Platelet aggregation inhibition (PAI) of ≥95% has been associated with improved outcomes after percutaneous coronary intervention (PCI) and glycoprotein IIb/IIIa inhibitor treatment. A greater thrombotic burden in acute ST-segment elevation myocardial infarction (STEMI) might require higher doses and/or intracoronary delivery of glycoprotein IIb/IIIa inhibitors to achieve optimal PAI. Using a 2 × 2 factorial placebo-controlled design, 105 patients with STEMI who had been referred for primary PCI within 6 hours of symptom onset were randomized to intracoronary (IC) or intravenous (IV) delivery of an abciximab bolus at a standard dose (0.25 mg/kg) or high dose (≥0.30 mg/kg) of abciximab. The primary end point was PAI measured at 10 minutes after the bolus of abciximab. Secondary end points included the acute and 6-month outcomes using angiographic parameters, cardiac biomarkers, cardiovascular magnetic resonance imaging, and clinical end points. At 10 minutes after the bolus, the proportion of patients with ≥95% PAI was not different between the IC and IV groups (53% vs 54%, p = 1.00) nor between the high-dose and standard-dose bolus groups (56% vs 51%, p = 0.70). Acutely, the angiographic myocardial blush grades, peak release of cardiac biomarkers, necrosis size, myocardial perfusion, and no reflow as assessed by magnetic resonance imaging, and clinical end points were similar between the groups and did not suggest a benefit for IC compared to IV or high-dose versus standard-dose bolus of abciximab. No increase occurred in bleeding complications with the high-dose bolus or IC delivery. The clinical, angiographic and cardiac magnetic resonance imaging outcomes at 6 and 12 months were similar between the 4 groups. In conclusion, in patients with STEMI presenting with symptom onset <6 hours and undergoing transradial primary PCI, PAI remained suboptimal, despite a higher dose bolus of abciximab. A higher dose bolus or IC delivery of abciximab bolus was not associated with improved acute or late results compared to the standard IV dosing and administration.
In the present study, our objective was to evaluate the effects of intracoronary (IC) versus intravenous (IV) delivery of an abciximab bolus at a high dose compared to a standard dose in patients with ST-segment elevation myocardial infarction (STEMI) referred for primary percutaneous coronary intervention (PCI) within 6 hours of symptom onset.
Methods
The EArly Discharge after Transradial Stenting of CoronarY Arteries in Acute Myocardial Infarction (EASY-MI) trial was a prospective randomized, double-blind, 2-by-2 factorial, and placebo-controlled trial comparing a high-dose bolus and standard-dose bolus and IC versus IV bolus administration of abciximab immediately before primary PCI for patients with STEMI. The specific entry criteria for the EASY-MI trial were as follows. Patients were >18 years old, with symptom onset <6 hours, and had a qualifying 12-lead electrocardiogram that fulfilled any of the following 4 criteria: (1) ≥2 mm of ST-segment elevation in ≥2 contiguous precordial electrocardiographic leads (anterior infarction); (2) ≥2 mm of ST-segment depression in V 1 , V 2 or V 2 , V 3 coupled with a reciprocal 1-mm ST-segment elevation in lead II, augmented unipolar foot lead (aVF), and V 6 (posterior infarction); (3) ≥1 mm of ST-segment elevation in ≥2 contiguous limb electrocardiographic leads (other infarction); or (4) new left bundle branch block. The patients were excluded from randomization if they had received previous thrombolytic therapy or glycoprotein IIb/IIIa inhibitors, had any allergy or intolerance to aspirin or thienopyridines, had an international normalized ratio >2.0 or a contraindication to abciximab administration, or had uncontrolled high blood pressure, cardiogenic shock, or infarction caused by in-stent thrombosis or restenosis. Health Canada and the Quebec Heart-Lung Institute research ethics board approved the protocol, which was registered on the Clinicaltrials.gov web site (NCT00440778). All patients signed an informed consent form before the procedure.
The patients were randomly assigned to receive IC or IV bolus administration of abciximab (ReoPro, Centocor, Malvern, Pennsylvania) versus placebo, at a standard-dose bolus (0.25 mg/kg) or high-dose bolus (calculated as the sum of the standard 0.25 mg/kg bolus amount plus the standard infusion amount), followed by an infusion of 0.125 μg/kg/min (to a maximum of 10 μg/min) of abciximab versus placebo for 12 hours, in a 2 × 2 factorial design. All placebo volumes were matched to the corresponding abciximab volumes.
All patients were pretreated with aspirin (325 mg) and clopidogrel (recommended loading dose of 600 mg as soon as possible after the initial medical contact) and underwent coronary angiography and angioplasty using transradial artery access. Randomization was performed immediately after identification of the culprit lesion by the opening of sealed envelopes. The IC boluses of abciximab and placebo were given through the guiding catheter before the first balloon inflation. The IV and IC boluses were administered simultaneously within ∼1 minute. Predilation was allowed, and the sirolimus-eluting stent (Cypher Select+, Cordis, Johnson & Johnson, Miami, Florida) was recommended. The vascular sheaths were removed at the end of the procedure, and a hemostasis band was applied in place until hemostasis had completed. All patients were prescribed post-PCI aspirin (80 mg/day) and clopidogrel (75 mg/day) for ≥12 months.
Hematologic tests and chemistry profiles were performed before and after the procedure, according to the hospital’s standard practice. Troponin T, total creatine kinase, and creatine kinase-MB were evaluated on samples collected immediately before the procedure and every 8 hours for the first 48 hours after PCI. To assess the necrosis size, we used the peak values, as previously reported. The study personnel performed the clinical follow-up examinations of all patients the day after PCI and 30 ± 7 days, 3 months ± 30 days, 6 months ± 30 days, and 12 months ± 30 days and recorded any clinically relevant adverse events. Repeat angiography was scheduled at 6 months after PCI.
Platelet aggregation was measured immediately before the intervention (baseline) and at 10 minutes and 6 hours after the abciximab/placebo bolus, using the VerifyNow IIb/IIIa assay (Accumetrics, San Diego, California). The proportion of patients with platelet aggregation inhibition (PAI) of ≥95% (maximal PAI) at 10 minutes after the abciximab bolus and the mean PAI at 10 minutes (mean PAI) and 6 hours after the abciximab bolus were assessed.
The coronary angiograms, obtained at baseline, at completion of the stenting procedure, and at 6 months of follow-up, were analyzed by technicians who remained unaware of the treatment group assignment, using a computer-based off-line analysis system (CMS, version 7.0, Medis Medical Imaging Systems, Leiden, The Netherlands). The quantitative coronary angiographic analyses were done at our core laboratory. The angiographic projections used were those that allowed evaluation of the Thrombolysis In Myocardial Infarction flow and myocardial blush grade, as previously described. All measurements were performed on angiograms recorded after intracoronary administration of nitroglycerin. Care was taken to choose identical projections of the target lesion for all assessed angiograms. Using the baseline angiogram, we measured the minimal luminal diameter and reference vessel diameter of the lesion. Using the postintervention and follow-up angiograms, we measured the in-stent minimal lumen diameter, minimal lumen diameter in the reference segment, and percentage of diameter stenosis. In-stent late luminal loss was calculated as the difference between the final in-stent minimal lumen diameter after the intervention and the in-stent minimal lumen diameter at follow-up angiography. Angiographic restenosis was defined as ≥50% in-segment stenosis. The baseline and follow-up left ventricular angiograms filmed in 30° right anterior oblique view were manually traced using the same software package.
Late gadolinium-enhanced cardiac magnetic resonance imaging was used to assess myocardial injury at baseline and at 6 months of follow-up, as previously described. Image analysis was performed off-line by technicians unaware of the treatment assignment according to the 16-segment model (CMR MASS software system, version 6.2.3, Medis Medical Imaging Systems). Myocardial perfusion was assessed by the kinetics of myocardial enhancement during rapid intravenous injection of gadolinium contrast. The interval to 50% maximum upslope on the contrast kinetics curve was compared for each segment to the upslope of the left ventricular blood pool as a reference. Late gadolinium enhancement was quantified by semiautomatic detection using the full-width half-maximum approach to maximize accuracy and reproducibility. In the event of microvascular obstruction, as evidenced by a dark core circumscribed within a hyperenhanced border on late gadolinium enhancement (LGE) images, this area of “no reflow” was included in the measurement of the LGE volume. The LGE size, as a marker of necrosis size, was reported in milliliters indexed to body surface area and calculated as a percentage of the total left ventricular myocardium volume. Microvascular obstruction was manually traced by a single experienced operator and reported as a volume. Bland-Altman analyses, performed on 40 studies, indicated a mean difference of 0.4% (95% limits of agreement ±3.2%) between 2 readers (interobserver) and mean differences of 0.3% (95% limits of agreement ±3.2%) between 2 readings by a single reader (intraobserver). The κ statistic for the dichotomous presence/absence of LGE was 0.96 for intraobserver and 0.92 for interobserver variability.
The primary end points of the present study were the maximum and mean PAI at 10 minutes after administration of the abciximab bolus. The PAI at 6 hours after the bolus was a secondary end point. All other assessments were also secondary end points, including the angiographic end points (ie, the proportion of patients having myocardial blush grade 2 to 3 and Thrombolysis In Myocardial Infarction 3 flow at the end of PCI in the culprit vessel, magnetic resonance imaging measurements during the in-hospital phase and at 6 months, and the restenosis rate [diameter stenosis ≥50%], and late loss in the culprit vessel at 6 months). The clinical end points were the 30-day rates of death from any cause, stroke, repeat myocardial infarction, urgent target vessel revascularization (any unplanned revascularization, PCI, or coronary artery bypass grafting for ischemia), and major bleeding episodes (according to the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events [REPLACE]-2 trial criteria), and the composite of death, repeat myocardial infarction, and target vessel revascularization at 6 and 12 months.
The study sample size was determined by the primary end point of PAI at 10 minutes after the bolus of abciximab. Because no data on PAI after the abciximab bolus dose >0.25 mg/kg were available, we used previous data that had estimated the proportion of patients with maximal PAI after a standard 0.25 mg/kg bolus of abciximab to be 60%. A sample size of 104 subjects provided 80% power if that proportion would be increased to 82% in high-dose bolus patients using a significance level of α = 0.05. Because we did not anticipate a significant difference in PAI between the IC and IV abciximab groups, we estimated that a sample size of 100 patients would provide >95% power with a 2-sided α = 0.05 to detect a 30% improvement in the percentage of patients with a myocardial blush grade 2 to 3 with IC delivery compared to IV delivery, as shown in Bellandi et al.
The categorical variables are expressed as numbers and percentages, and continuous variables as the mean ± SD. The baseline and procedural characteristics and event rates in the randomized groups were analyzed using the chi-square test or Fisher’s exact test for proportions and Student’s t test for continuous variables. p Values <0.05 were considered significant. Statistical tests were performed with JMP software, version 7.0 (SAS Institute, Cary, North Carolina).
Results
From April 2007 to April 2008, of 410 patients referred for primary PCI at our institution, 105 met all the inclusion/exclusion criteria, were recruited, and underwent transradial coronary intervention. The baseline and procedural characteristics were similar between the groups, although more patients in the IC group received the 600 mg clopidogrel loading dose compared to the IV group (p = 0.03; Tables 1 and 2 ). Of the 105 patients, 60% had been transferred from referring centers, with a mean symptom-to-balloon time <180 minutes. All patients presented in Killip class I or II. Most (80% to 85%) procedures were performed with a 6Fr catheter and all procedures were completed using the transradial approach. Thrombectomy (Export, Medtronic, Minneapolis, Minnesota) was used before abciximab delivery in ∼40% of the cases. Most received ≥1 sirolimus-eluting stents in the culprit vessel, although 5 patients did not receive drug-eluting stents, and 1 patient underwent only balloon angioplasty. IC abciximab delivery did not induce any untoward hemodynamic or arrhythmic events.
| Variable | Abciximab Bolus Route | Abciximab Bolus Dose | ||||
|---|---|---|---|---|---|---|
| IC (n = 53) | IV (n = 52) | p Value | HDB (n = 50) | SDB (n = 55) | p Value | |
| Age (years) | 59 ± 9 | 59 ± 9 | 0.96 | 59 ± 10 | 60 ± 8 | 0.79 |
| Men | 41 (77%) | 43 (83%) | 0.63 | 37 (74%) | 47 (85%) | 0.15 |
| Diabetes mellitus | 4 (8%) | 5 (10%) | 0.74 | 3 (6%) | 6 (11%) | 0.49 |
| Treated hypertension | 23 (43%) | 23 (44%) | 1.00 | 22 (44%) | 24 (44%) | 1.00 |
| Treated dyslipidemia | 24 (45%) | 26 (50%) | 0.70 | 21 (42%) | 29 (53%) | 0.33 |
| Tobacco use (current and past) | 37 (70%) | 40 (77%) | 0.51 | 33 (66%) | 44 (80%) | 0.13 |
| Previous myocardial infarction | 6 (11%) | 9 (17%) | 0.42 | 7 (14%) | 8 (15%) | 1.00 |
| Previous percutaneous coronary intervention | 3 (6%) | 6 (12%) | 0.32 | 5 (10%) | 4 (7%) | 0.73 |
| Previous coronary artery bypass surgery | 0 (0%) | 1 (2%) | 0.50 | 0 (0%) | 1 (2%) | 1.00 |
| Height (cm) | 170 ± 7 | 170 ± 9 | 0.91 | 169 ± 8 | 171 ± 8 | 0.34 |
| Weight (kg) | 78 ± 15 | 80 ± 15 | 0.50 | 77 ± 15 | 80 ± 15 | 0.32 |
| Patients from referring center | 31 (58%) | 32 (62%) | 0.84 | 28 (56%) | 35 (64%) | 0.43 |
| Symptoms to balloon time (minutes) | 177 ± 73 | 178 ± 77 | 0.97 | 182 ± 84 | 173 ± 65 | 0.50 |
| Door-to-balloon time (minutes) | 90 ± 43 | 87 ± 39 | 0.76 | 91 ± 43 | 86 ± 39 | 0.53 |
| Variable | Abciximab Bolus Route | Abciximab Bolus Dose | ||||
|---|---|---|---|---|---|---|
| IC (n = 53) | IV (n = 52) | p Value | HDB (n = 50) | SDB (n = 55) | p Value | |
| Infarct-related coronary artery | ||||||
| Right | 26 (49%) | 29 (56%) | 0.48 | 26 (52%) | 29 (53%) | 0.96 |
| Left anterior descending | 22 (42%) | 21 (40%) | 21 (42%) | 22 (40%) | ||
| Circumflex | 5 (9%) | 2 (4%) | 3 (6%) | 4 (7%) | ||
| Clopidogrel 600 mg | 47 (89%) | 37 (71%) | 0.030 | 39 (78%) | 45 (82%) | 0.64 |
| Aspiration catheter | 21 (40%) | 23 (44%) | 0.69 | 20 (40%) | 24 (44%) | 0.84 |
| Procedure duration (minutes) | 36 ± 19 | 43 ± 37 | 0.23 | 36 ± 15 | 44 ± 38 | 0.13 |
| Initial activated clotting time (seconds) | 199 ± 55 | 197 ± 53 | 0.87 | 208 ± 48 | 189 ± 57 | 0.075 |
| Postbolus activated clotting time (seconds) | 284 ± 78 | 313 ± 93 | 0.097 | 291 ± 86 | 306 ± 87 | 0.39 |
| Maximum creatine kinase (U/L) | 1,529 ± 1825 | 1,632 ± 1424 | 0.75 | 1,472 ± 1411 | 1,677 ± 1810 | 0.52 |
| Maximum creatine kinase-MB (μg/L) | 143 ± 146 | 166 ± 158 | 0.44 | 143 ± 138 | 164 ± 164 | 0.49 |
| Maximum troponin T (μg/L) | 3.93 ± 4.07 | 4.37 ± 3.91 | 0.58 | 4.09 ± 4.22 | 4.21 ± 3.79 | 0.88 |
At 10 minutes and 6 hours after the bolus of abciximab, no difference was found in the maximum and mean PAI between the groups ( Figure 1 ). Necrosis size, as assessed by cardiac biomarker measurement, was also similar between groups ( Table 2 ). Most patients presented with an occluded Thrombolysis In Myocardial Infarction 0 to 1 vessel before PCI. After PCI, the Thrombolysis In Myocardial Infarction flow grade was not significantly different among the groups. The incidence of myocardial blush grade 2 and 3 was slightly greater in the IC group than in the IV group (88% vs 75%, respectively; p = 0.13). However, no difference was found between the high-dose and standard-dose bolus groups ( Table 3 ). Overall, the in-stent late loss with sirolimus-eluting stents was 0.14 ± 0.48 mm. At the 6-month angiographic follow-up, 1 silent stent occlusion in a mid-left anterior descending artery was noted, but no other restenosis (diameter stenosis >50%) was observed.
| Variable | Abciximab Bolus Route | Abciximab Bolus Dose | ||||
|---|---|---|---|---|---|---|
| IC | IV | p Value | HDB | SDB | p Value | |
| Thrombolysis In Myocardial Infarction flow grade | ||||||
| Before percutaneous coronary intervention | ||||||
| 0 | 31 (57%) | 31 (60%) | 0.69 | 28 (56%) | 34 (61%) | 0.45 |
| 1 | 6 (11%) | 8 (15%) | 9 (18%) | 5 (9%) | ||
| 2 | 14 (26%) | 9 (17%) | 9 (18%) | 14 (25%) | ||
| 3 | 3 (6%) | 4 (8%) | 4 (8%) | 3 (5%) | ||
| After percutaneous coronary intervention | ||||||
| 0 | 1 (2%) | 0 (0%) | 0.46 | 0 (0%) | 1 (2%) | 0.17 |
| 1 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | ||
| 2 | 3 (6%) | 5 (10%) | 6 (12%) | 2 (4%) | ||
| 3 | 50 (93%) | 47 (90%) | 44 (88%) | 53 (95%) | ||
| Myocardial blush grade at end of procedure | ||||||
| 0–1 | 6 (12%) | 13 (25%) | 0.13 | 10 (21%) | 9 (17%) | 0.80 |
| 2–3 | 44 (88%) | 38 (75%) | 38 (79%) | 44 (83%) | ||
| Left ventricular ejection fraction (%) | ||||||
| Initial | 64 ± 12 | 64 ± 10 | 0.96 | 63 ± 11 | 64 ± 11 | 0.60 |
| Follow-up | 69 ± 11 | 67 ± 10 | 0.28 | 69 ± 10 | 67 ± 11 | 0.35 |
| Quantitative coronary analysis | ||||||
| Stent size (mm) | 3.1 ± 0.4 | 3.1 ± 0.3 | 0.32 | 3.1 ± 0.4 | 3.0 ± 0.4 | 0.22 |
| Stent length (mm) | 20.8 ± 7.9 | 21.3 ± 7.8 | 0.71 | 21.9 ± 7.4 | 20.3 ± 8.2 | 0.21 |
| Stented length (mm) | 30.5 ± 14.7 | 29.2 ± 16.9 | 0.67 | 30.7 ± 14.8 | 29.1 ± 16.8 | 0.59 |
| Minimal lumen diameter before stenting (mm) | 0.37 ± 0.50 | 0.31 ± 0.45 | 0.51 | 0.34 ± 0.46 | 0.34 ± 0.48 | 0.97 |
| Reference diameter before stenting (mm) | 3.03 ± 0.45 | 2.96 ± 0.44 | 0.45 | 2.99 ± 0.38 | 2.99 ± 0.49 | 0.95 |
| Stenosis before stenting (%) | 88 ± 16 | 89 ± 16 | 0.71 | 88 ± 15 | 88 ± 16 | 0.95 |
| Minimal lumen diameter after stenting (mm) | 2.76 ± 0.39 | 2.70 ± 0.33 | 0.44 | 2.81 ± 0.35 | 2.67 ± 0.36 | 0.048 |
| Reference diameter after stenting (mm) | 3.12 ± 0.38 | 3.07 ± 0.35 | 0.42 | 3.17 ± 0.34 | 3.03 ± 0.37 | 0.064 |
| Stenosis after stenting (%) | 12 ± 4 | 12 ± 4 | 0.99 | 11 ± 3 | 12 ± 4 | 0.33 |
| Minimal lumen diameter at follow-up (mm) | 2.56 ± 0.75 | 2.63 ± 0.45 | 0.60 | 2.76 ± 0.44 | 2.45 ± 0.72 | 0.018 |
| Reference diameter at follow-up (mm) | 3.18 ± 0.37 | 3.14 ± 0.38 | 0.59 | 3.25 ± 0.40 | 3.08 ± 0.34 | 0.040 |
| Stenosis follow-up (%) | 20 ± 20 | 16 ± 9 | 0.29 | 15 ± 6 | 21 ± 20 | 0.080 |
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