.16 0.47
69 (51) 45 (33) 22 (16)
8 (44) 5 (28) 5 (28)
68 96 54 37 13 77
0.19 89 37 8 2
(65) (27) (6) (2)
236 (164–407) 30 (23–40) 135 135 136 136 135 18 127
(99) (99) (100) (100) (99) (13) (94)
15 (83) 1 (6) 2 (11) 0 202 (122–325) 27 (17–41) 18 (99) 18 (100) 18 (100) 18 (100) 18 (100) 2 (11) 18 (100)
0.07 0.61 0.90 0.72 1.00 1.00 0.72 0.80 0.26
As in Table 1.
4. Discussion This is the first study using aborted MI as an endpoint to identify pharmacological strategies to improve myocardial perfusion and outcome after primary PCI in STEMI. The major findings are as follows: 1) IC abciximab application results in a significantly higher incidence of aborted MI as compared to standard IV administration; 2) IC abciximab application is a significant independent predictor of true aborted MI without detectable myocardial necrosis; and 3) the excellent prognosis of an aborted MI after primary PCI could be confirmed. Thus, this study demonstrates the ability of IC abciximab administration to improve the incidence of aborted MI, a strong surrogate parameter of effective treatment and clinical outcome in STEMI patients. 4.1. Intracoronary versus intravenous abciximab application in STEMI The dose-dependent anti-platelet and anti-thrombotic features of abciximab suggest that higher local platelet inhibitor concentrations
0.91
0.53
23 78 575 1.1 0.1 15.1 48.0
(29) (67–100) (359–863) (0.0–3.7) (0.0–1.6) (6.1–25.2) (38.5–52.7)
25 70 736 3.4 1.1 23.4 46.1
(32) (45–84) (416–1304) (0.1–7.3) (0.0–2.8) (13.6–33.2) (36.4–50.4)
0.006 0.007 0.01 0.02 0.01 0.71
Data are presented as median and interquartile range. TIMI=Thrombolysis in Myocardial Infarction; PCI=percutaneous coronary intervention; MO=microvascular obstruction; AUC=area under the curve; CK=creatine kinase.
Fig. 2. Incidence of aborted MI and true aborted MI according to abciximab drug delivery group.
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I. Eitel et al. / International Journal of Cardiology 153 (2011) 21–25 Table 4 Angiographic, electrocardiographic, enzymatic and cardiac magnetic resonance results of patients with aborted MI versus non-aborted MI. Variable
Non-aborted MI (n = 136)
Aborted MI (n = 18)
TIMI-flow grade pre PCI; no. (%) 0 92 (68) 4 (22) 1 14 (10) 0 2 7 (5) 3 (17) 3 23 (17) 11 (61) TIMI-flow grade after PCI; no. (%) ≤2 23 (17) 0 3 113 (83) 18 (100) Collateral circulation grade; no. (%) ≤1 (absent or weak collateral 93 (69) 12 (67) flow) N1 (significant collateral flow) 41 (31) 6 (33) ST-segment resolution (%) 73 (55–88) 92 (74–100) AUC of CK release (μmol l− 1 h− 1) 660 (479–1067) 148 (63–223) Early MO (%LV) 2.8 (0.2–6.1) 0 (0.0–0.0) Late MO (%LV) 0.8 (0.0–2.5) 0 (0.0–0.0) Infarct size (%LV) 20.8 (12.4–32.3) 2.9 (1.0–5.3) Ejection fraction (%) 43.6 (36.9–50.1) 57.6 (52.1–65.0)
P b0.001
0.31
0.18
b0.001 b0.001 b0.001 b0.001 b0.001 b0.001
As in Table 2.
Table 5 Significant predictors of aborted MI in univariable and multivariable logistic regression analysis. Predictors
Abciximab intracoronary group Symptom-onset-toreperfusion time TIMI-flow before PCI
Univariable analysis
Multivariable analysis
OR
95% CI
OR
95% CI
2.93
0.99–8.66
P 0.05
3.02
0.93–9.85
P 0.07
0.99
0.98–1.00
0.09
0.99
0.98–1.00
0.08
2.35
1.55–3.54
b0.001
2.40
1.56–3.71
b 0.001
OR=odds ratio; CI=confidence interval; MI=myocardial infarction; TIMI=Thrombolysis in Myocardial Infarction; PCI=percutaneous coronary intervention. Fig. 3. A, B: Patient with non-aborted MI. T2-weighted images showing inferoseptal oedema in the short-axis view (A). Late enhancement MRI demonstrating transmural scar with microvascular obstruction (arrows) (B). C, D: Patient with fulfilled criteria of aborted MI but detected scar formation (arrows) in late enhancement imaging. E, F: Patient with true aborted MI. T2 weighted images demonstrating oedema consistent with acute myocardial injury (E) in the absence of late enhancement (F).
may translate into further clinical improvements [19]. Very high local platelet inhibitor concentrations can be obtained by the direct administration of abciximab into the infarct-related artery. IC abciximab bolus administration may be favourable in dissolution of thrombi and microemboli with subsequent improved myocardial microcirculation and reduced no-reflow and infarct size [8]. Currently, clinical experience in the efficacy of IC abciximab administration is limited to case reports, retrospective registries, and small randomized trials [7,10–12]. We have recently shown in the first adequately powered randomized trial of IC versus IV abciximab administration in high-risk STEMI patients that IC abciximab administration reduces infarct size and no-reflow assessed by MRI [9]. This improved myocardial perfusion also translated into a better clinical outcome after 30 days [9] and 6 months, as shown in the current study. Notably, the IC abciximab administration was safe with no adverse events during its administration and no increased risk of bleeding.
enzyme rise ≥ 2 the upper normal limit, as also used in the current trial [13,17,18]. However, these current established diagnostic criteria have significant limitations in the setting of infarct size measurement. Indeed, Vasile et al have shown that the frequency of aborted MI is 0% when using troponin at the 99th percentile cutoff in STEMI patients treated with primary PCI [24]. Moreover, in a recent trial we demonstrated that approximately half of the patients with fulfilled aborted MI criteria had detectable myocardial necrosis using late enhancement MRI [14]. As in some patients troponin levels are elevated despite no detectable myocardial injury [25,26] we proposed cardiac MRI as diagnostic measure for a true aborted MI with total obviation of necrosis. MRI has the unique advantage of visualization of even microinfarctions at very high spatial resolution and might therefore be more suitable in diagnosing true aborted MIs as compared to previous definitions (including troponin) [14]. Using MRI to detect true aborted MI resulted in the discovery that the proportion of really aborted MIs was 4% and not 12% as detected with the clinical criteria. Table 6 Significant predictors of true aborted MI in univariable and multivariable logistic regression analysis. Predictors
4.2. Aborted myocardial infarction and intracoronary abciximab administration There is no current standardized definition of aborted MI. Thus, various investigators have used different definitions for aborted MI [17,18,20–24]. Most commonly, aborted MI is defined by major (≥50%) ST-segment resolution and a lack of subsequent cardiac
Univariable analysis
Multivariable analysis
OR
OR
95% CI
P
95% CI
P
Abciximab intracoronary 3.54 1.22–10.20 0.02 3.83 1.19–12.34 0.02 group Symptom-onset-to0.98 0.97–1.00 0.05 0.99 0.98–1.00 0.04 reperfusion time TIMI flow before PCI 2.26 1.53–3.32 b0.001 2.34 1.54–3.54 b0.001 As in Table 5.
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True aborted MIs without detectable myocardial necrosis in late enhancement MRI were exclusively observed in the abciximab IC group and IC application of abciximab was an independent predictor of true aborted MI. Mechanisms, by which IC abciximab application can influence and enhance aborted MI, might be explained by the high local doses, which may facilitate the diffusion of the antibody to platelets inside the flow-limiting thrombus, thus resulting in improved dissolution of thrombi and microemboli at the ruptured plaque and further downstream in the microcirculation. Another potential mechanism of high local concentrations might be related to the dose-dependent anti-inflammatory properties of abciximab [8]. By modulating inflammatory cell response due to non glycoprotein IIb/IIIa effects in combination with enhanced inhibition of the glycoprotein IIb/IIIa receptor, IC abciximab may favourably influence reperfusion injury, resulting in a further reduction of infarct size and no-reflow as compared to the standard IV approach. Concentrations that produced complete platelet disaggregation also induced partial displacement of platelet-bound fibrinogen, which might also play a role in the clinical setting [19]. Other factors might also influence the occurrence of aborted MI. In line with previous studies, time from symptom onset to reperfusion (especially in true aborted MI patients) and TIMI-flow before PCI were major determinants of aborted MI [13,14]. Finally, our trial unequivocally confirms the excellent prognostic value of an aborted MI. At 6-month follow-up no MACE was observed in the aborted MI group. These findings are in general agreement with previous studies reporting favourable outcome data in patients with aborted MI after fibrinolysis [17,18,23]. The confirmed prognostic relevance of aborted MI makes it a meaningful end point in future MI studies, intended to test new reperfusion therapy efficacy. 4.3. Limitations This is a retrospective analysis of data collected prospectively. Although all angiographic, ECG, and MRI measurements were blinded, patients and interventionalists were aware of the group assignment. Thus, a potential investigator bias cannot be ruled out entirely. The occurrence of previous angina was not evaluated which may allow the assessment of potential preconditioning effects. However, angina onset and recurrence is generally subjective and difficult to assess. 4.4. Conclusions IC bolus application of abciximab in primary PCI results in a higher incidence of aborted MI with subsequent improved clinical outcome at 6-month follow-up. Larger randomized multicenter trials using rigorous clinical end points such as death and MI are required to further substantiate the clinical benefits of this mode of drug delivery. Acknowledgement The authors of this manuscript have certified that they comply with the principles of ethical publishing in the International Journal of Cardiology [27]. References [1] Montalescot G, Barragan P, Wittenberg O, et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001;344:1895–903. [2] Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002;346: 957–66.
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Am Heart J 2004;147:509–15. [19] Marciniak Jr SJ, Mascelli MA, Furman MI, et al. An additional mechanism of action of abciximab: dispersal of newly formed platelet aggregates. Thromb Haemost 2002;87:1020–5. [20] Lamfers EJ, Hooghoudt TE, Uppelschoten A, Stolwijk PW, Verheugt FW. Effect of prehospital thrombolysis on aborting acute myocardial infarction. Am J Cardiol 1999;84:928–???. [21] Hassan AK, Jukema JW, van der Laarse A, et al. Incidence, patient characteristics and predictors of aborted myocardial infarction in patients undergoing primary PCI: prospective study comparing pre- and in-hospital abciximab pretreatment. EuroIntervention 2009;4:662–8. [22] Sciagra R, Parodi G, Sotgia B, Antoniucci D, Pupi A. Determinants of final infarct size and incidence of aborted infarction in patients treated with primary coronary intervention and adjunctive abciximab therapy. Nuklearmedizin 2008;47:56–61. [23] Taher T, Fu Y, Wagner GS, et al. 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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Aborted myocardial infarction in intracoronary compared with standard intravenous abciximab administration in patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction Ingo Eitel a,⁎, Steffen Desch a, Kathrin Schindler b, Georg Fuernau a, Gerhard Schuler a, Holger Thiele a a b
University of Leipzig, Heart Center, Department of Internal Medicine, Cardiology, Leipzig Germany University of Leipzig, Heart Center, Department of Diagnostic and Interventional Radiology, Leipzig Germany
a r t i c l e
i n f o
Article history: Received 22 February 2010 Received in revised form 5 July 2010 Accepted 7 August 2010 Available online 6 September 2010 Keywords: Myocardial infarction Aborted myocardial infarction Abciximab Glycoprotein IIb/IIIa inhibitor Magnetic resonance imaging
a b s t r a c t Backgound: Abciximab reduces major adverse cardiac events (MACEs) in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Intracoronary (IC) abciximab bolus application might be more effective than a standard intravenous (IV) bolus. So far the occurrence of aborted MI, a new therapeutic target of effective treatment in STEMI, has not been evaluated in IC versus IV abciximab administration in STEMI patients undergoing primary PCI. Methods: To investigate the extent of aborted MI, 154 patients undergoing primary PCI were randomized to either IC (n = 77) or IV (n = 77) bolus abciximab administration with subsequent 12-hour intravenous infusion. For assessment of infarct size and extent of microvascular obstruction, all patients underwent late enhancement magnetic resonance imaging (MRI). Aborted MI was defined by major (≥ 50%) ST-segment resolution and a lack of subsequent cardiac enzyme rise ≥ 2 the upper normal limit. We also assessed the occurrence of true aborted MI defined as the absence of myocardial necrosis in MRI. Results: The incidence of aborted MI was significantly higher in the IC group (p = 0.04); true aborted MI was only observed in the IC abciximab group (p = 0.01). At multivariable logistic regression analysis, IC abciximab application was a significant independent predictor of true aborted MI (p = 0.03). Aborted MI patients had an excellent prognosis at 6-month follow-up with no MACE as compared to 24 events in patients with non-aborted MI. Conclusions: IC bolus application of abciximab in STEMI patients undergoing primary PCI results in a higher incidence of aborted MI and subsequent improved clinical outcome. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Randomized clinical trials have collectively shown that adjunctive intravenous (IV) abciximab administration can improve coronary microcirculation and therefore reduces major adverse cardiac events (MACEs) after primary percutaneous coronary intervention (PCI) [1–6]. However, abciximab is rapidly bound with a high affinity to exposed glycoprotein IIb/IIIa receptors on the surface of circulating platelets, limiting the number of antibodies entering the culprit vessel via the IV application route. The intracoronary (IC) bolus administration provides high abciximab concentrations at the culprit lesion, facilitating dosedependent anti-platelet effects, which could translate in further MACE reduction [7,8]. We have previously shown that IC bolus administration of abciximab is superior to standard IV treatment with respect to reduction in infarct size, extent of microvascular obstruction (MO), and
improvement of perfusion in primary PCI [9]. However, data of this mode of drug delivery are limited and mainly based on retrospective registries and small randomized trials [7,10–12]. Recently, aborted MI has emerged as a new therapeutic target in reperfusion trials [13]. Owing to the prognostic relevance and preservation of myocardium, aborted MI represents the ultimate goal in reperfusion therapy in patients with ST-elevation myocardial infarction (STEMI) [13,14]. We hypothesized that IC abciximab administration results in a higher incidence of aborted MI as compared with standard IV abciximab administration. Therefore, we performed a subanalysis of the randomized Leipzig Immediate PercutaneouS coronary Intervention Abciximab IV versus IC in ST-Elevation Myocardial Infarction Trial (LIPSIA-STEMI) to comprehensively analyze aborted MI in patients undergoing primary PCI for STEMI. 2. Methods
⁎ Corresponding author. Department of Internal Medicine/Cardiology, University of Leipzig, Heart Center, Strümpellstr. 39, 04289 Leipzig, Germany. Tel.: + 49 341 865 1428; fax: + 49 341 865 1461. E-mail address: [email protected] (I. Eitel). 0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.08.027
The present study is a subanalysis of the LIPSIA-STEMI trial, which compared IC versus IV abciximab administration in STEMI patients. In this randomized, controlled trial, IC abciximab bolus application with subsequent 12 h continuous intravenous infusion showed reduced no-reflow and infarct size as assessed by contrast-enhanced
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magnetic resonance imaging (MRI). The detailed design and main results of the trial have been previously published [9]. In brief, patients with STEMI undergoing primary PCI were eligible for this trial, if symptoms lasted b12 h and if ST-segment elevation of at least 0.1 mV in ≥ 2 extremity leads or at least 0.2 mV in ≥2 precordial leads were present. 2.1. Primary percutaneous coronary intervention Per protocol, the abciximab bolus administration was to be performed before PCI. In the IC group, bolus administration was recommended after infarct-related artery recanalization by the PCI wire before balloon dilatation to allow high abciximab concentration in the target region. The bolus was administered directly within 1 min through the PCI guiding catheter. All patients were treated with aspirin, unfractionated heparin and clopidogrel. The use of angiotensin-converting-enzyme inhibitors, beta-blockers and statins was strongly recommended according to guidelines [15]. 2.2. Angiographic, electrocardiographic and enzymatic analysis Coronary angiography of the target lesion was performed, as described previously [9]. In brief, angiographic analysis included initial (before abciximab administration) and final flow of the culprit vessel. Collateral circulation to the infarct-related artery was graded using the scoring scheme proposed by Rentrop [16]. Visual assessments were performed offline in the angiographic core laboratory by 2 blinded observers. For electrocardiographic interpretation cumulative ST-segment resolution approximately 90 min after PCI expressed as percentage was calculated by 2 blinded observers as defined previously [9]. The infarct size was measured indirectly by the area under the curve of the creatine kinase release derived from measurements every 6 h over 2 days. 2.3. Cardiac magnetic resonance imaging Infarct size and MO were determined by a 1.5-T MRI scanner (Philips Intera CV, Best, The Netherlands) at days 1–4 after the index event, as described previously [9]. In brief, left ventricular (LV) function was assessed by a standard steady-state free precession technique. For acute infarct determination, short-axis slices covering the whole ventricle using a T2-weighted turbo spin echo sequence were obtained. Enhancement images covering the whole ventricle were acquired approximately 1 (for early MO assessment) and 15 min (for late MO and infarct size assessment) after intravenous administration of 0.2 mmol/kg bodyweight of gadobutrol (Gadovist, Schering, Germany). A 3D inversion-recovery turbo gradient echo sequence was used for image acquisition. All measurements were performed by fully blinded operators at the MRI core laboratory, as previously described [9]. 2.4. Definition of aborted myocardial infarction The diagnosis of aborted MI was made according to previous definitions: 1) if creatine kinase (CK) and CK-MB fraction concentrations did not increase by ≥2 the normal concentration; and 2) the ST-segment resolution was ≥ 50% within 2 h after treatment [13,17,18]. We also examined the incidence of a so called true aborted MI which we recently defined as the absence of myocardial necrosis in late enhancement MRI [14].
Table 1 Patient characteristics. Variable
Intracoronary abciximab (n = 77)
Age (years); median (IQR) Male sex; no. (%) Cardiovascular risk factors; no. (%) Current smoking Hypertension Hypercholesterolemia Diabetes mellitus Prior myocardial infarction; no. (%) Anterior myocardial infarction; no. (%) Number of diseased vessels; no. (%) 1 2 3 Killip-class on admission; no. (%) 1 2 3 4 Reperfusion times (minutes) Symptom-onset-to-reperfusion Door-to-balloon time Concomitant medications; no. (%) Beta-blockers ACE-inhibitors/AT-1 antagonist Aspirin Clopidogrel Statins Aldosterone antagonist Completion of abciximab infusion
Intravenous abciximab (n = 77)
P
64 (54–70) 63 (82)
66 (54–73) 59 (77)
0.33 0.73
38 54 27 24 8 44
(49) (70) (35) (31) (10) (57)
39 (51) 57 (74) 31 (40) 22 (29) 7 (9) 40 (52)
0.98 0.72 0.62 0.86 1.00 0.63 0.89
40 (52) 24 (31) 13 (17)
37 (48) 26 (34) 14 (18)
53 17 5 2
51 (66) 21 (27) 5 (7) 0
0.66 (68) (22) (7) (3)
244 (163–433) 31 (22–40) 76 76 77 77 76 10 73
(99) (99) (100) (100) (99) (13) (95)
218 (159–323) 29 (21–40) 76 77 77 77 77 10 72
(99) (100) (100) (100) (100) (13) (94)
0.47 0.77 1.00 0.97 1.00 1.00 0.97 1.00 0.97
Data are presented as median and interquartile range. TIMI = Thrombolysis in Myocardial Infarction; ACE = angiotensin-converting-enzyme; AT-1 = angiotensin-1.
3. Results Of the 154 patients enrolled, 77 were randomly assigned to IC and 77 to IV abciximab administration (Fig. 1). This was an all-comers study, and no eligible patients were excluded during the study period. Demographic and clinical characteristics are shown in Table 1. There were no significant differences between groups regarding baseline characteristics (age, gender), medications and reperfusion times. Discontinuation of glycoprotein IIb/IIIa inhibitor administration was necessary in 4 IC (n = 2 groin bleeding, n = 1 hematemesis, n = 1 pericardial effusion) and 5 IV group patients (n = 3 groin bleeding, n = 1 pericardial effusion, n = 1 diffuse bleeding caused by thrombocytopenia) (p = 0.93). 3.1. Magnetic resonance imaging
2.5. Clinical endpoints The clinical endpoint evaluated in this study was the occurrence of MACE defined as a composite of death, reinfarction, urgent target vessel revascularization and new congestive heart failure within 30 days and 6 months after the index event. The diagnosis of reinfarction and new congestive heart failure were defined as previously described [9]. To avoid double counting of patients with N 1 event, each patient contributed only once to the composite MACE endpoint (death N re-MI N urgent target vessel revascularization N congestive heart failure).
Results of MRI were available in 67 (87%) of the IC and in 71 (92%) of the IV abciximab group patients (Fig. 1). The median time between randomization and MRI
2.6. Statistical analysis Each categorical variable is expressed as number and percentage of patients. Most continuous variables had non-normal distribution (as evaluated by Kolmogorov– Smirnov tests) and are therefore presented as medians together with interquartile range. Differences between groups were assessed by Fisher's exact or the Chi-square test for categorical variables and by the student t-test for continuous data with normal distribution. Otherwise the nonparametric Wilcoxon rank-sum test was used. Multivariable logistic regression analysis was applied to identify predictors of aborted MI. At this scope, all variables showing a significant or borderline association (p ≤ 0.1) with aborted MI at univariable analysis were included in the model. For univariable analyses, all variables of Table 1 as well as TIMI-flow before and after PCI and collateral circulation grade were tested. For the combined clinical end point, the Kaplan–Meier method was applied, and differences were assessed by the log-rank test. All statistical tests were performed with SPSS software, version 17.0 (SPSS Inc. Illinois, MS). A 2-tailed p-value b 0.05 was considered statistically significant.
Fig. 1. Study flow diagram.
I. Eitel et al. / International Journal of Cardiology 153 (2011) 21–25 was 2 days (interquartile range, 2 to 3 days) for both groups (p = 0.94). The significant differences in infarct size and extent of MO between the groups have been reported previously (Table 2) [9].
3.2. Angiographic, electrocardiographic and enzymatic analysis TIMI-flow grades before and after PCI as well as the ST-segment resolution data have been reported previously (Table 2) [9]. In brief, TIMI-flow grades before and after PCI were similar between groups, but ST-segment resolution as a continuous variable was significantly better in the IC abciximab group (p = 0.006). The enzymatic infarct size assessed by the area under the curve of creatine kinase release was also significantly smaller in the IC group as compared with the IV abciximab group (Table 2).
3.3. Clinical outcome In line with our previously published 30-day clinical outcome data [9], there was a reduction of the composite MACE rate at 6-month follow-up (10% versus 21%) in the IC abciximab administration group (p = 0.07). There were 4 cardiac deaths (5%) in the IC and 4 (5%) in the IV abciximab group. Nonfatal reinfarctions occurred in 0 patients after IC and in 2 (3%) after IV abciximab application. The need for target vessel revascularization was 2 (3%) versus 4 (4%) and new congestive heart failure occurred in 2 (3%) and 6 (8%) patients, respectively.
3.4. Incidence and predictors of aborted myocardial infarction Characteristics of patients with aborted MI compared to patients with non-aborted MI are shown in Table 3. An aborted MI according to the established criteria was observed in 18 patients (12%) (Fig. 2). Of these, 6 patients (4%) showed no detectable myocardial necrosis in late enhancement MRI consistent with a true aborted MI (Fig. 3). Patients in the IC group had a significantly higher incidence of aborted MI as compared to the standard IV abciximab group (13 [16%] versus 5 [6%]; p = 0.04). True aborted MI was observed in 6 patients (8%) of the IC group and in 0 subjects of the IV group (p = 0.01) (Fig. 2). Patients with an aborted MI had a significantly smaller infarct size, extent of MO and better LV function (p b 0.001, respectively), as well as a trend to a shorter pain-toballoon time (p = 0.07) as compared with patients with non-aborted MI (Table 4). In a multivariable regression model adjusted for significant variables in univariable analysis using aborted MI as the dependent variable, the only significant predictor of aborted MI was TIMI-flow before PCI (p b 0.001) (Table 5). Using true aborted MI as the dependent variable in multivariable regression analysis adjusted for significant or borderline predictors in univariable analysis TIMIflow before PCI (p b 0.001), abciximab IC group (p = 0.02) and pain-to-balloon time (p = 0.04) emerged as significant predictors of true aborted MI without detectable myocardial necrosis in MRI (Table 6). Patients with aborted MI had no MACE at 6-month follow-up as compared to 24 events in patients with non-aborted MI (p = 0.07).
Table 2 Angiographic, electrocardiographic, enzymatic and cardiac magnetic resonance results. Variable
TIMI-flow grade pre PCI; no. (%) 0 1 2 3 TIMI-flow grade after PCI; no. (%) ≤2 3 Collateral circulation grade; no (%) ≤1 (absent or weak collateral flow) N1 (significant collateral flow) ST-segment resolution (%) AUC of CK release (μmol l− 1 h− 1) Early MO (%LV) Late MO (%LV) Infarct size (%LV) Ejection fraction (%)
Intracoronary abciximab (n = 77)
Intravenous abciximab (n = 77)
P
0.51 44 (57) 9 (12) 6 (8) 18 (23)
52 (67) 5 (7) 4 (5) 16 (21)
12 (16) 65 (84)
11 (14) 66 (86)
54 (71)
52 (68)
23
Table 3 Characteristics of patients with aborted MI compared to patients with non-aborted MI. Variable
Non-aborted MI (n = 136)
Age (years); median (IQR) Male sex; no. (%) Cardiovascular risk factors; no. (%) Current Smoking Hypertension Hypercholesterolemia Diabetes mellitus Prior myocardial infarction; no. (%) Anterior myocardial infarction; no. (%) Number of diseased vessels; no. (%) 1 2 3 Killip-class on admission; no. (%) 1 2 3 4 Reperfusion times (minutes) Symptom-onset-to-reperfusion Door-to-balloon time Concomitant medications; no. (%) Beta-blockers ACE-inhibitors/AT-1 antagonist Aspirin Clopidogrel Statins Aldosterone antagonist Completion of abciximab infusion
64 (53–72) 109 (80)
Aborted MI (n = 18)
P
66 (57–73) 13 (72)
0.47 0.44
(50) (71) (40) (27) (10) (57)
9 (50) 15 (83) 4 (22) 8 (44) 2 (11) 7 (39)
1.00 0.26 0.15 0.13 0.52 0.16 0.47
69 (51) 45 (33) 22 (16)
8 (44) 5 (28) 5 (28)
68 96 54 37 13 77
0.19 89 37 8 2
(65) (27) (6) (2)
236 (164–407) 30 (23–40) 135 135 136 136 135 18 127
(99) (99) (100) (100) (99) (13) (94)
15 (83) 1 (6) 2 (11) 0 202 (122–325) 27 (17–41) 18 (99) 18 (100) 18 (100) 18 (100) 18 (100) 2 (11) 18 (100)
0.07 0.61 0.90 0.72 1.00 1.00 0.72 0.80 0.26
As in Table 1.
4. Discussion This is the first study using aborted MI as an endpoint to identify pharmacological strategies to improve myocardial perfusion and outcome after primary PCI in STEMI. The major findings are as follows: 1) IC abciximab application results in a significantly higher incidence of aborted MI as compared to standard IV administration; 2) IC abciximab application is a significant independent predictor of true aborted MI without detectable myocardial necrosis; and 3) the excellent prognosis of an aborted MI after primary PCI could be confirmed. Thus, this study demonstrates the ability of IC abciximab administration to improve the incidence of aborted MI, a strong surrogate parameter of effective treatment and clinical outcome in STEMI patients. 4.1. Intracoronary versus intravenous abciximab application in STEMI The dose-dependent anti-platelet and anti-thrombotic features of abciximab suggest that higher local platelet inhibitor concentrations
0.91
0.53
23 78 575 1.1 0.1 15.1 48.0
(29) (67–100) (359–863) (0.0–3.7) (0.0–1.6) (6.1–25.2) (38.5–52.7)
25 70 736 3.4 1.1 23.4 46.1
(32) (45–84) (416–1304) (0.1–7.3) (0.0–2.8) (13.6–33.2) (36.4–50.4)
0.006 0.007 0.01 0.02 0.01 0.71
Data are presented as median and interquartile range. TIMI=Thrombolysis in Myocardial Infarction; PCI=percutaneous coronary intervention; MO=microvascular obstruction; AUC=area under the curve; CK=creatine kinase.
Fig. 2. Incidence of aborted MI and true aborted MI according to abciximab drug delivery group.
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I. Eitel et al. / International Journal of Cardiology 153 (2011) 21–25 Table 4 Angiographic, electrocardiographic, enzymatic and cardiac magnetic resonance results of patients with aborted MI versus non-aborted MI. Variable
Non-aborted MI (n = 136)
Aborted MI (n = 18)
TIMI-flow grade pre PCI; no. (%) 0 92 (68) 4 (22) 1 14 (10) 0 2 7 (5) 3 (17) 3 23 (17) 11 (61) TIMI-flow grade after PCI; no. (%) ≤2 23 (17) 0 3 113 (83) 18 (100) Collateral circulation grade; no. (%) ≤1 (absent or weak collateral 93 (69) 12 (67) flow) N1 (significant collateral flow) 41 (31) 6 (33) ST-segment resolution (%) 73 (55–88) 92 (74–100) AUC of CK release (μmol l− 1 h− 1) 660 (479–1067) 148 (63–223) Early MO (%LV) 2.8 (0.2–6.1) 0 (0.0–0.0) Late MO (%LV) 0.8 (0.0–2.5) 0 (0.0–0.0) Infarct size (%LV) 20.8 (12.4–32.3) 2.9 (1.0–5.3) Ejection fraction (%) 43.6 (36.9–50.1) 57.6 (52.1–65.0)
P b0.001
0.31
0.18
b0.001 b0.001 b0.001 b0.001 b0.001 b0.001
As in Table 2.
Table 5 Significant predictors of aborted MI in univariable and multivariable logistic regression analysis. Predictors
Abciximab intracoronary group Symptom-onset-toreperfusion time TIMI-flow before PCI
Univariable analysis
Multivariable analysis
OR
95% CI
OR
95% CI
2.93
0.99–8.66
P 0.05
3.02
0.93–9.85
P 0.07
0.99
0.98–1.00
0.09
0.99
0.98–1.00
0.08
2.35
1.55–3.54
b0.001
2.40
1.56–3.71
b 0.001
OR=odds ratio; CI=confidence interval; MI=myocardial infarction; TIMI=Thrombolysis in Myocardial Infarction; PCI=percutaneous coronary intervention. Fig. 3. A, B: Patient with non-aborted MI. T2-weighted images showing inferoseptal oedema in the short-axis view (A). Late enhancement MRI demonstrating transmural scar with microvascular obstruction (arrows) (B). C, D: Patient with fulfilled criteria of aborted MI but detected scar formation (arrows) in late enhancement imaging. E, F: Patient with true aborted MI. T2 weighted images demonstrating oedema consistent with acute myocardial injury (E) in the absence of late enhancement (F).
may translate into further clinical improvements [19]. Very high local platelet inhibitor concentrations can be obtained by the direct administration of abciximab into the infarct-related artery. IC abciximab bolus administration may be favourable in dissolution of thrombi and microemboli with subsequent improved myocardial microcirculation and reduced no-reflow and infarct size [8]. Currently, clinical experience in the efficacy of IC abciximab administration is limited to case reports, retrospective registries, and small randomized trials [7,10–12]. We have recently shown in the first adequately powered randomized trial of IC versus IV abciximab administration in high-risk STEMI patients that IC abciximab administration reduces infarct size and no-reflow assessed by MRI [9]. This improved myocardial perfusion also translated into a better clinical outcome after 30 days [9] and 6 months, as shown in the current study. Notably, the IC abciximab administration was safe with no adverse events during its administration and no increased risk of bleeding.
enzyme rise ≥ 2 the upper normal limit, as also used in the current trial [13,17,18]. However, these current established diagnostic criteria have significant limitations in the setting of infarct size measurement. Indeed, Vasile et al have shown that the frequency of aborted MI is 0% when using troponin at the 99th percentile cutoff in STEMI patients treated with primary PCI [24]. Moreover, in a recent trial we demonstrated that approximately half of the patients with fulfilled aborted MI criteria had detectable myocardial necrosis using late enhancement MRI [14]. As in some patients troponin levels are elevated despite no detectable myocardial injury [25,26] we proposed cardiac MRI as diagnostic measure for a true aborted MI with total obviation of necrosis. MRI has the unique advantage of visualization of even microinfarctions at very high spatial resolution and might therefore be more suitable in diagnosing true aborted MIs as compared to previous definitions (including troponin) [14]. Using MRI to detect true aborted MI resulted in the discovery that the proportion of really aborted MIs was 4% and not 12% as detected with the clinical criteria. Table 6 Significant predictors of true aborted MI in univariable and multivariable logistic regression analysis. Predictors
4.2. Aborted myocardial infarction and intracoronary abciximab administration There is no current standardized definition of aborted MI. Thus, various investigators have used different definitions for aborted MI [17,18,20–24]. Most commonly, aborted MI is defined by major (≥50%) ST-segment resolution and a lack of subsequent cardiac
Univariable analysis
Multivariable analysis
OR
OR
95% CI
P
95% CI
P
Abciximab intracoronary 3.54 1.22–10.20 0.02 3.83 1.19–12.34 0.02 group Symptom-onset-to0.98 0.97–1.00 0.05 0.99 0.98–1.00 0.04 reperfusion time TIMI flow before PCI 2.26 1.53–3.32 b0.001 2.34 1.54–3.54 b0.001 As in Table 5.
I. Eitel et al. / International Journal of Cardiology 153 (2011) 21–25
True aborted MIs without detectable myocardial necrosis in late enhancement MRI were exclusively observed in the abciximab IC group and IC application of abciximab was an independent predictor of true aborted MI. Mechanisms, by which IC abciximab application can influence and enhance aborted MI, might be explained by the high local doses, which may facilitate the diffusion of the antibody to platelets inside the flow-limiting thrombus, thus resulting in improved dissolution of thrombi and microemboli at the ruptured plaque and further downstream in the microcirculation. Another potential mechanism of high local concentrations might be related to the dose-dependent anti-inflammatory properties of abciximab [8]. By modulating inflammatory cell response due to non glycoprotein IIb/IIIa effects in combination with enhanced inhibition of the glycoprotein IIb/IIIa receptor, IC abciximab may favourably influence reperfusion injury, resulting in a further reduction of infarct size and no-reflow as compared to the standard IV approach. Concentrations that produced complete platelet disaggregation also induced partial displacement of platelet-bound fibrinogen, which might also play a role in the clinical setting [19]. Other factors might also influence the occurrence of aborted MI. In line with previous studies, time from symptom onset to reperfusion (especially in true aborted MI patients) and TIMI-flow before PCI were major determinants of aborted MI [13,14]. Finally, our trial unequivocally confirms the excellent prognostic value of an aborted MI. At 6-month follow-up no MACE was observed in the aborted MI group. These findings are in general agreement with previous studies reporting favourable outcome data in patients with aborted MI after fibrinolysis [17,18,23]. The confirmed prognostic relevance of aborted MI makes it a meaningful end point in future MI studies, intended to test new reperfusion therapy efficacy. 4.3. Limitations This is a retrospective analysis of data collected prospectively. Although all angiographic, ECG, and MRI measurements were blinded, patients and interventionalists were aware of the group assignment. Thus, a potential investigator bias cannot be ruled out entirely. The occurrence of previous angina was not evaluated which may allow the assessment of potential preconditioning effects. However, angina onset and recurrence is generally subjective and difficult to assess. 4.4. Conclusions IC bolus application of abciximab in primary PCI results in a higher incidence of aborted MI with subsequent improved clinical outcome at 6-month follow-up. Larger randomized multicenter trials using rigorous clinical end points such as death and MI are required to further substantiate the clinical benefits of this mode of drug delivery. Acknowledgement The authors of this manuscript have certified that they comply with the principles of ethical publishing in the International Journal of Cardiology [27]. References [1] Montalescot G, Barragan P, Wittenberg O, et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001;344:1895–903. [2] Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002;346: 957–66.
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