Efficacy of Intracoronary versus Intravenous Abciximab in Cardiac Inflammatory  Markers and Cardiac Function in Myocardial Infarctionn Patients

Objective: we aim to compare Intracoronary versus Intravenous abciximab regarding inflammatory markers and cardiac fuction.Materials and Methods: We conducted a computer search of four authentic databases. We included randomized controlled trials (RCTs) compared IC versus IV abciximab in myocardial infarction patients. Data were extracted from eligible studies and pooled in a meta-analysis model using RevMan software package (ver. 5.2; Cochrane collaboration, Oxford, UK). Our primary outcome was Thrombolysis in myocardial infarction flow grade 3 (TIMI). Our secondary outcomes were different inflammatory markers, Left ventricular ejection fraction and ST-segment resolution. Results: 15 RCTs with total number of patients 4904 were included in our final analysis. Our analysis indicated no significant differences in both routes of abciximab in TIMI flow grade 3 (RR= 1.01, 95% CI [0.99, 1.04], p=0.26). The inflammatory markers (peak troponin, peak creatine kinase, peak creatine kinase myocardial band) favors intracoronary more than the intravenous route of abciximab. Intracoronary abciximab is associated with better left ventricular ejection fraction versus intravenous route, (MD= 3.31, 95% CI [1.46, 5.16], p=0.0005). Intracoronary abciximab is significantly better than intravenous one regarding ST-segment resolution (RR= 1.09, 95% CI [1.02, 1.17], p=0.02). Conclusion: IC abciximab can be used instead of IV route due to greater benefits linked to IC abciximab administration. 1. Introduction:Myocardial infarction (MI), commonly identified as heart attack, stands to be irreversible necrosis and death of the heart muscle occurs when a portion of the cardiac muscle is deprived of oxygen due to blockage of a coronary artery [1]. Percutaneous coronary intervention (PCI) is considered a non-surgical procedure. In patients with ST-elevation myocardial infarction (STEMI), PCI can be critical to survival as it reduces mortality [2,3]. However, suboptimal myocardial perfusion continues to be a major limitation of PCI [4]. Inhibition of platelet aggregation remains one of the main cornerstones in the setting of STEMI [5]. Abciximab (glycoprotein IIb/ IIIa inhibitor) administration during performing PCI decreases major adverse cardiac events. Intracoronary (IC) abciximab bolus administration during PCI results in more local platelet aggregation inhibition, and more recovery in myocardial reperfusion in comparison with standard intravenous bolus injection [6,7]. In addition, the study by Eitel [8], showing 6-month follow-up of 154 STEMI patients undergoing PCI, Intracoronary (IC) or intravenous (IV) bolus abciximab administration realized the infarct size was significantly lower in the IC abciximab group when compared with the intravenous group . However, Several clinical trials suggested that no differences between intracoronary and intravenous abciximab administration on myocardial damage, infarct size and/or reperfusion injury [9, 10]. The aim of this systematic review and metaanalysis is to determine the feasibility of Intracoronary versus intravenous bolus abciximab application in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention from recently published randomized clinical trials. 2. Methods:We performed this systematic review and meta-analysis in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [11]. We followed The PRISMA (Preferred Reporting Items for Systematic reviews and meta-analysis) statement guidelines during the preparation of this review and meta-analysis [12]. 2.1. Literature searchWe performed a comprehensive electronic literature search of four databases (PubMed, Cochrane library, Scopus and ISI Web of science of Clinical Trials) .we used the following search strategy; (intracoronary OR intravenous) AND (abciximab OR glycoprotein iib/iiia receptor inhibitors OR ReoPro) AND (myocardial infarction OR heart failure OR angina OR heart attack OR cardiovascular disease OR coronary thrombosis). There were no restrictions by the language of the study or the year of publication. 2.2. Eligibility criteriaWe included the studies according to following inclusion criteria: (I) population: Patients who were in urgent myocardial infarction (ii) intervention: Intracoronary abciximab; (iii) comparator: Intravenous abciximab; (IV) study outcomes: Inflammatory markers; Peak troponin, peak creatine kinase (CK), peak creatine kinase myocardial band (CK-MB), left ventricular ejection fraction (LV-EF) and ST-segment resolution; and (V) study design: randomized controlled trials (RCTs) only. Eligibility screening was conducted in a two step-wise manner (title and abstract screening then full-text screening). Each step was performed by Ahmed Abdelhakim independently. 2.3. Data extractionWe extracted the data from included studies on a standardized data collection Excel sheet. We collected the following data: list of authors, year of publication, sample size and baseline characteristics of study participants. We also extracted the following outcome data: Peak troponin, peak creatine kinase (CK), peak creatine kinase myocardial band (CK-MB), left ventricular ejection fraction (LV-EF) and ST-segment resolution. 2.4. Risk of bias assessmentWe evaluated the quality of included studies and the risk of bias using the Cochrane risk of bias assessment tool, clearly described in (chapter 8.5) of the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 [13]. The Cochrane risk of bias assessment tool includes the following domains: selection bias, performance bias (blinding of participant and personnel), detection bias (blinding of outcome assessment), attrition bias, reporting bias and other potential sources of bias. The authors’ judgment is categorized as “Low risk,” “High risk,”or “Unclear risk” of bias. 2.4. Data synthesisWe used outcome measures as the following; for dichotomous data, we used pooled risks ratios (RR), and for continuous data, we used weighted mean difference (MD) using Mantel-Haenszel method. All statistical analyses were performed using the Revman software package (ver. 5.2; Cochrane Collaboration, Oxford, UK). We assessed statistical heterogeneity using the Chi-Square test, and its extent was measured using the I-Square test [14]. The random effects model was used in case of heterogeneity between studies; otherwise, the fixed-effects model was used. We performed a sensitivity analysis to assess the contribution of each study to the pooled estimate by excluding one trial at a time and recalculating the pooled mean difference for the remaining studies. 3. Results:3.1. Results of the literature search:We retrieved 1640 studies after searching in different databases. After title and abstract screening, 20 articles were reliable for full-text screening. We excluded six of them and finally, 15 studies with a total number of 4904 patients matched our inclusion and were included in the final analysis. The PRISMA flow diagram of study selection is shown in figure 1.3.2. Characteristics of included studies:A total of 15 randomized controlled trials (RCTs) met our inclusion criteria [5–10,15–23] . The included studies compared intracoronary versus intravenous abciximab in myocardial infarction after percutaneous coronary intervention. Our primary outcome was Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 after PCI, different cardiac markers which were peak troponin, peak creatine kinase (CK) and peak creatine kinase myocardial band (CK-MB). Our secondary outcomes were different cardiac markers as: peak troponin, peak creatine kinase (CK) and peak creatine kinase myocardial band (CK-MB), left ventricular ejection fraction and ST-segment resolution. The summary of the included studies, their chief results, and the baseline characteristics are shown in table 1.3.3. Risk of bias assessment:The included RCTs were of from moderate to high quality as stated by the Cochrane risk of bias assessment tool. The summary of risk of bias assessment of RCTs is shown in figure 2 and the judgments are shown in supplementary file no.1. 3.4. Outcomes:3.4.1 TIMI grade 3 post-PCI:TIMI grade 3 post-PCI was reported in 13 studies. The pooled risk ratio (RR) showed no significant difference between intracoronary abciximab and intravenous abciximab (RR= 1.01, 95% CI [0.99, 1.04], p=0.26), figure 3. The pooled studies were homogeneous (p=0.33, I² = 11%); therefore, fixed effects model was conducted. 3.4.2. Peak troponin:Peak troponin was reported in five studies. The pooled standardized mean difference (SMD) showed a significant superiority of intracoronary abciximab in comparison with intravenous abciximab (SMD= -0.26, 95% CI [-0.43, -0.09], p=0.003), figure 4. The pooled studies were homogenous (p=0.13, I² = 44%); therefore, fixed effects model was conducted.3.4.3. Peak creatine kinase:Peak creatine kinase was reported in five studies. The pooled standardized mean difference (SMD) showed no significant difference in both intracoronary abciximab and intravenous abciximab (SMD= -0.18, 95% CI [-0.40, 0.03], p=0.003), figure 5. The pooled studies were heterogeneous (p=0.04, I² = 61%); therefore, random effects model was conducted. We resolved this heterogeneity by removal of both Bertrand et al. and thiele et al. favoring intracoronary abciximab in comparison with intravenous abciximab, (SMD= -0.33, 95% CI [-0.61, -0.05], p=0.03), (p=0.20, I² = 37%), figure 6.3.4.4. Peak creatine kinase myocardial band (CK-MB):Peak CK-MB was reported in three studies. The pooled standardized mean difference (SMD) favored intracoronary abciximab more than intravenous abciximab (SMD= -0.28, 95% CI [-0.48, -0.09], p=0.005), figure 7. The pooled studies were homogeneous (p=0.19, I² = 39%); therefore, fixed effects model was conducted.3.4.5 Left ventricular ejection fraction:Left ventricular ejection fraction was reported in five studies. The pooled mean difference (MD) favored intracoronary abciximab versus intravenous abciximab (MD= 3.31, 95% CI [1.46, 5.16], p=0.0005), figure 8. The pooled studies were homogeneous (p=0.24, I² = 27%); therefore, fixed effects model was conducted.3.4.6 ST-segment resolution:ST-segment resolution was reported in six studies. The pooled risk ratio (RR) favored intracoronary abciximab versus intravenous abciximab (RR= 1.09, 95% CI [1.02, 1.17], p=0.02), figure 9. The pooled studies were homogeneous (p=0.23, I² = 28%); therefore, fixed effects model was conducted.4. Discussion:In the last few years, a lot of pharmacological strategies have been suggested to further increase the survival of myocardial infarction patients performing primary PCI. Adjunctive abciximab use has been revealed to improve survival and myocardial perfusion and decline re-infarction risk [24–26]. A lot of attention has been increased on IC abciximab administration that could offer potential advantages over IV abciximab, due to more effective inhibition of glycoprotein IIb/ IIIa receptors and possible values from abciximib anti-inflammatory effects. However, we found a lot of debates in different studies about the greater benefits of IC versus IV abciximab. In this meta-analysis, we found intracoronary abciximab is similar to intravenous abciximab post-procedural in thrombolysis in myocardial infarction (TIMI) flow grade 3. Moreover, intracoronary abciximab is superior in reducing different inflammatory markers including peak troponin (Tn), peak creatine kinase (Ck) and peak creatine kinase myocardial band (CK-MB) more than intravenous abciximab. Intracoronary abciximab is linked to more improvement in left ventricular ejection fraction and ST-segment resolution. Abciximab represents a potent platelet aggregation inhibitor mainly by competitively attaching to the GP IIb/IIIa receptor on the plane of activated human platelets. Due to the higher attractiveness to this receptor, it prevents fibrinogen and von Willebrand factor attachment to activated platelets, inhibiting the final common pathway for platelet aggregation [27]. In addition, abciximab has dose-dependent antiplatelet, anti-inflammatory, antithrombotic actions, and help in disaggregation of the thrombus [27]. The interaction of abciximab with different receptors, such as the vitronectin [28] or the Mac-1 receptor [29], may also be responsible for preventing leukocyte-intervened microvessels injury ultimately related to reperfusion. Furthermore, sCD40L is thought to be responsible for atherosclerosis expansion and platelet-rich thrombi maintenance inside the vessels [30]. Different studies supposed that the IC abciximab acts by enabling the disbanding of the standing and newly formed platelet-rich thrombi [31], augmenting the vitronectin receptors inhibition in the endothelial cells of the culprit vessel [32], and prevents the pro-inflammatory [33] actions of sCD40L. All these mechanisms may accountable for the great decline in sCD40L levels in IC Group compared to IV Group.These verdicts propose that higher local concentration accomplished by intracoronary administration resulting local platelet inhibition, thrombi dissolution and dislodgment of platelet fibrin thrombi causing improvement in different outcomes. Despite all of IC abciximab benefits, Desch et al. [6] realized that, although intracoronary abciximab leads to more occupied glycoprotein IIb/ IIIa receptors in contrast with the intravenous method, these properties are not extended more than 30 minutes following bolus administration. Accordingly, absence of constantly higher glycoprotein IIb/IIIa receptor occupied with time with IC abciximab may be linked to the different adverse clinical and reperfusion results. Two recent randomized clinical trials found a similarity between IC and IV abciximab in post-procedural TMI flow grade 3 supporting our finding [15,16]. However, another study realized more myocardial infarction patients experienced TIMI flow grade 3 in IC abciximab but the results were not statistically significant [23]. Timing of glycoprotein IIb/IIIa inhibitor administration stands to be very crucial where different clinical trials have concluded that earlier use produces higher pre-interventional TIMI flow grades with consequently progress in perfusion grades after doing PCI [34,35]. Regarding our selected inflammatory markers, Bertrand et al. established no significant benefit of intracoronary over intravenous abciximab in reducing the inflammatory markers contradicting our results [16]. Furthermore, peak troponin level is similar in both groups of abciximab as suggested by secco et al. [21] conflicting what we concluded. However, Gu et al. supported our finding where they concluded intracoronary abciximab is superior to intravenous abciximab in diminution of various markers associated with inflammation [23]. Moreover, a randomized controlled trial deduced more significant decline in peak troponin levels in IC abciximab [17]. Several studies have reported improved myocardial salvage, left ventricular functional recovery, and a smaller infarct size after intracoronary administration of abciximab (12). Moreover, Belandi et al. established more significant ventricular ejection fraction in patients who administrated IC abciximab assisting our verdict [7]. However, Bertrand et al did not show any significant difference regarding left ventricular ejection fraction opposing our results [16]. Another study opposed our results where it concluded no significant differences between intracoronary and intravenous abciximab in LV ejection fraction [10]. The ischemic injury relies on the microcirculation functional status. Many potential important factors were capable of interfering with microvascular function, such as diabetes, hyperlipidemia, hypertension, and smoking [7]. In a subgroup analysis study done by Piccolo et al. included all diabetic patients realized IC abciximab resulted in more significant improvement of the PCI effectiveness than IV abciximab, including increase in left ventricular function, myocardial salvage indicator and diminished death risk [36]. Bedjaoui et al realized both groups of abciximab are comparable in ST-segment resolution experienced by the patients opposing what we found [7]. However, Bellandi et al supported our results where they concluded intracoronary abciximab is significantly superior to intravenous one in achieving more patients with ST-segment resolution [7]. New application systems such as the ClearWay RX perfusion dedicated catheter (Atrium Medical Corporation, Hudson, New Hampshire) may add more improvement in the efficacy of intracoronary abciximab delivery. The system contains a perfusion balloon that obstructs antegrade blood flow while medications are infused through a microporous polytetrafluoroethylene surface. This design permits for high local drug concentrations in the vessel lumen and wall at the thrombus site together. In a randomized controlled trial of patients chose with severe acute coronary syndrome, abciximab delivery through this dedicated catheter caused significant decline in the amount of thrombus burden and increased microvascular flow in comparison with the conventional intracoronary drug administration through a guide catheter [37]. We should remark that GP IIb/IIIa receptor antagonists use in patients with acute STEMI performing PCI and receiving dual antiplatelet therapy is not habitually advised [38]. In fact, some recommendations stated that the GP IIb/IIIa receptor antagonist adjuvants administration should be directed to selected patients, such as those with large thrombus load or inadequate thienopyridine burden [38].To the best of our knowledge, this study provides great outstanding effectiveness of intracoronary abciximab over intravenous abciximab. Our limitations are limited number of included studies, large number of patients who were lost during their follow-up and we do not assess other inflammatory markers. We did not assess different safety outcomes between IC and IV abciximab including myocardial infarction incidence and bleeding rates. Our recommendations are to increase the number of double blinded randomized controlled trials with considering the priority of left ventricular ejection fraction and inflammatory markers other than troponin, CK, and CK-MB to be the main outcomes. Many microcirculatory function imaging modalities, including contrast echocardiography, or invasive coronary flow reserve measures may be used to add further understanding of microcirculation reperfusion in the coming studies. References:[1] White HD, Chew DP. Acute myocardial infarction. The Lancet [Internet]. 2008 [cited 2019 Apr 6];372:570–584. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0140673608612374.[2] Thomas MP, Bates ER. Percutaneous coronary intervention strategies in patients with ST-segment elevation myocardial infarction and multivessel coronary artery disease. Current Opinion in Cardiology [Internet]. 2017 [cited 2019 Apr 6];32:755–760. Available from: http://insights.ovid.com/crossref?an=00001573-201711000-00016.[3] Sandhu K, Nadar SK. Percutaneous coronary intervention in the elderly. International Journal of Cardiology [Internet]. 2015 [cited 2019 Apr 6];199:342–355. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0167527315013583.[4] Bedjaoui A, Allal K, Lounes MS, et al. Cardiovascular Topics Intracoronary or intravenous abciximab after aspiration thrombectomy in patients with STEMI undergoing primary percutaneous coronary intervention. 2018;1–7.[5] Thiele Eitel et al. Intravenous Abciximab in Patients Myocardial Infarction Percutaneous Desch A, et al. inhibition and GP IIb/IIIa receptor by intracoronary versus intravenous bolus administration of abciximab in patients with ST-elevation myocardial infarction. Clinical in Bellandi et al. of myocardial salvage and left ventricular function recovery with intracoronary abciximab of the coronary in patients with acute myocardial infarction with primary coronary intervention. and Cardiovascular Eitel et al. Intracoronary versus intravenous bolus abciximab application in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: 6-month effects on infarct size and left ventricular Clinical in Bertrand et al. Intracoronary to Intravenous Abciximab and to in Patients Myocardial Infarction Percutaneous a Journal of Cardiology [Internet]. Available from: Eitel et al. Intracoronary Intravenous Abciximab Percutaneous in Myocardial Journal of the of Cardiology [Internet]. Available from: Cochrane Handbook for Systematic Reviews of Interventions [Internet]. [cited Available from: A, et al. Reporting Items for Systematic Reviews and The PRISMA [Internet]. [cited Available from: Cochrane Cochrane risk of bias in included studies. Cochrane Handbook Systematic Reviews of in [cited Available from: Bedjaoui A, Allal K, Lounes MS, et al. Intracoronary or intravenous abciximab after aspiration thrombectomy in patients with STEMI undergoing primary percutaneous coronary intervention. Cardiovascular Journal of Bertrand et al. A Intracoronary Intravenous Abciximab in Patients Myocardial Infarction Percutaneous After Journal of Cardiology [Internet]. Available from: A, et al. Intracoronary versus intravenous abciximab administration in patients with ST-elevation myocardial infarction undergoing thrombus aspiration during primary percutaneous coronary on et al. Intracoronary Abciximab the of Percutaneous A et al. Intracoronary compared to intravenous abciximab in patients with elevation myocardial infarction with primary percutaneous coronary intervention reduces vessel and after A, A, et al. Intracoronary compared to intravenous bolus abciximab during primary percutaneous coronary intervention in ST-segment Myocardial Infarction patients reduces mortality and vessel A randomized Journal of A, et al. anti-inflammatory effects of intracoronary and intravenous Abciximab during primary percutaneous coronary intervention: A randomized Journal of Cardiovascular Thiele et al. Intracoronary versus intravenous bolus abciximab during primary percutaneous coronary intervention in patients with acute ST-elevation myocardial A The Gu et al. Intracoronary versus intravenous administration of abciximab in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention with thrombus The comparison of intracoronary versus intravenous et al. Abciximab as Adjunctive to in Acute Myocardial [Internet]. [cited 2019 Apr Available from: Risk and benefits from inhibitors patients with ST-segment elevation myocardial infarction with primary a analysis of randomized trials. Journal [Internet]. [cited 2019 Apr Available from: K, et al. glycoprotein inhibitors in primary results data Journal of and [Internet]. [cited 2019 Apr Available from: et al. for intracoronary administration of abciximab. Thrombolysis [Internet]. [cited 2019 Apr Available from: et al. 3 to the of [Internet]. [cited 2019 Apr Available from: et al. directed the platelet glycoprotein IIb/IIIa with the Mac-1 and to fibrinogen and and [Internet]. [cited 2019 Apr Available from: et al. thrombi by a [Internet]. [cited 2019 Apr Available from: et al. of of of newly formed platelet and [Internet]. [cited 2019 Apr Available from: K, et al. of abciximab and on vitronectin receptors in human endothelial and muscle Journal of [Internet]. [cited 2019 Apr Available from: et al. of with in human Journal of [Internet]. [cited 2019 Apr Available from: et al. versus administration of abciximab for primary A pooled analysis of studies. Journal [Internet]. [cited 2019 Apr Available from: Bellandi et al. Abciximab in Acute Myocardial Infarction Journal of the of Cardiology [Internet]. [cited 2019 Apr Available from: Piccolo Eitel et al. Intracoronary abciximab in diabetic patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. [Internet]. Available from: et al. Intracoronary of Abciximab in Patients Acute Cardiovascular Interventions [Internet]. [cited 2019 Apr Available from: et al. for the of Patients Myocardial Infarction the and and on Percutaneous the and [Internet]. [cited 2019 Apr Available from: