Intracoronary Versus Intravenous Administration of Abciximab in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention With Thrombus Aspiration: The Comparison of Intracoronary Versus Intravenous Abciximab Administration During Emergency Reperfusion of ST-Segment Elevation Myocardial Infarction (CICERO) Trial

The Comparison of Intracoronary Versus Intravenous Abciximab Administration During Emergency Reperfusion of ST-Segment Elevation Myocardial Infarction (CICERO) trial was a single-center, prospective, randomized, open-label trial with blinded evaluation of end points. The detailed study design has been published previously.¹³ Between September 2008 and April 2010, consecutive STEMI patients undergoing primary PCI were randomly assigned to either an intracoronary or an intravenous bolus of abciximab (0.25 mg/kg body weight; ReoPro 2 mg/mL; Centocor BV, Leiden, the Netherlands). This study was performed at a high-volume university medical center providing 24-hour emergency cardiac care with 7 referral hospitals in a region of 750 000 inhabitants. The study was approved by the Medical Ethics Review Committee of the University Medical Center of Groningen. All patients gave informed consent.

All STEMI patients who were candidates for primary PCI were considered eligible for participation. STEMI was defined as chest pain suggestive of myocardial ischemia for at least 30 minutes before hospital admission, time from symptom onset of <12 hours, and an ECG with new ST-segment elevation in 2 or more contiguous leads of ≥0.2 mV in leads V₂ to V₃ and/or ≥0.1 mV in other leads or a new-onset left bundle-branch block. Exclusion criteria were rescue PCI after thrombolytic therapy, need for emergency coronary artery bypass grafting, presence of cardiogenic shock, a life expectancy of <6 months, inability to provide informed consent, age <18 years, and contraindications for the use of abciximab, including active internal bleeding, history of stroke within 2 years, recent major surgery or trauma, intracranial neoplasm, arteriovenous malformation or aneurysm, bleeding diathesis, severe uncontrolled hypertension, thrombocytopenia, vasculitis, hypertensive or diabetic retinopathy, severe liver or kidney failure, and hypersensitivity to murine proteins.

Patients were pretreated with aspirin (500 mg), heparin (5000 IU), and high-dose clopidogrel (600 mg), usually in the ambulance. When prasugrel became available in certain ambulances in 2010, use of prasugrel (60 mg) instead of clopidogrel was allowed. After diagnostic coronary angiography was performed, patients who met the eligibility criteria were randomized by means of sealed envelopes. After randomization, a bolus of abciximab was administered through the guiding catheter proximal to the lesion in the infarct-related artery over a period of 1 minute in patients assigned to intracoronary administration directly after first restoration of antegrade flow. The preferred initial treatment step to restore antegrade flow consisted of manual thrombus aspiration (Export Aspiration Catheter; Medtronic Inc, Santa Rosa, Calif) under continuous suction. In patients assigned to intravenous administration, abciximab was administered during PCI, but the exact timing of administration was not specified by protocol. Additional predilatation or postdilatation with a balloon and stent implantation were at the discretion of the operator. Intracoronary administration of nitroglycerine (400 μg) was administered periprocedurally at the operator's discretion. During PCI, additional low-dose weight-adjusted heparin was administered as guided by the activated clotting time (target, 200 to 250 seconds). No 12-hour infusion was initiated after PCI. Standard therapy after PCI included aspirin, clopidogrel, β-blockers, lipid-lowering agents, and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, according to current international guidelines.¹⁴

The primary end point was the incidence of restored myocardial reperfusion, defined as complete ST-segment resolution (STR). Secondary end points of myocardial reperfusion included myocardial blush grade (MBG) and residual ST-segment deviation. Other secondary end points included incidence of Q waves, postprocedural Thrombolysis in Myocardial Infarction (TIMI) flow and angiographically visible distal embolization, enzymatic infarct size, all-cause mortality, and major adverse cardiac events (a combined end point of cardiac mortality, reinfarction, and target vessel revascularization) at 30 days. A safety end point consisted of in-hospital bleeding, defined according to the TIMI bleeding classification.¹⁵

For evaluation of the ECG end points, a 12-lead ECG was acquired at the time of presentation and at 30 to 60 minutes after primary PCI. The magnitude of ST-segment deviation was measured 60 ms from the J point. STR was assessed by comparing the ST-segment deviation in the infarct-related area on the ECG after PCI with the ECG at presentation and was categorized as complete (>70%), partial (30% to 70%), or absent (<30%), as previously described.¹⁶ On the ECG after PCI, residual ST-segment deviation was categorized as <2, 2 to 5, 5 to 10, or >10 mm by summing the residual ST-segment deviation as previously described.¹⁷ New-onset Q waves on the ECG after PCI were defined as an initial negative deflection of the QRS complex of >0.1 mV and >40 ms in an ECG lead related to the myocardial area of infarction together with all pathological Q waves.¹⁸ All ECG recordings were analyzed by a physician blinded to treatment allocation and clinical data. When in doubt, the recordings were reviewed by 2 additional physicians until consensus was reached.

MBG was categorized as follows¹⁹: 0=no myocardial blush, or contrast density; 1=minimal myocardial blush; 2=moderate myocardial blush but less than that obtained during angiography of a contralateral or ipsilateral non–infarct-related coronary artery; and 3=normal myocardial blush comparable to that obtained during angiography of a contralateral or ipsilateral non–infarct-related coronary artery. In addition, MBG was measured with the quantitative blush evaluator, which provides a computer-assisted and continuous score.²⁰ TIMI flow was defined as previously described.²¹ Distal embolization after PCI was defined as a new circumscribed filling defect and/or abrupt cutoff of the vessel distal to the target lesion.²² Thrombus was assessed according to the criteria of the TIMI group.²³ Coronary angiograms were analyzed by 2 physicians blinded to treatment allocation and clinical data until consensus was reached.

Infarct size was estimated by serial measurements of cardiac markers, including creatine kinase, creatine kinase-MB, and cardiac troponin T. Blood was sampled at baseline and at 3, 6, 9, 12, 18, 24, and 48 hours after PCI in patients who were hospitalized in this center after PCI. Peak release, time to peak release, and area under the curve over the first 48 hours were determined. If patients were observed for shorter periods, the area under the curve was estimated by multiplying the time-averaged mean level by 48 hours (adjusted values).

Clinical follow-up was obtained from the central personal records database, hospital records, and interviews with the patients and/or their general practitioners. Mortality was considered cardiac unless an unequivocal noncardiac cause of death was established. Reinfarction was defined as recurrent symptoms suggestive of ischemia with new ST-segment elevation and/or elevation of the levels of cardiac markers.²⁴ Target vessel revascularization was defined as ischemia-driven revascularization of the infarct-related artery with PCI or coronary artery bypass grafting. Clinical events were adjudicated by a committee consisting of 3 physicians blinded to treatment allocation.

In previously published data, complete STR was achieved in 56.6% of STEMI patients treated with thrombus aspiration.⁸ To detect a 25% increase in the incidence of this primary end point in patients randomized to the intracoronary group, a total of 530 patients were required to achieve 90% power at a 5% significance level (2 sided), allowing 10% of ECGs to be not assessable for the primary end point. Statistical analyses were performed by intention to treat. Statistical significance was considered at a 2-tailed value of P<0.05. Differences between group means were assessed with the 2-tailed Student t test or Mann-Whitney U test if samples were not normally distributed. The χ² or Fisher exact test was used to test differences between proportions. Statistical analyses were performed with the Statistical Package for the Social Sciences version 16.0.2 (SPSS Inc, Chicago, Ill). Investigators had full access to all primary data.

The primary end point of complete STR was achieved in 64% of the intracoronary group and 62% of the intravenous group (P=0.562). STR could not be assessed in 20 of 271 patients (7.4%) in the intracoronary group and 26 of 263 patients (9.9%) of the intravenous group (P=0.302) because no pre-PCI ECG was available (n=11), no post-PCI ECG was available (n=24), or conduction abnormalities or arrhythmias were seen on the ECG (n=11). Patients without primary end-point analysis were slightly older, had a longer ischemic time, and more often had hypercholesterolemia, multivessel disease, and the left main, graft, or right coronary artery as the infarct-related artery. Concordantly, there were no differences in the distributions of residual ST-segment deviation between the intracoronary and intravenous groups (P=0.662; Figure 2). The incidence and number of Q waves on the postprocedural ECG were similar in both groups (77% versus 82%; P=0.143; median, 2 [IQR, 1 to 3] versus 2 [IQR, 1 to 4]; P=0.114). The median time from abciximab administration to the ECG after PCI was 4 minutes shorter for the intracoronary than for the intravenous group (38 minutes [IQR, 31 to 49 minutes] versus 42 minutes [IQR, 33 to 74 minutes]; P<0.001).

Coronary angiograms were assessable in 526 of 534 patients (99%). In contrast to the distribution of ECG end points, the distribution of MBG was borderline significant in favor of patients randomized to intracoronary administration (P=0.052; Figure 2). Moreover, the incidence of MBG 2/3 was significantly higher in the intracoronary than in the intravenous group (76% versus 67%; P=0.022). When measured quantitatively with the quantitative blush evaluator (available in 75% of patients), myocardial reperfusion was slightly better in the intracoronary group than in the intravenous group, but this was not statistically significant (10.1±3.5 versus 9.7±3.6; P=0.269). After thrombus aspiration, assessable in 90% of patients, flow was restored (TIMI grade 2/3) in 211 of 235 patients (90%) in the intracoronary group and 201 of 232 patients (87%) in the intravenous group (P=0.291). Postprocedural TIMI grade 3 flow was achieved in 89% and 86% of the intracoronary and intravenous groups, respectively (P=0.261). Postprocedural distal embolization occurred at similar frequencies between both groups (12% and 13%, respectively; P=0.635). The median time from abciximab administration to the angiographic run containing the blush sequence was 1 minute shorter for the intracoronary than for the intravenous group (8 minutes [IQR, 5 to 12 minutes] versus 9 minutes [IQR, 6 to 15 minutes]; P=0.006).

Data on enzymatic infarct size could be assessed in 248 of 534 patients (46%). Infarct size was ≈30% smaller in the intracoronary group than in the intravenous group (1214 U/L [IQR, 488 to 2184 U/L] versus 1746 U/L [IQR, 733 to 3383 U/L] for creatine kinase, P=0.008; 154 U/L [IQR, 62 to 262 U/L] versus 232 U/L [IQR, 90 to 400 U/L] for creatinine kinase-MB, P=0.003; and 3.03 μg/L [IQR, 0.95 to 5.81 μg/L] versus 4.36 μg/L [IQR, 1.43 to 8.56 μg/L] for cardiac troponin T, P=0.008; Table 2).

In total, 12 patients (2.2%) died within 30 days. All-cause mortality was 1.8% and 2.7% in the intracoronary and intravenous groups, respectively (P=0.524; Table 3). The incidence of major adverse cardiac events was low and not significantly different between the 2 groups (5.5% in the intracoronary group versus 6.1% in the intravenous group; P=0.786).

There were no adverse procedural events related to intracoronary abciximab administration. The incidence of in-hospital major and minor bleeding was low and similar between the intracoronary and intravenous groups (for major bleeding, 3.7% versus 3.4%, P=0.867; for minor bleeding, 7.7% versus 6.8%, P=0.688). In-hospital thrombocytopenia <150×10⁹/L developed in patients randomized to intracoronary and intravenous administration at similar frequencies (12% versus 13%; P=0.794).

First, we performed an open-label study because blinding of the operator was not feasible. However, all end points were assessed in a blinded manner. Second, this study was powered on STR instead of a clinical end point. However, STR is strongly related to clinical outcomes and therefore is widely accepted as a surrogate marker. In addition, STR was measured in this study only as a categorization into 3 groups, thereby preventing direct comparison between this study and previous studies reporting on continuous STR. In general, categorization makes a measurement less sensitive to treatment differences. However, STR categorized into 3 groups is frequently used in medium-scale interventional trials to detect a clinically relevant improvement in STR. Third, we analyzed enzymatic infarct size in the subset of patients who were hospitalized in this center after PCI. However, the choice to stay in this center was based on geographical reasons and not biased by randomization. Fourth, all patients in this study received abciximab in a bolus-only strategy, which is not currently recommended.¹⁴ Bolus-only use is supported by studies showing that bolus-only use reduces bleeding complications and is not inferior to abciximab bolus with subsequent 12-hour infusion in stable and moderate- to high-risk patients with acute coronary syndromes.³⁵,³⁶ In this study, we did not compare the bolus-only strategy with the standard bolus with subsequent 12-hour infusion strategy. However, because infusion was not initiated in either randomization group, it has not influenced our comparison of intracoronary and intravenous administration. Finally, we did not investigate the effect of timing of intracoronary administration. Although previous studies have reported on intracoronary administration after wire passage but before restoration of epicardial flow, we chose to perform intracoronary administration after restoration of flow to have an optimal local concentration through the coronary artery both at the culprit site and in the distal microvasculature.

In STEMI patients undergoing primary PCI with thrombus aspiration, intracoronary administration of abciximab is not superior to intravenous administration in improving myocardial reperfusion assessed by STR as the primary end point. However, intracoronary administration is associated with improved myocardial reperfusion as assessed by MBG and, in the subset of patients with evaluable infarct size, a smaller enzymatic infarct size. Larger randomized multicenter trials are required to evaluate whether intracoronary administration reduces clinical adverse events.