The use of glycoprotein (GP) IIb/IIIa inhibitors during percutaneous coronary interventions (PCI) in the acute phase of myocardial infarction (AMI) is still a matter of debate. The aim of the present study was to compare the outcomes of patients with acute ST-segment elevation myocardial infarction who underwent primary PCI and were concomitantly treated with GP IIb/IIIa inhibitors with those who were not treated with these drugs. Between January 1996 and November 2003, a total of 418 consecutive patients underwent PCI in the setting of ST-segment elevation AMI. At the operator’s discretion, 287 patients were concomitantly treated with GP IIb/IIIa inhibitors and 115 patients were not. Angiographic success and final TIMI 3 flow in the infarct-related artery was achieved more frequently in patients treated with GP IIb/IIIa inhibitors (90% vs. 77%; p = 0.001). The in-hospital composite endpoint of death, reinfarction and bleeding complications was significantly better in patients treated with GP IIb/IIIa inhibitors (4% vs. 12 %; p = 0.005). Furthermore, the adjusted 12-month survival rate was significantly better in these patients (RR: 2.99, CI: 1.29–6.9; p = 0.01). Therefore, adjunctive therapy with GP IIbIIIa inhibitors during primary PCI is associated with improved short-term outcomes and one-year survival without an increased risk of bleeding.

       In the last decade, primary percutaneous coronary intervention (PCI) has emerged as a superior strategy compared to thrombolytic therapy for coronary reperfusion in acute myocardial infarction patients.^1–4 It is associated with lower mortality and reinfarction rates, less recurrent ischemia, fewer hospital readmissions and less need for repeated revascularization, as compared to thrombolytic therapy, both within the first 30 days and during long-term follow-up. Nevertheless, recurrent ischemia and the need for further improvement in survival rates emphasized the need to find new techniques and adjunctive pharmacological therapy in order to reduce these events .^1,4–6
       The combined use of stents and platelet glycoprotein (GP) IIb/IIIa inhibitors has been validated in patients undergoing elective PCI,^7,8 but there has been ample controversy regarding their use in the setting of acute myocardial infarction (AMI). Several studies have assessed the role of GP IIb/IIIa inhibitors as an adjunctive therapy in AMI with conflicting results regarding their routine use during stenting.^5,9,10 The aim of the present study was to compare the outcomes of ST-segment elevation AMI patients who underwent primary PCI and were concomitantly treated with GP IIb/IIIa inhibitors versus patients who were not treated with GP IIb/IIIa inhibitors.

Methods
       Patient population and methods. Since January 1996, we prospectively included in an ongoing registry all consecutive ST-segment elevation AMI patients who underwent primary PCI. We retrospectively analyzed the clinical and angiographic characteristics and outcomes of AMI patients concomitantly treated with and without GP IIb/IIIa inhibitors during primary PCI. All patients underwent coronary intervention via the transfemoral approach according to current guidelines with conventional catheter-based systems. Weight-adjusted heparin dosage was administered at the beginning of the procedure in order to maintain an activated clotting time of 250–300 seconds and was routinely discontinued at the end of the procedure. Patients received aspirin 200–325 mg before the procedure and continued indefinitely afterwards. Patients who underwent stenting were treated concomitantly with ticlopidine 250 mg twice daily, or clopidogrel 75 mg/day for 4 weeks. GP IIb/IIIa inhibitors (abciximab, eptifibatide, or tirofiban) were initiated during the catheterization after crossing of the culprit lesion with the guidewire, and were administered at the operator’s discretion according to standard doses: eptifibatide (Integrilin^®, COR Therapeutics, South San Francisco, California) bolus 180 µg/kg, followed by a second bolus of 180 µg/kg after 10 minutes and by a 2.0 µg/kg/hour continuous infusion; abciximab (ReoPro^®, Centocor, B.V. Leiden, The Netherlands) bolus 0.25 µg/kg, followed by 0.125 µg/kg/min infusion; and tirofiban (Aggrastat^®, Merck & Co., Inc., Whitehouse Station, New Jersey) was administered intravenously with a loading dose of 0.4 µg/kg/minute for 30 minutes, followed by infusion of 0.1 µg/kg/minute. Maintenance infusions were given for 14–16 hours. Femoral access sheaths were removed manually 4 hours after the procedure.
       Definitions. ST-segment elevation AMI was defined as the presence of ST-elevation > 0.1 mV in at least two contiguous precordial leads, or two adjacent limb leads in patients who had symptoms consistent with AMI. We included in the registry patients who presented within 12 hours from symptom onset and who were not treated by pharmacological reperfusion therapy. Angiographic success was defined as < 50% diameter residual stenosis with Thrombolysis in Myocardial Infarction (TIMI) flow grade 3. Blood samples were routinely obtained from all patients pre- and post-intervention for the assessment of creatine kinase at 3-hour intervals until peak value was reached and values began decreasing back to normal. Major adverse cardiac events in-hospital included death, myocardial infarction, target-vessel revascularization, or bleeding complications. Bleeding definitions were based on modified TIMI criteria and classified as major bleeding in cases of hemorrhagic stroke, retroperitoneal bleeding, or a drop in hemoglobin of > 5 g/dL. Minor bleeding was defined as clinically overt signs of hemorrhage, with a drop in hemoglobin of <= 5 g/dL. Large hematoma was defined as a palpable swelling of > 4 cm at the vascular access site. Baseline demographics, angiographic features, and in-hospital outcomes were prospectively recorded and entered into a dedicated database. Mortality records were obtained from hospital and state records.

Figure 3

Kaplan-Meier one-year survival curve.

       Statistical analysis. Continuous variables are presented as mean ± SD and dichotomous variables as percentages. Differences between the two groups were compared using an unpaired Student's t-test for continuous variables and the Chi-square test for dichotomous variables. Survival was estimated by the Kaplan-Meier method. The Cox proportional-hazards model was used to calculate relative risk ratios and 95% confidence intervals of prognostic factors affecting survival after adjustment for the following baseline clinical characteristics: age, gender, Killip class, three-vessel disease, anterior MI, GP IIbIIIa inhibitors, and year of procedure. Data were analyzed with Excel (version 2002; Microsoft), GraphPad Prism (version 3.0; GraphPad Software, Inc.) and Statview statistical package. The level selected for statistical significance was set at probability value p < 0.05.

Results
       Between January 1996 and November 2003, a total of 418 consecutive patients underwent coronary angiography during the acute phase of ST-segment elevation myocardial infarction at our institution. PCI was not performed in 16 of these patients, and they were excluded from the analysis (5 patients died during the catheterization before the interventional procedure, 6 patients required urgent surgery and did not undergo PCI, and 5 patients did not undergo PCI due to unsuitable coronary anatomy). A total of 402 patients were included in the present analysis and 287 patients (71%) were concomitantly treated with GP IIb/IIIa inhibitors. Abciximab was used in 87 patients, eptifibatide in 190, and tirofiban in 10 patients.
       During the years that the study comprised, the number of patients treated by PCI as a primary reperfusion strategy in our institution steadily increased. Also, the use of GP IIb/IIIa inhibitors gradually increased from 50% in 1996, to 77% in 2003. Patients treated with GP IIb/IIIa inhibitors were younger than those patients who did not receive GP IIb/IIIa inhibitors; mean age 57 ± 12 and 60 ± 13 years (p = 0.01), respectively (Table 1). The use of stents was similar in both groups (81% in patients treated with GP IIb/IIIa inhibitors group versus 74% among those who did not receive GP IIb/IIIa inhibitors). Although there was a higher incidence of anterior wall myocardial infarction among patients treated with GP IIb/IIIa inhibitors, there was a lower incidence of shock upon arrival in this group of patients (Table 1). Other baseline clinical characteristics were similar between the two groups, as shown in Table 1. The symptom onset-to-balloon time was < 4 hours in 50% of patients not treated with GP IIb/IIIa inhibitors, compared to 56% of patients treated with GP IIb/IIIa inhibitors (p = NS).
       The angiographic characteristics are shown in Table 2. The incidence of three-vessel coronary artery disease was higher in the group who did not receive GP IIb/IIIa inhibitors. Although baseline TIMI coronary blood flow grade was similar in both groups, angiographic success and final TIMI 3 blood flow were more frequently achieved in patients who were treated with GP IIb/IIIa inhibitors. The short-term outcomes regarding in-hospital death and reinfarction were significantly better in patients treated with GP IIb/IIIa inhibitors (Figure 1). The incidence of major and minor bleeding and local vascular complications was low and similar between the two groups (Figure 2). The Kaplan-Meier 12-month survival curve was significantly better in patients treated with GP IIb/IIIa inhibitors (Figure 3). By multivariate analysis, independent predictors of 12-month mortality were Killip grade > 1 (RR: 8.8, CI = 3.4–22.6; p < 0.001), three-vessel disease (RR: 3.1, CI = 1.3–7.1; p = 0.009), and non-use of GP IIb/IIIa inhibitors (RR: 2.99, CI = 1.29–6.9; p = 0.01). Most patients who died in-hospital were in shock. Three patients died without preceding shock in the group of patients who did not receive GP IIb/IIIa inhibitors and two patients in the group treated with GP IIb/IIIa inhibitors. After exclusion of shock patients during hospital stay, GP IIb/IIIa inhibitor use had an even larger positive effect on survival (OR 6.8, CI = 2.1–21.8; p = 0.001). Among patients who died during the 12-month follow-up period, the use of stents was similar between the two groups (70% and 75%, with and without GP IIb/IIIa inhibitors, respectively). In patients who survived one year, use of stents was non-significantly higher in the group who received GP IIb/IIIa inhibitors and was also similar in both groups (81% versus 75%, with and without GP IIb/IIIa inhibitors respectively).

Discussion
       In our routine daily practice, approximately 75% of patients who undergo PCI in the acute phase of MI are currently treated with GP IIb/IIIa inhibitors. The number of patients treated with PCI as a primary reperfusion strategy, and the number of patients concomitantly treated by GP IIb/IIIa inhibitors is progressively increasing. According to our data, based on our experience from the last 8 years, patients who were treated with these drugs were usually younger, had more simple coronary disease, and were more likely to have an anterior infarction, but a lower incidence of cardiogenic shock. These patients achieved a better TIMI coronary blood flow grade at the end of the procedure and had significantly better short- and long-term outcomes. In-hospital mortality and reinfarction rates were lower, without a significant increase in major bleeding complications. Furthermore, one-year survival was significantly higher in patients who were treated with GP IIb/IIIa inhibitors.
       Although in randomized, primary PCI trials that assessed the use of GP IIb/IIIa inhibitors, the administration of these drugs was associated with reduced 30-day reinfarction rates and less need for target vessel revascularization, it was important for us to assess whether the outcomes for general population patients in routine clinical practice are also safe and effective. Our data have shown that there was a significant improvement in both short- and long-term outcomes in patients treated with GP IIb/IIIa inhibitors who underwent primary PCI.
       Previous studies. In previous randomized trials that assessed the value of GP IIb/IIIa administration during primary PCI, such as the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC), ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT), and Intracoronary Stenting and Antithrombotic Regimen (ISAR-2); GP IIb/IIIa inhibitors were initiated in the catheterization suite.^5,9,12 Despite proving a significant benefit on the short-term outcomes, they failed to show a benefit after 6 months. In the RAPPORT study, treatment with abciximab improved 30-day outcomes, mostly by reducing target vessel revascularization rates and the composite endpoint of death, reinfarction, or urgent target vessel revascularization (p = 0.03).9 Likewise, in the ISAR-2 trial, adjunctive therapy with abciximab during stenting improved the 30-day composite of death, re-infarction, or target vessel revascularization (5.0% versus 10.5% in placebo; p = 0.04).¹² After 6 months, no benefit was observed compared to the placebo group. In contrast to these trials, 26% of the patients in the Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up (ADMIRAL) trial received abciximab early and before the initiation of the procedure as an upstream therapy in the emergency room or ambulance.¹⁰ As compared with placebo, abciximab significantly reduced the incidence of the primary endpoint at 30 days (composite of death, reinfarction, or urgent revascularization of the target vessel; 6% versus 14.6% in the placebo group). Also, a non-significant 55% reduction in mortality at 6 months was observed in patients who had been randomized to the abciximab arm. These superior results could have been related to the early administration of abciximab. The CADILLAC trial was the largest study to address the use of GP IIb/IIIa inhibitors during primary PCI.^5,13 This study assessed the effectiveness of adding coronary stents or GP IIb/IIIa inhibitors, or both, to balloon angioplasty during AMI. In this study, stenting alone was superior to percutaneous balloon angioplasty, and stenting alone was not inferior to balloon angioplasty plus abciximab. Abciximab treatment was associated with a significant reduction in the composite endpoint of death, MI, ischemia-driven target vessel revascularization, or disabling stroke at 30 days. Subacute thrombosis also was significantly reduced with abciximab treatment. At 12 months, however, rates of the composite endpoint did not differ significantly between the groups.^5,13 Smaller studies performed with eptifibatide and tirofiban have shown an improvement in coronary blood flow in patients treated with these drugs.^14,15 Conversely, in the recently published Ongoing Tirofiban in Myocardial Infarction Evaluation (On-TIME) trial16, early initiation of tirofiban did not have a significant impact on coronary blood flow or clinical outcomes when compared to initiation of tirofiban during the procedure. The benefit of early administration of GP IIb/IIIa inhibitors in AMI, therefore, has not been established.
       In our patients, GP IIb/IIIa inhibitors were initiated during the procedure following the diagnostic angiography and before the initiation of the interventional procedure itself. The significant improvement in survival in these patients is encouraging. It is important to note that there are some differences between our patients and those in the above-mentioned trials. In some of those trials, stents were used only as a bail-out therapy (RAPPORT), and in others (CADILLAC), only one type of stent was used, whereas in our center, the diversity of stents available probably enabled optimal stent selection. Furthermore, the marginally improved clinical outcomes observed with adjunctive therapy using GP IIb/IIIa inhibitors in AMI is usually offset by an increased rate of bleeding complications. In our registry, the rate of bleeding and vascular complications was low and not significantly different between the two groups. Although the use of upstream GP IIb/IIIa inhibitors was not addressed in our study, upstream therapy does not seem to increase the risk of bleeding complications and might have a beneficial role regarding outcomes. We believe that if there is an early decision to use GP IIb/IIIa inhibitors, they should be given as early as possible (ambulance or emergency room), especially if there is a chance of a delay prior to the procedure.
       Limitations. There are several limitations in the present study. This was a retrospective analysis, and thus the results and conclusions are subject to the limitations inherent in all such reports. Although the number of patients referred to primary PCI as a reperfusion strategy is growing at our institution, we aim to perform primary PCI in patients who are considered to have a large area of myocardium under jeopardy, such as patients with anterior wall MI, extensive posterior infarction, or those patients with hemodynamic compromise. Given the ambiguity of the beneficial effects of GP IIb/IIIa inhibitors during primary PCI in AMI patients, interventional cardiologists might have different views concerning their use, and therefore their administration may vary according to the operator and his/her individual performance. Still, operator decisions involving the use of GP IIb/IIIa inhibitors could include factors that were not incorporated into the analysis.
Thus, the concomitant use of GP IIb/IIIa inhibitors in AMI patients who underwent primary PCI had a favorable impact in the short- and long-term outcomes, without a significant increase in vascular and bleeding complications.

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