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Intracoronary versus intravenous abciximab administration in patients with ST-elevation myocardial infarction undergoing thrombus aspiration during primary percutaneous coronary intervention—Effects on soluble CD40 ligand concentrations
Atherosclerosis 206 (2009) 523–527
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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Intracoronary versus intravenous abciximab administration in patients with ST-elevation myocardial infarction undergoing thrombus aspiration during primary percutaneous coronary intervention—Effects on soluble CD40 ligand concentrations Alberto Dominguez-Rodriguez a,∗ , Pedro Abreu-Gonzalez b , Pablo Avanzas c , Francisco Bosa-Ojeda a , Sima Samimi-Fard a , Francisco Marrero-Rodriguez a , Juan Carlos Kaski d a
Department of Cardiology, University Hospital of Canarias, Tenerife, Spain Department of Physiology, University of La Laguna, School of Medicine, Tenerife, Spain c Hospital Central Asturias, Department of Cardiology, Asturias, Spain d Cardiovascular Biology Research Centre, Division of Cardiac and Vascular Sciences, St. George’s University of London, United Kingdom b
a r t i c l e
i n f o
Article history: Received 14 January 2009 Received in revised form 10 February 2009 Accepted 10 March 2009 Available online 25 March 2009 Keywords: Soluble CD40 ligand Abciximab Intracoronary ST-elevation myocardial infarction Percutaneous coronary intervention
a b s t r a c t Introduction: CD40 ligand has been suggested to play a pathogenic role in atherogenesis and coronary artery disease progression. Clinical studies suggest that intravenous (IV) abciximab administration attenuates the acute inflammatory response associated with percutaneous coronary intervention (PCI). The anti-inflammatory effects of intracoronary (IC) versus IV administration of abciximab have not been systematically investigated. We assessed changes in soluble CD40 ligand (sCD40L) concentrations in response to IC versus IV abciximab in patients with ST-elevation myocardial infarction (STEMI) undergoing thrombus-aspirating device during primary PCI. Methods: Patients were randomized to receive IC (n = 25) or IV (n = 25) bolus abciximab followed in every case by a 12-h IV abciximab infusion. sCD40L was measured immediately before the administration of abciximab (baseline) and 60 min post bolus administration. Results: Clinical baseline and angiographic characteristics were similar in both patient groups. Similarly, there were no significant differences in baseline serum sCD40L levels in the IC group compared to IV group (116.6 ± 42.13 pg/mL vs 124.9 ± 43.04 pg/mL, P = 0.49). At 60 min post PCI, however, sCD40L levels decreased by 23% (P < 0.001) in the IC group and by 11% (P < 0.001) in the IV group. sCD40L levels 60 min post PCI were significantly reduced, particularly in the IC group compared to the IV group (73.04 ± 12.21 pg/mL vs 99.92 ± 25.89 pg/mL, P < 0.001). Conclusion: In STEMI patients undergoing primary PCI, IC bolus administration of abciximab was associated with a larger reduction in sCD40L levels compared to standard IV bolus. Whether this more powerful anti-inflammatory effect of IC abciximab translates into improved clinical outcomes deserves investigation. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction ST-elevation myocardial infarction (STEMI) is caused by the rupture or erosion of atherosclerotic coronary plaques, resulting in intralumenal thrombosis with partial or complete vessel occlusion [1]. Primary percutaneous coronary intervention (PCI) is the preferred treatment for STEMI and it is effective in opening the
∗ Corresponding author at: Coronary Care Unit, University Hospital of Canarias, Ofra s/n La Cuesta E-38320, Tenerife, Spain. Tel.: +34 922 679030; fax: +34 922 362716. E-mail address: [email protected] (A. Dominguez-Rodriguez). 0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.03.011
infarct-related artery [2]. However, microvascular obstruction with diminished myocardial perfusion occurs in a large proportion of patients with a patent epicardial vessel after primary PCI. A recent randomized, controlled trial of thrombectomy in acute myocardial infarction by Svilaas et al. [3] showed improvement in markers of myocardial reperfusion after thrombectomy. Meta-analyses of previous studies have reached similar conclusions [4,5]. Abciximab administration is an established therapy to improve coronary microcirculation function and it also reduces major cardiac adverse events [6,7]. The intravenous (IV) administration of abciximab in patients with acute coronary syndrome undergoing PCI has become standard clinical practice based on results of several randomized trials showing a consistent improvement of post-intervention
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outcome [8]. Moreover, data from previous studies demonstrated that intracoronary (IC) abciximab bolus administration results in the dissolution of thrombi and reduced microembolization with subsequent improvement of the myocardial microcirculation [9–12]. Platelets are a central player in the thrombotic and inflammatory processes characteristic of coronary atherosclerosis [13]. In addition to forming circulating aggregates with leukocytes, platelets regulate inflammation by secreting a variety of inflammatory modulators, including CD40 ligand (CD40L). CD40L is an essential component in the pathophysiology of atherosclerosis and platelets are the predominant source of circulating soluble CD40L (sCD40L) [13]. Furthermore, platelet surface CD40L induces a thrombo-inflammatory reaction in endothelial cells and activated platelets also release large amounts of sCD40L over a period of minutes to hours [14]. Abciximab has been reported to inhibit the release of sCD40L in vitro [15,16]. Furman et al. reported that IV glycoprotein IIb/IIIa antagonists reduce circulating sCD40L in acute coronary syndrome patients undergoing PCI [17]. The aim of this study was to compare the effects of IC versus IV abciximab bolus administration on sCD40L levels in patients with STEMI undergoing thrombus aspiration during primary PCI. 2. Materials and methods 2.1. Patients From May 2008 to September 2008, 50 consecutive patients with STEMI undergoing thrombus aspiration during primary PCI were randomly assigned to receive IC or IV bolus abciximab (0.25 mg/kg body weight). After bolus administration of abciximab all patients received a 12-h abciximab IV infusion at a dose of 0.125 g/(kg min) (maximum, 18 g/(kg min)). Inclusion criteria were the presence of typical angina symptoms <6 h, ST-segment elevation of at least 0.1 mV in ≥2 extremity leads or at least 0.2 mV in ≥2 precordial leads. Assessment was carried out from 08.00 AM to 3 PM to avoid diurnal variation of the sCD40 levels, as shown recently by our group [18]. Exclusion criteria were prior fibrinolysis, known allergy to heparin, aspirin or abciximab, active severe bleeding, pregnancy, history of major surgery <4 weeks, presence of any active infection, autoimmune diseases, collagen tissue diseases, malignancies, illicit drug consumption, ongoing radiotherapy, presence of acute or chronic renal or liver diseases, immunosuppressive treatment, and cardiogenic shock. The study was approved by the local ethics committee, and all patients gave written informed consent.
of the thrombolysis in myocardial infarction (TIMI) flow [19]. Visual assessments were performed offline in the angiographic core laboratory by two blinded observers (F.B.-O. and F.M.R.). We defined angiographic no-reflow as a final TIMI flow of ≤2 or final TIMI flow of 3 with a myocardial blush grade <2 [20]. Pharmacological treatment before PCI included the administration of aspirin (a loading dose of 300 mg) and clopidogrel (a loading dose of 300 mg). All patients received an initial weightadjusted intravenous bolus of heparin, and further boluses were administered with the aim of obtaining an activated clotting time of 250–300 s. Standard therapies after PCI included aspirin, clopidogrel, beta-blockers, lipid-lowering agents, and angiotensinconverting-enzyme inhibitors or angiotensin-II-receptor blockers, according to current guidelines [2]. 2.3. Analytical methods Blood samples were drawn from the arterial sheath immediately before initiation of PCI and administration of abciximab (baseline) and 60 min post PCI. The blood sample was allowed for the formation of clot at room temperature during 15 min. The blood was centrifuged at 3000 rpm for 10 min and the serum aliquoted and frozen at −70 ◦ C. Serum sCD40L concentrations were measured using a high sensitivity, quantitative sandwich enzyme immunoassay (Bender MedSystems GMBH, Vienna, Austria). According to the package insert, the Bender ELISA is suitable for measuring sCD40L in serum and plasma. The analytical range of assay is (8–500 pg/ml). Each serum sample was diluted 1:2 with sample diluent into each well. In this assay, the lowest detection limit of sCD40L was 7.92 pg/ml. The coefficients of variation were 5.5% and 7.0% for intraand inter-assay, respectively. All tests were done in duplicate. Serum levels of cardiac enzymes (CK and CK-MB fraction) and troponin I were measured every 8 h during the first day and every 24 h in the following 3 days according to hospital protocol. 2.4. ST-segment resolution For ECG interpretation, blinded observer (A.D.-R.) measured the sum of ST-segment elevation 20 ms after the end of the QRS complex in the ECG before and that obtained early after PCI after transfer to the intensive care unit. ST-segment resolution was calculated as the sum of ST elevation before minus the sum of ST elevation after PCI divided by the sum of ST elevation before PCI. ST-segment resolution was expressed as percentage change [21]. 2.5. Statistical analyses
2.2. Study protocol Right femoral approach was used with all patients. The first procedural step was the passing of a floppy, steerable guidewire through the target lesion. Then, a 6-French Export Aspiration Catheter (Medtronic; crossing profile, 0.068 in) was advanced into the target coronary segment during continuous aspiration. In the IC group, abciximab bolus was administrated after thrombectomy to allow high abciximab concentration in the target region. The bolus was administered directly within 1 min through the PCI guiding catheter. In the IV group, abciximab bolus was administrated after thrombus aspiration. In all patients, after restoration of antegrade flow, IC nitrates were given to ensure maximal epicardial vasodilation, in order to determine the size and length of the stent and to facilitate stent placement. Coronary angiography of the target lesion was performed before and after PCI in the same projections. Angiographic projections used were those that allowed optimal evaluation
Results for normally distributed continuous variables are expressed as the mean value ± standard deviation (S.D.) and categorical variables as percentages. Continuous variables were tested for normal distribution with the Kolmogorov–Smirnov test and for homogeneity of variances with Levene’s test. Differences were initially evaluated by one-way analysis of variance (ANOVA) and the differences between treatment groups were determined using the Tukey’s post hoc test. Categorical data were analyzed using the Fisher’s exact test. Differences were considered to be statistically significant if the null hypothesis could be rejected with >95% confidence. The SPSS 14.0 statistical software package (SPSS Inc., Chicago, IL, USA) was used for all calculations. 3. Results Of the 50 patients enrolled, 25 were randomly assigned to IC abciximab plus 12-h infusion (IC Group) and 25 to IV abciximab
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plus 12-h infusion (IV Group) as adjuvant therapy. The characteristics of the study population are summarized in Table 1. Both groups were treated with thrombus aspiration. In the IC Group, retrieval of atherothrombotic material was effective in 23/25 patients (92%) and in the IV Group 21/25 patients (84%). In the IC Group, aspiration and direct stent implantation were performed in 11 patients (44%), and balloon dilation was performed before stent implantation in 14 patients (56%). In the IV Group, aspiration and direct stent implantation were performed in 10 patients (40%), and balloon dilation was performed before stent implantation in 15 patients (60%). No-reflow phenomenon was present after the procedure in 12% of patients in Group IC and 32% of those in Group IV (P = 0.08). The treatment of no-reflow in both groups was carried with nitroprusside. There were no adverse events during IC abciximab bolus administration. Discontinuation of abciximab infusion was necessary in two (groin bleeding) IC Group patients and in three (n = 2 groin bleeding, n = 1 epistaxis) IV Group patients (P = 0.94). During hospital stay, none of the patients died or had re-infarction. Reperfusion times were similar in both groups with a median time from symptom onset to PCI of 107 min (interquartile range, 64–297 min) in the IC Group and 117 min (interquartile range, 64–314 min) in the IV Group (P = 0.55). The door-to-balloon time was 21 min (IC Group, interquartile range, 12–30 min) versus 19 min (IV Group, interquartile range, 11–30 min; P = 0.87). The median time from treatment to the post-procedural ECG was 34 min (interquartile range, 15–53 min) in the IC Group and 33 min (interquartile range, 15–51) in the IV Group (P = 0.45). In the IC Group, there was a trend towards an improvement in the ST-segment resolution, measured as a continuous variable [79.8% (interquartile range, 64.7–100%)]
Table 1 Clinical, angiographic and procedural characteristics of the study population. IC Group (n = 25)
IV Group (n = 25)
P
Age (years) Male sex, n (%)
66 ± 19 18 (72)
70 ± 15 20 (80)
0.41 0.68
Risk factors, n (%) Smoke Hypertension Hypercholesterolemia Diabetes mellitus Positive family history
22 (88) 14 (56) 18 (72) 13 (52) 2 (8)
20 (80) 13 (52) 21 (84) 15 (60) 3 (12)
0.90 0.78 0.60 0.85 0.56
Body-mass index
29 ± 4
32 ± 8
0.10
Diseased vessels, n (%) 1 2 3
13 (52) 9 (36) 3 (12)
15 (60) 8 (32) 2 (8)
Infarct-related vessel, n (%) Left descending artery Left circumflex artery Right coronary artery
14 (56) 6 (24) 5 (20)
16 (64) 4 (16) 5 (20)
TIMI flow grade before PCI, n (%) 0 1 2 3
21 (84) 4 (16) 0 0
20 (80) 5 (20) 0 0
TIMI flow grade after PCI, n (%) 0 1 2 3
0 0 3 (12) 22 (88)
0 3 (12) 5 (20) 17 (68)
Thrombus score 4–5, n (%) Stent length (mm) Stent diameter (mm)
14 (56) 19.5 ± 9.4 3.0 ± 0.9
17 (68) 19.8 ± 9.1 3.1 ± 1.1
0.84
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Fig. 1. Soluble CD40 ligand serum levels in patients with ST-elevation myocardial infarction (STEMI) treated with thrombus aspiration during primary percutaneous coronary intervention (PCI), with abciximab bolus intracoronary (IC) compared to intravenous (IV). General ANOVA P < 0.0001; * P < 0.05 versus post-dilatation (PD). In this box plot diagram, the horizontal line, within each box represents the median; the limits of each box, interquartile range (lower and upper); the whiskers, the minimum and maximum value for each respective group. In each lower box, the number represents the mean ± S.D. of each group.
compared to the IV Group [72% (interquartile range, 43.2–85.5%), P = 0.09]. Post-treatment mean peak of troponin I showed a statistically significant reduction in the IC Group compared with IV Group (70 ± 32 ng/mL vs 95 ± 27 ng/mL, P = 0.004). No significant differences were detected in terms of mortality, re-infarction, need for urgent or any revascularization at 30-day follow-up. There were no significant differences in the serum levels of sCD40L in the IC Group compared with IV Group at baseline (116.6 ± 42.13 pg/mL vs 124.9 ± 43.04 pg/mL, P = 0.49). At 60 min post PCI, sCD40L decreased by 23% (P < 0.001) in the IC Group and by 11% (P < 0.001) in the IV Group. Remarkable, levels of sCD40L at 60 min post PCI showed a statistically significant reduction that was higher in the IC Group compared with IV Group (73.04 ± 12.21 pg/mL vs 99.92 ± 25.89 pg/mL, P < 0.001) (Fig. 1). Interestingly, in the subgroup of patients with diabetes mellitus, there were no significant differences in the serum levels of sCD40L in both groups at baseline (IC Group, 106.3 ± 46.17 pg/mL vs IV Group, 126.9 ± 42.25 pg/mL, P = 0.23). However, levels of sCD40L at 60 min post PCI showed a borderline significant reduction that was higher in the IC Group compared to IV Group (71.38 ± 14.51 pg/mL vs 87.70 ± 26.13 pg/mL, P = 0.05). 4. Discussion
0.78
0.92
0.08
0.75 0.90 1
Values are mean ± S.D.; TIMI, thrombolysis in myocardial infarction; PCI, percutaneous coronary intervention.
This study provides evidence for the first time that in STEMI patients undergoing thrombus aspiration during primary PCI, IC administration of a systemic-dose bolus of abciximab is associated with a higher reduction of the platelet-dependent circulating inflammatory marker sCD40L compared to IV administration. Mechanical removal of a thrombus before PCI reduces the existing source of embolization but it does not necessarily address the problem of platelet aggregates that are generated during and after PCI. These can be abolished with the use of platelet inhibitors [22]. sCD40L is integral to the development and progression of atherosclerosis and to the stabilization of platelet-rich thrombi. sCD40L binds to platelets via ␣IIb 3 -dependent mechanism and results in platelet activation [23,24]. The IC administration of abciximab may facilitate the dissolution of existing platelet-rich thrombus and dispersion of newly formed platelet aggregates [25–27], enhance the inhibition of the vitronectin receptors in the
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endothelial cells of the culprit vessel [28], and inhibit the proinflammatory [29,30] effects of sCD40L. All these mechanisms may concur to induce the observed acute reduction of sCD40L levels in IC Group compared to IV Group. By protocol, in our study, the bolus administration of abciximab in both groups was carried out after the aspiration of atherothrombotic material. The larger effects on circulating sCD40L concentrations in the IC group compared to the IV group might be explained by the higher local levels of abciximab achieved during IC administration, 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. These considerations are supported by experimental data showing a dose-dependent platelet disaggregation with abciximab. Concentrations that produced complete platelet disaggregation also induced partial displacement of platelet-bound fibrinogen, which might play a role in this clinical setting [27]. In the IV Group, both the anti-inflammatory and anti-thrombotic effects of abciximab might be limited compared to the IC administration [25]. Interestingly, our findings are in agreement with the previous observation of a more pronounced clinical benefit of IC abciximab compared to IV administration in patients with acute coronary syndrome [9,10,12,31,32]. Recently, a randomized, controlled trial, demonstrated that in STEMI patients with an occluded infarctrelated artery treated with primary PCI, IC bolus administration of abciximab was superior to standard IV treatment with respect to infarct size, extent of microvascular obstruction, and myocardial perfusion [33]. Likewise, in a small randomized clinical trial of 45 patients, there was a significantly higher degree of myocardial salvage with subsequent lower infarct size as assessed by serial scintigraphy [9]. In our study, the IC Group exhibited lower mean levels of post-procedural cardiac enzymes. Furthermore, there was a trend towards improved myocardial perfusion as assessed by ST-segment resolution. This agrees with, and extends, previous findings by others authors, who observed a more pronounced clinical benefit of IC abciximab administration in relation to infarct size [9,10,12,31,32]. A possible cause of the lower myocardial damage associated with IC administration could be that the greater and more rapid platelet inhibition would mean that the phenomenon of reperfusion would be less damaging to the myocardium [34]. This aspect of reduced platelet aggregation along with less distal microembolization and local anti-inflammatory effect [35] could, in our opinion, represent the benefits of this route of administration. This study has limitations that may affect the interpretation of the results. This is a pilot small randomized and open-label trial. We determined sCD40L concentrations in peripheral venous blood samples, rather than in blood from the coronary sinus. Thus, we have assumed that serum sCD40L concentrations reflect the inflammatory process that occurs in area of the coronary artery. On the other hand, we did not measure other inflammatory markers. Likewise, the limited number of patients in our study could account the absence of significant differences in the incidence of events. The confirmation of the results with respect to the clarification of the long-term effects on clinical outcome requires a larger trial. Although all angiographic and ECG measurements were blinded, patients and interventional cardiologists were aware of the group assignment. Thus, a potential investigator bias cannot be ruled out entirely. On the other hand, the findings of this study are limited to patients presenting within 6 h of symptom onset and therefore cannot be extended to patients treated 6–12 h after symptom onset. Moreover, ST-segment resolution was the unique marker of myocardial perfusion examined in the present study. Other imaging modalities of microcirculatory function, such as contrast echocardiography, or invasive measures of coronary flow reserve may provide further insights into microcirculation reperfusion. In our
study, the prevalence of no-reflow seems higher than those previously reported [36], however, comparable data have been shown in studies that utilized a definition of no-reflow similar to ours [20]. In conclusion, IC bolus administration of abciximab is superior to standard IV treatment with respect to acute reduction in sCD40L levels in thrombus aspiration during primary PCI. Therefore, it is possible that the combined use of aspiration and IC abciximab in patients with STEMI will have a synergistic effect. Prospective, randomized trials are needed to further assess this positive effect. References [1] Davies MJ, Thomas A. Thrombosis and acute coronary–artery lesions in sudden cardiac ischemia death. N Engl J Med 1984;310:1137–40. [2] Silber S, Albertsson P, Avilés FF, et al. Task force for percutaneous coronary interventions of the European Society of Cardiology. Guidelines for percutaneous coronary interventions. Eur Heart J 2005;26:804–47. 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Intracoronary versus intravenous abciximab administration in patients with ST-elevation myocardial infarction undergoing thrombus aspiration during primary percutaneous coronary intervention—Effects on soluble CD40 ligand concentrations Alberto Dominguez-Rodriguez a,∗ , Pedro Abreu-Gonzalez b , Pablo Avanzas c , Francisco Bosa-Ojeda a , Sima Samimi-Fard a , Francisco Marrero-Rodriguez a , Juan Carlos Kaski d a
Department of Cardiology, University Hospital of Canarias, Tenerife, Spain Department of Physiology, University of La Laguna, School of Medicine, Tenerife, Spain c Hospital Central Asturias, Department of Cardiology, Asturias, Spain d Cardiovascular Biology Research Centre, Division of Cardiac and Vascular Sciences, St. George’s University of London, United Kingdom b
a r t i c l e
i n f o
Article history: Received 14 January 2009 Received in revised form 10 February 2009 Accepted 10 March 2009 Available online 25 March 2009 Keywords: Soluble CD40 ligand Abciximab Intracoronary ST-elevation myocardial infarction Percutaneous coronary intervention
a b s t r a c t Introduction: CD40 ligand has been suggested to play a pathogenic role in atherogenesis and coronary artery disease progression. Clinical studies suggest that intravenous (IV) abciximab administration attenuates the acute inflammatory response associated with percutaneous coronary intervention (PCI). The anti-inflammatory effects of intracoronary (IC) versus IV administration of abciximab have not been systematically investigated. We assessed changes in soluble CD40 ligand (sCD40L) concentrations in response to IC versus IV abciximab in patients with ST-elevation myocardial infarction (STEMI) undergoing thrombus-aspirating device during primary PCI. Methods: Patients were randomized to receive IC (n = 25) or IV (n = 25) bolus abciximab followed in every case by a 12-h IV abciximab infusion. sCD40L was measured immediately before the administration of abciximab (baseline) and 60 min post bolus administration. Results: Clinical baseline and angiographic characteristics were similar in both patient groups. Similarly, there were no significant differences in baseline serum sCD40L levels in the IC group compared to IV group (116.6 ± 42.13 pg/mL vs 124.9 ± 43.04 pg/mL, P = 0.49). At 60 min post PCI, however, sCD40L levels decreased by 23% (P < 0.001) in the IC group and by 11% (P < 0.001) in the IV group. sCD40L levels 60 min post PCI were significantly reduced, particularly in the IC group compared to the IV group (73.04 ± 12.21 pg/mL vs 99.92 ± 25.89 pg/mL, P < 0.001). Conclusion: In STEMI patients undergoing primary PCI, IC bolus administration of abciximab was associated with a larger reduction in sCD40L levels compared to standard IV bolus. Whether this more powerful anti-inflammatory effect of IC abciximab translates into improved clinical outcomes deserves investigation. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction ST-elevation myocardial infarction (STEMI) is caused by the rupture or erosion of atherosclerotic coronary plaques, resulting in intralumenal thrombosis with partial or complete vessel occlusion [1]. Primary percutaneous coronary intervention (PCI) is the preferred treatment for STEMI and it is effective in opening the
∗ Corresponding author at: Coronary Care Unit, University Hospital of Canarias, Ofra s/n La Cuesta E-38320, Tenerife, Spain. Tel.: +34 922 679030; fax: +34 922 362716. E-mail address: [email protected] (A. Dominguez-Rodriguez). 0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.03.011
infarct-related artery [2]. However, microvascular obstruction with diminished myocardial perfusion occurs in a large proportion of patients with a patent epicardial vessel after primary PCI. A recent randomized, controlled trial of thrombectomy in acute myocardial infarction by Svilaas et al. [3] showed improvement in markers of myocardial reperfusion after thrombectomy. Meta-analyses of previous studies have reached similar conclusions [4,5]. Abciximab administration is an established therapy to improve coronary microcirculation function and it also reduces major cardiac adverse events [6,7]. The intravenous (IV) administration of abciximab in patients with acute coronary syndrome undergoing PCI has become standard clinical practice based on results of several randomized trials showing a consistent improvement of post-intervention
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outcome [8]. Moreover, data from previous studies demonstrated that intracoronary (IC) abciximab bolus administration results in the dissolution of thrombi and reduced microembolization with subsequent improvement of the myocardial microcirculation [9–12]. Platelets are a central player in the thrombotic and inflammatory processes characteristic of coronary atherosclerosis [13]. In addition to forming circulating aggregates with leukocytes, platelets regulate inflammation by secreting a variety of inflammatory modulators, including CD40 ligand (CD40L). CD40L is an essential component in the pathophysiology of atherosclerosis and platelets are the predominant source of circulating soluble CD40L (sCD40L) [13]. Furthermore, platelet surface CD40L induces a thrombo-inflammatory reaction in endothelial cells and activated platelets also release large amounts of sCD40L over a period of minutes to hours [14]. Abciximab has been reported to inhibit the release of sCD40L in vitro [15,16]. Furman et al. reported that IV glycoprotein IIb/IIIa antagonists reduce circulating sCD40L in acute coronary syndrome patients undergoing PCI [17]. The aim of this study was to compare the effects of IC versus IV abciximab bolus administration on sCD40L levels in patients with STEMI undergoing thrombus aspiration during primary PCI. 2. Materials and methods 2.1. Patients From May 2008 to September 2008, 50 consecutive patients with STEMI undergoing thrombus aspiration during primary PCI were randomly assigned to receive IC or IV bolus abciximab (0.25 mg/kg body weight). After bolus administration of abciximab all patients received a 12-h abciximab IV infusion at a dose of 0.125 g/(kg min) (maximum, 18 g/(kg min)). Inclusion criteria were the presence of typical angina symptoms <6 h, ST-segment elevation of at least 0.1 mV in ≥2 extremity leads or at least 0.2 mV in ≥2 precordial leads. Assessment was carried out from 08.00 AM to 3 PM to avoid diurnal variation of the sCD40 levels, as shown recently by our group [18]. Exclusion criteria were prior fibrinolysis, known allergy to heparin, aspirin or abciximab, active severe bleeding, pregnancy, history of major surgery <4 weeks, presence of any active infection, autoimmune diseases, collagen tissue diseases, malignancies, illicit drug consumption, ongoing radiotherapy, presence of acute or chronic renal or liver diseases, immunosuppressive treatment, and cardiogenic shock. The study was approved by the local ethics committee, and all patients gave written informed consent.
of the thrombolysis in myocardial infarction (TIMI) flow [19]. Visual assessments were performed offline in the angiographic core laboratory by two blinded observers (F.B.-O. and F.M.R.). We defined angiographic no-reflow as a final TIMI flow of ≤2 or final TIMI flow of 3 with a myocardial blush grade <2 [20]. Pharmacological treatment before PCI included the administration of aspirin (a loading dose of 300 mg) and clopidogrel (a loading dose of 300 mg). All patients received an initial weightadjusted intravenous bolus of heparin, and further boluses were administered with the aim of obtaining an activated clotting time of 250–300 s. Standard therapies after PCI included aspirin, clopidogrel, beta-blockers, lipid-lowering agents, and angiotensinconverting-enzyme inhibitors or angiotensin-II-receptor blockers, according to current guidelines [2]. 2.3. Analytical methods Blood samples were drawn from the arterial sheath immediately before initiation of PCI and administration of abciximab (baseline) and 60 min post PCI. The blood sample was allowed for the formation of clot at room temperature during 15 min. The blood was centrifuged at 3000 rpm for 10 min and the serum aliquoted and frozen at −70 ◦ C. Serum sCD40L concentrations were measured using a high sensitivity, quantitative sandwich enzyme immunoassay (Bender MedSystems GMBH, Vienna, Austria). According to the package insert, the Bender ELISA is suitable for measuring sCD40L in serum and plasma. The analytical range of assay is (8–500 pg/ml). Each serum sample was diluted 1:2 with sample diluent into each well. In this assay, the lowest detection limit of sCD40L was 7.92 pg/ml. The coefficients of variation were 5.5% and 7.0% for intraand inter-assay, respectively. All tests were done in duplicate. Serum levels of cardiac enzymes (CK and CK-MB fraction) and troponin I were measured every 8 h during the first day and every 24 h in the following 3 days according to hospital protocol. 2.4. ST-segment resolution For ECG interpretation, blinded observer (A.D.-R.) measured the sum of ST-segment elevation 20 ms after the end of the QRS complex in the ECG before and that obtained early after PCI after transfer to the intensive care unit. ST-segment resolution was calculated as the sum of ST elevation before minus the sum of ST elevation after PCI divided by the sum of ST elevation before PCI. ST-segment resolution was expressed as percentage change [21]. 2.5. Statistical analyses
2.2. Study protocol Right femoral approach was used with all patients. The first procedural step was the passing of a floppy, steerable guidewire through the target lesion. Then, a 6-French Export Aspiration Catheter (Medtronic; crossing profile, 0.068 in) was advanced into the target coronary segment during continuous aspiration. In the IC group, abciximab bolus was administrated after thrombectomy to allow high abciximab concentration in the target region. The bolus was administered directly within 1 min through the PCI guiding catheter. In the IV group, abciximab bolus was administrated after thrombus aspiration. In all patients, after restoration of antegrade flow, IC nitrates were given to ensure maximal epicardial vasodilation, in order to determine the size and length of the stent and to facilitate stent placement. Coronary angiography of the target lesion was performed before and after PCI in the same projections. Angiographic projections used were those that allowed optimal evaluation
Results for normally distributed continuous variables are expressed as the mean value ± standard deviation (S.D.) and categorical variables as percentages. Continuous variables were tested for normal distribution with the Kolmogorov–Smirnov test and for homogeneity of variances with Levene’s test. Differences were initially evaluated by one-way analysis of variance (ANOVA) and the differences between treatment groups were determined using the Tukey’s post hoc test. Categorical data were analyzed using the Fisher’s exact test. Differences were considered to be statistically significant if the null hypothesis could be rejected with >95% confidence. The SPSS 14.0 statistical software package (SPSS Inc., Chicago, IL, USA) was used for all calculations. 3. Results Of the 50 patients enrolled, 25 were randomly assigned to IC abciximab plus 12-h infusion (IC Group) and 25 to IV abciximab
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plus 12-h infusion (IV Group) as adjuvant therapy. The characteristics of the study population are summarized in Table 1. Both groups were treated with thrombus aspiration. In the IC Group, retrieval of atherothrombotic material was effective in 23/25 patients (92%) and in the IV Group 21/25 patients (84%). In the IC Group, aspiration and direct stent implantation were performed in 11 patients (44%), and balloon dilation was performed before stent implantation in 14 patients (56%). In the IV Group, aspiration and direct stent implantation were performed in 10 patients (40%), and balloon dilation was performed before stent implantation in 15 patients (60%). No-reflow phenomenon was present after the procedure in 12% of patients in Group IC and 32% of those in Group IV (P = 0.08). The treatment of no-reflow in both groups was carried with nitroprusside. There were no adverse events during IC abciximab bolus administration. Discontinuation of abciximab infusion was necessary in two (groin bleeding) IC Group patients and in three (n = 2 groin bleeding, n = 1 epistaxis) IV Group patients (P = 0.94). During hospital stay, none of the patients died or had re-infarction. Reperfusion times were similar in both groups with a median time from symptom onset to PCI of 107 min (interquartile range, 64–297 min) in the IC Group and 117 min (interquartile range, 64–314 min) in the IV Group (P = 0.55). The door-to-balloon time was 21 min (IC Group, interquartile range, 12–30 min) versus 19 min (IV Group, interquartile range, 11–30 min; P = 0.87). The median time from treatment to the post-procedural ECG was 34 min (interquartile range, 15–53 min) in the IC Group and 33 min (interquartile range, 15–51) in the IV Group (P = 0.45). In the IC Group, there was a trend towards an improvement in the ST-segment resolution, measured as a continuous variable [79.8% (interquartile range, 64.7–100%)]
Table 1 Clinical, angiographic and procedural characteristics of the study population. IC Group (n = 25)
IV Group (n = 25)
P
Age (years) Male sex, n (%)
66 ± 19 18 (72)
70 ± 15 20 (80)
0.41 0.68
Risk factors, n (%) Smoke Hypertension Hypercholesterolemia Diabetes mellitus Positive family history
22 (88) 14 (56) 18 (72) 13 (52) 2 (8)
20 (80) 13 (52) 21 (84) 15 (60) 3 (12)
0.90 0.78 0.60 0.85 0.56
Body-mass index
29 ± 4
32 ± 8
0.10
Diseased vessels, n (%) 1 2 3
13 (52) 9 (36) 3 (12)
15 (60) 8 (32) 2 (8)
Infarct-related vessel, n (%) Left descending artery Left circumflex artery Right coronary artery
14 (56) 6 (24) 5 (20)
16 (64) 4 (16) 5 (20)
TIMI flow grade before PCI, n (%) 0 1 2 3
21 (84) 4 (16) 0 0
20 (80) 5 (20) 0 0
TIMI flow grade after PCI, n (%) 0 1 2 3
0 0 3 (12) 22 (88)
0 3 (12) 5 (20) 17 (68)
Thrombus score 4–5, n (%) Stent length (mm) Stent diameter (mm)
14 (56) 19.5 ± 9.4 3.0 ± 0.9
17 (68) 19.8 ± 9.1 3.1 ± 1.1
0.84
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Fig. 1. Soluble CD40 ligand serum levels in patients with ST-elevation myocardial infarction (STEMI) treated with thrombus aspiration during primary percutaneous coronary intervention (PCI), with abciximab bolus intracoronary (IC) compared to intravenous (IV). General ANOVA P < 0.0001; * P < 0.05 versus post-dilatation (PD). In this box plot diagram, the horizontal line, within each box represents the median; the limits of each box, interquartile range (lower and upper); the whiskers, the minimum and maximum value for each respective group. In each lower box, the number represents the mean ± S.D. of each group.
compared to the IV Group [72% (interquartile range, 43.2–85.5%), P = 0.09]. Post-treatment mean peak of troponin I showed a statistically significant reduction in the IC Group compared with IV Group (70 ± 32 ng/mL vs 95 ± 27 ng/mL, P = 0.004). No significant differences were detected in terms of mortality, re-infarction, need for urgent or any revascularization at 30-day follow-up. There were no significant differences in the serum levels of sCD40L in the IC Group compared with IV Group at baseline (116.6 ± 42.13 pg/mL vs 124.9 ± 43.04 pg/mL, P = 0.49). At 60 min post PCI, sCD40L decreased by 23% (P < 0.001) in the IC Group and by 11% (P < 0.001) in the IV Group. Remarkable, levels of sCD40L at 60 min post PCI showed a statistically significant reduction that was higher in the IC Group compared with IV Group (73.04 ± 12.21 pg/mL vs 99.92 ± 25.89 pg/mL, P < 0.001) (Fig. 1). Interestingly, in the subgroup of patients with diabetes mellitus, there were no significant differences in the serum levels of sCD40L in both groups at baseline (IC Group, 106.3 ± 46.17 pg/mL vs IV Group, 126.9 ± 42.25 pg/mL, P = 0.23). However, levels of sCD40L at 60 min post PCI showed a borderline significant reduction that was higher in the IC Group compared to IV Group (71.38 ± 14.51 pg/mL vs 87.70 ± 26.13 pg/mL, P = 0.05). 4. Discussion
0.78
0.92
0.08
0.75 0.90 1
Values are mean ± S.D.; TIMI, thrombolysis in myocardial infarction; PCI, percutaneous coronary intervention.
This study provides evidence for the first time that in STEMI patients undergoing thrombus aspiration during primary PCI, IC administration of a systemic-dose bolus of abciximab is associated with a higher reduction of the platelet-dependent circulating inflammatory marker sCD40L compared to IV administration. Mechanical removal of a thrombus before PCI reduces the existing source of embolization but it does not necessarily address the problem of platelet aggregates that are generated during and after PCI. These can be abolished with the use of platelet inhibitors [22]. sCD40L is integral to the development and progression of atherosclerosis and to the stabilization of platelet-rich thrombi. sCD40L binds to platelets via ␣IIb 3 -dependent mechanism and results in platelet activation [23,24]. The IC administration of abciximab may facilitate the dissolution of existing platelet-rich thrombus and dispersion of newly formed platelet aggregates [25–27], enhance the inhibition of the vitronectin receptors in the
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endothelial cells of the culprit vessel [28], and inhibit the proinflammatory [29,30] effects of sCD40L. All these mechanisms may concur to induce the observed acute reduction of sCD40L levels in IC Group compared to IV Group. By protocol, in our study, the bolus administration of abciximab in both groups was carried out after the aspiration of atherothrombotic material. The larger effects on circulating sCD40L concentrations in the IC group compared to the IV group might be explained by the higher local levels of abciximab achieved during IC administration, 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. These considerations are supported by experimental data showing a dose-dependent platelet disaggregation with abciximab. Concentrations that produced complete platelet disaggregation also induced partial displacement of platelet-bound fibrinogen, which might play a role in this clinical setting [27]. In the IV Group, both the anti-inflammatory and anti-thrombotic effects of abciximab might be limited compared to the IC administration [25]. Interestingly, our findings are in agreement with the previous observation of a more pronounced clinical benefit of IC abciximab compared to IV administration in patients with acute coronary syndrome [9,10,12,31,32]. Recently, a randomized, controlled trial, demonstrated that in STEMI patients with an occluded infarctrelated artery treated with primary PCI, IC bolus administration of abciximab was superior to standard IV treatment with respect to infarct size, extent of microvascular obstruction, and myocardial perfusion [33]. Likewise, in a small randomized clinical trial of 45 patients, there was a significantly higher degree of myocardial salvage with subsequent lower infarct size as assessed by serial scintigraphy [9]. In our study, the IC Group exhibited lower mean levels of post-procedural cardiac enzymes. Furthermore, there was a trend towards improved myocardial perfusion as assessed by ST-segment resolution. This agrees with, and extends, previous findings by others authors, who observed a more pronounced clinical benefit of IC abciximab administration in relation to infarct size [9,10,12,31,32]. A possible cause of the lower myocardial damage associated with IC administration could be that the greater and more rapid platelet inhibition would mean that the phenomenon of reperfusion would be less damaging to the myocardium [34]. This aspect of reduced platelet aggregation along with less distal microembolization and local anti-inflammatory effect [35] could, in our opinion, represent the benefits of this route of administration. This study has limitations that may affect the interpretation of the results. This is a pilot small randomized and open-label trial. We determined sCD40L concentrations in peripheral venous blood samples, rather than in blood from the coronary sinus. Thus, we have assumed that serum sCD40L concentrations reflect the inflammatory process that occurs in area of the coronary artery. On the other hand, we did not measure other inflammatory markers. Likewise, the limited number of patients in our study could account the absence of significant differences in the incidence of events. The confirmation of the results with respect to the clarification of the long-term effects on clinical outcome requires a larger trial. Although all angiographic and ECG measurements were blinded, patients and interventional cardiologists were aware of the group assignment. Thus, a potential investigator bias cannot be ruled out entirely. On the other hand, the findings of this study are limited to patients presenting within 6 h of symptom onset and therefore cannot be extended to patients treated 6–12 h after symptom onset. Moreover, ST-segment resolution was the unique marker of myocardial perfusion examined in the present study. Other imaging modalities of microcirculatory function, such as contrast echocardiography, or invasive measures of coronary flow reserve may provide further insights into microcirculation reperfusion. In our
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