Comparison Between Glycoprotein IIb/IIIa Blockade and Distal Protection Device for the Restoration of Myocardial Perfusion Durin

The key treatment strategy for patients with acute ST-segment elevation myocardial infarction (MI) is rapid complete restoration of antegrade coronary flow.^1–6 Recognition of distal embolization of atherothrombotic debris in the microvasculature⁷ highlighted the significance of tissue level myocardial reperfusion⁸ in both fibrinolytic⁹ and catheter-based^10,11 therapies. Indeed, the “no-reflow” phenomenon occurs in >= 25% of patients with brisk antegrade flow following recanalization of anterior MI.¹² Indeed, the occurrence of “no-reflow” and distal embolization during direct percutaneous coronary intervention (PCI) portends a poorer outcome.¹³ Several adjunctive pharmacological agents have been developed to improve microvascular perfusion and outcomes,^14–18 especially potent antiplatelet agents.¹⁹ The use of abciximab in patients undergoing coronary stenting for acute MI was associated with better coronary flow, regional and global left ventricular systolic function.¹⁵ Another approach to reduce embolic burden is to remove atherothrombotic debris. Several occlusion or filter devices have been shown to be safe and efficacious during vein graft^20,21 and carotid^22,23 interventions. However, the relative impact of glycoprotein (GP) IIb/IIIa blockade and distal protection in restoring microvascular flow is unclear. Therefore, we compared the angiographic markers of myocardial perfusion between patients receiving abciximab and distal balloon occlusion device (DBOD) during PCI of ST-segment elevation MI. Materials and Methods Patient population. A total of 803 consecutive patients who underwent direct PCI from February 1999 to September 2002 = 2 mm in >= 2 contiguous precordial leads or >= 1 mm in >= 2 contiguous limb leads) or left bundle branch block were identified from a prospective registry. Only those treated with bolus and infusion of abciximab initiated at the Emergency Room or DBOD only were included regardless of age, hemodynamic status or infarct territory. Patients undergoing rescue angioplasty for failed fibrinolytic therapy were excluded. Only 114 patients met these criteria and were analyzed. Clinical data were obtained from the case notes and follow-up was conducted using physician office visits or telephone calls. All patients received loading doses of aspirin (300 mg), and ticlopidine (500 mg) or clopidogrel (300 mg) in the emergency room. Following the procedure, aspirin 100 mg daily was continued indefinitely and ticlopdine 250 mg twice daily or clopidogrel 75 mg daily for 4 weeks. The use of other medicines was left to the discretion of the attending physician. The study protocol was approved by the Ethics Committee. Death was defined as mortality from any cause. Recurrent MI has occurred when there was recurrence of chest pain with new electrocardiographic changes or elevation of creatine phosphokinase (CPK >= 2 times the upper limit or the last known value). The composite endpoint consisted of the occurrence of death, repeat MI or target vessel revascularization (TVR). Angioplasty procedures. Coronary angioplasty was performed using standard techniques via the femoral approach. The use of coronary stents was left to the discretion of the operator. Among those treated with abciximab, the bolus dose (0.25 mg/kg) and 12-hour infusion (0.125 µg/kg/min, upto a maximum of 10 µg/min) were initiated at the Emergency Room. Prior to angioplasty, 50 U/kg of heparin was administered to this group of patients, which has been previously shown to adequate in inhibiting thrombin generation.²⁴ Conversely, those in the DBOD group were treated with a heparin dose of 100 U/kg. The GuardWire^™ balloon occlusion device (Medtronic, Santa Rosa, California) was used for distal protection. After crossing the lesion with the 0.014-inch hollow core GuardWire, the distal vessel was usually opacified and its size could be estimated. The proximal end of the wire was attached to the MicroSeal^™ adaptor to inflate distal elastometric balloon at the tip (range of inflated diameter, 3–6 mm) using the EZ Flator^™ filled with diluted radiographic contrast. Subsequently, the wire was disconnected from the adaptor and the 5 French aspiration Export^™ catheter was advanced over the wire until it was just proximal to the occlusion balloon. The proximal end of the Export catheter was connected to a syringe and 20 to 40 mL of blood was aspirated through the length of the lesion. After retrieving the Export catheter, the occlusion balloon was deflated and antegrade flow was restored. This process was repeated with each treatment, either balloon or stent, of the lesion. The door-to-balloon time was computed based on the use of the first treatment device following initial aspiration of the culprit lesion. A 12-lead electrocardiogram was performed after the procedure to determine the amount of ST-segment resolution. Qualitative and quantitative angiographic core laboratory analyses were performed blinded to clinical outcomes. Electronic calipers were used for quantitative coronary angiography. Antegrade flow in the infarct-related artery was assessed using the TIMI grades.¹ Although myocardial perfusion can be determined using visual assessment on the rate of entry and exit of contrast into and out of the territory⁹ and the intensity of contrast in territory of the myocardium supplied by the infarct-related artery,¹⁰ the densitometric is likely to be superior to the dynamic technique.²⁵ Therefore, the myocardial blush grade (MBG) is used in this study to quantify perfusion of the micro-circulation. Data management and statistical analysis. Data management and statistical analysis were performed using Statistical Package for Social Sciences (SPSS) for Windows (Chicago, Illinois). Continuous variables were expressed as median with 25th and 75th percentile in parenthesis, and mean with standard deviation. Categorical variables were expressed in percentages. For continuous variables, the Mann-Whitney U-test was used to analyze differences between the 2 groups. For categorical variables, the chi-square or Fischer’s exact tests were used to analyze differences between the 2 groups. All p-values were 2-tailed. Multivariable analysis was performed using logistic and linear regression modeling to determine the use of DBOD with the occurrence of good MBG (2 or 3) and relationship with corrected TIMI frame count, adjusting for covariates, respectively. The variables included in the models were age, and significant differences in baseline characteristics (p Baseline characteristics. Of 114 patients, 40 received bolus and infusion of abciximab and another 74 patients were treated with DBOD. Baseline clinical characteristics were comparable between the 2 groups except the proportions of patients with diabetes and hypertension were higher among those treated by DBOD (Table 1). Patients in the DBOD group were slightly older and the proportion with anterior MI was marginally lower. Although the duration of infarction from onset was similar between the 2 groups, those treated with DBOD had a longer door-to-balloon time (Table 2). Peak CPK levels and left ventricular ejection fraction were similar between the 2 groups. While the proportion of patients receiving stents was similar between the 2 groups, stent size was larger among those in the DBOD group. Angiographic characteristics. (Table 3). At initial coronary angiography, the proportion of patients with a patent infarct-related vessel (TIMI flow grade >= 2) was higher in the abciximab group (37.5% versus 18.9%; p = 0.03). Correspondingly, the corrected TIMI frame count was significantly lower and the proportion of patients with MBG >= 2 was higher (12.5% versus 5.4%; p = 0.015). Although the reference diameter of the infarct-related artery was smaller in the abciximab group, the minimal luminal diameter was larger, resulting in a less severe diameter stenosis. At the end of the angioplasty procedure, the proportion of patients with TIMI flow grade 3 was similar between the 2 groups. There was no additional injury, such as dissection or perforation, caused by the DBOD. However, there was a significantly greater proportion of patients with MBG >= 2 (50.0% versus. 75.0%; p = 0.008) and a lower corrected TIMI frame count in the DBOD group. After adjusting for significant baseline differences, the odds for achieving a MBG >= 2 with DBOD was 4.1 (95% confidence interval [CI], 1.3 to 13.3; p = 0.017) compared with the use of abciximab. Similarly, the use of DBOD was associated with an adjusted reduction of 11 corrected TIMI frame counts (95% CI, 5 to 18; p = 0.001). Clinical outcomes. There was little difference in 30-day and 6-month adverse clinical outcomes, including TVR, between these 2 groups of patients (Table 4). Peak CPK level and left ventricular ejection fraction were comparable between 2 groups. There was 1 patient in the abciximab group who had severe gastrointestinal bleeding resulting in death, and 2 (2.7%) patients with minor bleeding complications in the DBOD group. The median time for the electrocardiogram following intervention was similar between patients receiving abciximab (58 minutes, interquartile range, 48, 69) and DBOB (58 minutes, interquartile range, 47, 67). Although the distribution pattern of the degree of ST-segment resolution following PCI differed between the 2 groups, it was not statistically significant (Figure 1). The proportions of patients with >= 70% ST-segment resolution were 27.5% and 41.9% for the abciximab and DBOB groups (p = 0.13), respectively. Clinical outcomes were better with greater degree of ST-segment resolution. The occurrences of 30-day death or MI was substantially lower among those with >= 70%, 30–69%, and 26 These mechanical and morphological changes increase fibrin exposure and improve endogenous fibrinolysis providing better coronary artery patency. Furthermore, GP IIb/IIIa receptor inhibition is associated with ~50% reduction microvasculature thrombosis in a murine stroke model,²⁷ and a smaller cerebral ischemic volume. Its actions on platelet aggregates, leucocytes plugging and endothelial function improve coronary blood flow in the infarct zone,¹⁵ and reduce re-occlusion of the infarct-related artery^17,28 and reperfusion injury. Beyond these promising bench results, the value of abciximab was established in clinical studies. Regional and global left ventricular systolic function, and microvascular integrity were better preserved,^15,29 as microvascular obstruction portends a poor prognosis.30 Our study showed that abciximab provided faster restoration of coronary flow, with lower pre-treatment corrected TIMI frame count and slightly better MBG. Although abciximab improved 6-month survival (92.6% versus 84.1%; p = 0.02) among patients with acute MI undergoing coronary stenting in the Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-term Follow-up (ADMIRAL) trial,²⁸ this favorable result was not corroborated by the larger Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) study.³¹ In this trial, however, ~10% non-abciximab groups crossover to receive the agent. Conversely, in an elective setting, the benefit of abciximab in patients was amplified in the large-scale Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial.³² Large peri-procedural MI (CPK-MB >= 5-fold) and 1-year mortality (2.4% versus 1.0%) were reduced by >50 % among those treated with abciximab. The ADMIRAL investigators attributed the benefit of abciximab to the early restoration of normal flow prior to PCI (16.8% versus 5.4%; p = 0.01).²⁸ Similarly, the proportion of patients with pre-angioplasty TIMI flow grade 3 was marginally higher among our patients treated with abciximab, as with those in the CADILLAC study (23.9% versus 20.3%; p = 0.056).³¹ The reason for these large absolute differences is unclear and may be related to the time of administration of abciximab. In the ADMIRAL study,²⁸ abciximab was administered in the mobile intensive care or Emergency Room in 26% of patients, while the drug was administered in the cardiac catheterization laboratory in the CADILLAC trial.³¹ Is there a need for distal protection? Although abciximab improved outcomes of patients with MI, little benefit can be expected from GP IIb/IIIa blockade if atheromatous debris is large. Abciximab did not improve outcomes during vein graft PCI,^33,34 likely due to the embolism of particulate rather than thrombus material.³⁵ Similarly, atherosclerotic gruel and thrombus may be dislodged during acute intervention of MI.³⁶ Therefore, the use of DBOD appears to be an attractive strategy to prevent microvascular obstruction. Results from vein graft interventions have been very encouraging,²⁰ even among those receiving GP IIb/IIIa inhibitors. In other heterogenous groups of MI patients, DBOD in acute MI provided superior outcomes.^37,38 Using an elastometric balloon to block flow in an already occluded artery for an additional few minutes is unlikely to increase further myocardial injury. We found that during acute intervention for ST-segment-elevation MI, DBOD provided a lower corrected TIMI frame count and better MBG. Due to the small number of patients and short duration of follow-up, we were unable to determine differences in clinical outcome. The elastometric balloon and repeated passage of the Export^TM catheter did not induce additional damage in our patients as evident by similar 6-month TVR rates. However, whether the combination of GP IIb/IIIa blockade and distal protection is superior remains unknown as during the passage of the GuardWire, distal embolization can still occur. Other mechanical techniques such as thrombectomy aspiration^39,41 and ultrasounic fibrinolysis⁴² have also been used to prevent distal embolization. By breaking down and removing clot and debris, these devices are believed to be superior to filtration or aspiration only. The early experiences with the X-sizer^39,40 and rheolytic thrombectomy⁴¹ in thrombus-containing lesions have been encouraging. Limitations. As this was not a randomized trial, there could be selection bias. Choice of strategy was unlikely influenced by operator preference because abciximab and DBOD were utilized in consecutive time periods. Nonetheless, there were differences in baseline characteristics. The longer door-to-balloon time was attributed to the initial aspiration prior to balloon dilatation or stent deployment among patients treated with DBOD. Also, when the DBOD was first available in our center, the size of the distal elastometric balloon size ranged from 3–6 mm. Therefore, the reference diameter of the infarct-related artery was correspondingly larger. These baseline differences were adjusted for in multivariable models. Alternate techniques of assessing coronary microcirculation, such as flow wire, could also be utilized. Currently, a large prospective randomized control trial is required to validate these findings and determine if these benefits translate to better clinical outcomes. The Enhanced Myocardial Efficiency and Removal by Aspiration of Liberated Debris (EMERALD), conducted in North America, may provide further insight. A total of 500 patients were randomized to either standard or protected, using the GuardWire system, during PCI for acute MI

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