Improved Clinical Outcomes with Intracoronary Compared to Intravenous Abciximab in Patients with Acute Coronary Syndromes Underg

   ABSTRACT: Background. Intracoronary (IC) administration of abciximab may increase local drug levels by several orders of magnitude compared to intravenous (IV) treatment and may improve clinical outcomes in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). In the absence of results from large multicenter, randomized trials, we performed a systematic review and meta-analysis of available studies comparing IC to IV abciximab in these patients.    Methods. Eight studies were identified, including five randomized trials and three retrospective studies. Data from 2,301 patients, including 997 with ST-segment-elevation myocardial infarction (STEMI) and 1,304 with non-STEMI or unstable angina, were analyzed.    Results. The studies were conducted from 1996–2008, 24% of patients had diabetes and thienopyridine pretreatment was frequently suboptimal, compared to the current standard of care. Pooled analysis of the data demonstrated significantly reduced mortality (odds ratio [OR] 0.57, 95% confidence interval [CI] 0.35–0.94; p = 0.028), and a trend toward a reduction of major adverse cardiac events (MACE, OR 0.62, 95% CI 0.38–1.03; p = 0.066) during up to 12 months of follow up with IC compared to IV abciximab. Meta-regression analysis of important covariables showed heterogeneity of in- dividual study results because of different follow-up periods and inclusion of patients without STEMI. Subanalyses showed significant MACE reduction after 1 month of follow up, and in studies exclusively composed of patients with STEMI, respectively.     Conclusions. This first systematic review and meta-analysis of available studies suggests that compared to standard IV administration, IC abciximab can improve clinical outcomes in patients with ACS undergoing PCI, especially patients with STEMI undergoing primary PCI. J INVASIVE CARDIOL 2010;22:278–282    Administration of abciximab diminishes the occurrence of major adverse cardiac events (MACE) in patients undergoing percutaneous coronary intervention (PCI), especially patients with high-risk acute coronary syndromes (ACS) with or without ST- segment elevation, patients with complex coronary lesions, or when used as bail-out therapy for periprocedural complications.^1,2 Abciximab is a murine-human chimeric Fab fragment of a monoclonal antibody against the platelet glycoprotein (GP) IIb/IIIa receptor that strongly inhibits platelet aggregation and also may have anti-inflammatory effects, although the clinical significance of the latter remains unproven.³ The rationale for the accepted current intravenous (IV) dose of abciximab, i.e., an initial 0.25 mg/kg body weight bolus followed by a 0.125 μg/kg/min 12-hour infusion, was based on studies where this dose was required to occupy ≥ 80% platelet GP IIb/IIIa receptors and reduce platelet aggregation to 4,5 In patients with ST-segment elevation myocardial infarction (STEMI), however, higher levels of platelet GP IIb/IIIa receptor occupancy have been associated with im- proved myocardial perfusion.^6,7 Moreover, GP IIb/IIIa-dependent or non-GP IIb/IIIa-dependent effects of abciximab, e.g., dispersal of newly formed platelet aggregates, thrombus “remodeling” and anti-inflammatory actions may be increased by higher drug concentrations, suggesting a potential for localized intracoronary (IC) administration of abciximab, which may increase the local drug level by several orders of magnitude, to improve clinical outcomes after PCI.⁸ In the absence of results from large multicenter randomized trials, we performed a systematic review and meta-analysis of available results of all published studies comparing effects of IC and IV abciximab on rates of death and MACE after PCI in patients with acute coronary syndromes.

Methods

   Search strategy. We searched in the PubMed, Embase and Cochrane electronic databases for all published studies that examined IC versus IV abciximab in patients with acute coronary syndromes undergoing PCI. We searched without time or language limitations and up to November 2009. The following keywords were used: abciximab, ReoPro, monoclonal antibodies, coronary, myocardial infarction, and angioplasty. A manual search was also conducted and reference lists of the retrieved articles were screened as well. Published studies were considered eligible if they examined patients with acute coronary syndromes, i.e., STEMI, non-STEMI, and unstable angina pectoris, assigned to receive IC or IV abciximab bolus during PCI. Eligible studies had to provide the numbers of deaths and MACE in each treatment group and have a follow-up period of at least 4 weeks. Studies that did not meet these criteria were excluded.    Data extraction and synthesis. Demographic data and numbers of death and MACE (death, nonfatal MI, repeat revascularization) in treatment groups were extracted from every study. The authors independently performed the search, data extraction, and data evaluation, and there was complete agreement between the authors on the final results. We chose odds ratio (OR) for outcome measure and pooled the calculated ORs using the numbers of dead versus survivors and MACE versus no MACE in the two treatment arms of each study. Chi-square was used to test heterogeneity, with p > 0.05 indicating data homogeneity. We calculated I-squared (I2) for variation in weighted mean differences between studies attributable to heterogeneity. A value of I2 above 20% was considered statistically significant. We used weighted random effects model analysis to validate the overall results, and p 2 were considered statistically significant. Meta- and meta-regression analyses were performed using the meta-analytic and statistic package of STATA version 10 (STATA Corp., College Station, Texas).

Results

    Search results. The search resulted in detection of 979 articles. After exclusion of non-relevant articles by title (n = 910) or by abstract (n = 58), eleven articles published in peer-review journals were retrieved for full text evaluation. Three of these did not include control groups and/or follow-up after discharge, and were therefore excluded.^9–11 Eight studies fulfilled all inclusion criteria and were selected for the meta-analyses.^12–19 Supplementary data were provided from a completed study from our own institution (protocol registered at ClinicalTrials.gov [NCT00927615]), where MACE and death rates after 30 days have been reported in abstract form.¹⁹ The flow chart of the systematic search process is shown in Figure 1.    Studies and patient characteristics. There were three retrospective studies, where standard-dose abciximab bolus was administered by IC or IV injection according to the operators discretion,^12,13,17 and five randomized trials of the two abciximab administration routes (Table 1).^{14–16,18,19} The inclusion periods of studies varied considerably, i.e., 1996–2001,¹² 2001–2002,^13,14 2004,¹⁵ 2003–2005,¹⁷ 2006,¹⁶ 2008¹⁸ and 2006–2008.¹⁹ The largest study¹⁷ (n = 208 in IC group, n = 797 in IV group) was a retrospective subanalysis of a randomized trial that demonstrated equivalence in deaths and MACE rates between abciximab bolus-only and bolus followed by 12- hour IV infusion in patients undergoing nonemergent PCI.^20,21 In the other studies, abciximab bolus was followed by standard-dose 12-hour IV infusion in all patients. Patients presented with STEMI (947 patients) or N-STEMI or unstable angina (1,304 patients) and four trials exclusively randomized patients with STEMI undergoing primary PCI.^14,16,18,19 All studies reported data on deaths and MACE, except for one study that reported only deaths,¹⁴ and another study that reported only MACE.¹⁸    Patients had a mean age of 62 ± 12 years, 78% were male and 24% had diabetes (Table 1). Catheterization was performed through the femoral or radial approach and IC abciximab was injected directly through the PCI guiding catheter in all but one study, where abciximab was administered distally to the coronary occlusion through a dual-lumen catheter.¹⁴ All patients were pre-treated with aspirin and unfractionated heparin. Aspiration thrombectomy was utilized in one study.¹⁸ Almost all patients received intracoronary stents and a thienopyridine (ticlopidine 250 mg twice daily^12,14 or clopidogrel 300–600 mg loading dose followed by 75 mg daily^{12,13,15–19}) was initiated either before,^17–19 before or during,^15,16 or immediately after^12–14 the procedure, respectively, and continued for at least 30 days. No safety issues were reported to be associated with IC compared to IV abciximab administration. Follow-up periods ranged from 1–12 months.    Meta-analysis of deaths and MACE rates. Data from a total of 2,301 patients, including 997 with STEMI and 1,304 with N-STEMI or unstable angina, were analyzed, of which 984 received IC and 1,338 received IV abciximab. There were 38 (3.9%) and 39 (2.9%) deaths in the IC and IV groups, respectively, and as shown in Figure 2, the analysis demonstrated a significant reduction in mortality with IC compared to IV abciximab (OR 0.57, 95% confidence interval [CI] 0.35–0.94; Z score = 2.19, and p = 0.028). The mortality data were homogenous and showed no significant variation between the studies (chi- square = 4.2, p = 0.650 and I2 = 0.0%). Although the mortality rate increased by 1% with IC compared to IV abciximab (3.9% vs. 2.9%), the overall OR reduction with the IC administration route was primarily caused by the increased statistical weight of the two studies with relatively large numbers of deaths that displayed significant mortality benefits with IC abciximab.^12,19 The results of the study by Bertrand et al¹⁷ had a skewed effect on death percentages but limited effect on the overall results due to the few events in that study (statistical weight only 8%), while results of the studies of Wöhrle et al¹² and Iversen et al¹⁹ combined had a dominating weight of 69% in the analysis. The relatively fewer events in the study of Bertrand et al may be attributed to a selective inclusion of non-STEMI and unstable angina cases, i.e., without high-risk STEMI patients.¹⁷ When this study was excluded from the analysis, percentages of deaths in the IC vs. IV arm were 4.8% vs. 6.5%, respectively, and when the meta-analysis was repeated without the study, the pooled OR for death was 0.51 (95% CI 0.30–0.86; p = 0.012), in favor of the IC group.    During follow up, 101 (10.3%) and 162 (12.1%) MACE occurred in the IC and IV groups, respectively. As shown in Figure 3, the analysis showed a nonsignificant trend towards reduced MACE with IC compared to IV abciximab (OR 0.62, 95% CI 0.38–1.03; Z score = 1.65, and p = 0.066), but the MACE data demonstrated considerable heterogeneity (p = 0.019 and I2 = 66.5%). To explore the source of heterogeneity, we performed sensitivity analysis by step-wise exclusion of the included studies, but data homogeneity could not be achieved (all p-values > 0.05 or I2 > 20%; not shown). Since the different follow-up periods and relative distribution of patients with STEMI vs. N-STEMI and unstable angina, respectively, in individual studies were likely to have influenced the results, we performed a meta-regression analysis by including the following baseline covariables for each study in the regression model: age, gender, diabetes mellitus, hypertension, hyperlipidemia, duration of follow up (1 month vs. > 1 month) and ratio of STEMI patients (100% vs. 0.1), except for the duration of follow up and the ratio of STEMI patients in each study (p 2 for both). We therefore explored the dependence between clinical outcomes and length of the follow-up period, or ratio of STEMI patients, respectively. The first analysis was done by examining separately results of the five short-term studies with 1 month of follow up,^{12,14,16,18,19} and results of the three long-term studies with 6–12 months of follow up.^13,15,17 Short-term studies demonstrated significant reductions of death (p = 0.011) and MACE (p = 0.001) with IC compared to IV abciximab, while long-term studies did not demonstrate significant differences in outcomes between the two abciximab administration routes (p > 0.05). The second analysis examined separately studies that only included patients with STEMI^14,16,18,19 and studies that also included patients with non-STEMI and unstable angina.^12,13,15,17 In the STEMI studies, a significant reduction in MACE (p Discussion    The current work is, to our knowledge, the first systematic review and meta-analysis of available studies of outcomes after IC compared to IV abciximab in patients with ACS undergoing PCI. We found that IC abciximab was associated with significantly reduced mortality and a trend towards reduced MACE rates compared to the standard IV administration route. These benefits were most apparent in patients with STEMI undergoing primary PCI, and in studies with short-term (1 month) follow up.    The mechanistic rationale for local delivery of abciximab to the target coronary artery in patients undergoing PCI primarily relies on the premise that increased local drug concentrations can pro- mote higher levels of platelet GP IIb/IIIa receptor occupancy and thrombus disaggregation, which in turn may reduce the incidence of microvascular thromboembolism, increase myocardial perfusion and ultimately improve clinical outcomes.^6–8 Although benefits observed with IC compared to IV abciximab in our meta-analysis are compatible with this hypothesis, the results should be cautiously interpreted, and since the reduction of MACE was not significant in the overall analysis, the validity of the favorable effects of IC abciximab in patients with STEMI and in studies with short- term follow up remains to be determined. None of the included studies were powered for detection of differences in mortality endpoints, and some heterogeneity of results was observed. The clinical setting of the studies varied considerably, e.g., patients were recruited in the period from 1996–2008, and we included both randomized trials and observational studies. Indeed, in retrospective cohorts, where the abciximab administration route was likely to be confounded by the clinical situation, lesion complexity and PCI procedural results, the IC group was probably subjected to negative selection bias, i.e., high-risk patients received IC abciximab, leading to underestimation of the clinical benefits of this administration route. Furthermore, the relationship between the degree of measurable platelet inhibition and angiographic outcome after primary PCI has been questioned, and the former is dependent on the type of platelet function assay used.^5,22 Evidence has also indicated that abciximab is most effective in high-risk ACS with presence of IC thrombus, i.e., predominantly patients with STEMI, and for patients with unstable angina that comprised a substantial part of our meta-analysis population, the > 80% inhibition of platelet aggregation obtained with standard IV abciximab may have been sufficient to achieve full clinical benefit of the agent. In agreement with this notion, the studies reporting most consistent benefits of IC abciximab were the ones that exclusively dealt with patients with STEMI undergoing primary PCI,^14,16,18,19 and here the amelioration of clinical outcomes with IC compared to IV abciximab were corroborated by favorable effects on other endpoints, e.g., ST-segment resolution, myocardial infarct size, myocardial microvascular obstruction and soluble platelet CD40 ligand levels.^14,16,18 Moreover, it may be difficult to integrate results of older pivotal studies with IV abciximab into a more contemporary setting, where patients with different risk profiles and acuity receive a high-dose clopidogrel loading dose and more emergent PCI. For example, after optimal pretreatment with clopidogrel, i.e., 600 mg at least 2 hours (or 300 mg at least 6 hours), before PCI, benefits conferred by abciximab in patients with ACS without ST-segment elevation are confined to troponin-positive cases, and with optimal clopidogrel pre-treatment, the efficacy of standard IV abciximab even in patients with STEMI undergoing primary PCI may be confined to high risk patients only.^1,2,23–26 Although pre-treatment with thienopyridine was generally suboptimal in the studies included in the current meta-analysis, it may in selected cases have offset favorable effects of abciximab, irrespective of its administration route.    It may be argued that in presence of an indication for abciximab according to current guidelines, there are no drawbacks to IC administration of the initial bolus of the agent. In patients with STEMI undergoing primary PCI, however, early (emergency department or ambulance) as compared to late (catheterization laboratory) administration of abciximab may improve ST-segment resolution, coronary perfusion and clinical outcomes in patients with STEMI undergoing primary PCI.^27,28 The treatment delay required for catheterization laboratory IC abciximab administration may therefore per se diminish the benefit of the drug. It is notable, however, that recent register data have demonstrated that in the US, only one-third of patients actually receive GP IIb/IIIa inhibitors and clopidogrel before primary PCI, while > 90% are treated within 24 hours.²⁹ On the other hand, even in STEMI patients receiving IV abciximab upstream before primary PCI, there may be an association between the level of GP IIb/IIIa receptor occupancy and achievement of optimal reperfusion, suggesting a rationale for IC administration.⁷ Interestingly, the small-molecule GP IIb/IIIa receptor antagonist, eptifibatide, which is considerably cheaper and is currently used more frequently in the U.S. than abciximab for patients with STEMI undergoing primary PCI, has also been found to be feasible for IC use, and favorable preliminary results have also been reported with IC tirofiban.^30–32 Finally, the efficacy and safety of GP IIb/IIIa inhibitors have not been defined in the new era of antithrombotic regimens including bivalirudin, fondaparinux and prasugrel as adjunctive therapy to IC thrombectomy devices and with the use of novel delivery strategies. For example, IC vs. IV abciximab is currently being tested in randomized trials of patients with STEMI undergoing primary PCI with thrombus aspiration and with administration through a newly developed IC catheter, respectively. ^33,34    In conclusion, the current meta-analysis of the limited randomized and retrospective studies of outcomes after IC compared to IV abciximab in patients with ACS undergoing PCI indicated that the IC administration route was associated with reduced mortality and a trend towards reduced MACE rates. These benefits were most apparent in patients with STEMI undergoing primary PCI, and in studies with short-term follow up. No safety issues were apparent with administration of IC abciximab. The results of large multicenter randomized trials in a contemporary clinical setting are awaited.

_________________________________________________ From the *Department of Cardiology P, Gentofte University Hospital, Hellerup, Denmark and the §Division of Cardiology, Department of Medicine M, Glostrup University Hospital, Glostrup, Denmark. The authors report no conflicts of interest regarding the content herein. Manuscript submitted January 4, 2010, provisional acceptance given February 1, 2010, final version accepted February 12, 2010. Address for correspondence: Peter Riis Hansen MD, DMSc, Department of Cardiology P, Gentofte University Hospital, Niels Andersensvej 65, DK-2900 Hellerup, Denmark. E-mail: prh@dadlnet.dk

1. Silber S, Albertsson P, Aviles FF et al. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Car- diology. Eur Heart J 2005;26:804–847.
2. King SB 3rd, Smith SC Jr, Hirshfeld JW Jr et al. 2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: A re- port of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention. Cir- culation 2008;117:261–295.
3. Kereiakes DJ. Effects of GP IIb/IIIa inhibitors on vascular inflammation, coronary micro- circulation, and platelet function. Rev Cardiovasc Med 2006; 7 (Suppl 4):S3–S11.
4. Tcheng JE, Ellis SG, George BS et al. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin abtiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation 1994;90:1757–1764.
5. Coller BS. Monitoring platelet GP IIb/IIIa antagonist activity. Circulation 1998;97:5–9.
6. Gibson CM, Jennings LK, Murphy SA et al. Association between platelet receptor occu- pancy after eptifibatide (Integrilin) therapy and patency, myocardial perfusion, and ST- segment resolution among patients with ST-segment elevation myocardial infarcion: An INTEGRITI (Integrillin and Tenecteplase in Acute Myocardial Infaction) substudy. Cir- culation 2004;110:679–684.
7. De Prado AP, Fern√°ndez-V√°squez F, Cuellas JC, et al. Association between the level of platelet inhibition after early use of abciximab and myocardial reperfusion in ST-elevation acute myocardial infarction treated by primary percutaneous coronary intervention. Am J Cardiol 2006;97:798-803.
8. Romagnoli E, Burzotta F, Trani C et al. Rationale for intracoronary administration of ab- ciximab. J Thromb Thrombolysis 2007;23:57–63.
9. Sharma S, Makkar R, Lardizabal J. Intracoronary administration of abciximab during percutaneous interventions: Should this approach be the routine and preferred approach? J Cardiovasc Pharmacol Ther 2006;11:136–141.
10. Patel SS, Rana H, Mascarenhas DAN. Intracoronary abciximab use in patients undergoing PCI at a community hospital: A single operation experience. J Cardiovasc Pharmacol Ther 2008;13:89–93.
11. Romagnoli E, Burzotta F, Trani C, et al. Angiographic evaluation of the effects of intra- coronary abciximab administration in patients undergoing urgent PCI. Int J Cardiol 2005;105:250–255.
12. Wöhrle J, Grebe OC, Nusser T, et al. Reduction of major adverse cardiac events with in- tracoronary compared with intravenous bolus application of abciximab in patients with acute myocardial infarction or unstable angina undergoing coronary angioplasty. Circula- tion 2003;107:1840–1843.
13. Kakkar AK, Moustapha A, Hanley HG, et al. Comparison of intracoronary vs. in- travenous administration of abciximab in coronary stenting. Catheter Cardiovasc In- terv 2004; 61:31–34.
14. Bellandi F, Maiolli M, Gallopin M, et al. Increase of myocardial salvage and left ventricular function recovery with intracoronary abciximab downstream of the coronary occlusion in patients with acute myocardial infarction treated with primary coronary intervention. Catheter Cardiovasc Interv 2004;62:186–192.
15. Galache Osuna JG, Sánchez-Rubio J, Calvo I, et al. Does intracoronary abciximab improve the outcome of percutaneous coronary interventions? A randomised controlled trial. Rev Esp Cardiol 2006;59:567–574.
16. Thiele H, Schindler K, Friedenberger J, et al. Intracoronary compared with intravenous bolus abciximab application in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation 2008;118:49–57.
17. Bertrand OF, Rodés-Cabau J, Larose E, et al. Effects of intracoronary compared to intra- venous abciximab administration in patients undergoing transradial percutaneous coronary intervention: A sub-analysis of the EASY trial. Int J Cardiol 2009;136:165–170.
18. Dominguez-Rodriguez A, Abreu-Gonzales P, Avanzas P, et al. Intracoronary versus intra- venous abciximab administration in patients with ST-elevations myocardial infarction un- dergoing thrombus aspiration during primary percutaneous coronary intervention — Effects on soluble CD-40 ligand concentrations. Atherosclerosis 2009;206:523–527.
19. Iversen A, Abildgaard U, Gall√∏e A, et al. Intracoronary compared to intravenous bolus Abciximab during primary percutaneous coronary intervention in STEMI patients reduces 30-days mortality and target vessel revascularization. A randomized trial. (Submitted).
20. Bertrand OF, De Larochellière R, Rodés-Cabau J, et al. A randomised study comparing same-day home discharge and abciximab bolus only to overnight hospitalization and ab- ciximab colus and infusion after transradial coronary stent implantation. Circulation 2006;114:2636–2643.
21. Bertrand OF, Rodés-Cabau J, Larose E, et al. One year clinical outcome after abciximab bolus-only compared with abciximab bolus and 12-hour infusion in the Randomised Early discharge after Transradial Stenting of CoronarY Arteries (EASY) study. Am Heart J 2008;156:135–140.
22. Ernst NMSJ, Suryapranata H, Miedema K, et al. Achieved platelet aggregation inhibition after different antiplatelet regimens during percutaneous coronary intervention for ST- segment elevation myocardial infarction. J Am Coll Cardiol 2004;44:1187–1193.
23. Kastrati A, Mehilli J, Schühlen H et al. A clinical trial of abciximab in elective percutaneous intervention after pre-treatment with clopidogrel. N Engl J Med 2004;350:232–238.
24. Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab in patients with acute coronary syn- dromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: The ISAR-REACT 2 randomized trial. JAMA 2006;295:1531–1538.
25. Mehilli J, Kastrati A, Schultz S, et al. Abciximab in patients with acute ST-segment- elevation myocardial infarction undergoing primary percutaneous coronary inter- vention after clopidogrel loading. A randomised double-blind trial. Circulation 2009;119:1933–1940.
26. DeLucaG,NavereseE,MarinoP.RiskprofileandbenefitsfromGPIIb/IIIain- hibitors among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: A meta-regression analysis of randomised trials. Eur Heart J 2009;30:2705–2713.
27. Maioli M, Bellandi F, Leoncini M, et al. Randomised early versus late abciximab in acute myocardial infarction treated with primary coronary intervention (RELAx-AMI trial). J Am Coll Cardiol 2007;49:1517–1524.
28. De Luca G, Gibson CM, Bellandi F, et al. Early glycoprotein IIb-IIIa inhibitors in primary angioplasty (EGYPT) cooperation: An individual patient data meta-analysis. Heart 2008;94:1548–1558.
29. Alexander D, Mann N, Fang-Shu O, et al. Patterns of upstream antiplatelet therapy use before primary percutaneous coronary intervention for acute ST-elevation myocardial in- farction (from the CRUSADE National Quality Improvement Initiative). Am J Cardiol 2008;102:1335–1340.
30. Pinto DS, Kirtane AJ, Ruocco NA, et al. Administration of intracoronary eptifibatide dur- ing ST-elevation myocardial infarction. Am J Cardiol 2005;96:1494–1497.
31. Gurm HS, Smith DE, Collins JS, et al. The relative safety and efficacy of abciximab and eptifibatide in patients undergoing primary percutaneous coronary intervention: Insights from a large regional registry of contemporary percutaneous coronary intervention. J Am Coll Cardiol 2008;51:529–535.
32. Wu TG, Huang WG, Wei JR, et al. Effect of intracoronary tirofiban in patients un- dergoing percutaneous coronary intervention for acute coronary syndrome. Circ J 2008;72:1605–1609.
33. Gu YL, Fokkema ML, Kampinga MA, et al. Intracoronary versus intravenous abciximab in ST-segment elevation myocardial infarction: rationale and design of the CICERO trial in patients undergoing primary percutaneous coronary intervention with thrombus aspi- ration. Trials 2009;10:90.
34. Sardella G, Sangiorgi GM, Mancone M, et al. A multicenter randomized study to evaluate intracoronary abciximab with the ClearWay catheter to improve outcomes with lysis (IC ClearLy): Trial study design and rationale. J Cardiovasc Med (Hagerstown) 2009 Nov 13. [Epub ahead of print].